CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

42. Infections: Bacterial & Spirochetal

John W. Ogle, MD

Marsha S. Anderson, MD

BACTERIAL INFECTIONS

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Streptococcal pharyngitis:

 Clinical diagnosis based entirely on symptoms; signs and physical examination unreliable.

 Throat culture or rapid antigen detection test positive for group A streptococci.

 Impetigo:

 Rapidly spreading, highly infectious skin rash.

 Erythematous denuded areas and honey-colored crusts.

 Group A streptococci are grown in culture from most (not all) cases.

 General Considerations

Group A streptococci (GAS) are common gram-positive bacteria producing a wide variety of clinical illnesses, including acute pharyngitis, impetigo, cellulitis, and scarlet fever, the generalized illness caused by strains that elaborate erythrogenic toxin. GAS can also cause pneumonia, septic arthritis, osteomyelitis, meningitis, and other less common infections. GAS infections may also produce nonsuppurative sequelae (rheumatic fever and acute glomerulonephritis).

The cell walls of streptococci contain both carbohydrate and protein antigens. The C-carbohydrate antigen determines the group, and the M- or T-protein antigens determine the specific type. In most strains, the M protein appears to confer virulence, and antibodies developed against the M protein are protective against reinfection with that type.

Almost all GAS are β-hemolytic. These organisms may be carried without symptoms on the skin and in the pharynx, rectum, and vagina. All GAS are sensitive to penicillin. Resistance to erythromycin is common in some countries and has increased in the United States.

 Prevention

GAS pharyngitis usually occurs after contact with respiratory secretions of a person infected with GAS. Crowding facilitates spread of GAS and outbreaks of pharyngitis and impetigo can be seen. Prompt recognition and institution of antibiotics may decrease spread. Treatment with antibiotics prevents acute rheumatic fever.

 Clinical Findings

A. Symptoms and Signs

1. Respiratory infections

A. INFANCY AND EARLY CHILDHOOD (AGE < 3 YEARS)—The onset is insidious, with mild symptoms (low-grade fever, serous nasal discharge, and pallor). Otitis media is common. Exudative pharyngitis and cervical adenitis are uncommon in this age group.

B. CHILDHOOD TYPE—Onset is sudden, with fever and marked malaise and often with repeated vomiting. The pharynx is sore and edematous, and generally there is tonsillar exudate. Anterior cervical lymph nodes are tender and enlarged. Small petechiae are frequently seen on the soft palate. In scarlet fever, the skin is diffusely erythematous and appears sunburned and roughened (sandpaper rash). The rash is most intense in the axillae, groin, and on the abdomen and trunk. It blanches except in the skin folds, which do not blanch and are pigmented (Pastia sign). The rash usually appears 24 hours after the onset of fever and rapidly spreads over the next 1–2 days. Desquamation begins on the face at the end of the first week and becomes generalized by the third week. Early in the course of infection, there is circumoral pallor and the surface of the tongue is coated white, with the papillae enlarged and bright red (white strawberry tongue). Subsequently desquamation occurs, and the tongue appears beefy red (strawberry tongue). Petechiae may be seen on all mucosal surfaces.

C. ADULT TYPE—The adult type of GAS is characterized by exudative or nonexudative tonsillitis with fewer systemic symptoms, lower fever, and no vomiting. Scarlet fever is uncommon in adults.

2. Impetigo—Streptococcal impetigo begins as a papule that vesiculates and then breaks, leaving a denuded area covered by a honey-colored crust. Both Staphylococcus aureus and GAS are isolated in some cases. The lesions spread readily and diffusely. Local lymph nodes may become swollen and inflamed. Although the child often lacks systemic symptoms, a high fever and toxicity may be present. If flaccid bullae are noted, the disease is called bullous impetigo and is caused by an epidermolytic toxin-producing strain of S aureus.

3. Cellulitis—The portal of entry is often an insect bite or superficial abrasion. A diffuse, rapidly spreading cellulitis occurs that involves the subcutaneous tissues and extends along the lymphatic pathways with only minimal local suppuration. Local acute lymphadenitis occurs. The child is usually acutely ill, with fever and malaise. In classic erysipelas, the involved area is bright red, swollen, warm, and very tender. The infection may extend rapidly from the lymphatics to the bloodstream.

Streptococcal perianal cellulitis is an entity peculiar to young children. Pain with defecation often leads to constipation, which may be the presenting complaint. The child is afebrile and otherwise well. Perianal erythema, tenderness, and painful rectal examination are the only abnormal physical findings. Scant rectal bleeding with defecation may occur. A perianal swab culture usually yields heavy growth of GAS. A variant of this syndrome is streptococcal vaginitis in prepubertal girls. Symptoms are dysuria and pain; marked erythema and tenderness of the introitus and blood-tinged discharge are seen.

4. Necrotizing fasciitis—This dangerous disease is reported sporadically and may occur as a complication of varicella infection. About 20%–40% of cases are due to GAS; 30%–40% are due to S aureus; and the rest are a result of mixed bacterial infections. The disease is characterized by extensive necrosis of superficial fasciae, undermining of surrounding tissue, and usually systemic toxicity. Initially the skin overlying the infection is tender and pale red without distinct borders, resembling cellulitis. Blisters or bullae may appear. The color deepens to a distinct purple or in some cases becomes pale. Tenderness out of proportion to the clinical appearance, skin anesthesia (due to infarction of superficial nerves), or “woody” induration suggest necrotizing fasciitis. Involved areas may develop mild to massive edema. Early recognition and aggressive debridement of necrotic tissue are essential.

5. Group A streptococcal infections in newborn nurseries—GAS epidemics occur occasionally in nurseries. The organism may be introduced into the nursery from the vaginal tract of a mother or from the throat or nose of a mother or a staff member. The organism then spreads from infant to infant. The umbilical stump is colonized while the infant is in the nursery. Like staphylococcal infections, there may be no or few clinical manifestations while the infant is still in the nursery. Most often, a colonized infant develops a chronic oozing omphalitis days later. The organism may spread from the infant to other family members. Serious and even fatal infections may develop, including sepsis, meningitis, empyema, septic arthritis, and peritonitis.

6. Streptococcal sepsis—Serious illness from GAS sepsis is now more common both in children and in adults. Rash and scarlet fever may be present. Prostration and shock result in high mortality rates. Pharyngitis is uncommon as an antecedent illness. Underlying disease is a predisposing factor.

7. Streptococcal toxic shock syndrome (STSS)—Toxic shock syndrome caused by GAS has been defined. Like S aureus–associated toxic shock, multiorgan system involvement is a prominent part of the illness. The diagnostic criteria include (1) isolation of GAS from a normally sterile site, (2) hypotension or shock, and (3) at least two of the following: renal impairment (creatinine > two times the upper limit of normal for age), thrombocytopenia (< 100,000/mm³), or coagulopathy, liver involvement (transaminases > two times normal), acute respiratory distress syndrome, generalized erythematous macular rash or soft tissue necrosis (myositis, necrotizing fasciitis, gangrene). In cases that otherwise meet clinical criteria, isolation of GAS from a nonsterile site (throat, wound, or vagina) is indicative of a probable cause.

B. Laboratory Findings

Leukocytosis with a marked shift to the left is seen early. Eosinophilia regularly appears during convalescence. β-Hemolytic streptococci are cultured from the throat or site of infection. For suspected GAS pharyngitis, the throat should be swabbed and the specimen sent for GAS testing (rapid antigen detection tests and/or culture for GAS) because the clinical features of some viral infections may overlap with the clinical features of GAS. In children and adolescents, negative rapid antigen tests should be backed up by a culture. Patients with positive rapid strep antigen tests do not need a confirmation by throat culture, since the specificities of antigen tests are high. The organism may be cultured from the skin and by needle aspiration from subcutaneous tissues and other involved sites such as infected nodes. Occasionally blood cultures are positive.

Antistreptolysin O (ASO) titers rise about 150 units within 2 weeks after acute infection. Elevated ASO and anti-DNase B titers are useful in documenting prior throat infections in cases of acute rheumatic fever. The streptozyme test detects antibodies to streptolysin O, hyaluronidase, streptokinase, DNase B, and NADase. It is somewhat more sensitive than the measurement of ASO titers.

Proteinuria, cylindruria, and minimal hematuria may be seen early in children with streptococcal infection. True poststreptococcal glomerulonephritis is seen 1–4 weeks after the respiratory or skin infection.

 Differential Diagnosis

Streptococcal infection in early childhood must be differentiated from adenovirus and other respiratory virus infections. The pharyngitis in herpangina (coxsackievirus A) is vesicular or ulcerative. Herpes simplex also causes ulcerative lesions, which most commonly involve the anterior pharynx, tongue, and gums. In infectious mononucleosis, the pharyngitis is also exudative, but splenomegaly and generalized adenopathy are typical, and laboratory findings are often diagnostic (atypical lymphocytes, elevated liver enzymes, and a positive heterophile or other serologic test for mononucleosis). Uncomplicated streptococcal pharyngitis improves within 24–48 hours if penicillin is given and by 72–96 hours without antimicrobials.

Group G and group C streptococci are uncommon causes of pharyngitis but have been implicated in epidemics of sore throat in college students. Acute rheumatic fever does not occur following group G or group C infection, although acute glomerulonephritis (AGN) is a complication. Arcanobacterium hemolyticum may cause pharyngitis with scarlatina-like or maculopapular truncal rash. In diphtheria, systemic symptoms, vomiting, and fever are less marked; pharyngeal pseudomembrane is confluent and adherent; the throat is less red; and cervical adenopathy is prominent. Pharyngeal tularemia causes white rather than yellow exudate. There is little erythema, and cultures for β-hemolytic streptococci are negative. A history of exposure to rabbits and a failure to respond to antimicrobials may suggest the diagnosis. Leukemia and agranulocytosis may present with pharyngitis and are diagnosed by bone marrow examination.

Scarlet fever must be differentiated from other exanthematous diseases (principally rubella), erythema due to sunburn, drug reactions, Kawasaki disease, toxic shock syndrome (TSS), and staphylococcal scalded skin syndrome (see also Table 40–3).

 Complications

Suppurative complications of GAS infections include sinusitis, otitis, mastoiditis, cervical lymphadenitis, pneumonia, empyema, septic arthritis, and meningitis. Spread of streptococcal infection from the throat to other sites—principally the skin (impetigo) and vagina—is common and should be considered in every instance of chronic vaginal discharge or chronic skin infection, such as that complicating childhood eczema. Both acute rheumatic fever and AGN are nonsuppurative complications of GAS infections.

A. Acute Rheumatic Fever (See Chapter 20)

B. Acute Glomerulonephritis

AGN can follow streptococcal infections of either the pharynx or the skin—in contrast to rheumatic fever, which follows pharyngeal infection only. AGN may occur at any age, even infancy. In most reports of AGN, males predominate by a ratio of 2:1. Rheumatic fever occurs with equal frequency in both sexes. Certain M types are associated strongly with poststreptococcal glomerulonephritis (nephritogenic types). The serotypes producing disease on the skin often differ from those found in the pharynx.

The incidence of AGN after streptococcal infection is variable and has ranged from 0% to 28%. Several outbreaks of AGN in families have involved 50%–75% of siblings of affected patients in 1- to 7-week periods. Second attacks of glomerulonephritis are rare. The median period between infection and the development of glomerulonephritis is 10 days. In contrast, acute rheumatic fever occurs after a median of 18 days.

C. Poststreptococcal Reactive Arthritis

Following an episode of group A streptococcal pharyngitis, a reactive arthritis develops in some patients. This reactive arthritis is believed to be due to immune complex deposition and is seen about 1–2 weeks following the acute infection. Patients with poststreptococcal reactive arthritis do not have the full constellation of clinical and laboratory criteria needed to fulfill the Jones criteria for a diagnosis of acute rheumatic fever.

 Treatment

A. Specific Measures

Treatment is directed toward both eradication of acute infection and prevention of rheumatic fever. In patients with pharyngitis, antibiotics should be started early to relieve symptoms and should be continued for 10 days to prevent rheumatic fever. Although early therapy has not been shown to prevent AGN, it seems advisable to treat impetigo promptly in sibling contacts of patients with poststreptococcal nephritis. Neither sulfonamides nor trimethoprim-sulfamethoxazole (TMP-SMX) is effective in the treatment of streptococcal infections. Although topical therapy for impetigo with antimicrobial ointments (especially mupirocin) is as effective as systemic therapy, it does not eradicate pharyngeal carriage and is less practical for extensive disease.

1. Penicillin—For GAS pharyngitis, the following regimens can be used. Except for penicillin-allergic patients, penicillin V (phenoxymethyl penicillin) is the drug of choice. Penicillin resistance has never been documented. For children weighing less than 27 kg, the regimen is 250 mg, given orally two or three times a day for 10 days. For heavier children, adolescents, or adults 500 mg two or three times a day is recommended. Giving penicillin V twice daily is as effective as more frequent oral administration or intramuscular therapy. Once-daily oral amoxicillin (50 mg/kg, maximum 1000 mg) has been shown to be as effective as penicillin V given three times a day. Another alternative for treatment of pharyngitis and impetigo is a single dose of benzathine penicillin G, given intramuscularly (600,000 units for children weighing < 60 lb [27.2 kg] and 1.2 million units for children weighing > 60 lb [27.2 kg]). Intramuscular delivery ensures compliance, but is painful. Parenteral therapy is indicated if vomiting or sepsis is present. Mild cellulitis due to GAS may be treated orally or intramuscularly.

Cellulitis requiring hospitalization can be treated with aqueous penicillin G (150,000 U/kg/d, given intravenously in four to six divided doses) or cefazolin (100 mg/kg/d, given intravenously in three divided doses) until there is marked improvement. Penicillin V (50 mg/kg/d in four divided doses) or cephalexin (50–75 mg/kg/d in four divided doses) may then be given orally to complete a 10-day course. Acute cervical lymphadenitis may require incision and drainage. Treatment of necrotizing fasciitis requires emergency surgical debridement followed by high-dose parenteral antibiotics appropriate to the organisms cultured.

2. Other antibiotics—Cephalexin and cefadroxil are other effective oral antimicrobials. For penicillin-allergic patients with pharyngitis or impetigo the following alternative regimens have been used: azithromycin (12 mg/kg/d; maximum 500 mg per dose) once daily for 5 days, or clindamycin (20–30 mg/kg/d in three divided doses; maximum 300 mg per dose) for 10 days. Patients with immediate, anaphylactic hypersensitivity to penicillin should not receive cephalosporins, because up to 15% will also be allergic to cephalosporins. Macrolide resistance rates vary and may be high in some areas of the world. In general, macrolide resistance rates in most areas of the US are between 5% and 8%. If macrolide resistance rates are known to be high in a given region, an alternative agent can be selected. In most studies, bacteriologic failures after cephalosporin therapy are less frequent than failures following penicillin. However, there are few conclusive data on the ability of these agents to prevent rheumatic fever. Therefore, penicillin remains the agent of choice for nonallergic patients. Many strains are resistant to tetracycline.

For infections requiring intravenous therapy, aqueous penicillin G (250,000 U/kg in six divided doses) given intravenously is usually the drug of choice. Cefazolin (100 mg/kg/d intravenously or intramuscularly in three divided doses); clindamycin (30–40 mg/kg/d intravenously in four divided doses); and vancomycin (40 mg/kg/d intravenously in four divided doses) are alternatives in penicillin-allergic patients. Clindamycin should not be used alone empirically for severe, suspected GAS infections because a small percentage of isolates in the United States are resistant to it. Some physicians use both penicillin and clindamycin in patients with necrotizing fasciitis or STSS.

3. Serious GAS disease—Serious GAS infections, such as pneumonia, osteomyelitis, septic arthritis, sepsis, endocarditis, meningitis, and STSS, require parenteral antimicrobial therapy. Penicillin G is the drug of choice for these invasive infections. Clindamycin, in addition to penicillin G, is advocated by many experts for STSS or necrotizing fasciitis. Necrotizing fasciitis requires prompt surgical debridement. In STSS, volume status and blood pressure should be monitored and patients evaluated for a focus of infection, if not readily apparent. Intravenous immune globulin (in addition to antibiotics) has been used in severe cases.

4. Treatment failure—Even when compliance is perfect, organisms will be found in cultures in 5%–35% of children after cessation of therapy. Reculture is indicated only in patients with relapse or recrudescence of pharyngitis or those with a personal or family history of rheumatic fever. Repeat treatment at least once with an oral cephalosporin or clindamycin is indicated in patients with recurrent culture-positive pharyngitis.

5. Prevention of recurrences in rheumatic individuals—The preferred prophylaxis for rheumatic individuals is benzathine penicillin G, 1.2 million units (600,000 units for patients weighing less than 27 kg) intramuscularly every 4 weeks. If the risk of streptococcal exposure is high, every-3-week dosing is preferred. One of the following alternative oral prophylactic regimens may be used: penicillin V, 250 mg twice daily; or sulfadiazine, 0.5 g once a day (if < 27 kg) or 1 g once a day (if > 27 kg). In patients allergic to both penicillin and sulfonamide drugs, erythromycin 250 mg twice daily orally can be used. If carditis is absent, continued prophylaxis is recommended for at least 5 years after the last episode of acute rheumatic fever or until 21 years of age (whichever is longer). Prophylaxis should be continued longer if the risk of contact with persons with GAS is high (eg, parents of school-aged children, pediatric nurses, and teachers). In the presence of carditis without residual heart or valvular disease, a minimum of 10 years after the last episode of acute rheumatic fever or until 21 years of age (whichever is longer) is the minimum duration. If the patient has residual valvular heart disease, many recommend lifelong prophylaxis. These patients should be at least 10 years from their last episode of rheumatic disease and at least 40 years of age before considering discontinuation of prophylaxis. Those with severe valvular heart disease or with risk of ongoing exposure to GAS may benefit from lifelong prophylaxis. A similar approach to the prevention of recurrences of glomerulonephritis may be used during childhood when there is a suspicion that repeated streptococcal infections coincide with flare-ups of glomerulonephritis.

6. Poststreptococcal reactive arthritis—In contrast to rheumatic fever, nonsteroidal agents may not dramatically improve joint symptoms. However, like patients with rheumatic fever, some patients with poststreptococcal reactive arthritis have developed carditis several weeks to months after their arthritis symptoms began. Patients should be monitored for development of carditis for the next 1–2 years. Some experts recommend antibiotic prophylaxis of these patients (same prophylaxis regimens as in prevention of recurrences of acute rheumatic fever) for 1–2 years and monitoring for signs of carditis (see recommendations for prevention of recurrences of rheumatic fever, above). If carditis does not develop, prophylaxis could then be discontinued. If carditis develops, the patient should be considered to have acute rheumatic fever and prophylaxis continued as described above.

B. General Measures

Acetaminophen is useful for pain or fever. Local treatment of impetigo may promote earlier healing. Crusts should first be soaked off. Areas beneath the crusts should then be washed with soap daily.

C. Treatment of Complications

Rheumatic fever is best prevented by early and adequate penicillin treatment of the streptococcal infection.

D. Treatment of Carriers

Identification and treatment of GAS carriers is difficult. There are no established clinical or serologic criteria for differentiating carriers from the truly infected. Between 10% and 15% of school-aged children in some studies are asymptomatic pharyngeal carriers of GAS. Streptococcal carriers are individuals who do not mount an immune response to the organism and are therefore believed to be at low risk for nonsuppurative sequelae.

Some children receive multiple courses of antimicrobials, with persistence of GAS in the throat, leading to a “streptococcal neurosis” on the part of families.

In certain circumstances, eradication of carriage may be desirable: (1) when a family member has a history of rheumatic fever; (2) when an episode of STSS or necrotizing fasciitis has occurred in a household contact; (3) multiple, recurring, documented episodes of GAS in family members despite adequate therapy; and (4) during an outbreak of rheumatic fever or GAS-associated glomerulonephritis. Clindamycin (20–30 mg/kg/d, given orally in three divided doses; maximum dose 300 mg) or a combination of rifampin (20 mg/kg/d, given orally for 4 days) and penicillin in standard dosage given orally has been used to attempt eradication of carriage.

 Prognosis

Death is rare except in infants or young children with sepsis or pneumonia. The febrile course is shortened and complications eliminated by early and adequate treatment with penicillin.

Shulman ST et al: Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis 2012;55(10):e86–e102 [PMID: 22965026].

Tanz RR, Shulman ST: Chronic pharyngeal carriage of group A streptococci. Pediatr Infect Dis J 2007;26:175 [PMID: 17259882].

Wessels MR: Clinical practice: streptococcal pharyngitis. N Engl J Med 2011;364:648–655 [PMID: 21323542].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Early-onset neonatal infection:

 Newborn younger than age 7 days, with rapidly progressing overwhelming sepsis, with or without meningitis.

 Pneumonia with respiratory failure is frequent; chest radiograph resembles that seen in hyaline membrane disease.

 Leukopenia with a shift to the left.

 Blood or cerebrospinal fluid (CSF) cultures growing group B streptococci (GBS).

 Late-onset Infection:

 Meningitis, sepsis, or other focal infection in a child aged 1–16 weeks with blood or CSF cultures growing GBS.

 Prevention

Many women of childbearing age possess type-specific circulating antibody to the polysaccharide antigens for group B Streptococcus (GBS). These antibodies are transferred to the newborn via the placental circulation. GBS carriers delivering healthy infants have significant serum levels of IgG antibody to this antigen. In contrast, women delivering infants who develop either early- or late-onset GBS disease rarely have detectable antibody in their sera.

Monovalent and bivalent vaccines with type II or III polysaccharide antigens have been studied in pregnant women, with 80%–90% of vaccine recipients developing fourfold or greater increases in GBS capsular polysaccharide type-specific IgG. These reports suggest that a multivalent vaccine could be developed and given to pregnant women to prevent many cases of early-onset GBS disease.

The decline in early-onset GBS disease in young infants is attributed to widespread maternal screening for GBS and intrapartum prophylaxis. The Centers for Disease Control and Prevention (CDC) has issued culture-based maternal guidelines for the prevention of early-onset GBS disease, as well as recommendations for intrapartum prophylaxis and management of babies whose mothers received IAP for prevention of GBS or for chorioamnionitis.

 CDC Recommendations for Prevention of Perinatal GBS Disease

1. All pregnant women should be screened at 35–37 weeks’ gestation with a vaginal and rectal culture for GBS. Exceptions: Women with known GBS bacteriuria during the current pregnancy or women who have delivered a previous infant with GBS disease do not need screening—all these women need intrapartum prophylaxis—see Table 42–1.

2. Indications and nonindications for intrapartum antibiotic prophylaxis (IAP) to prevent early-onset group B streptococcal (GBS) disease—see Table 42–1.

3. Algorithm for screening for GBS colonization and use of intrapartum prophylaxis for women with preterm labor (PTL)—see Figure 42–1.

 Figure 42–1. Algorithm for screening for group B streptococcal (GBS) colonization and use of intrapartum prophylaxis for women with preterm* labor (PTL). (Verani JR, McGee L, Schrag SL: Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–32).

4. Algorithm for screening for GBS colonization and use of intrapartum prophylaxis for women with preterm premature rupture of membranes (pPROM)—see Figure 42–2.

 Figure 42–2. Algorithm for screening for group B streptococcal (GBS) colonization and use of intrapartum prophylaxis for women with preterm* premature rupture of membranes (pPROM). (Verani JR, McGee L, Schrag SL: Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–32).

5. Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset GBS disease—see Figure 42–3.

 Figure 42–3. Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal (GBS) disease.* (Verani JR, McGee L, Schrag SL: Prevention of perinatal Group B streptococcal disease. Revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–32).

6. Algorithm for secondary prevention of early-onset group B streptococcal (GBS) disease among newborns (management of a newborn whose mother received IAP for prevention of GBS or suspected chorioamnionitis)—see Figure 42–4.

 Figure 42–4. Algorithm for secondary prevention of early-onset group B streptococcal (GBS) disease among newborns. (Verani JR, McGee L, Schrag SL: Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC, 2010. MMWR Recomm Rep 2010;59(RR-10):1–32).

 Clinical Findings

The incidence of perinatal GBS disease has declined dramatically since screening of pregnant mothers and provision of intrapartum chemoprophylaxis began. Although most patients with GBS disease are infants younger than age 3 months, cases are seen in infants aged 4–5 months. Serious infection also occurs in women with puerperal sepsis, immunocompromised patients, patients with cirrhosis and spontaneous peritonitis, and diabetic patients with cellulitis. Two distinct clinical syndromes distinguished by differing perinatal events, age at onset, and serotype of the infecting strain occur in infants.

Risk factors for early-onset group GBS disease include maternal GBS colonization, gestational age less than 37 weeks, rupture of membranes > 18 hours prior to presentation, young maternal age, history of a previous infant with invasive GBS disease, African-American or Hispanic ethnic origin, and low or absent maternal GBS anticapsular antibodies.

A. Early-Onset Infection

“Early-onset” illness is observed in newborns younger than 7 days old. The onset of symptoms in the majority of these infants occurs in the first 48 hours of life, and most are ill within 6 hours. Apnea is often the first sign. Sepsis, shock, meningitis, apnea, and pneumonia are the most common clinical presentations. There is a high incidence of associated maternal obstetric complications, especially premature labor and prolonged rupture of the membranes. Newborns with early-onset disease are severely ill at the time of diagnosis, and more than 50% die. Although most infants with early-onset infections are full-term, premature infants are at increased risk for the disease. Newborns with early-onset infection acquire GBS in utero as an ascending infection or during passage through the birth canal. When early-onset infection is complicated by meningitis, more than 80% of the bacterial isolates belong to serotype III. Postmortem examination of infants with early-onset disease usually reveals pulmonary inflammatory infiltrates and hyaline membranes containing large numbers of GBS.

B. Late-Onset Infection

“Late-onset” infection occurs in infants between ages 7 days and 4 months (median age at onset, about 4 weeks). Maternal obstetric complications are not usually associated with late-onset infection. These infants are usually not as ill at the time of diagnosis as those with early-onset disease, and the mortality rate is lower. In recent series, about 37% of patients have meningitis and 46% have sepsis. Septic arthritis and osteomyelitis, meningitis, occult bacteremia, otitis media, ethmoiditis, conjunctivitis, cellulitis (particularly of the face or submandibular area), lymphadenitis, breast abscess, empyema, and impetigo have been described. Strains of GBS possessing the capsular type III polysaccharide antigen are isolated from more than 95% of infants with late-onset disease, regardless of clinical manifestations. The exact mode of transmission of the organisms is not well defined.

C. Laboratory Findings

Culture of GBS from a normally sterile site such as blood, pleural fluid, or CSF provides proof of diagnosis. Frequent false-positive results limit the usefulness of testing for GBS antigen in urine and CSF.

 Treatment

Intravenous ampicillin and an aminoglycoside is the initial regimen of choice for newborns with presumptive invasive GBS disease. For neonates 7 days of age or younger with meningitis, the recommended ampicillin dosage is 200–300 mg/kg/d, given intravenously in three divided doses. For infants older than 7 days of age, the recommended ampicillin dosage is 300 mg/kg/d, given intravenously in four divided doses.

Penicillin G can be used alone once GBS is identified and clinical and microbiologic responses have occurred. GBS are less susceptible than other streptococci to penicillin, and high doses are recommended, especially for meningitis. In infants with meningitis, the recommended dosage of penicillin G varies with age: for infants age 7 days or younger, 250,000–450,000 U/kg/d, given intravenously in three divided doses; for infants older than age 7 days, 450,000–500,000 U/kg/d, given intravenously in four divided doses.

A second lumbar puncture after 24–48 hours of therapy is recommended by some experts to assess efficacy. Duration of therapy is 2 weeks for uncomplicated meningitis; at least 4 weeks for osteomyelitis, cerebritis, ventriculitis, or endocarditis; and 10 days for bacteremia. Therapy does not eradicate carriage of the organism.

Although streptococci have been universally susceptible to penicillins, increasing minimum inhibitory concentrations (MICs) have been observed in some isolates. Resistance of isolates to clindamycin and erythromycin has increased significantly worldwide in the past few years.

Centers for Disease Control and Prevention (CDC): Prevention of perinatal group B streptococcal disease revised guidelines from CDC, 2010. MMWR 2010;59(RR-10):1–32. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5910.pdf

 General Considerations

Streptococci of groups other than A and B are part of the normal flora of humans and can occasionally cause disease. Group C or group G organisms occasionally produce pharyngitis (with an ASO rise), but without risk of subsequent rheumatic fever. AGN may occasionally occur. Group D streptococci and Enterococcus species are normal inhabitants of the gastrointestinal tract and may produce urinary tract infections, meningitis, and sepsis in the newborn, as well as endocarditis. Nosocomial infections caused by Enterococcus are frequent in neonatal and oncology units and in patients with central venous catheters. Nonhemolytic aerobic streptococci and β-hemolytic streptococci are normal flora of the mouth. They are involved in the production of dental plaque and probably dental caries and are the most common cause of subacute infective endocarditis. Finally, there are numerous anaerobic and microaerophilic streptococci, normal flora of the mouth, skin, and gastrointestinal tract, which alone or in combination with other bacteria may cause sinusitis, dental abscesses, brain abscesses, and intra-abdominal or lung abscesses.

 Prevention

Streptococci (other than group A or B) are common normal flora in humans. Some disease caused by these organisms can be prevented by maintaining good oral hygiene. Spread of vancomycin resistant enterococcal strains can be limited by good infection control practices in healthcare environments. Development of resistant strains can also be limited by antimicrobial stewardship. There are no vaccines that prevent infections with these organisms.

 Treatment

A. Enterococcal Infections

Enterococcus faecalis and Enterococcus faecium are the two most common and most important strains causing human infections. In general, E faecalis is more susceptible to antibiotics than E faecium, but antibiotic resistance is commonly seen with both species. Invasive enterococcal infections should be treated with ampicillin if the isolate is susceptible or vancomycin in combination with gentamicin. Gentamicin should be discontinued if susceptibility testing demonstrates high-level resistance to gentamicin. Isolates that are resistant to both ampicillin and vancomycin necessitate other therapeutic options.

1. Infections with ampicillin-susceptible enterococci—Lower tract urinary infections can be treated with oral amoxicillin. Pyelonephritis should be treated intravenously with ampicillin and gentamicin (gentamicin dosing may need to be adjusted for altered renal function). Sepsis or meningitis in the newborn should be treated intravenously with a combination of ampicillin and gentamicin. Peak serum gentamicin levels of 3–5 mcg/mL are adequate as gentamicin is used as a synergistic agent. Endocarditis requires 6 weeks of intravenous treatment. Ampicillin or penicillin in combination with gentamicin is used in susceptible strains. Consult the American Heart Association guidelines for infective endocarditis for treatment recommendations for endocarditis.

2. Infections with ampicillin-resistant or vancomycin-resistant enterococci—Ampicillin-resistant enterococci are often susceptible to vancomycin (40–60 mg/kg/d in four divided doses). Vancomycin-resistant enterococci are usually also resistant to ampicillin. Linezolid is approved for use in children only for vancomycin-resistant E faecium infections. Two other agents are approved in adults against certain vancomycin-resistant enterococci. Daptomycin is approved for adults with vancomycin-resistant E faecalis infections, Quinupristin-dalfopristin is approved for adults with vancomycin-resistant E faecium (not effective against E faecalis) infections. Isolates resistant to these newer agents (linezolid, daptomycin, quinupristin-dalfopristin) have been reported. Infectious disease consultation is recommended when use of these drugs is entertained or when vancomycin-resistant enterococcal infections are identified.

B. Viridans Streptococci Infections (Subacute Infective Endocarditis)

It is important to determine the penicillin sensitivity of the infecting strain as early as possible in the treatment of viridans streptococcal endocarditis. Resistant organisms are most commonly seen in patients receiving penicillin prophylaxis for rheumatic heart disease. Treatment of endocarditis varies depending on whether the patient has native valves or prosthetic valves/material and whether the organism is penicillin susceptible. Refer to the American Heart Guidelines on Infective Endocarditis for a complete discussion and recommendations.

C. Other Viridans Streptococci–Related Infections

Viridans streptococci are normal flora of the gastrointestinal tract, respiratory tract, and the mouth. In many cases, isolation of viridans streptococci from a blood culture is considered to be a “contaminant” in the absence of signs or symptoms of endocarditis or other invasive disease. However, in children who are immunocompromised, have congenital or acquired valvular heart disease, or those who have indwelling lines, these viridans streptococci may be a cause of serious morbidity. About one-third of bacteremias in patients with malignancies may be due to bacteria from the Streptococcus viridans group. Mucositis and gastrointestinal toxicity from chemotherapy are among the risk factors for developing disease. Even in children with normal immune systems, viridans streptococci sometimes cause serious infections. For example, viridans streptococci isolated from an abdominal abscess after sustained rupture of the appendix represents a true pathogen. Streptococcus anginosus, a member of the Streptococcus viridans group, is seen as a cause of intracranial abscess (often as a complication of sinusitis) and abdominal abscesses. In patients with risk factors or signs/symptoms for subacute endocarditis, isolation of one of the members of the Streptococcus viridans group should prompt consideration and evaluation for possible endocarditis (see previous section).

Increasing prevalence of antibiotic resistance has been seen over the last 10 years in isolates of the streptococci viridans group. Penicillin resistance varies with geographic region, institution, and the populations tested, but has ranged from 30% to 70% in oncology patients. Cephalosporin resistance is also relatively common. Therefore, it is important to obtain antibiotic susceptibilities to the organism to select effective therapy. Vancomycin, linezolid, and quinupristin-dalfopristin are still effective against most isolates.

Baddour M: Infective endocarditis: diagnosis and management. Circulation 2005;111:3167 [PMID: 15956145].

Butler KM: Enterococcal infection in children. Semin Pediatr Infect Dis 2006;17:128 [PMID: 16934707].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Bacteremia:

 High fever (> 39.4°C).

 Leukocytosis (> 15,000/μL).

 Age 6–24 months.

 Pneumonia:

 Fever, leukocytosis, and tachypnea.

 Localized chest pain.

 Localized or diffuse rales. Chest radiograph may show lobar infiltrate (with effusion).

 Meningitis:

 Fever, leukocytosis.

 Bulging fontanelle, neck stiffness.

 Irritability and lethargy.

 All types:

 Diagnosis confirmed by cultures of blood, CSF, pleural fluid, or other body fluid.

 General Considerations

Sepsis, sinusitis, otitis media, pneumonitis, meningitis, osteomyelitis, cellulitis, arthritis, vaginitis, and peritonitis are all part of a spectrum of pneumococcal infection. Clinical findings that correlate with occult bacteremia in ambulatory patients include age (6–24 months), degree of temperature elevation (> 39.4°C), and leukocytosis (> 15,000/μL). Although each of these findings is in itself nonspecific, a combination of them should arouse suspicion. This constellation of findings in a child who has no focus of infection may be an indication for blood cultures and antibiotic therapy. The cause of most of such bacteremic episodes is pneumococci.

Streptococcus pneumoniae is a common cause of acute purulent otitis media and is the organism responsible for most cases of acute bacterial pneumonia in children. The disease is indistinguishable on clinical grounds from other bacterial pneumonias. Effusions are common, although frank empyema is less common. Abscesses also occasionally occur.

The incidence rate of pneumococcal meningitis has decreased since incorporation of the pneumococcal conjugate vaccine into the infant vaccine schedule. However, pneumococcal meningitis is still more common than Haemophilus influenzae type b meningitis. Pneumococcal meningitis, sometimes recurrent, may complicate serious head trauma, particularly if there is persistent leakage of CSF. This has led some physicians to recommend the prophylactic administration of penicillin or other antimicrobials in such cases.

Children with sickle cell disease, other hemoglobinopathies, congenital or acquired asplenia, and some immunoglobulin and complement deficiencies are unusually susceptible to pneumococcal sepsis and meningitis. They often have a catastrophic illness with shock and disseminated intravascular coagulation (DIC). Even with excellent supportive care, the mortality rate is 20%–50%. The spleen is important in the control of pneumococcal infection by clearing organisms from the blood and producing an opsonin that enhances phagocytosis. Autosplenectomy may explain why children with sickle cell disease are at increased risk of developing serious pneumococcal infections. Children with cochlear implants are at higher risk for pneumococcal meningitis.

S pneumoniae rarely causes serious disease in the neonate. Although S pneumoniae does not normally colonize the vagina, transient colonization does occur. Serious neonatal disease—including pneumonia, sepsis, and meningitis—may occur and clinically is similar to GBS infection.

Historically, penicillin was the agent of choice for pneumococcal infections, and some strains are still highly susceptible to penicillin. However, pneumococci with moderately increased resistance to penicillin are found in most communities. The prevalence of these relatively penicillin-resistant strains in North America varies geographically. Pneumococci with high-level resistance to penicillin and multiple other drugs are increasingly encountered throughout the United States. Pneumococci from normally sterile body fluids should be routinely tested for susceptibility to penicillin as well as other drugs.

Pneumococci have been classified into more than 90 serotypes based on capsular polysaccharide antigens. The frequency distribution of serotypes varies at different times, in different geographic areas, and with different sites of infection.

 Prevention

Two pneumococcal vaccines are licensed for use in children in the United States: 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. The 13-valent pneumococcal conjugate vaccine was licensed in 2010 (replacing the 7-valent pneumococcal vaccine). This vaccine contains antigens from 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 10F, and 23F), and is the vaccine currently recommended for routine use in the infant and childhood immunization schedule. Use of the 13-valent conjugate vaccine is important in the prevention of pneumococcal disease because young children (age < 2 years), who are most at risk for the disease, are unable to immunologically mount a predictable response to the 23-valent polysaccharide vaccine. The 13-valent vaccine is currently recommended for (1) infant primary series and childhood booster dosing (replaces the 7-valent vaccine), (2) as a single supplemental dose in healthy children 14– 59 months of age who were fully immunized with the 7-valent pneumococcal conjugate vaccine, and (3) use in children aged less than 18 years who have certain underlying medical conditions that put them at high risk for pneumococcal disease. This vaccine and indications for use is discussed in detail in Chapter 10. For children > 2 years of age who are at high risk for invasive pneumococcal disease (sickle cell anemia, anatomic or functional asplenia, HIV-infected children, and persons with certain chronic illnesses), the 23-valent pneumococcal vaccine is recommended 8 weeks following completion of the pneumococcal conjugate vaccine series (see Chapter 10). A second dose of the 23-valent pneumococcal vaccine should be given 5 years after the first dose in children with HIV infection, sickle cell disease, functional or anatomic asplenia, or other immunocompromising conditions.

When a cochlear implant, splenectomy, or immune-compromising therapy is anticipated, the child should complete immunization with the 13-valent pneumococcal conjugate vaccine at least 2 weeks prior to surgery or institution of immune-compromising therapy if possible. If this is not possible due to the urgency of the procedure or therapy, the child should receive immunization as soon as possible thereafter. In children greater than 2 years of age, the 23-valent pneumococcal polysaccharide vaccine can be given at least 8 weeks after completion of the 13-valent pneumococcal conjugate vaccine (see Chapter 10).

 Clinical Findings

A. Symptoms and Signs

In pneumococcal sepsis, fever usually appears abruptly, often accompanied by chills. There may be no respiratory symptoms. In pneumococcal sinusitis, mucopurulent nasal discharge may occur. In infants and young children with pneumonia, fever, and tachypnea without auscultatory changes are the usual presenting signs. Respiratory distress is manifested by nasal flaring, chest retractions, and tachypnea. Abdominal pain is common. In older children, the adult form of pneumococcal pneumonia with signs of lobar consolidation may occur, but sputum is rarely bloody. Thoracic pain (from pleural involvement) is sometimes present, but is less common in children. With involvement of the right hemidiaphragm, pain may be referred to the right lower quadrant, suggesting appendicitis. Vomiting is common at onset but seldom persists. Convulsions are relatively common at onset in infants.

Meningitis is characterized by fever, irritability, convulsions, and neck stiffness. The most important sign in very young infants is a tense, bulging anterior fontanelle. In older children, fever, chills, headache, and vomiting are common symptoms. Classic signs are nuchal rigidity associated with positive Brudzinski and Kernig signs. With progression of untreated disease, the child may develop opisthotonos, stupor, and coma.

B. Laboratory Findings

Leukocytosis is often pronounced (20,000–45,000/μL), with 80%–90% polymorphonuclear neutrophils. Neutropenia may be seen early in very serious infections. The presence of pneumococci in the nasopharynx is not a helpful finding, because up to 40% of normal children carry pneumococci in the upper respiratory tract. Large numbers of organisms are seen on Gram-stained smears of endotracheal aspirates from patients with pneumonia. In meningitis, CSF usually shows an elevated white blood cell (WBC) count of several thousand, chiefly polymorphonuclear neutrophils, with decreased glucose and elevated protein levels. Gram-positive diplococci may be seen on some (but not all) stained smears of CSF sediment. Antigen detection tests are not useful. Isolation of S pneumoniae from a normally sterile site (eg, blood, cerebrospinal joint fluid, middle ear fluid) or from a suppurative focus confirms the diagnosis.

 Differential Diagnosis

There are many causes of high fever and leukocytosis in young infants; 90% of children presenting with these features have a disease other than pneumococcal bacteremia, such as human herpesvirus 6, enterovirus, or other viral infection; urinary tract infection; unrecognized focal infection elsewhere in the body; or early acute shigellosis.

Infants with upper respiratory tract infection who subsequently develop signs of lower respiratory disease are most likely to be infected with a respiratory virus. Hoarseness or wheezing is often present. A radiograph of the chest typically shows perihilar infiltrates and increased bronchovascular markings. Viral respiratory infection often precedes pneumococcal pneumonia; therefore, the clinical picture may be mixed.

Staphylococcal pneumonia may be indistinguishable early in its course from pneumococcal pneumonia. Later, pulmonary cavitation and empyema occur.

In primary pulmonary tuberculosis, children do not have a toxic appearance, and radiographs show a primary focus associated with hilar adenopathy and often with pleural involvement. Miliary tuberculosis presents a classic radiographic appearance.

Pneumonia caused by Mycoplasma pneumoniae is most common in children aged 5 years and older. Onset is insidious, with infrequent chills, low-grade fever, prominent headache and malaise, cough, and, often, striking radiographic changes. Marked leukocytosis (> 18,000/μL) is unusual.

Pneumococcal meningitis is diagnosed by lumbar puncture. Without a Gram-stained smear and culture of CSF, it is not distinguishable from other types of acute bacterial meningitis.

 Complications

Complications of sepsis include meningitis and osteomyelitis; complications of pneumonia include empyema, parapneumonic effusion, and, rarely, lung abscess. Mastoiditis, subdural empyema, and brain abscess may follow untreated pneumococcal otitis media. Both pneumococcal meningitis and peritonitis are more likely to occur independently without coexisting pneumonia. Shock, DIC, and Waterhouse-Friderichsen syndrome resembling meningococcemia are occasionally seen in pneumococcal sepsis, particularly in asplenic patients. Hemolytic-uremic syndrome may occur as a complication of pneumococcal pneumonia or sepsis.

 Treatment

A. Specific Measures

All S pneumoniae isolated from normally sterile sites should be tested for antimicrobial susceptibility. The term “nonsusceptible” is used to describe both intermediate and resistant isolates. Strains that are nonsusceptible to penicillin, ceftriaxone (or cefotaxime), and other antimicrobials are increasingly common globally. Antimicrobial susceptibility breakpoints for S pneumoniae to penicillin and ceftriaxone/cefotaxime are based on whether the patient has meningitis and the drug route (oral vs intravenous), see Table 42–2. Therapy of meningitis, empyema, osteomyelitis, and endocarditis due to nonsusceptible S pneumoniae is challenging, because penetration of antimicrobials to these sites is limited. Infectious disease consultation is recommended for advice regarding these problems. For empiric therapy of serious or life-threatening infections pending susceptibility test results, vancomycin and ceftriaxone (or cefotaxime) are recommended.

1. Bacteremia—In studies done prior to immunization of young children with conjugated pneumococcal vaccine, 3%–5% of blood cultures in patients younger than 2 years of age yielded S pneumoniae. These percentages decreased with the addition of conjugated pneumococcal vaccine to the vaccine schedule. The current 13-valent pneumococcal vaccine contains antigens to the pneumococcal serotypes that cause about 65% of invasive pneumococcal disease. Many experts treat suspected bacteremia in children that are not seriously ill with ceftriaxone (50 mg/kg, given intramuscularly or intravenously). Compared with oral amoxicillin (80–90 mg/kg/d), ceftriaxone may reduce fever and the need for hospitalization. However, meningitis occurs with the same frequency despite presumptive therapy. All children with blood cultures that grow pneumococci should be reexamined as soon as possible. The child who has a focal infection, such as meningitis, or who appears septic should be admitted to the hospital to receive parenteral antimicrobials. If the child is afebrile and appears well or mildly ill, outpatient management is appropriate. Severely ill or immunocompromised children, in whom invasive infection with S pneumoniae is suspected, should be treated with vancomycin (in addition to other appropriate antibiotics to cover other suspected pathogens). If meningitis is also suspected, use ceftriaxone or cefotaxime in addition to vancomycin until the susceptibilities of the organism are known.

2. Pneumonia—For infants (1 month of age or older) with susceptible organisms appropriate regimens include ampicillin (150–200 mg/kg/d intravenously in four divided doses) aqueous penicillin G (250,000–400,000 U/kg/d, given intravenously in four to six divided doses), cefotaxime (50 mg/kg intravenously every 8 hours), or ceftriaxone (50 mg/kg intravenously every 12–24 hours). If susceptibilities are not known and the patient is severely ill or immunocompromised, vancomycin should be used as part of the regimen to provide coverage for penicillin- or cephalosporin-resistant pneumococcus. Once results of susceptibility testing are available, the regimen can be tailored. Mild pneumonia may be treated with amoxicillin (80–90 mg/kg/d) for 7–10 days. Alternative regimens include oral macrolides (resistance may be high) and cephalosporins.

3. Otitis media—Most experts recommend oral amoxicillin (80–90 mg/kg/d, divided in two doses) as first-line therapy. The standard course of therapy is 10 days; however, many physicians treat uncomplicated, mild cases in children 6 years of age or older for 5–7 days. Treatment failures may be treated with amoxicillin-clavulanate (80–90 mg/kg/d of the amoxicillin component in the 14:1 formulation), intramuscular ceftriaxone, cefuroxime axetil, or cefdinir. Azithromycin can also be used in patients with type I hypersensitivity reactions to penicillin or cephalosporin, but resistance to macrolides may be high.

4. Meningitis—Until bacteriologic confirmation and susceptibility testing are completed, patients should receive vancomycin (60 mg/kg/d, given intravenously in four divided doses) and cefotaxime (225–300 mg/kg/d intravenously in four divided doses), OR vancomycin (see previous dosage) and ceftriaxone (100 mg/kg/d, given intravenously in two divided doses). Patients with serious hypersensitivity to beta-lactam antibiotics allergy (eg, penicillins, cephalosporins) can be treated with a combination of vancomycin (see previous dosage) and rifampin (20 mg/kg/day in two divided doses). Use of vancomycin alone or use of rifampin alone is not recommended. Vancomycin and meropenem is an alternative for penicillin or cephalosporin allergic patients and this regimen provides additional gram-negative coverage until culture and susceptibility results are obtained. Corticosteroids (dexamethasone, 0.6 mg/kg/d, in four divided doses for 4 days) are controversial but are recommended by many experts as adjunctive therapy for pneumococcal meningitis. A repeat lumbar puncture at 24–48 hours should be considered to ensure sterility of the CSF if dexamethasone is given, if resistant pneumococci are isolated, or if the patient is not demonstrating expected improvement after 24–48 hours on therapy.

If the isolate is determined to be penicillin-susceptible, aqueous penicillin G can be administered (300,000– 400,000 U/kg/d, given intravenously in four to six divided doses for 10–14 days). Alternatively, use of ceftriaxone or cefotaxime is an acceptable alternative therapy for penicillin- and cephalosporin-susceptible isolates. Consult an infectious disease specialist or the Red Book (American Academy of Pediatrics, 2012) for a complete discussion of pneumococcal meningitis and for therapeutic options for isolates that are nonsusceptible to penicillin or cephalosporins.

 Prognosis

In children, case fatality rates of less than 1% should be achieved except for meningitis, where rates of 5%–20% still prevail. The presence of large numbers of organisms without a prominent CSF inflammatory response or meningitis due to a penicillin-resistant strain indicates a poor prognosis. Serious neurologic sequelae, particularly hearing loss, are frequent following pneumococcal meningitis.

Advisory Committee on Immunization Practices: Pneumococcal vaccination for cochlear implant candidates and recipients: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2003;52:739 [PMID: 12908457].

Bradley JS et al: The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis 2011 Oct;53(7):617–630 [PMID: 21890766].

Centers for Disease Control and Prevention (CDC): Prevention of pneumococcal disease among infants and children—use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010 Dec 10;59(RR-11):1–18 [PMID: 21150868].

Pickering LK (ed): Red Book 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

 General Considerations

Staphylococcal infections are common in childhood and range from local mild infections to overwhelming systemic infections. Examples of disease caused by staphylococci include, but are not limited to, furuncles, carbuncles, scalded skin syndrome, osteomyelitis, pyomyositis, septic arthritis, pneumonia, bacteremia, endocarditis, meningitis, and toxic shock syndrome. Staphylococci are the major cause of osteomyelitis and of septic arthritis and are an uncommon but important cause of bacterial pneumonia. A toxin produced by certain strains causes staphylococcal food poisoning. Staphylococci are responsible for many infections of artificial heart valves. Finally, they are found in infections at all ages and in multiple sites, particularly when infection is introduced from the skin or upper respiratory tract or when closed compartments become infected (pericarditis, sinusitis, cervical adenitis, surgical wounds, abscesses in the liver or brain, and abscesses elsewhere in the body).

Staphylococci that do not produce the enzyme coagulase are termed coagulase-negative and are seldom speciated in the clinical microbiology laboratory. Most S aureus strains produce coagulase. S aureus and coagulase-negative staphylococci are normal flora of the skin and respiratory tract. The latter rarely cause disease except in compromised hosts, the newborn, or patients with indwelling lines.

Most strains of S aureus elaborate β-lactamase that confers penicillin resistance. This can be overcome in clinical practice by the use of a cephalosporin or a penicillinase-resistant penicillin, such as oxacillin, nafcillin, cloxacillin, or dicloxacillin. Methicillin-resistant S aureus (MRSA) are resistant in vivo to all of these penicillinase-resistant penicillins and cephalosporins. MRSA has dramatically increased in prevalence globally as both a healthcare-associated and a community-associated pathogen. Healthcare-associated infections are likely to be multidrug resistant. Community-associated MRSA may be susceptible to clindamycin and/or TMP-SMX, but resistance rates to these agents vary widely geographically. MRSA strains with intermediate susceptibility to vancomycin are occurring more frequently and occasionally vancomycin-resistant strains are isolated. The existence of such strains is of concern because of the inherent virulence of most strains of S aureus and because of the limited choices for therapy.

S aureus produces a variety of exotoxins, most of which are of uncertain importance. Two toxins are recognized as playing a central role in specific diseases: exfoliatin and staphylococcal enterotoxin. The former is largely responsible for the various clinical presentations of scalded skin syndrome. Enterotoxin causes staphylococcal food poisoning. The exoprotein toxin most commonly associated with TSS has been termed TSST-1. Panton-Valentine leukocidin (PVL) is an exotoxin produced by some clinical isolates of methicillin-susceptible S aureus (MSSA) and MRSA strains. PVL is a virulence factor that causes leukocyte destruction and tissue necrosis. PVL-producing S aureus strains are often community-acquired, and have most commonly produced boils and abscesses. However, they also have been associated with severe cellulitis, osteomyelitis, and deaths from necrotizing pneumonia in otherwise healthy children and young adults.

 Prevention

No licensed vaccines are available. Patients with recurrent skin infections with S aureus should practice good skin hygiene to try to prevent recurrences. Keeping fingernails short, good skin hygiene, not sharing towels or other personal items, and use of a clean towel daily may help prevent recurrences.

 Clinical Findings

A. Symptoms and Signs

1. Staphylococcal skin diseases—Dermal infection with S aureus causes pustules, furuncles, carbuncles, or cellulitis. Community-associated MRSA and MSSA frequently cause skin and soft tissue infections. Currently MRSA furuncles and abscesses are extraordinarily common in clinical practice. Parents initially may think the child has a spider bite. Skin lesions can be seen anywhere on the body but are commonly seen on the buttocks in infants and young children. Factors that facilitate transmission of MRSA or MSSA include crowding, compromised skin (eg, eczema), participation on contact sports teams, day care attendance, bare skin contact with surfaces used by others (exercise mats, sauna benches), and sharing towels or other personal items.

S aureus are often found along with streptococci in impetigo. If the strains produce exfoliatin, localized lesions become bullous (bullous impetigo).

Scalded skin syndrome is a toxin-mediated illness caused by exfoliative toxins A and B produced by certain strains of S aureus. The initial infection may begin at any site but is in the respiratory tract in most cases. There is a prodromal phase of erythema, often beginning around the mouth, accompanied by fever and irritability. The involved skin becomes tender, and a sick infant will cry when picked up or touched. A day or so later, exfoliation begins, usually around the mouth. The inside of the mouth is red, and a peeling rash is present around the lips, often in a radial pattern. Generalized, painful peeling may follow, involving the limbs and trunk but often sparing the feet. More commonly, peeling is confined to areas around body orifices. If erythematous but unpeeled skin is rubbed sideways, superficial epidermal layers separate from deeper ones and slough (Nikolsky sign). Generally, if secondary infection does not occur, there is healing without scarring. In the newborn, the disease is termed Ritter disease and may be fulminant.

2. Osteomyelitis and septic arthritis—(See Chapter 26.) MRSA invasive disease, including osteomyelitis and septic arthritis is being seen increasingly.

3. Staphylococcal pneumonia—Staphylococcal pneumonia in infancy is characterized by abdominal distention, high fever, respiratory distress, and toxemia. It may occur without predisposing factors or after minor skin infections. The organism is necrotizing, producing bronchoalveolar destruction. Pneumatoceles, pyopneumothorax, and empyema are frequently encountered. Rapid progression of disease is characteristic. Frequent chest radiographs to monitor the progress of disease are indicated. Presenting symptoms may be typical of paralytic ileus, suggestive of an abdominal catastrophe.

Invasive MRSA infections are on the rise and increasing numbers of MRSA pneumonias have been reported in all age groups. Many of these reports are in patients who develop MRSA pneumonia as a complication of influenza. MRSA or MSSA pneumonias are rapidly progressive, severe, and often devastating. Complicated pneumonias are frequent including necrotizing pneumonia, pneumatoceles, and/or empyemas. Purulent pericarditis occurs by direct extension in about 10% of cases, with or without empyema.

4. Staphylococcal food poisoning—Staphylococcal food poisoning is a result of ingestion of enterotoxin produced by staphylococci growing in uncooked and poorly refrigerated food. The disease is characterized by vomiting, prostration, and diarrhea occurring 2–6 hours after ingestion of contaminated foods.

5. Staphylococcal endocarditis—S aureus may produce infection of normal heart valves, of valves or endocardium in children with congenital or rheumatic heart disease, or of artificial valves. About 25% of all cases of endocarditis are due to S aureus. The great majority of artificial heart valve infections involve either S aureus or coagulase-negative staphylococci. Infection usually begins in an extracardiac focus, often the skin. Involvement of the endocardium should be considered when blood cultures grow S aureus, particularly when cultures are persistently positive. Suspicion must be highest in the presence of congenital heart disease, particularly ventricular septal defects with aortic insufficiency but also simple ventricular septal defect, patent ductus arteriosus, and tetralogy of Fallot.

The presenting symptoms in staphylococcal endocarditis are fever, weight loss, weakness, muscle pain or diffuse skeletal pain, poor feeding, pallor, and cardiac decompensation. Signs include splenomegaly, cardiomegaly, petechiae, hematuria, and a new or changing murmur. The course of S aureus endocarditis is rapid, although subacute disease occurs occasionally. Peripheral septic embolization and uncontrollable cardiac failure are common, even when optimal antibiotic therapy is administered, and may be indications for surgical intervention (see later in the section “Staphylococcal Endocarditis”).

6. Toxic shock syndrome—TSS is characterized by fever, blanching erythroderma, diarrhea, vomiting, myalgia, prostration, hypotension, and multiorgan dysfunction. It is due to S aureus focal infection, usually without bacteremia. Large numbers of cases have been described in menstruating adolescents and young women using vaginal tampons. TSS has also been reported in boys and girls with focal staphylococcal infections and in individuals with wound infections due to S aureus. Additional clinical features include sudden onset; conjunctival suffusion; mucosal hyperemia; desquamation of skin on the palms, soles, fingers, and toes during convalescence; DIC in severe cases; renal and hepatic functional abnormalities; and myolysis. The mortality rate with early treatment is now about 2%. Recurrences are seen during subsequent menstrual periods in as many as 60% of untreated women who continue to use tampons. Recurrences occur in up to 15% of women given antistaphylococcal antibiotics who stop using tampons. The disease is caused by strains of S aureus that produce TSST-1 or one of the related enterotoxins.

7. Coagulase-negative staphylococcal infections—Localized and systemic coagulase-negative staphylococcal infections occur primarily in immunocompromised patients, high-risk newborns, and patients with plastic prostheses or catheters. Coagulase-negative staphylococci are the most common nosocomial pathogen in hospitalized low-birth-weight neonates in the United States. Intravenous administration of lipid emulsions and indwelling central venous catheters are risk factors contributing to coagulase-negative staphylococcal bacteremia in newborn infants. In patients with an artificial heart valve, a Dacron patch, a ventriculoperitoneal shunt, or a central venous catheter, coagulase-negative staphylococci are a common cause of sepsis or catheter infection, often necessitating removal of the foreign material and protracted antibiotic therapy. Because blood cultures are frequently contaminated by this organism, diagnosis of genuine localized or systemic infection is often difficult.

B. Laboratory Findings

Moderate leukocytosis (15,000–20,000/μL) with a shift to the left is occasionally found, although normal counts are common, particularly in infants. The sedimentation rate is elevated. Blood cultures are frequently positive in systemic staphylococcal disease and should always be obtained when it is suspected. Similarly, pus from sites of infection should always be aspirated or obtained surgically, examined with Gram stain, and cultured both aerobically and anaerobically. There are no useful serologic tests for staphylococcal disease.

 Differential Diagnosis

Staphylococcal skin disease takes many forms; therefore, the differential list is long. Staphylococcal skin abscesses, furuncles, and carbuncles are often confused initially with a spider bite. Bullous impetigo must be differentiated from chemical or thermal burns, from drug reactions, and, in the very young, from the various congenital epidermolytic syndromes or even herpes simplex infections. Staphylococcal scalded skin syndrome may resemble scarlet fever, Kawasaki disease, Stevens-Johnson syndrome, erythema multiforme, and other drug reactions. A skin biopsy may be critical in establishing the diagnosis. Varicella lesions may become superinfected with exfoliatin-producing staphylococci and produce a combination of the two diseases (bullous varicella).

Severe, rapidly progressing pneumonia with formation of abscesses, pneumatoceles, and empyemas is typical of S aureus infection and GAS but may occasionally be produced by pneumococci, H influenzae, and GAS.

Staphylococcal food poisoning is often epidemic. It is differentiated from other common-source gastroenteritis syndromes (Salmonella, Clostridium perfringens, and Vibrio parahaemolyticus) by the short incubation period (2–6 hours), the prominence of vomiting (as opposed to diarrhea), and the absence of fever.

Endocarditis is suspected with S aureus bacteremia, particularly when a significant heart murmur or preexisting cardiac disease is present (see Chapter 20).

Newborn infections with S aureus can resemble infections with streptococci and a variety of gram-negative organisms. Umbilical and respiratory tract colonization occurs with many pathogenic organisms (GBS, Escherichia coli,and Klebsiella), and both skin and systemic infections occur with virtually all of these organisms.

TSS must be differentiated from Rocky Mountain spotted fever, leptospirosis, Kawasaki disease, drug reactions, adenovirus, and measles (see also Table 42–3).

 Treatment

A. Specific Measures

Community-acquired MRSA infections are on the rise. The incidence of community-acquired MRSA isolates varies greatly geographically, but in many communities in the United States MRSA is the most common pathogen isolated from patients with skin and soft tissue infections. For empiric coverage of potentially life-threatening infections with suspected S aureus (in which susceptibilities are not known) initial therapy should include vancomycin in combination with either nafcillin or oxacillin (in addition to appropriate antibiotic therapy for other suspected pathogens). Antibiotic therapy can then be adjusted based on identification of the organism and susceptibility results.

Currently, most community-acquired MRSA strains are susceptible to TMP-SMX and some are susceptible to clindamycin. Less serious infections in nontoxic patients may be initially treated using one of these agents while awaiting cultures and susceptibility data. Knowledge of the community MRSA susceptibility patterns is useful in guiding empiric therapy while awaiting susceptibility test results.

For MSSA strains, a β-lactamase–resistant penicillin is the drug of choice (oxacillin or nafcillin). In serious systemic disease, in osteomyelitis, and in the treatment of large abscesses, intravenous therapy is indicated initially (oxacillin or nafcillin, 100–150 mg/kg/d in four divided doses). In serious or life-threatening illness, consultation with an infectious disease physician is recommended.

Cephalosporins may be considered for MSSA infections in patients with a history of penicillin sensitivity unless there is a history of type 1 hypersensitivity reaction (ie, anaphylaxis, wheezing, edema, and hives). Cefazolin, 100–150 mg/kg/d, given intravenously in three divided doses, or cephalexin, 50–100 mg/kg/d, given orally in four divided doses, can be used once a child is able to take oral antibiotics. The third-generation cephalosporins should not generally be used for staphylococcal infections.

For serious S aureus infections, initial therapy with vancomycin (15 mg/kg/dose intravenously every 6 hours) plus nafcillin or oxacillin is recommended until susceptibilities are available. For nosocomially acquired MRSA infections, vancomycin should be used until results of susceptibility testing are available to guide therapy (isolates are frequently clindamycin and TMP-SMX–resistant). Infections due to MRSA do not respond to cephalosporins despite in vitro testing that suggests susceptibility. For treatment of meningitis, vancomycin must be given in higher doses (60 mg/kg/d divided into four doses). The addition of rifampin is advocated by some (rifampin should not be used alone to treat this condition).

1. Skin infections—Treatment of skin and soft tissue infections depends, in part, on the extent of the lesion, immunocompetence of the host, and the toxicity of the patient. Afebrile, well-appearing patients with small abscesses may do well with incision and drainage (with or without the addition of oral antimicrobials). More serious infections or infections in immunocompromised patients should be treated more aggressively. Hospitalization and intravenous antibiotics may be required. Culture and susceptibility testing help guide therapy regardless of whether the patient initially is started on antibiotics. Results of these tests facilitate therapeutic decisions in cases in which patients do not respond to initial management or empiric intravenous antibiotic therapy was initiated.

For patients who are not sick enough to require hospitalization or intravenous therapy, selection of the best empiric antimicrobial depends on local rates of MRSA and local susceptibilities. β-Lactam antibiotics, such as penicillins and cephalosporins, can no longer be depended on as single agents for the majority of cases in communities with high MRSA rates. TMP-SMX and clindamycin (depending on local susceptibility patterns) may be used for empiric staphylococcal coverage. However, GAS are generally resistant to TMP-SMX and in a small number of cases may also be resistant to clindamycin. Many clinicians empirically use a combination of TMP-SMX and cefazolin for initial treatment until susceptibilities are known. Linezolid is another option, although the cost of this drug is high.

2. Osteomyelitis and septic arthritis—Treatment should be begun intravenously, with antibiotics selected to cover the most likely organisms (staphylococci in hematogenous osteomyelitis; meningococci, pneumococci, staphylococci in children younger than age 3 years with septic arthritis; staphylococci and gonococci in older children with septic arthritis). Knowledge of local MRSA rates will help guide empiric therapy. Antibiotic levels should be kept high at all times.

Clinical studies support the use of intravenous treatment for osteomyelitis until fever and local symptoms and signs have subsided—usually at least 3–5 days—followed by oral therapy, For both osteomyelitis and joint infections, good compliance with oral therapy is important for successful cure.

For methicillin-susceptible S aureus strains, nafcillin, oxacillin, or cefazolin can be used for intravenous therapy. Clindamycin is an alternative agent if the organism is susceptible and the patient does not have a severe or life-threatening infection or ongoing bacteremia. Dicloxacillin, 100–150 mg/kg/d in four divided doses or cephalexin, 100–150 mg/kg/d in four divided doses) can be used when the patient is ready for oral therapy.

For MRSA osteomyelitis, vancomycin can be used initially while awaiting final susceptibilities. Antibiotic regimens for MRSA osteomyelitis should be based on susceptibility results; isolates may be susceptible to clindamycin or linezolid, but susceptibility patterns vary geographically.

In arthritis, where drug diffusion into synovial fluid is good, intravenous therapy need be given only for a few days, followed by adequate oral therapy for at least 3 weeks.

The C-reactive protein (in the first or second week after therapy is started) and the erythrocyte sedimentation rate (usually measured weekly) are good indicators of response to therapy. Surgical drainage of osteomyelitis or septic arthritis is often required (see Chapter 26).

3. Staphylococcal pneumonia—In the few areas of the country where MRSA is not prevalent, or if the isolate is known to be MSSA, nafcillin and oxacillin are the usual drugs of choice. Vancomycin can be used empirically until results of cultures and susceptibility tests are obtained if MRSA rates are high. In sicker patients, vancomycin plus nafcillin or vancomycin plus oxacillin can be used (in addition to coverage of other pathogens) until the etiologic agent and susceptibilities are established. Linezolid has been reported to be as efficacious as vancomycin for the treatment of resistant gram-positive pneumonia and soft tissue infections.

Empyema and pyopneumothorax require drainage. The choice of chest tube versus thoracoscopic drainage depends on the practitioner’s experience and skill. If staphylococcal pneumonia is treated promptly and empyema drained, resolution in children often is complete.

4. Staphylococcal food poisoning—Therapy is supportive and usually not required except in severe cases or for small infants with marked dehydration.

5. Staphylococcal endocarditis—The treatment of staphylococcal endocarditis depends on whether the patient has a prosthetic valve or material in the heart and on the susceptibilities of the organism. Please see the American Heart Association’s Guidelines on Infective Endocarditis: Diagnosis and Management and consult an infectious disease physician for this serious and sometimes complicated problem. High-dose, prolonged parenteral treatment is indicated. Methicillin-susceptible isolates, in the absence of prosthetic material, are often treated with oxacillin or nafcillin. Some experts also recommend addition of gentamicin for the first 3–5 days. In penicillin-allergic patients (type 1 hypersensitivity or anaphylaxis) or patients with MRSA isolates, vancomycin should be used.

For patients (without penicillin allergy) with prosthetic material in the heart and who have methicillin susceptible isolates, nafcillin (or oxacillin) plus rifampin is used; gentamicin is added during the first 2 weeks. For patients with MRSA endocarditis with prosthetic material present, vancomycin plus rifampin is recommended; gentamicin is added for the first 2 weeks. Therapy lasts in all instances for at least 6 weeks.

Occasionally, medical treatment fails. Signs of treatment failure are (1) recurrent fever without apparent treatable other cause (eg, thrombophlebitis, respiratory or urinary tract infection, drug fever), (2) persistently positive blood cultures, (3) intractable and progressive congestive heart failure, and (4) recurrent (septic) embolization. In such circumstances—particularly (2), (3), and (4)—evaluation for valve replacement becomes necessary. Antibiotics are continued for at least another 4 weeks. Persistent or recurrent infection may require a second surgical procedure.

6. Toxic shock syndrome—Treatment is aimed at expanding blood volume, maintaining perfusion pressure with inotropic agents, ensuring prompt drainage of a focus of infection (or removal of tampons or foreign bodies), and giving intravenous antibiotics.

Vancomycin, in addition to a β-lactam antibiotic (oxacillin or nafcillin), can be used for empiric therapy. Many experts also add clindamycin, since clindamycin is a protein synthesis inhibitor and may turn off toxin production. Clindamycin should not be used empirically as a single agent until susceptibilities (when an isolate grows) are known; some strains of S aureus are clindamycin-resistant.

Intravenous immune globulin has been used as adjunctive therapy. Some experts believe that corticosteroid therapy may be effective if given to patients with severe illness early in the course of their disease.

7. Vancomycin-resistants aureus infections (VRSA)—Reports of VRSA isolates are rare but are likely to increase in frequency in the future. Such isolates are sometimes susceptible to clindamycin or TMP-SMX. If not, therapeutic options are limited and include use of quinupristin-dalfopristin, linezolid, or daptomycin, assuming the strain is susceptible to these agents. Quinupristin-dalfopristin is not FDA approved for children less than 16 years of age; daptomycin is not FDA approved for children less than 18 years of age. Consultation with an infectious disease specialist is recommended.

8. Coagulase-negative staphylococcal infections—Bacteremia and other serious coagulase-negative staphylococcal infections are treated initially with vancomycin, with susceptibility results guiding subsequent therapy. Coagulase-negative staphylococci are uncommonly resistant to vancomycin (see Chapter 39 for dosing).

Baddour M: Infective endocarditis: diagnosis and management. Circulation 2005;111:3167 [PMID: 15956145]. Available at: http://circ.ahajournals.org/content/111/23/e394.full.pdf

Daum RS: Clinical practice. Skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus. N Engl J Med 2007;357:380 [PMID: 17652653].

Liu C et al: Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:285–322 [PMID: 21217178]. Available at: http://cid.oxfordjournals.org/content/52/3/e18.long

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Fever, headache, vomiting, convulsions, shock (meningitis).

 Fever, shock, petechial or purpuric skin rash (meningococcemia).

 Diagnosis confirmed by culture of normally sterile body fluids.

 General Considerations

Meningococci (Neisseria meningitidis) may be carried asymptomatically for many months in the upper respiratory tract. Less than 1% of carriers develop disease. Meningitis and sepsis are the two most common forms of illness, but septic arthritis, pericarditis, pneumonia, chronic meningococcemia, otitis media, conjunctivitis, and vaginitis also occur. The incidence of invasive diseases in the United States is about 1.2 cases per 100,000 people. An estimated 2400–3000 cases occur in the United States annually. The highest attack rate for meningococcal meningitis is in the first year of life. There also is an elevated attack rate during the teen years. The development of irreversible shock with multiorgan failure is a significant factor in the fatal outcome of acute meningococcal infections.

Meningococci are gram-negative organisms containing endotoxin in their cell walls. Endotoxins cause capillary vascular injury and leak as well as DIC. Meningococci are classified serologically into groups: A, B, C, Y, and W-135 are the groups most commonly implicated in systemic disease. The serologic groups serve as markers for studying outbreaks and transmission of disease. Currently in the United States, serogroups B accounts for 20% of cases, serogroup C accounts for 30% of cases and, and serogroup Y account for about 48% of cases. Serogroup A causes periodic epidemics in developing countries, but only occasionally is associated with cases of meningococcal disease in the United States. Sulfonamide resistance is common in non–serotype-A strains. N meningitidis with increased MICs to penicillin G are reported from South Africa and Spain. A small number of these isolates are reported in the United States. The resistance in these strains is low-level and not due to β-lactamase. Resistant isolates are susceptible to third-generation cephalosporins. Few isolates are resistant to rifampin.

Children develop immunity from asymptomatic carriage of meningococci (usually nontypeable, nonpathogenic strains) or other cross-reacting bacteria. Patients deficient in one of the late components of complement (C6, C7, C8, or C9) are uniquely susceptible to meningococcal infection, particularly group A meningococci. Deficiencies of early and alternate pathway complement components also are associated with increased susceptibility.

 Prevention

A. Chemoprophylaxis

Household contacts, day care center contacts, and hospital personnel directly exposed to the respiratory secretions of patients are at increased risk for developing meningococcal infection and should be given chemoprophylaxis with rifampin. The secondary attack rate among household members is about 1000 times the attack rate in the general population. Children between the ages of 3 months and 2 years are at greatest risk, presumably because they lack protective antibodies. Secondary cases may occur in day care centers and in classrooms. Hospital personnel are not at increased risk unless they have had contact with a patient’s oral secretions, for example, during mouth-to-mouth resuscitation, intubation, or suctioning procedures. Approximately 50% of secondary cases in households have their onset within 24 hours of identification of the index case. Exposed contacts should be notified promptly. If they are febrile, they should be fully evaluated and given high doses of penicillin or another effective antimicrobial pending the results of blood cultures.

All high-risk contacts should receive chemoprophylaxis for meningococcal disease as soon as an index case is identified. High-risk contacts are defined as:

• All household contacts (especially children < 2 years of age)

• Persons with child care or preschool contact with the index patient at any time in the 7 days prior to illness onset

• Persons with direct exposure to index patients secretions (sharing of drinks, straws, cigarettes, toothbrushes, eating utensils, kissing, etc) at any time in the 7 days prior to illness onset

• Persons who have performed mouth-to-mouth resuscitation or performed unprotected endotracheal intubation of the index patient at any time in the 7 days prior to illness onset

• Persons who have slept in the same dwelling as the index patient within 7 days of illness onset

• Passengers who were seated directly next to the index patient on a flight of more than 8 hours duration

The most commonly used agent for meningococcal chemoprophylaxis is rifampin, given orally in the following dosages twice daily for 2 days: 600 mg for adults; 10 mg/kg for children older than 1 month (maximum dosage 600 mg); and 5 mg/kg for infants younger than 1 month. Rifampin may stain a patient’s tears (and contact lenses), sweat, and urine orange; it may also affect the reliability of oral contraceptives, and alternative contraceptive measures should therefore be employed when rifampin is administered. Rifampin should not be given to pregnant women. Instead, intramuscular ceftriaxone is the preferred agent: 125 mg given as a single dose if the patient is younger than 15 years; 250 mg given as a single dose if older than 15 years. Penicillin and most other antibiotics (even with parenteral administration) are not effective chemoprophylactic agents, because they do not eradicate upper respiratory tract carriage of meningococci. Ciprofloxacin (20 mg/kg as a single dose, maximum dose 500 mg) effectively eradicates nasopharyngeal carriage in adults and children but is not approved for use in children or in pregnant women. Throat cultures to identify carriers are not useful.

B. Vaccine

Two types of vaccines are currently licensed in the United States. A quadrivalent polysaccharide vaccine (MSPV-4) prepared from purified meningococcal polysaccharides (A, C, Y, and W-135) is available in the United States for children and adults older than 2 years of age. Quadrivalent meningococcal conjugate vaccines (see Chapter 10) are licensed for use in children and adults between the ages of 2 months and 55 years, and meningococcal conjugate vaccine is preferred over the polysaccharide vaccine. In general, conjugate vaccines provide longer-lasting immunity and a more robust immune response than polysaccharide vaccines. See Chapter 10 for a discussion on meningococcal vaccines.

 Clinical Findings

A. Symptoms and Signs

Many children with clinical meningococcemia also have meningitis, and some have other foci of infection. All children with suspected meningococcemia should have a lumbar puncture.

1. Meningococcemia—A prodrome of upper respiratory infection is followed by high fever, headache, nausea, marked toxicity, and hypotension. Purpura, petechiae, and occasionally bright pink, tender macules or papules over the extremities and trunk are seen. The rash usually progresses rapidly. Occasional cases lack rash. Fulminant meningococcemia (Waterhouse-Friderichsen syndrome) progresses rapidly and is characterized by DIC, massive skin and mucosal hemorrhages, and shock. This syndrome also may be caused by H influenzae, S pneumoniae, or other bacteria. Chronic meningococcemia is characterized by periodic bouts of fever, arthralgia or arthritis, and recurrent petechiae. Splenomegaly often is present. Patients may be free of symptoms between bouts. Chronic meningococcemia occurs primarily in adults and mimics Henoch-Schönlein purpura.

2. Meningitis—In many children, meningococcemia is followed within a few hours to several days by symptoms and signs of acute purulent meningitis, with severe headache, stiff neck, nausea, vomiting, and stupor. Children with meningitis generally fare better than children with meningococcemia alone, probably because they have survived long enough to develop clinical signs of meningitis.

B. Laboratory Findings

The peripheral WBC count may be either low or elevated. Thrombocytopenia may be present with or without DIC (see Chapter 30). If petechial or hemorrhagic lesions are present, meningococci can sometimes be seen microscopically in tissue fluid expressed from a punctured lesion. CSF is generally cloudy and contains more than 1000 WBCs/μL, with many polymorphonuclear neutrophils and gram-negative intracellular diplococci. A total hemolytic complement assay may reveal absence of late components as an underlying cause.

 Differential Diagnosis

The skin lesions of H influenzae or pneumococci, enterovirus infection, endocarditis, leptospirosis, Rocky Mountain spotted fever, other rickettsial diseases, Henoch-Schönlein purpura, and blood dyscrasias may be similar to meningococcemia. Severe S aureus sepsis has been reported in some patients to present with purpura. Other causes of sepsis and meningitis are distinguished by appropriate Gram stain and cultures.

 Complications

Meningitis may lead to permanent central nervous system (CNS) damage, with deafness, convulsions, paralysis, or impaired intellectual function. Hydrocephalus may develop and requires ventriculoperitoneal shunt. Subdural collections of fluid are common but usually resolve spontaneously. Extensive skin necrosis, loss of digits or extremities, intestinal hemorrhage, and late adrenal insufficiency may complicate fulminant meningococcemia.

 Treatment

Blood cultures should be obtained for all children with fever and purpura or other signs of meningococcemia, and antibiotics should be administered immediately as an emergency procedure. There is a good correlation between survival rates and prompt initiation of antibiotic therapy. Purpura and fever should be considered a medical emergency.

Children with meningococcemia or meningococcal meningitis should be treated as though shock were imminent even if their vital signs are stable when they are first seen. If hypotension already is present, supportive measures should be aggressive, because the prognosis is grave in such situations. Treatment should be started emergently and in an intensive care setting but should not be delayed for the sake of transporting the patient. Shock may worsen following antimicrobial therapy due to endotoxin release. To minimize the risk of nosocomial transmission, patients should be placed in respiratory isolation for the first 24 hours of antibiotic treatment.

A. Specific Measures

Antibiotics should be initiated promptly. Because other bacteria, such as S pneumoniae, S aureus, or other gram-negative organisms, can cause identical syndromes, initial therapy should be broad. Vancomycin and cefotaxime (or ceftriaxone) are preferred initial coverage. Once N meningitidis has been isolated, penicillin G, cefotaxime, or ceftriaxone intravenously for 7 days are the drugs of choice. Relative penicillin resistance is uncommon but has been reported in the United States.

B. General Measures

Most cases of invasive meningococcal disease are treated with intravenous antibiotics for 7 days.

1. Cardiovascular—(See Chapter 14 for management of septic shock.) Corticosteroids are not beneficial. Sympathetic blockade and topically applied nitroglycerin have been used locally to improve perfusion.

2. Hematologic—Adjunctive therapy with heparin is controversial. Because hypercoagulability is frequently present in patients with meningococcemia, some experts believe heparin should be considered for those with DIC. Recombinant tissue plasminogen activator, concentrated antithrombin III, and recombinant protein-C infusions have been tried experimentally to reverse coagulopathy (see Chapter 30 for the management of DIC).

 Prognosis

Unfavorable prognostic features include shock, DIC, and extensive skin lesions. The case fatality rate in fulminant meningococcemia is over 30%. In uncomplicated meningococcal meningitis, the fatality rate is much lower (10%–20%).

Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC): Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-7):1 [PMID: 15917737]. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm

Brayer AF, Humiston SF: Invasive meningococcal disease in childhood. Pediatr Rev 2011;32:152–161 [PMID: 21460092].

Centers for Disease Control and Prevention (CDC): Meningococcal disease. Available at: http://www.cdc.gov/meningococcal/index.html

Centers for Disease Control and Prevention: Updated recommendations for use of meningococcal conjugate vaccines—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2011;60:72–76.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Purulent urethral discharge with intracellular gram negative diplococci on smear in male patients (usually adolescents).

 Purulent, edematous, sometimes hemorrhagic conjunctivitis with intracellular gram-negative diplococci in 2- to 4-day-old infants.

 Fever, arthritis (often polyarticular) or tenosynovitis, and maculopapular peripheral rash that may be vesiculopustular or hemorrhagic.

 Positive culture of blood, pharyngeal, or genital secretions.

 General Considerations

Neisseria gonorrhoeae is a gram-negative diplococcus. Although morphologically similar to other neisseriae, it differs in its ability to grow on selective media and to ferment carbohydrates. The cell wall of N gonorrhoeae contains endotoxin, which is liberated when the organism dies and is responsible for the production of a cellular exudate. The incubation period is short, usually 2–5 days.

Nearly 310,000 cases of gonorrhea were reported in the United States in 2010. Gonococcal disease in children may be transmitted sexually or nonsexually. Prepubertal gonococcal infection outside the neonatal period should be considered presumptive evidence of sexual contact or child abuse. Prepubertal girls usually manifest gonococcal vulvovaginitis because of the neutral to alkaline pH of the vagina and thin vaginal mucosa.

In the adolescent or adult, the workup of every case of gonorrhea should include a careful and accurate inquiry into the patient’s sexual practices, because pharyngeal infection resulting from oral sex must be detected if present and may be difficult to eradicate. Efforts should be made to identify and provide treatment to all sexual contacts. When prepubertal children are infected, epidemiologic investigation should be thorough.

Antimicrobial-resistant gonococci are a serious problem. N gonorrhoeae infections resistant to tetracyclines, penicillins, and fluoroquinolones are common. Fluoroquinolone antimicrobials are no longer recommended for therapy in the United States. In some cases, clinicians will have very limited choices for therapy. Many clinical laboratories do not routinely perform antimicrobial susceptibility tests on N gonorrhoeae, and many infections are documented by nonculture methods.

 Clinical Findings

A. Symptoms and Signs

1. Asymptomatic gonorrhea—The ratio of asymptomatic to symptomatic gonorrheal infections in adolescents and adults is probably 3–4:1 in women and 0.5–1:1 in men. Asymptomatic infections are as infectious as symptomatic ones.

2. Uncomplicated genital gonorrhea

A. MALE WITH URETHRITIS—Urethral discharge is sometimes painful and bloody and may be white, yellow, or green. There may be associated dysuria. The patient usually is afebrile.

B. PREPUBERTAL FEMALE WITH VAGINITIS—The only clinical findings initially may be dysuria and polymorphonuclear neutrophils in the urine. Vulvitis characterized by erythema, edema, and excoriation accompanied by a purulent discharge may follow.

C. POSTPUBERTAL FEMALE WITH CERVICITIS—Symptomatic disease is characterized by a purulent, foul-smelling vaginal discharge, dysuria, and occasionally dyspareunia. Fever and abdominal pain are absent. The cervix is frequently hyperemic and tender when touched. This tenderness is not worsened by moving the cervix, nor are the adnexa tender to palpation.

D. RECTAL GONORRHEA—Rectal gonorrhea often is asymptomatic. There may be purulent discharge, edema, and pain during evacuation.

3. Pharyngeal gonorrhea—Pharyngeal infection usually is asymptomatic. There may be some sore throat and, rarely, acute exudative tonsillitis with bilateral cervical lymphadenopathy and fever.

4. Conjunctivitis and iridocyclitis—Copious, usually purulent exudate is characteristic of gonococcal conjunctivitis. Newborns are symptomatic on days 2–4 of life. In the adolescent or adult, infection probably is spread from infected genital secretions by the fingers.

5. Pelvic inflammatory disease (salpingitis)—The interval between initiation of genital infection and its ascent to the uterine tubes is variable and may range from days to months. Menses frequently are the initiating factor. With the onset of a menstrual period, gonococci invade the endometrium, causing transient endometritis. Subsequently salpingitis may occur, resulting in pyosalpinx or hydrosalpinx. Rarely infection progresses to peritonitis or perihepatitis. Gonococcal salpingitis occurs in an acute, a subacute, or a chronic form. All three forms have in common tenderness on gentle movement of the cervix and bilateral tubal tenderness during pelvic examination.

Gonococci or Chlamydia trachomatis are the cause of about 50% of cases of pelvic inflammatory disease. A mixed infection caused by enteric bacilli, Bacteroides fragilis, or other anaerobes occur in the other 50%.

6. Gonococcal perihepatitis (Fitz-Hugh and Curtis syndrome)—In the typical clinical pattern, the patient presents with right upper quadrant tenderness in association with signs of acute or subacute salpingitis. Pain may be pleuritic and referred to the shoulder. Hepatic friction rub is a valuable but inconstant sign.

7. Disseminated gonorrhea—Dissemination follows asymptomatic more often than symptomatic genital infection and often results from gonococcal pharyngitis or anorectal gonorrhea. The most common form of disseminated gonorrhea is polyarthritis or polytenosynovitis, with or without dermatitis. Monoarticular arthritis is less common, and gonococcal endocarditis and meningitis are fortunately rare.

A. POLYARTHRITIS—Disease usually begins with the simultaneous onset of low-grade fever, polyarthralgia, and malaise. After a day or so, joint symptoms become acute. Swelling, redness, and tenderness occur, frequently over the wrists, ankles, and knees but also in the fingers, feet, and other peripheral joints. Skin lesions may be noted at the same time. Discrete, tender, maculopapular lesions 5–8 mm in diameter appear that may become vesicular, pustular, and then hemorrhagic. They are few in number and noted on the fingers, palms, feet, and other distal surfaces and may be single or multiple. In patients with this form of the disease, blood cultures are often positive, but joint fluid rarely yields organisms. Skin lesions often are positive by Gram stain but rarely by culture. Genital, rectal, and pharyngeal cultures must be performed.

B. MONOARTICULAR ARTHRITIS—In this somewhat less common form of disseminated gonorrhea, fever is often absent. Arthritis evolves in a single joint. Dermatitis usually does not occur. Systemic symptoms are minimal. Blood cultures are negative, but joint aspirates may yield gonococci on smear and culture. Genital, rectal, and pharyngeal cultures must be performed.

B. Laboratory Findings

Demonstration of gram-negative, kidney-shaped diplococci in smears of urethral exudate in males is presumptive evidence of gonorrhea. Positive culture confirms the diagnosis. Negative smears do not rule out gonorrhea. Gram-stained smears of cervical or vaginal discharge in girls are more difficult to interpret because of normal gram-negative flora, but they may be useful when technical personnel are experienced. In girls with suspected gonorrhea, both the cervical os and the anus should be cultured. Gonococcal pharyngitis requires culture for diagnosis.

Cultures for N gonorrhoeae are plated on a selective chocolate agar containing antibiotics (eg, Thayer-Martin agar) to suppress normal flora. If bacteriologic diagnosis is critical, suspected material should be cultured on chocolate agar as well. Because gonococci are labile, agar plates should be inoculated immediately and placed without delay in an atmosphere containing CO₂ (candle jar). When transport of specimens is necessary, material should be inoculated directly into Transgrow medium prior to shipment to an appropriate laboratory. In cases of possible sexual molestation, notify the laboratory that definite speciation is needed, because nongonococcal Neisseria species can grow on the selective media.

Nucleic acid amplification tests on urine or genital specimens now enable detection of N gonorrhoeae and C trachomatis. These tests have excellent sensitivity and are replacing culture in many laboratories. All children or adolescents with a suspected or established diagnosis of gonorrhea should have serologic tests for syphilis and HIV.

 Differential Diagnosis

Urethritis in the male may be gonococcal or nongonococcal (NGU). NGU is a syndrome characterized by discharge (rarely painful), mild dysuria, and a subacute course. The discharge is usually scant or moderate in amount but may be profuse. C trachomatis is the only proven cause of NGU. Doxycycline (100 mg orally twice a day for 7 days) is efficacious. Single-dose azithromycin, 1 g orally, may achieve better compliance. C trachomatis has been shown to cause epididymitis in males and salpingitis in females.

Vulvovaginitis in a prepubertal female may be due to infection caused by miscellaneous bacteria, including Shigella and GAS, Candida, and herpes simplex. Discharges may be caused by trichomonads, Enterobius vermicularis(pin-worm), or foreign bodies. Symptom-free discharge (leukorrhea) normally accompanies rising estrogen levels.

Cervicitis in a postpubertal female, alone or in association with urethritis and involvement of Skene and Bartholin glands, may be due to infection caused by Candida, herpes simplex, Trichomonas, or discharge resulting from inflammation caused by foreign bodies (usually some form of contraceptive device). Leukorrhea may be associated with birth control pills.

Salpingitis may be due to infection with other organisms. The symptoms must be differentiated from those of appendicitis, urinary tract infection, ectopic pregnancy, endometriosis, or ovarian cysts or torsion.

Disseminated gonorrhea presents a differential diagnosis that includes meningococcemia, acute rheumatic fever, Henoch-Schönlein purpura, juvenile rheumatoid arthritis, lupus erythematosus, leptospirosis, secondary syphilis, certain viral infections (particularly rubella, but also enteroviruses and parvovirus), serum sickness, type B hepatitis (in the prodromal phase), infective endocarditis, and even acute leukemia and other types of cancer. The fully evolved skin lesions of disseminated gonorrhea are remarkably specific, and genital, rectal, or pharyngeal cultures, plus cultures of blood and joint fluid, usually yield gonococci from at least one source.

 Prevention

Prevention of gonorrhea is principally a matter of sex education, condom use, and identification and treatment of contacts.

 Treatment

A. Uncomplicated Urethral, Endocervical, or Rectal Gonococcal Infections in Adolescents

Ceftriaxone (250 mg intramuscularly in a single dose), and doxycycline (100 mg orally twice a day for 7 days), or azithromycin (1 g orally in a single dose) is recommended. Ceftizoxime, cefotaxime, and cefotetan parenterally are alternative single-dose therapies. Fluoroquinolones are no longer recommended for therapy due to increasing rates of resistance. If ceftriaxone cannot be used, cefixime (400 mg orally in a single dose) and doxycycline (100 mg orally twice daily for 7 days) is recommended. Azithromycin (2 g orally once) can be used in the case of severe cephalosporin allergy. A repeated culture 7 days after therapy should be done if either oral regimen has been used.

Tetracyclines should be avoided in pregnancy, and repeated doses may stain the teeth of young children. Erythromycin or amoxicillin is recommended for therapy of C trachomatis in pregnant women; azithromycin is an alternative regimen. Repeat testing 3 weeks after completion of therapy is recommended in pregnant women.

Spectinomycin (2 g intramuscularly in a single dose) is used for penicillin- and cephalosporin-allergic patients, but is not currently available in the United States. A repeat culture after completion of therapy is not necessary in asymptomatic adolescents after the ceftriaxone–doxycycline regimen. A repeat culture after completion of therapy should be obtained from infants and children.

B. Pharyngeal Gonococcal Infection

Ceftriaxone (250 mg intramuscularly in a single dose) and azithromycin 1 g is a single dose or doxycycline 100 mg twice daily for 7 days should be used; neither spectinomycin nor amoxicillin is recommended.

C. Disseminated Gonorrhea

Recommended regimens include ceftriaxone (1 g intramuscularly or intravenously once daily) or cefotaxime (1 g intravenously every 8 hours or ceftizoxime (1 g intravenously every 8 hours). Oral therapy may follow parenteral therapy 24–48 hours after improvement. Recommended regimens include cefixime (400 mg) twice daily to complete 7 days of therapy. Fluoroquinolones are not recommended. If concurrent infection with Chlamydia is present or has not been excluded, a course of doxycycline, azithromycin, or erythromycin should also be prescribed.

D. Pelvic Inflammatory Disease

Doxycycline (100 mg twice a day orally) and either cefoxitin (2 g intramuscularly or intravenously every 6 hours) or cefotetan (2 g intramuscularly or intravenously every 12 hours) are given until the patient is clinically improved, then doxycycline is administered by mouth to complete 14 days of therapy. Clindamycin and gentamicin given intravenously until the patient improves clinically may be used rather than cefoxitin. Many other regimens have been used for therapy of pelvic inflammatory disease, although comparative efficacy data are limited.

E. Prepubertal Gonococcal Infections

1. Uncomplicated genitourinary, rectal, or pharyngeal infections—These infections may be treated with ceftriaxone (50 mg/kg/d to a maximum of 125 mg intramuscularly in a single dose). Children older than age 8 years should also receive doxycycline (100 mg orally twice daily for 7 days). The physician should evaluate all children for evidence of sexual abuse and coinfection with syphilis, Chlamydia, and HIV.

2. Disseminated gonorrhea—This should be treated with ceftriaxone (50 mg/kg once daily parenterally for 7 days).

Centers for Disease Control and Prevention (CDC) et al: Sexually transmitted diseases treatment guidelines, 2010. MMWR 2010;59(RR12):1 [PMID: 21160459].

Centers for Disease Control and Prevention (CDC): Update to CDC’s sexually transmitted diseases treatment guidelines, 2012: oral cephalosporins no longer recommended treatment for gonococcal infections. MMWR 2012;61(31):6590 [PMID: 22874837].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Dry mucous membranes.

 Nausea and vomiting.

 Diplopia; dilated, unreactive pupils.

 Descending paralysis.

 Difficulty in swallowing and speech occurring within 12–36 hours after ingestion of toxin-contaminated food.

 Multiple cases in a family or group.

 Hypotonia and constipation in infants.

 Diagnosis by clinical findings and identification of toxin in blood, stool, or implicated food.

 General Considerations

Botulism is a paralytic disease caused by Clostridium botulinum, an anaerobic, gram-positive, spore-forming bacillus normally found in soil. The organism produces an extremely potent neurotoxin. Of the seven types of toxin (A–G), types A, B, and E cause most human diseases. The toxin, a polypeptide, is so potent that 0.1 mg is lethal for humans.

Food-borne botulism usually results from ingestion of toxin-containing food. Preformed toxin is absorbed from the gut and produces paralysis by preventing acetylcholine release from cholinergic fibers at myoneural junctions. In the United States, home-canned vegetables are usually the cause. Commercially canned foods rarely are responsible. Virtually any food will support the growth of C botulinum spores into vegetative toxin-producing bacilli if an anaerobic, nonacid environment is provided. The food may not appear or taste spoiled. The toxin is heat-labile, but the spores are heat-resistant. Inadequate heating during processing (temperature < 115°C) allows the spores to survive and later resume toxin production. Boiling of foods for 10 minutes or heating at 80°C for 30 minutes before eating will destroy the toxin.

Infant botulism occurs in infants less than 12 months of age. The toxin appears to be produced by C botulinum organisms residing in the gastrointestinal tract. In some instances, honey has been the source of spores.

Annually, 10–15 cases of wound botulism are reported. Most cases occur in drug abusers with infection in intravenous or intramuscular injection sites.

Botulism, as a result of aerosolization of botulinum toxin, also could occur as the result of a bioterrorism event. Only three such cases of botulism have been reported; the incubation period was not well-defined, but was about 72 hours in the reported cases.

 Prevention

Infant botulism is acquired by ingestion of botulism spores which then sporulate into C botulinum organisms that can form botulinum toxin. Honey can contain botulism spores so it is recommended that honey not be consumed by infants less than 12 months of age. Corn syrups that have not been pasteurized may pose a theoretical risk and some organizations (American Academy of Pediatrics) recommend that infants less than 12 months should not consume unpasteurized corn syrup.

Food-borne botulism is acquired by ingesting preformed botulism toxin in food. In the United States, food-borne botulism is most commonly seen with ingestion of home canned foods of low acidity (ie, corn, asparagus, green beans). However, baked potatoes wrapped in aluminum foil that have not been kept hot and home-fermented fish have also been associated with cases of botulism. Persons who eat home-canned foods should consider boiling foods for at least 10 minutes (can destroy potential toxin). Safe food handling practices include keeping foods either refrigerated (< 45°F) or hot (> 185°F), and disposing of any cracked jars or bulging/dented cans.

 Clinical Findings

A. Symptoms and Signs

The incubation period for food-borne botulism is 8–36 hours. The initial symptoms are lethargy and headache. These are followed by double vision, dilated pupils, ptosis, and, within a few hours, difficulty with swallowing and speech. Pharyngeal paralysis occurs in some cases, and food may be regurgitated. The mucous membranes often are very dry. Descending skeletal muscle paralysis may be seen. Death usually results from respiratory failure.

Botulism patients present with a “classic triad”: (1) afebrile; (2) symmetrical, flaccid, descending paralysis with prominent bulbar palsies; and (3) clear sensorium. Recognition of this triad is important in making the clinical diagnosis. Botulism is caused by a toxin, thus there is no fever unless secondary infection (eg, aspiration pneumonia) occurs. Common bulbar palsies seen include dysphonia, dysphagia, dysarthria, and diplopia (four “Ds”).

Infant botulism is seen in infants younger than age 12 months (peak onset 2–8 months). Infants younger than age 2 weeks rarely develop botulism. The initial symptoms are usually constipation and progressive, often severe, hypotonia. Loss of facial expression, weak cry, and drooling are often noted. Clinical findings include constipation, weak suck and cry, pooled oral secretions, cranial nerve deficits, generalized weakness, and, on occasion, apnea. The characteristic electromyographic pattern of brief, small, abundant motor-unit action potentials (BSAPs) may help confirm the diagnosis.

B. Laboratory Findings

The diagnosis is made by demonstration of C botulinum toxin in stool, gastric aspirate or vomitus, or serum. Serum and stool samples can be sent for toxin confirmation (done by toxin neutralization mouse bioassay at CDC or state health departments). In infant botulism, serum assays for C botulinum toxin may be negative. These tests take time and therapy should not be withheld awaiting testing results. Foods that are suspected to be contaminated should be kept refrigerated and given to public health personnel for testing. Laboratory findings, including CSF examination, are usually normal. Electromyography suggests the diagnosis if the characteristic brief, small abundant motor-unit action potentials (BSAP) abnormalities are seen. A nondiagnostic electromyogram does not exclude the diagnosis.

 Differential Diagnosis

Guillain-Barré syndrome is characterized by ascending paralysis, sensory deficits, and elevated CSF protein without pleocytosis.

Other illnesses that should be considered include poliomyelitis, post diphtheritic polyneuritis, certain chemical intoxications, tick paralysis, and myasthenia gravis. The history and elevated CSF protein characterize postdiphtheritic polyneuritis. Tick paralysis presents with a flaccid ascending motor paralysis. An attached tick should be sought. Myasthenia gravis usually occurs in adolescent girls. It is characterized by ocular and bulbar symptoms, normal pupils, fluctuating weakness, absence of other neurologic signs, and clinical response to cholinesterase inhibitors.

 Complications

Difficulty in swallowing leads to aspiration pneumonia. Serious respiratory paralysis may be fatal despite assisted ventilation and intensive supportive measures.

 Treatment

A. Specific Measures

Patients with suspected botulism should be hospitalized and monitored closely for signs of impending respiratory failure and inability to manage secretions. Early treatment of botulism with antitoxin (food-borne or wound botulism) or passive human botulism immune globulin (infant botulism) is beneficial. Treatment should begin as soon as the clinical diagnosis is made (prior to microbiologic or toxin confirmation). Contact your State Health Department’s emergency 24-hour telephone number immediately when a case of botulism is suspected to assist in therapeutic decisions and to help obtain treatment product.

For suspected wound or food-borne botulism (noninfant botulism), patients should be treated with the heptavalent botulinum antitoxin (HBAT), which is only available from the CDC under an investigational new drug protocol. HBAT is an equine derived antitoxin and contains antibodies to all seven known botulinum toxin types (A through G). The treatment protocol (available from the CDC) includes detailed instructions for intravenous administration of antitoxin. State Health Departments can assist practitioners in obtaining the antitoxin; if State Health Department officials are unavailable, the CDC ([770] 488-7100) can be contacted for help in obtaining the product and for consultation. In addition, epidemic assistance, and laboratory testing services are available from the CDC through state health departments.

For treatment of infant botulism, intravenous human botulism immune globulin (Baby-BIG) is approved by the U.S. Food and Drug Administration (FDA) for use. Baby-BIG is a product containing high titers of neutralizing antibodies against type A and B toxin and is made from pooled plasma of adults who were immunized with a botulism toxoid vaccine. Results of a placebo-controlled clinical trial of use in infant botulism showed reduction in the mean hospital stay (2.5 weeks in treated patients vs 5.5 weeks in the placebo group) and decrease in mechanical ventilation time in the Baby-BIG–treated group. Although the cost of the preparation is very high, it still is cost-saving since there is a substantial reduction in hospital days, intensive care unit stay, and ventilator time in treated infants. Baby-BIG is not indicated for use in any form of botulism (wound, food-borne) other than infant botulism. To obtain Baby-BIG (in any state), contact the Infant Botulism Treatment and Prevention Program at: (510) 231-7600.

B. General Measures

General and supportive therapy consists of bed rest, ventilatory support (if necessary), fluid therapy, and enteral or parenteral nutrition. Aminoglycoside antimicrobials and clindamycin may exacerbate neuromuscular blockage and should be avoided.

 Prognosis

The mortality rate has declined substantially in recent years and currently is at 6%. In nonfatal cases, symptoms subside over 2–3 months and recovery is usually complete.

Centers for Disease Control and Prevention (CDC): Botulism technical information. Available at: http://www.cdc.gov/nczved/divisions/dfbmd/diseases/botulism/technical.html

Centers for Disease Control and Prevention (CDC): Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR 2010;59(10);299 [PMID: 20300057].

Lawrence DT et al: Food poisoning. Emerg Med Clin North Am 2007;25(2):357 [PMID: 17482025].

Long SS: Infant botulism and treatment with BIG-IV (BabyBIG). Pediatr Infect Dis J 2007;26:261 [PMID: 17484226].

Underwood K et al: Infant botulism: a 30-year experience spanning the introduction of botulism immune globulin intravenous in the intensive care unit at Childrens Hospital Los Angeles. Pediatrics 2007;120:e1380–e1385 [PMID: 18055655].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Nonimmunized or partially immunized patient.

 History of skin wound.

 Spasms of jaw muscles (trismus).

 Stiffness of neck, back, and abdominal muscles, with hyperirritability and hyperreflexia.

 Episodic, generalized muscle contractions.

 Diagnosis is based on clinical findings and the immunization history.

 General Considerations

Tetanus is caused by Clostridium tetani, an anaerobic, gram-positive bacillus that produces a potent neurotoxin. In unimmunized or incompletely immunized individuals, infection follows contamination of a wound by soil containing Clostridial spores from animal manure. The toxin reaches the CNS by retrograde axon transport, is bound to cerebral gangliosides, and appears to increase reflex excitability in neurons of the spinal cord by blocking function of inhibitory synapses. Intense muscle spasms result. Two-thirds of cases in the United States follow minor puncture wounds of the hands or feet. In many cases, no history of a wound can be obtained. Injecting substances and drug abuse may be risk factors (in individuals who are not tetanus-immune). In the newborn, usually in underdeveloped countries, infection generally results from contamination of the umbilical cord. The incubation period typically is 4–14 days but may be longer. In the United States, cases in young children are due to failure to immunize. Eighty-five percent of cases occur in adults older than 25 years.

 Prevention

A. Tetanus Toxoid

Active immunization with tetanus toxoid prevents tetanus. Immunity is almost always achieved after the third dose of vaccine. Tetanus immune globulin (TIG) is an additional agent used to prevent tetanus in persons who have received less than three doses of tetanus toxoid or in immunocompromised patients who do not make sufficient antibody (ie, HIV infection; see Chapter 10). A tetanus toxoid booster at the time of injury is needed if none has been given in the past 10 years—or within 5 years for heavily contaminated wounds. Nearly all cases of tetanus (99%) in the United States are in nonimmunized or incompletely immunized individuals. Many adolescents and adults lack protective antibody.

B. Wound Care and Prophylaxis for Tetanus-Prone Wounds

Wounds that are contaminated with soil, debris, feces, or saliva are at increased risk for tetanus. Puncture wounds or wounds that contain devitalized tissue are at increased risk of infection with C tetani. This includes wounds that result from crush injury, frostbite, burns, or avulsion. All wounds should be adequately cleaned, foreign material removed, and debrided if necrotic or devitalized tissue is present or if residual foreign matter is present. The decision to use tetanus toxoid–containing vaccine or human TIG depends on the type of injury and the tetanus immunization status of the patient (see Chapter 10; Table 10–5). TIG should be used in children with fewer than three previous tetanus toxoid immunizations (DPT, DPaT, DT, Td, Tdap) who have tetanus-prone wounds, and should be administered to HIV-infected children with tetanus-prone wounds, regardless of their immunization history. When TIG is indicated for wound, prophylaxis 250 units are given intramuscularly regardless of age. If tetanus immunization is incomplete, a dose of age-appropriate vaccine should be given. When both are indicated, tetanus toxoid and TIG should be administered concurrently at different sites using different syringes (see Chapter 10).

Prophylactic antimicrobials are useful if the child is unimmunized and TIG is not available.

 Clinical Findings

A. Symptoms and Signs

The first symptom often is mild pain at the site of the wound, followed by hypertonicity and spasm of the regional muscles. Characteristically, difficulty in opening the mouth (trismus) is evident within 48 hours. In newborns, the first signs are irritability and inability to nurse. The infant may then develop stiffness of the jaw and neck, increasing dysphagia, and generalized hyperreflexia with rigidity and spasms of all muscles of the abdomen and back (opisthotonos). The facial distortion resembles a grimace (risus sardonicus). Difficulty in swallowing and convulsions triggered by minimal stimuli such as sound, light, or movement may occur. Individual spasms may last seconds or minutes. Recurrent spasms are seen several times each hour, or they may be almost continuous. In most cases, the temperature is normal or only mildly elevated. A high or subnormal temperature is a bad prognostic sign. Patients are fully conscious and lucid. A profound circulatory disturbance associated with sympathetic overactivity may occur on the second to fourth day, which may contribute to the mortality rate. This is characterized by elevated blood pressure, increased cardiac output, tachycardia (> 20 beats/min), and arrhythmia.

B. Laboratory Findings

The diagnosis is made on clinical grounds. There may be a mild polymorphonuclear leukocytosis. The CSF is normal with the exception of mild elevation of opening pressure. Serum muscle enzymes may be elevated. Transient electrocardiographic and electroencephalographic abnormalities may occur. Anaerobic culture and microscopic examination of pus from the wound can be helpful, but C tetani is difficult to grow, and the drumstick-shaped gram-positive bacilli often cannot be found.

 Differential Diagnosis

Poliomyelitis is characterized by asymmetrical paralysis in an incompletely immunized child. The history of an animal bite and the absence of trismus may suggest rabies. Local infections of the throat and jaw should be easily recognized. Bacterial meningitis, phenothiazine reactions, decerebrate posturing, narcotic withdrawal, spondylitis, and hypocalcemic tetany may be confused with tetanus.

 Complications

Complications include sepsis, malnutrition, pneumonia, atelectasis, asphyxial spasms, decubitus ulcers, and fractures of the spine due to intense contractions. They can be prevented in part by skilled supportive care.

 Treatment

A. Specific Measures

Human TIG in a single dose of 3000–6000 units, intramuscularly, is given to children and adults. Doses of 500 units have been used in infants. Infiltration of part of the TIG dose around the wound is recommended. If TIG is indicated, but not available, intravenous immune globulin in a dose of 200–400 mg/kg intravenously can be used (although it is not licensed for this indication). In countries where TIG or immune globulin are not available, equine tetanus antitoxin may be available. Surgical debridement of wounds is indicated, but more extensive surgery or amputation to eliminate the site of infection is not necessary. Antibiotics are given to attempt to decrease the number of vegetative forms of the bacteria to decrease toxin production: oral or intravenous metronidazole (30 mg/kg/d in four divided doses; maximum 4 g/d) for 10–14 days is the preferred agent.

B. General Measures

The patient is kept in a quiet room with minimal stimulation. Control of spasms and prevention of hypoxic episodes are crucial. Benzodiazepines can be used to help control spasms and provide some sedation. Mechanical ventilation and muscle paralysis are necessary in severe cases. Nasogastric or intravenous feedings should be used to limit stimulation of feedings and prevent aspiration.

 Prognosis

The fatality rate in newborns and heroin-addicted individuals is high. The overall mortality rate in the United States is 11%. The fatality rate depends on the quality of supportive care, the patient’s age, and the patient’s vaccination history. Many deaths are due to pneumonia or respiratory failure. If the patient survives 1 week, recovery is likely.

Brook I: Current concepts in the management of Clostridium tetani infection. Expert Rev Anti Infect Ther 2008;6(3):327–336 [PMID: 18588497].

Centers for Disease Control and Prevention (CDC): Tetanus. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/tetanus.pdf

Gibson K, Bonaventure UJ, Kiviri W: Tetanus in developing countries: a case series and review. Can J Anaesth 2009;56(4):307–315 [PMID: 19296192].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Contamination of a wound with soil or feces.

 Massive edema, skin discoloration, bleb formation, and pain in an area of trauma.

 Serosanguineous exudate from wound.

 Crepitation of subcutaneous tissue.

 Rapid progression of signs and symptoms.

 Clostridia cultured or seen on stained smears.

 General Considerations

Gas gangrene (Clostridial myonecrosis) is a necrotizing infection that follows trauma or surgery and is caused by several anaerobic, gram-positive, spore-forming bacilli of the genus Clostridium. Occasionally the source is the gastrointestinal tract and muscles are hematogenously seeded. The spores are found in soil, feces, and vaginal secretions. In devitalized tissue, the spores germinate into vegetative bacilli that proliferate and produce toxins, causing thrombosis, hemolysis, and tissue necrosis. C perfringens, the species causing approximately 80% of cases of gas gangrene, produces at least eight such toxins. The areas involved most often are the extremities, abdomen, and uterus. Clostridium septicum may also cause myonecrosis and causes septicemia in patients with neutropenia. Nonclostridial infections with gas formation can mimic clostridial infections and are more common. Neutropenia is a risk factor for this severe infection.

 Prevention

Gas gangrene can be prevented by the adequate cleansing and debridement of all wounds. It is essential that foreign bodies and dead tissue be removed. A clean wound does not provide a suitable anaerobic environment for the growth of Clostridial species.

 Clinical Findings

A. Symptoms and Signs

The onset of gas gangrene usually is sudden, often 1 day after trauma or surgery (mean, 3–4 days), but can be delayed up to 20 days. The skin around the wound becomes discolored (pale, red, or purple), with hemorrhagic bullae, serosanguineous exudate, and crepitus may be observed the subcutaneous tissues. The absence of crepitus does not rule out the diagnosis. Pain and swelling usually are intense. Systemic illness appears early and progresses rapidly to intravascular hemolysis, jaundice, shock, toxic delirium, and renal failure.

B. Laboratory Findings

Isolation of the organism requires anaerobic culture. Gram-stained smears may demonstrate many gram-positive rods and few inflammatory cells.

C. Imaging

Radiographs may demonstrate gas in tissues, but this is a late finding and is also seen in infections with other gas-forming organisms or may be due to air introduced into tissues during trauma or surgery.

D. Operative Findings

Direct visualization of the muscle at surgery may be necessary to diagnose gas gangrene. Early, the muscle is pale and edematous and does not contract normally; later, the muscle may be frankly gangrenous.

 Differential Diagnosis

Gangrene and cellulitis caused by other organisms and Clostridial cellulitis (not myonecrosis) must be distinguished. Necrotizing fasciitis may resemble gas gangrene.

 Treatment

A. Specific Measures

Penicillin G (300,000–400,000 U/kg/d intravenously in six divided doses) should be given, combined with clindamycin or metronidazole. Clindamycin, metronidazole, meropenem, and imipenem/cilastatin are alternatives for penicillin-allergic patients. Some experts recommend a combination of penicillin and clindamycin. Clindamycin is a protein synthesis inhibitor and may inhibit toxin production.

B. Surgical Measures

Surgery should be prompt and extensive, with removal of all necrotic tissue. Compartment syndromes can occur even if there are few cutaneous findings. Checking compartment pressures in patients with severe pain and any signs of compartment syndrome is prudent.

C. Hyperbaric Oxygen

Hyperbaric oxygen therapy is controversial but good outcomes have been reported in nonrandomized studies using hyperbaric oxygen in combination with surgery and antibiotics.

 Prognosis

Clostridial myonecrosis is fatal if untreated. With early diagnosis, antibiotics, and surgery, the mortality rate is 20%–60%. Involvement of the abdominal wall, leukopenia, intravascular hemolysis, renal failure, and shock are ominous prognostic signs.

Langham M, Arnold L: Clostridial myonecrosis in an adolescent male. Pediatrics 2005;116:e737 [PMID: 16199671]. Available at: http://pediatrics.aappublications.org/content/116/5/e735.full.pdf

Smith-Slatas CL et al: Clostridium septicum infections in children: a case report and review of the literature. Pediatrics 2006;117:e796 [PMID: 16567392].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Gray, adherent pseudomembrane, most often in the pharynx but also in the nasopharynx or trachea.

 Sore throat, serosanguinous nasal discharge, hoarseness, and fever in a nonimmunized child.

 Peripheral neuritis or myocarditis.

 Positive culture.

 Treatment should not be withheld pending culture results.

 General Considerations

Diphtheria is an acute infection of the upper respiratory tract or skin caused by toxin-producing Corynebacterium diphtheriae. Diphtheria in the United States is rare; five cases have been reported since 2000; none since 2003. However, significant numbers of elderly adults and unimmunized children are susceptible to infection. Diphtheria still occurs in epidemics in countries where immunization is not universal. Travelers to these areas may acquire the disease.

Corynebacteria are gram-positive, club-shaped rods with a beaded appearance on Gram stain. The capacity to produce exotoxin is conferred by a lysogenic bacteriophage and is not present in all strains of C diphtheriae. In immunized communities, infection probably occurs through spread of the phage among carriers of susceptible bacteria rather than through spread of phage-containing bacteria themselves. Diphtheria toxin kills susceptible cells by irreversible inhibition of protein synthesis.

The toxin is absorbed into the mucous membranes and causes destruction of epithelium and a superficial inflammatory response. The necrotic epithelium becomes embedded in exuding fibrin and WBCs and RBCs (red blood cells), forming a grayish pseudomembrane over the tonsils, pharynx, or larynx. Any attempt to remove the membrane exposes and tears the capillaries, resulting in bleeding. The diphtheria bacilli within the membrane continue to produce toxin, which is absorbed and may result in toxic injury to heart muscle, liver, kidneys, and adrenals, and is sometimes accompanied by hemorrhage. The toxin also produces neuritis, resulting in paralysis of the soft palate, eye muscles, or extremities. Death may occur as a result of respiratory obstruction or toxemia and circulatory collapse. The patient may succumb after a somewhat longer time as a result of cardiac damage. The incubation period is 2–7 days.

 Clinical Findings

A. Symptoms and Signs

1. Pharyngeal diphtheria—Early manifestations of diphtheritic pharyngitis are mild sore throat, moderate fever, and malaise, followed fairly rapidly by prostration and circulatory collapse. The pulse is more rapid than the fever would seem to justify. A pharyngeal membrane forms and may spread into the nasopharynx or the trachea, producing respiratory obstruction. The membrane is tenacious and gray and is surrounded by a narrow zone of erythema and a broader zone of edema. The cervical lymph nodes become swollen, and swelling is associated with brawny edema of the neck (so-called bull neck). Laryngeal diphtheria presents with stridor, which can progress to obstruction of the airway.

2. Other forms—Cutaneous, vaginal, and wound diphtheria account for up to one-third of cases and are characterized by ulcerative lesions with membrane formation.

B. Laboratory Findings

Diagnosis is clinical. Direct smears are unreliable. Material is obtained from the nose, throat, or skin lesions, if present, for culture, but specialized culture media are required. Between 16 and 48 hours is required before identification of the organism. A toxigenicity test is then performed. Cultures may be negative in individuals who have received antibiotics. The WBC count usually is normal, but hemolytic anemia and thrombocytopenia are frequent.

 Differential Diagnosis

Pharyngeal diphtheria resembles pharyngitis secondary to β-hemolytic streptococcus, Epstein-Barr virus, or other viral respiratory pathogens. A nasal foreign body or purulent sinusitis may mimic nasal diphtheria. Other causes of laryngeal obstruction include epiglottitis and viral croup. Guillain-Barré syndrome, poliomyelitis, or acute poisoning may mimic the neuropathy of diphtheria.

 Complications

A. Myocarditis

Diphtheritic myocarditis is characterized by a rapid, thready pulse; indistinct heart sounds, ST-T wave changes, conduction abnormalities, dysrhythmias, or cardiac failure; hepatomegaly; and fluid retention. Myocardial dysfunction may occur from 2 to 40 days after the onset of pharyngitis.

B. Polyneuritis

Neuritis of the palatal and pharyngeal nerves occurs during the first or second week. Nasal speech and regurgitation of food through the nose are seen. Diplopia and strabismus occur during the third week or later. Neuritis may also involve peripheral nerves supplying the intercostal muscles, diaphragm, and other muscle groups. Generalized paresis usually occurs after the fourth week.

C. Bronchopneumonia

Secondary pneumonia is common in fatal cases.

 Prevention

A. Immunization

Immunization with diphtheria toxoid combined with pertussis and tetanus toxoids (DTaP) should be used routinely for infants and children (see Chapter 10).

B. Care of Exposed Susceptibles

Children exposed to diphtheria should be examined, and nose and throat cultures obtained. If signs and symptoms of early diphtheria are found, antibiotic treatment should be instituted. Immunized asymptomatic individuals should receive diphtheria toxoid if a booster has not been received within 5 years. Unimmunized close contacts should receive either erythromycin orally (40 mg/kg/d in four divided doses) for 7 days or benzathine penicillin G intramuscularly (25,000 U/kg), active immunization with diphtheria toxoid, and observation daily.

 Treatment

A. Specific Measures

1. Antitoxin—To be effective, diphtheria antitoxin should be administered within 48 hours (see Chapter 9).

2. Antibiotics—Penicillin G (150,000 U/kg/d intravenously or intramuscularly) should be given for 14 days. For penicillin- allergic patients, erythromycin (40 mg/kg/d) is given orally for 14 days.

B. General Measures

Bed rest in the hospital for 10–14 days is usually required. All patients must be strictly isolated for 1–7 days until respiratory secretions are noncontagious. Isolation may be discontinued when two successive nose and throat cultures at 24-hour intervals are negative. These cultures should not be taken until at least 24 hours have elapsed since the cessation of antibiotic treatment.

C. Treatment of Carriers

All carriers should receive treatment. Erythromycin (40 mg/kg/d orally in three or four divided doses), penicillin V potassium (50 mg/kg/d) for 10 days, or benzathine penicillin G (600,000–1,200,000 units intramuscularly) should be given. All carriers must be quarantined. Before they can be released, carriers must have two negative cultures of both the nose and the throat taken 24 hours apart and obtained at least 24 hours after the cessation of antibiotic therapy.

 Prognosis

Mortality varies from 3% to 25% and is particularly high in the presence of early myocarditis. Neuritis is reversible; it is fatal only if an intact airway and adequate respiration cannot be maintained. Permanent heart damage from myocarditis occurs rarely.

Byard RW: Diphtheria—the “strangling angel of children.” J Forensic Leg Med 2013;20(2):65 [PMID: 23357389].

Centers for Disease Control and Prevention (CDC): Diphtheria. Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/diptheria_t.htm

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Diarrhea by several different mechanisms due to E coli.

 Hemorrhagic colitis and hemolytic-uremic syndrome.

 Neonatal sepsis or meningitis.

 Urinary tract infection.

 Opportunistic infections.

 Diagnosis confirmed by culture.

 General Considerations

Enterobacteriaceae are a family of gram-negative bacilli that are normal flora in the gastrointestinal tract and are also found in water and soil. They cause gastroenteritis, urinary tract infections, neonatal sepsis and meningitis, and opportunistic infections. E coli is the organism in this family that most commonly causes infection in children, but Klebsiella, Morganella, Enterobacter, Serratia, Proteus, and other genera are also important, particularly in the compromised host. Shigella and Salmonella are discussed in separate sections.

E coli strains capable of causing diarrhea were originally termed enteropathogenic E coli (EPEC) and were recognized by serotype. It is now known that E coli may cause diarrhea by several distinct mechanisms. Classic EPEC strains cause a characteristic histologic injury in the small bowel termed adherence and effacement. Enterotoxigenic E coli (ETEC) causes a secretory, watery diarrhea. ETEC adheres to enterocytes and secretes one or more plasmid-encoded enterotoxins. One of these, heat-labile toxin, resembles cholera toxin in structure, function, and mechanism of action. Enteroinvasive E coli (EIEC) are very similar to Shigella in their pathogenetic mechanisms. Shigella-toxin producing E coli (STEC) cause hemorrhagic colitis and the hemolytic-uremic syndrome. The most common STEC serotype is O157:H7, although several other serotypes cause the same syndrome. These strains elaborate one of several cytotoxins, closely related to Shiga toxin produced by Shigella dysenteriae. Outbreaks of hemolytic-uremic syndrome associated with STEC have followed consumption of inadequately cooked ground beef. Thorough heating to 68–71°C is necessary. Unpasteurized fruit juice, various uncooked vegetables, and contaminated water also have caused infections and epidemics. The common source for SREC in all of these foods and water is the feces of cattle. Person-to-person spread including spread in day care centers by the fecal-oral route has been reported. Over 5400 cases of STEC were reported in the United States in 2010.

E coli that aggregate on the surface of hep cells in tissue culture are termed enteroaggregative E coli (EAggEC). EAggEC causes diarrhea by a distinct but unknown mechanism.

Eighty percent of E coli strains causing neonatal meningitis possess specific capsular polysaccharide (K1 antigen), which, alone or in association with specific somatic antigens, confers virulence. Approximately 90% of urinary tract infections in children are caused by E coli. E coli binds to the uroepithelium by P-fimbriae, which are present in more than 90% of E coli that cause pyelonephritis. Other bacterial cell surface structures, such as O and K antigens, and host factors are also important in the pathogenesis of urinary tract infections.

Klebsiella, Enterobacter, Serratia, and Morganella are normally found in the gastrointestinal tract and in soil and water. Klebsiella may cause a bronchopneumonia with cavity formation. Klebsiella, Enterobacter, and Serratia are often hospital-acquired opportunists associated with antibiotic usage, debilitated states, and chronic respiratory conditions. They frequently cause urinary tract infection or sepsis. Many of these infections are difficult to treat because of antibiotic resistance. Antibiotic susceptibility tests are necessary. Parenteral third-generation cephalosporins are usually more active than ampicillin, but resistance due to high-level production of chromosomal cephalosporinase may occur. Enterobacter and Serratia strains broadly resistant to cephalosporins also cause infections in hospitalized newborns and children. Aminoglycoside antibiotics are usually effective but require monitoring of serum levels to ensure therapeutic and nontoxic levels. Carbapenem-resistant Enterobacteriaceae are a serious concern due to limited options for therapy.

 Clinical Findings

A. Symptoms and Signs

1. E coli gastroenteritis—E coli may cause diarrhea of varying types and severity. ETEC usually produce mild, self-limiting illness without significant fever or systemic toxicity, often known as traveler’s diarrhea. However, diarrhea may be severe in newborns and infants, and occasionally an older child or adult will have a cholera-like syndrome. EIEC strains cause a shigellosis-like illness, characterized by fever, systemic symptoms, blood and mucus in the stool, and leukocytosis, but currently are uncommon in the United States. STEC strains cause hemorrhagic colitis. Diarrhea initially is watery and fever usually is absent. Abdominal pain and cramping occur; diarrhea progresses to blood streaking or grossly bloody stools. Hemolytic-uremic syndrome occurs within a few days of diarrhea in 2%–5% of children and is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure (see Chapter 24).

2. Neonatal sepsis—Findings include jaundice, hepatosplenomegaly, fever, temperature lability, apneic spells, irritability, and poor feeding. Respiratory distress develops when pneumonia occurs; it may appear indistinguishable from respiratory distress syndrome in preterm infants. Meningitis is associated with sepsis in 25%–40% of cases. Other metastatic foci of infection may be present, including pneumonia and pyelonephritis. Sepsis may lead to severe metabolic acidosis, shock, DIC, and death.

3. Neonatal meningitis—Findings include high fever, full fontanelles, vomiting, coma, convulsions, pareses or paralyses, poor or absent Moro reflex, opisthotonos, and occasionally hypertonia or hypotonia. Sepsis coexists or precedes meningitis in most cases. Thus, signs of sepsis often accompany those of meningitis. CSF usually shows a cell count of over 1000/μL, mostly polymorphonuclear neutrophils, and bacteria on Gram stain. CSF glucose concentration is low (usually less than half that of blood), and the protein is elevated above the levels normally seen in newborns and premature infants (> 150 mg/dL).

4. Acute urinary tract infection—Symptoms include dysuria, increased urinary frequency, and fever in the older child. Nonspecific symptoms such as anorexia, vomiting, irritability, failure to thrive, and unexplained fever are seen in children younger than age 2 years. Young infants may present with jaundice. As many as 1% of school-aged girls and 0.05% of boys have asymptomatic bacteriuria. Screening for and treatment of asymptomatic bacteriuria is not recommended.

B. Laboratory Findings

Because E coli are normal flora in the stool, a positive stool culture alone does not prove that the E coli in the stool are causing disease. Serotyping, tests for enterotoxin production or invasiveness, and tests for P-fimbriae are performed in research laboratories. MacConkey agar with sorbitol substituted for lactose (SMAC agar) is useful to screen stool for STEC. Serotyping and testing for enterotoxin are available at many state health departments and increasingly from commercial and hospital laboratories. Blood cultures are positive in neonatal sepsis. Cultures of CSF and urine should also be obtained. The diagnosis of urinary tract infections is discussed in Chapter 24.

 Differential Diagnosis

The clinical picture of EPEC infection may resemble that of salmonellosis, shigellosis, or viral gastroenteritis. Neonatal sepsis and meningitis caused by E coli can be differentiated from other causes of neonatal infection only by blood and CSF culture.

 Treatment

A. Specific Measures

1. E coli gastroenteritis—Gastroenteritis due to EPEC seldom requires antimicrobial treatment. Fluid and electrolyte therapy, preferably given orally, may be required to avoid dehydration. Bismuth subsalicylate reduces stool volume by about one-third in infants with watery diarrhea, probably including ETEC. In nursery outbreaks, E coli gastroenteritis has been treated with neomycin (100 mg/kg/d orally in three divided doses for 5 days). Clinical efficacy is not established. Traveler’s diarrhea may be treated with azithromycin in children and with fluoroquinolones in adults, although resistance to these drugs is increasing. The risk of hemolytic-uremic syndrome is not proven to be increased by antimicrobial therapy of EHEC cases, but most experts recommend no treatment of suspected cases.

2. E coli sepsis and pneumonia—The drugs of choice are ampicillin (150–200 mg/kg/d, given intravenously or intramuscularly in divided doses every 4–6 hours), cefotaxime (150–200 mg/kg/d, given intravenously or intramuscularly in divided doses every 6–8 hours), ceftriaxone (50–100 mg/kg/d, given intramuscularly as single dose or in two divided doses), and gentamicin (5.0–7.5 mg/kg/d, given intramuscularly or intravenously in divided doses every 8 hours). Initial therapy often includes at least two drugs until microbial etiology is established and susceptibility testing is completed. Treatment is continued for 10–14 days. Amikacin or tobramycin may be used instead of gentamicin if the strain is susceptible. Third-generation cephalosporins are often an attractive alternative as single-drug therapy and do not require monitoring for toxicity.

3. E coli meningitis—Third-generation cephalosporins such as cefotaxime (200 mg/kg/d intravenously in four divided doses) are given for a minimum of 3 weeks. Ampicillin (200–300 mg/kg/d intravenously in four to six divided doses) and gentamicin (5.0–7.5 mg/kg/d intramuscularly or intravenously in three divided doses) also are effective for susceptible strains. Treatment with intrathecal and intraventricular aminoglycosides does not improve outcome. Serum levels need to be monitored.

4. Acute urinary tract infection—(See Chapter 24.)

 Prognosis

Death due to gastroenteritis leading to dehydration can be prevented by early fluid and electrolyte therapy. Neonatal sepsis with meningitis is still associated with a mortality rate of over 50%. Most children with recurrent urinary tract infections do well if they have no underlying anatomic defects. The mortality rate in opportunistic infections usually depends on the severity of infection and the underlying condition.

Centers for Disease Control and Prevention (CDC): Diarrheagenic Escherichia coli. Available at: http://www.cdc.gov/ecoli/

Denno DM et al: Diarrhea etiology in a pediatric emergency department: a case control study. Clin Infect Dis 2012;55(7):897 [PMID: 22700832].

DuPont HL: Therapy for and prevention of traveler’s diarrhea. Clin Infect Dis 2007;45(Suppl 1):78 [PMID: 17582576].

Nitschke M et al: Association between azithromycin therapy and duration of bacterial shedding among patients with shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA 2012;307(10):1046 [PMID: 22416100].

Qazi SA, Stsoll BJ: Neonatal sepsis: a major global public health challenge. Pediatr Infect Dis J 2009;28(Suppl 1):1 [PMID: 19106756].

Rosales A et al: German-Austrian HUS study group. Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae. Clin Infect Dis 2012;54(10):1413 [PMID: 22412065].

Wikswo ME, Hall AJ; Centers for Disease Control and Prevention: Outbreaks of acute gastroenteritis transmitted by person-to-person contact—United States, 2009–2010. MMWR Surveill Summ 2012;61(9):1 [PMID: 23235338].

Wong CS et al: Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis 2012;55(1):33 [PMID: 22431799].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Opportunistic infection.

 Confirmed by cultures.

 General Considerations

Pseudomonas aeruginosa is an aerobic gram-negative rod with versatile metabolic requirements. The organism may grow in distilled water and in commonly used disinfectants, complicating infection control in medical facilities. P aeruginosa is both invasive and destructive to tissue as well as toxigenic due to secreted exotoxins, all factors that contribute to virulence. Other genera previously classified as Pseudomonas frequently cause nosocomial infections and infections in immunocompromised children. Stenotrophomonas maltophilia (previously Pseudomonas maltophilia) and Burkholderia cepacia (previously Pseudomonas cepacia) are the most frequent.

P aeruginosa is an important cause of infection in children with cystic fibrosis, neoplastic disease, neutropenia, or extensive burns and in those receiving antibiotic therapy. Infections of the urinary and respiratory tracts, ears, mastoids, paranasal sinuses, eyes, skin, meninges, and bones are seen. Pseudomonas pneumonia is a common nosocomial infection in patients receiving assisted ventilation.

P aeruginosa sepsis may be accompanied by characteristic peripheral lesions called ecthyma gangrenosum. Ecthyma gangrenosum also may occur by direct invasion through intact skin in the groin, axilla, or other skinfolds. P aeruginosa is an infrequent cause of sepsis in previously healthy infants and may be the initial sign of underlying medical problems. P aeruginosa osteomyelitis often complicates puncture wounds of the feet. P aeruginosa is a frequent cause of malignant external otitis media and of chronic suppurative otitis media. Outbreaks of vesiculopustular skin rash have been associated with exposure to contaminated water in whirlpool baths and hot tubs.

P aeruginosa infects the tracheobronchial tree of nearly all patients with cystic fibrosis. Mucoid exopolysaccharide, an exuberant capsule, is characteristically overproduced by isolates from patients with cystic fibrosis. Although bacteremia seldom occurs, patients with cystic fibrosis ultimately succumb to chronic lung infection with P aeruginosa. Infection due to B cepacia has caused a rapidly progressive pulmonary disease in some colonized patients and may be spread by close contact.

Osteomyelitis of the calcaneus or other foot bones occurs after punctures such as stepping on a nail and is commonly due to P aeruginosa.

 Clinical Findings

The clinical findings depend on the site of infection and the patient’s underlying disease. Sepsis with these organisms resembles gram-negative sepsis with other organisms, although the presence of ecthyma gangrenosum suggests the diagnosis. The diagnosis is made by culture. Pseudomonas infection should be suspected in neonates and neutropenic patients with clinical sepsis. A severe necrotizing pneumonia occurs in patients on ventilators.

Patients with cystic fibrosis have a persistent bronchitis that progresses to bronchiectasis and ultimately to respiratory failure. During exacerbations of illness, cough and sputum production increase with low-grade fever, malaise, and diminished energy.

The purulent aural drainage without fever in patients with chronic suppurative otitis media is not distinguishable from that due to other causes.

 Prevention

A. Infections in Debilitated Patients

Colonization of extensive second- and third-degree burns by P aeruginosa can lead to fatal septicemia. Aggressive debridement and topical treatment with 0.5% silver nitrate solution, 10% mafenide cream, or silver sulfadiazine will greatly inhibit P aeruginosa contamination of burns. (See Chapter 12 for a discussion of burn wound infections and prevention.)

B. Nosocomial Infections

Faucet aerators, communal soap dispensers, disinfectants, improperly cleaned inhalation therapy equipment, infant incubators, and many other sources that usually are associated with wet or humid conditions all have been associated with Pseudomonas epidemics. Infant-to-infant transmission by nursery personnel carrying Pseudomonas on the hands is frequent in neonatal units. Careful maintenance of equipment and enforcement of infection control procedures are essential to minimize nosocomial transmission.

C. Patients with Cystic Fibrosis

Chronic infection of the lower respiratory tract occurs in nearly all patients with cystic fibrosis. The infecting organism is seldom cleared from the respiratory tract, even with intensive antimicrobial therapy, and the resultant injury to the lung eventually leads to pulmonary insufficiency. Treatment is aimed at controlling signs and symptoms of the infection.

 Treatment

P aeruginosa is inherently resistant to many antimicrobials and may develop resistance during therapy. Mortality rates in hospitalized patients exceed 50%, owing both to the severity of underlying illnesses in patients predisposed to Pseudomonas infection and to the limitations of therapy. Antibiotics effective against Pseudomonas include the amino-glycosides, ureidopenicillins (ticarcillin and piperacillin), β-lactamase inhibitor with a ureidopenicillin (ticarcillin-clavulanate and piperacillin-tazobactam), expanded-spectrum cephalosporins (ceftazidime and cefepime), imipenem, meropenem, and ciprofloxacin. Colistin has been used in some children with multidrug resistance. Antimicrobial susceptibility patterns vary from area to area, and resistance tends to appear as new drugs become popular. Treatment of infections is best guided by clinical response and susceptibility tests.

Gentamicin or tobramycin (5.0–7.5 mg/kg/d, given intramuscularly or intravenously in three divided doses) or amikacin (15–22 mg/kg/d, given in two or three divided doses) in combination with ticarcillin (200–300 mg/kg/d, given intravenously in four to six divided doses) or with another antipseudomonal β-lactam antibiotic is recommended for treatment of serious Pseudomonas infections. Ceftazidime (150–200 mg/kg/d, given in four divided doses) or cefepime (150 mg/kg/d, given in three divided doses) has excellent activity against P aeruginosa. Treatment should be continued for 10–14 days. Treatment with two active drugs is recommended for all serious infections.

Pseudomonas osteomyelitis due to punctures requires thorough surgical debridement and antimicrobial therapy for 2 weeks. Pseudomonas folliculitis does not require antibiotic therapy.

Oral or intravenous ciprofloxacin is also effective against susceptible P aeruginosa, but is not approved by the FDA for use in children except in the case of urinary tract infection. Nonetheless, in some circumstances of antimicrobial resistance, or when the benefits clearly outweigh the small risks, ciprofloxacin may be used.

Chronic suppurative otitis media responds to intravenous ceftazidime (150–200 mg/kg/d in three or four divided doses) given until the drainage has ceased for 3 days. Twice-daily ceftazidime with aural debridement and cleaning given on an outpatient basis has also been successful. Swimmer’s ear may be caused by P aeruginosa and responds well to topical drying agents (alcohol–vinegar mix) and cleansing.

 Prognosis

Because debilitated patients are most frequently affected, the mortality rate is high. These infections may have a protracted course, and eradication of the organisms may be difficult.

Paksu MS et al: Old agent, new experience: colistin use in the paediatric intensive care unit—a multicentre study. Int J Antimicrob Agents 2012;40(2):140 [PMID: 22727770].

Proesmans M et al: Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros 2013;12(1):29 [PMID: 22762867].

Schneider H et al: Pseudomonas aeruginosa outbreak in a pediatric oncology care unit caused by an errant water jet into contaminated siphons. Pediatr Infect Dis J 2012;31(6):648 [PMID: 22333699].

Tamma PD et al: Does the piperacillin minimum inhibitory concentration for Pseudomonas aeruginosa influence clinical outcomes of children with pseudomonal bacteremia? Clin Infect Dis 2012;55(6):799 [PMID: 22696019].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Nausea, vomiting, headache, meningismus.

 Fever, diarrhea, abdominal pain.

 Culture or organism from stool, blood, or other specimens.

 General Considerations

Salmonellae are gram-negative rods that frequently cause food-borne gastroenteritis and occasionally bacteremic infection of bone, meninges, and other foci. Approximately 2400 serotypes of Salmonella enterica are recognized. Salmonella typhimurium is the most frequently isolated serotype in most parts of the world. Although 54,000 cases were reported in 2010, it is estimated that 100 or more occur for each one reported. This yields an estimate or more than 5 million cases yearly in the United States.

Salmonellae are able to penetrate the mucin layer of the small bowel and attach to epithelial cells. Organisms penetrate the epithelial cells and multiply in the submucosa. Infection results in fever, vomiting, and watery diarrhea; the diarrhea occasionally includes mucus and polymorphonuclear neutrophils in the stool. Although the small intestine is generally regarded as the principal site of infection, colitis also occurs. S typhimurium frequently involves the large bowel.

Salmonella infections in childhood occur in two major forms: (1) gastroenteritis (including food poisoning), which may be complicated by sepsis and focal suppurative complications; and (2) enteric fever (typhoid fever and paratyphoid fever) (see section on Typhoid Fever and Paratyphoid Fever). Although the incidence of typhoid fever has decreased in the United States, the incidence of Salmonella gastroenteritis has greatly increased in the past 15–20 years. The highest attack rates occur in children younger than age 6 years, with a peak in the age group from 6 months to 2 years.

Salmonellae are widespread in nature, infecting domestic and wild animals. Fowl and reptiles have a particularly high carriage rate. Transmission results primarily from ingestion of contaminated food. Transmission from human to human occurs by the fecal-oral route via contaminated food, water, and fomites. Numerous foods, including meats, milk, cheese, ice cream, chocolate, contaminated egg powder, and frozen whole egg preparations used to make ice cream, custards, and mayonnaise are associated with outbreaks. Eggs with contaminated shells that are consumed raw or undercooked have been incriminated in outbreaks and sporadic cases. Animal contact also can be a source for Salmonella.

Because salmonellae are susceptible to gastric acidity, the elderly, infants, and patients taking antacids or H₂-blocking drugs are at increased risk for infection. Most cases of Salmonella meningitis (80%) and bacteremia occur in infancy. Newborns may acquire the infection from their mothers during delivery and may precipitate outbreaks in nurseries. Newborns are at special risk for developing meningitis.

 Clinical Findings

A. Symptoms and Signs

There is a very wide range of severity of infection. Infants usually develop fever, vomiting, and diarrhea. The older child also may complain of headache, nausea, and abdominal pain. Stools are often watery or may contain mucus and, in some instances, blood, suggesting shigellosis. Drowsiness and disorientation may be associated with meningismus. Convulsions occur less frequently than with shigellosis. Splenomegaly occasionally occurs. In the usual case, diarrhea is moderate and subsides after 4–5 days, but it may be protracted.

B. Laboratory Findings

Diagnosis is made by isolation of the organism from stool, blood, or, in some cases, from urine, CSF, or pus from a suppurative lesion. The WBC count usually shows a polymorphonuclear leukocytosis but may show leukopenia. Salmonella isolates should be reported to public health authorities for epidemiologic purposes.

 Differential Diagnosis

In staphylococcal food poisoning, the incubation period is shorter (2–4 hours) than in Salmonella food poisoning (12–24 hours). Fever is absent, and vomiting rather than diarrhea is the main symptom. In shigellosis, many polymorphonuclear leukocytes usually are seen on a stained smear of stool, and the peripheral WBC count is more likely to slow a marked left shift, although some cases of salmonellosis are indistinguishable from shigellosis. Campylobacter gastroenteritis commonly resembles salmonellosis clinically. Culture of the stools is necessary to distinguish the causes of bacterial gastroenteritis.

 Complications

Unlike most types of infectious diarrhea, salmonellosis is frequently accompanied by bacteremia, especially in newborns and infants. Septicemia with extraintestinal infection is seen, most commonly with Salmonella choleraesuisbut also with Salmonella enterica, typhimurium, and paratyphi serotypes. The organism may spread to any tissue and may cause arthritis, osteomyelitis, cholecystitis, endocarditis, meningitis, pericarditis, pneumonia, or pyelonephritis. Patients with sickle cell anemia or other hemoglobinopathies have a predilection for the development of osteomyelitis. Severe dehydration and shock are more likely to occur with shigellosis but may occur with Salmonella gastroenteritis.

 Prevention

Measures for the prevention of Salmonella infections include thorough cooking of foodstuffs derived from contaminated sources, adequate refrigeration, control of infection among domestic animals, and meticulous meat and poultry inspections. Raw and undercooked fresh eggs should be avoided. Food handlers and child care workers with salmonellosis should have three negative stool cultures before resuming work. Asymptomatic children, who have recovered from Salmonella infection, do not need exclusion.

 Treatment

A. Specific Measures

In uncomplicated Salmonella gastroenteritis, antibiotic treatment does not shorten the course of the clinical illness and may prolong convalescent carriage of the organism. Colitis or secretory diarrhea due to Salmonella may improve with antibiotic therapy.

Because of the higher risk of sepsis and focal disease, antibiotic treatment is recommended in infants younger than age 3 months, in severely ill children, and in children with sickle cell disease, liver disease, recent gastrointestinal surgery, cancer, depressed immunity, or chronic renal or cardiac disease. Infants younger than age 3 months with positive stool cultures or suspected salmonellosis sepsis should be admitted to the hospital, evaluated for focal infection including cultures of blood and CSF, and given treatment intravenously. A third-generation cephalosporin is usually recommended due to frequent resistance to ampicillin and TMP-SMX. Older patients developing bacteremia during the course of gastroenteritis should receive parenteral treatment initially, and a careful search should be made for additional foci of infection. After signs and symptoms subside, these patients should receive oral medication. Parenteral and oral treatment should last a total of 7–10 days. Longer treatment is indicated for specific complications. If susceptibility tests indicate resistance to ampicillin, third-generation cephalosporins or TMP-SMX should be given. Fluoroquinolones also are efficacious but are not approved for administration to children. Fluoroquinolones or azithromycin are used for strains resistant to multiple other drugs.

Empiric therapy of gram-negative meningitis is with meropenem (120 mg/kg/d) intravenously in three divided doses or cefepime (150 mg/kg/d) in three divided doses with adjustment based on culture and susceptibility testing.

Often ampicillin (200–300 mg/kg/d intravenously in four to six divided doses) or a third-generation cephalosporin (cefotaxime, ceftriaxone) is used for 4–6 weeks to complete therapy.

Outbreaks on pediatric wards are difficult to control. Strict hand washing, cohorting of patients and personnel, and ultimately closure of the unit may be necessary.

B. Treatment of the Carrier State

About half of patients may have positive stool cultures after 4 weeks. Infants tend to remain convalescent carriers for up to a year. Antibiotic treatment of carriers is not effective.

C. General Measures

Careful attention must be given to maintaining fluid and electrolyte balance, especially in infants.

 Prognosis

In gastroenteritis, the prognosis is good. In sepsis with focal suppurative complications, the prognosis is more guarded. The case fatality rate of Salmonella meningitis is high in infants. There is a strong tendency to relapse if treatment is not continued for at least 4 weeks.

Centers for Disease Control and Prevention (CDC): FoodNet. Available at: http://www.cdc.gov/foodnet

Centers for Disease Control and Prevention (CDC): Salmonella infection (salmonellosis). Available at: http://www.cdc.gov/salmonella/

Chai SJ et al: Salmonella enterica serotype Enteritidis: increasing incidence of domestically acquired infections. Clin Infect Dis 2012;54(Suppl 5):488 [PMID: 22572674].

Gaffga NH et al: Outbreak of salmonellosis linked to live poultry from a mail-order5 hatchery. N Engl J Med 2012 May 31;366(22):2065 [PMID: 22646629].

Maki DG: Coming to grips with foodborne infection—peanut butter, peppers, and nationwide Salmonella outbreaks. N Engl J Med 2009;360(10):949 [PMID: 19213675].

Sotir MJ et al: Salmonella Wandsworth Outbreak Investigation Team: outbreak of Salmonella Wandsworth and Typhimurium infections in infants and toddlers traced to a commercial vegetable-coated snack food. Pediatr Infect Dis J 2009;28(12):1 [PMID: 19779390].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Insidious or acute onset of headache, anorexia, vomiting, constipation or diarrhea, ileus, and high fever.

 Meningismus, splenomegaly, and rose spots.

 Leukopenia; positive blood, stool, bone marrow, and urine cultures.

 General Considerations

Typhoid fever is caused by the gram-negative bacillus Salmonella typhi. Paratyphoid fevers, which are usually milder but may be clinically indistinguishable, are caused by S paratyphi A, Salmonella schottmülleri, or Salmonella hirschfeldii (formerly S paratyphi A, B, and C). Children have a shorter incubation period than do adults (usually 5–8 days instead of 8–14 days). The organism enters the body through the walls of the intestinal tract and, following a transient bacteremia, multiplies in the reticuloendothelial cells of the liver and spleen. Persistent bacteremia and symptoms then follow. Reinfection of the intestine occurs as organisms are excreted in the bile. Bacterial emboli produce the characteristic skin lesions (rose spots). Typhoid fever is transmitted by the fecal-oral route and by contamination of food or water. Unlike other Salmonella species, there are no animal reservoirs of S typhi; each case is the result of direct or indirect contact with the organism or with an individual who is actively infected or a chronic carrier.

About 460 cases per year were reported in the United States in 2010, 80% of which are acquired during foreign travel.

 Clinical Findings

A. Symptoms and Signs

In children, the onset of typhoid fever usually is sudden rather than insidious, with malaise, headache, crampy abdominal pains and distention, and sometimes constipation followed within 48 hours by diarrhea, high fever, and toxemia. An encephalopathy may be seen with irritability, confusion, delirium, and stupor. Vomiting and meningismus may be prominent in infants and young children. The classic lengthy three-stage disease seen in adult patients often is shortened in children. The prodrome may last only 2–4 days, the toxic stage only 2–3 days, and the defervescence stage 1–2 weeks.

During the prodromal stage, physical findings may be absent, but abdominal distention and tenderness, meningismus, mild hepatomegaly, and minimal splenomegaly may be present. The typical typhoidal rash (rose spots) is present in 10%–15% of children. It appears during the second week of the disease and may erupt in crops for the succeeding 10–14 days. Rose spots are erythematous maculopapular lesions 2–3 mm in diameter that blanch on pressure. They are found principally on the trunk and chest and they generally disappear within 3–4 days. The lesions usually number fewer than 20.

B. Laboratory Findings

Typhoid bacilli can be isolated from many sites, including blood, stool, urine, and bone marrow. Blood cultures are positive in 50%–80% of cases during the first week and less often later in the illness. Stool cultures are positive in about 50% of cases after the first week. Urine and bone marrow cultures also are valuable. Most patients will have negative cultures (including stool) by the end of a 6-week period. Serologic tests (Widal reaction) are not as useful as cultures because both false-positive and false-negative results occur. Leukopenia is common in the second week of the disease, but in the first week, leukocytosis may be seen. Proteinuria, mild elevation of liver enzymes, thrombocytopenia, and DIC are common.

 Differential Diagnosis

Typhoid and paratyphoid fevers must be distinguished from other serious prolonged fevers. These include typhus, brucellosis, malaria, tularemia, tuberculosis, psittacosis, vasculitis, lymphoma, mononucleosis, and Kawasaki disease. The diagnosis of typhoid fever often is made clinically in developing countries, but the accuracy of clinical diagnosis is variable. In developed countries, where typhoid fever is uncommon and physicians are unfamiliar with the clinical picture, the diagnosis often is not suspected until late in the course. Positive cultures confirm the diagnosis.

 Complications

The most serious complications of typhoid fever are gastrointestinal hemorrhage (2%–10%) and perforation (1%–3%). They occur toward the end of the second week or during the third week of the disease.

Intestinal perforation is one of the principal causes of death. The site of perforation generally is the terminal ileum or cecum. The clinical manifestations are indistinguishable from those of acute appendicitis, with pain, tenderness, and rigidity in the right lower quadrant.

Bacterial pneumonia, meningitis, septic arthritis, abscesses, and osteomyelitis are uncommon complications, particularly if specific treatment is given promptly. Shock and electrolyte disturbances may lead to death.

About 1%–3% of patients become chronic carriers of S typhi. Chronic carriage is defined as excretion of typhoid bacilli for more than a year, but carriage is often lifelong. Adults with underlying biliary or urinary tract disease are much more likely than children to become chronic carriers.

 Prevention

Routine typhoid vaccine is not recommended in the United States but should be considered for foreign travel to endemic areas. An attenuated oral typhoid vaccine produced from strain Ty21a has better efficacy and causes minimal side effects but is not approved for children younger than age 6 years. The vaccine is repeated after 5 years. A capsular polysaccharide vaccine (ViCPS) requires one intramuscular injection and may be given to children age 2 years and older. (See Chapter 10.)

 Treatment

A. Specific Measures

Third-generation cephalosporins such as cefotaxime (150 mg/kg divided in three doses), azithromycin (10 mg/kg on day 1, followed by 5 mg/kg for 7 days), or a fluoroquinolone are used for presumptive therapy. Antimicrobial susceptibility testing and local experience are used to direct subsequent therapy. Equally effective regimens for susceptible strains include the following: TMP-SMX (10 mg/kg trimethoprim and 50 mg/kg sulfamethoxazole per day orally in two or three divided doses), amoxicillin (100 mg/kg/d orally in four divided doses), and ampicillin (100–200 mg/kg/d intravenously in four divided doses). Aminoglycosides and first- and second-generation cephalosporins are clinically ineffective regardless of in vitro susceptibility results. Ciprofloxacin or other fluoroquinolones are efficacious but not approved in children, but may be used for multiply resistant strains. Treatment duration is 14–21 days. Patients may remain febrile for 3–5 days even with appropriate therapy.

B. General Measures

General support of the patient is exceedingly important and includes rest, good nutrition and hydration, and careful observation, with particular regard to evidence of intestinal bleeding or perforation. Blood transfusions may be needed even in the absence of frank hemorrhage.

 Prognosis

A prolonged convalescent carrier stage may occur in children. Three negative cultures after all antibiotics have been stopped are required before contact precautions are stopped. With early antibiotic therapy, the prognosis is excellent, and the mortality rate is less than 1%. Relapse occurs 1–3 weeks later in 10%–20% of patients despite appropriate antibiotic treatment.

Bhutta ZA, Threlfall J: Addressing the global disease burden of typhoid fever. JAMA 2009;302(8):898 [PMID: 19706867].

Martinez-Roig A et al: Pancreatitis in typhoid fever relapse. Pediatr Infect Dis J 2009;28(1):74 [PMID: 19034060].

Neil KP et al: A large outbreak of typhoid fever associated with a high rate of intestinal perforation in Kasese District, Uganda, 2008–2009. Clin Infect Dis 2012;54(8):1091 [PMID: 22357703].

Parry CM et al: Randomized controlled comparison of ofloxacin, azithromycin, and an ofloxacin-azithromycin combination for treatment of multidrug-resistant and nalidixic acid-resistant typhoid fever. Antimicrob Agents Chemother 2007;51:819 [PMID: 17145784].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Cramps and bloody diarrhea.

 High fever, malaise, convulsions.

 Pus and blood in diarrheal stools examined microscopically.

 Diagnosis confirmed by stool culture.

 General Considerations

Shigellae are nonmotile gram-negative rods of the family Enterobacteriaceae and are closely related to E coli. The genus Shigella is divided into four species: S dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. Approximately 15,000 to 20,000 cases of shigellosis are reported each year in the United States. S sonnei followed by S flexneri are the most common isolates.

S dysenteriae, which causes the most severe diarrhea of all species and the greatest number of extraintestinal complications, accounts for less than 1% of all Shigella infections in the United States.

Shigellosis may be a serious disease, particularly in young children, and without supportive treatment an appreciable mortality rate results. In older children and adults, the disease tends to be self-limited and milder. Shigella is usually transmitted by the fecal-oral route. Food- and water-borne outbreaks are increasing in occurrence, but are less important overall than person-to-person transmission. The disease is very communicable—as few as 200 bacteria can produce illness in an adult. The secondary attack rate in families is high, and shigellosis is a serious problem in day care centers and custodial institutions. Shigella organisms produce disease by invading the colonic mucosa, causing mucosal ulcerations and microabscesses. A plasmid-encoded gene is required for enterotoxin production, chromosomal genes are required for invasiveness, and smooth lipopolysaccharides are required for virulence. An experimental vaccine is under development and is safe and immunogenic in young children.

 Clinical Findings

A. Symptoms and Signs

The incubation period of shigellosis is usually 2–4 days. Onset is abrupt, with abdominal cramps, urgency, tenesmus, chills, fever, malaise, and diarrhea. Hallucinations and seizures sometimes accompany high fever. In severe forms, blood and mucus are seen in small stools (dysentery), and meningismus and convulsions may occur. In older children, the disease may be mild and may be characterized by watery diarrhea without blood. In young children, a fever of 39.4–40°C is common. Rarely there is rectal prolapse. Symptoms generally last 3–7 days.

B. Laboratory Findings

The total WBC count varies, but often there is a marked shift to the left. The stool may contain gross blood and mucus, and many neutrophils are seen if mucus from the stool is examined microscopically. Stool cultures are usually positive; however, they may be negative because the organism is somewhat fragile and present in small numbers late in the disease, and because laboratory techniques are suboptimal for the recovery of shigellae.

 Differential Diagnosis

Diarrhea due to rotavirus infection is a winter rather than a summer disease. Usually children with viral gastroenteritis are not as febrile or toxic as those with shigellosis, and the stool does not contain gross blood or neutrophils. Intestinal infections caused by Salmonella or Campylobacter are differentiated by culture. Grossly bloody stools in a patient without fever or stool leukocytes suggest E coli O157:H7 infection. Amebic dysentery is diagnosed by microscopic examination of fresh stools or sigmoidoscopy specimens. Intussusception is characterized by an abdominal mass (so-called currant jelly stools) without leukocytes, and by absence of initial fever. Mild shigellosis is not distinguishable clinically from other forms of infectious diarrhea.

 Complications

Dehydration, acidosis, shock, and renal failure are the major complications. In some cases, a chronic form of dysentery occurs, characterized by mucoid stools and poor nutrition. Bacteremia and metastatic infections are rare but serious complications. Febrile seizures are common. Fulminating fatal dysentery and hemolytic-uremic syndrome occur rarely. Reiter syndrome may follow S flexneri infection.

 Treatment

A. Specific Measures

Resistance to TMP-SMX (10 mg/kg/d trimethoprim and 50 mg/kg/d sulfamethoxazole, given in two divided doses orally for 5 days) and ampicillin (100 mg/kg/d divided in four doses) is common and limits the use of these drugs to cases where results of susceptibility testing are known. Amoxicillin is not effective. Parenteral ceftriaxone is effective. Azithromycin (12 mg/kg/d on day 1, then 6 mg/kg/d for 2 days) is effective, but laboratories do not routinely perform susceptibility testing for azithromycin. Ciprofloxacin (500 mg, given twice daily for 5 days) is efficacious in adults but is not approved for use in children. However, it may be used in children who remain symptomatic and in need of therapy, and when multiply resistant strains limit other preferred choices. Successful treatment reduces the duration of fever, cramping, and diarrhea and terminates fecal excretion of Shigella. Presumptive therapy should be limited to children with classic shigellosis or known outbreaks. Afebrile children with bloody diarrhea are more commonly infected with EHEC. Antimicrobial therapy of EHEC may increase the likelihood of hemolytic-uremic syndrome, and is not recommended.

B. General Measures

In severe cases, immediate rehydration is critical. A mild form of chronic malabsorption syndrome may supervene and require prolonged dietary control.

 Prognosis

The prognosis is excellent if vascular collapse is treated promptly by adequate fluid therapy. The mortality rate is high in very young, malnourished infants who do not receive fluid and electrolyte therapy. Convalescent fecal excretion of Shigella lasts 1–4 weeks in patients not receiving antimicrobial therapy. Long-term carriers are rare.

Centers for Disease Control and Prevention (CDC): Shigellosis. Available at: www.cdc.gov/nczved/divisions/dfbmd/diseases/shigellosis/

Shiferaw B et al: Antimicrobial susceptibility patterns of Shigella isolates in Foodborne Diseases Active Surveillance Network (FoodNet) sites, 2000–2010. Clin Infect Dis 2012;54(Suppl 5):458 [PMID: 22572670].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Sudden onset of severe watery diarrhea.

 Persistent vomiting without nausea or fever.

 Extreme and rapid dehydration and electrolyte loss, with rapid development of vascular collapse.

 Contact with a case of cholera or with shellfish, or the presence of cholera in the community.

 Diagnosis confirmed by stool culture.

 General Considerations

Cholera is an acute diarrheal disease caused by the gram-negative organism Vibrio cholerae. It is transmitted by contaminated water or food, especially contaminated shellfish. Epidemics are common in impoverished areas where hygiene and safe water supply are limited. Typical disease is generally so dramatic that in endemic areas the diagnosis is obvious. Individuals with mild illness and young children may play an important role in transmission of the infection.

Asymptomatic infection is far more common than clinical disease. In endemic areas, rising titers of vibriocidal antibody are seen with increasing age. Infection occurs in individuals with low titers. The age-specific attack rate is highest in children younger than age 5 years and declines with age. Cholera is unusual in infancy.

Cholera toxin is a protein enterotoxin that is primarily responsible for symptoms. Cholera toxin binds to a regulatory subunit of adenylyl cyclase in enterocytes, causing increased cyclic adenosine monophosphate and an outpouring of NaCl and water into the lumen of the small bowel.

Nutritional status is an important factor determining the severity of the diarrhea. Duration of diarrhea is prolonged in adults and children with severe malnutrition.

Cholera is endemic in India and southern and Southeast Asia and in parts of Africa. The most recent pandemic, caused by the El Tor biotype of V cholerae 01, began in 1961 in Indonesia. Epidemic cholera spread in Central and South America, with a total of 1 million cases and 9500 deaths reported through 1994. A severe cholera outbreak is ongoing in Haiti since October 2010. More than 500,000 cases and 6000 deaths are estimated. V choleraeserogroups 0139 has been recognized in Asia as a cause of cholera illness. Cases in the United States occurred in the course of foreign travel or as a result of consumption of contaminated imported food. Cholera is increasingly associated with consumption of shellfish. Interstate shipment of oysters has resulted in cholera in several inland states. Cholera is now rare in the United States with 10 to 15 cases per year reported.

V cholerae is a natural inhabitant of shellfish and cope-pods in estuarine environments. Seasonal multiplication of V cholerae may provide a source of outbreaks in endemic areas. Chronic cholera carriers are rare. The incubation period is short, usually 1–3 days.

 Clinical Findings

A. Symptoms and Signs

Many patients infected with V cholerae have mild disease, with 1%–2% developing severe diarrhea. During severe cholera, there is a sudden onset of massive, frequent, watery stools, generally light gray in color (so-called rice-water stools) and containing some mucus but no pus. Vomiting may be projectile and is not accompanied by nausea. Within 2–3 hours, the tremendous loss of fluids results in life-threatening dehydration, hypochloremia, and hypokalemia, with marked weakness and collapse. Renal failure with uremia and irreversible peripheral vascular collapse will occur if fluid therapy is not administered. The illness lasts 1–7 days and is shortened by appropriate antibiotic therapy.

B. Laboratory Findings

Markedly elevated hemoglobin (20 g/dL) and marked acidosis, hypochloremia, and hyponatremia are seen. Stool sodium concentration may range from 80 to 120 mEq/L. Culture confirmation requires specific media and takes 16–18 hours for a presumptive diagnosis and 36–48 hours for a definitive bacteriologic diagnosis.

 Prevention

Cholera vaccine is available outside of the United States and provides 50%–75% efficacy. Protection lasts 3–6 months. Cholera vaccine is not generally recommended for travelers. Tourists visiting endemic areas are at little risk if they exercise caution in what they eat and drink and maintain good personal hygiene. In endemic areas, all water and milk must be boiled, food protected from flies, and sanitary precautions observed. Simple filtration of water is highly effective in reducing cases. Thorough cooking of shellfish prevents transmission. All patients with cholera should be isolated.

Chemoprophylaxis is indicated for household and other close contacts of cholera patients. It should be initiated as soon as possible after the onset of the disease in the index patient. Tetracycline (500 mg/d for 5 days) is effective in preventing infection. TMP-SMX may be substituted in children.

 Treatment

Physiologic saline or lactated Ringer solution should be administered intravenously in large amounts to restore blood volume and urine output and prevent irreversible shock. Potassium supplements are required. Sodium bicarbonate, given intravenously, also may be needed initially to overcome profound metabolic acidosis from bicarbonate loss in the stool. Moderate dehydration and acidosis can be corrected in 3–6 hours by oral therapy alone, because the active glucose transport system of the small bowel is normally functional. The optimal composition of the oral solution (in milliequivalents per liter [mEq/L]) is as follows: Na⁺, 90; Cl⁻, 80; and K⁺, 20 (with glucose, 110 mmol/L).

Treatment with tetracycline (50 mg/kg/d orally in four divided doses for 2–5 days) or azithromycin (10 mg/kg/d in one dose for 1–5 days) shortens the duration of the disease in children and prevents clinical relapse but is not as important as fluid and electrolyte therapy. Tetracycline resistance occurs in some regions, and ciprofloxacin may be used depending on local resistance patterns. TMP-SMX or azithromycin should be used in children younger than age 9 years.

 Prognosis

With early and rapid replacement of fluids and electrolytes, the case fatality rate is 1%–2% in children. If significant symptoms appear and no treatment is given, the mortality rate is over 50%.

Barzilav EJ et al: Cholera surveillance during the Haiti epidemic—the first two years. N Eng J Med 2013;368(7):599 [PMID: 23301694].

Centers for Disease Control and Prevention: Cholera. Available at: www.cdc.gov/cholera/index.html

Chin CS et al: The origin of the Haitian cholera outbreak strain. N Engl J Med 2011;364:33 [PMID: 21142692].

Nelson EJ et al: Antibiotics for both moderate and severe cholera. N Engl J Med 2011;364:5 [PMID: 21142691].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Fever, vomiting, abdominal pain, diarrhea.

 Presumptive diagnosis by darkfield or phase contrast microscopy of stool wet mount or modified Gram stain.

 Definitive diagnosis by stool culture.

 General Considerations

Campylobacter species are small gram-negative, curved or spiral bacilli that are commensals or pathogens in many animals. Campylobacter jejuni frequently causes acute enteritis in humans. In the 1990s, C jejuni was responsible for 3%–11% of cases of acute gastroenteritis in North America and Europe. In many areas, enteritis due to C jejuni is more common than that due to Salmonella or Shigella. Campylobacter fetus causes bacteremia and meningitis in immunocompromised patients. C fetus may cause maternal fever, abortion, stillbirth, and severe neonatal infection. Helicobacter pylori (previously called Campylobacter pylori) causes gastritis and peptic ulcer disease in both adults and children (see Chapter 21).

Campylobacter colonizes domestic and wild animals, especially poultry. Numerous cases have been associated with sick puppies or other animal contacts. Contaminated food and water, improperly cooked poultry, and person-to-person spread by the fecal-oral route are common routes of transmission. Outbreaks associated with day care centers, contaminated water supplies, and raw milk have been reported. Newborns may acquire the organism from their mothers at delivery.

 Clinical Findings

A. Symptoms and Signs

C jejuni enteritis can be mild or severe. In tropical countries, asymptomatic stool carriage is common. The incubation period is usually 1–7 days. The disease usually begins with sudden onset of high fever, malaise, headache, abdominal cramps, nausea, and vomiting. Diarrhea follows and may be watery or bile-stained, mucoid, and bloody. The illness is self-limiting, lasting 2–7 days, but relapses may occur. Without antimicrobial treatment, the organism remains in the stool for 1–6 weeks.

B. Laboratory Findings

The peripheral WBC count generally is elevated, with many band forms. Microscopic examination of stool reveals erythrocytes and pus cells.

Isolation of C jejuni from stool is not difficult but requires selective agar, incubation at 42°C rather than 35°C, and incubation in an atmosphere of about 5% oxygen and 5% CO₂ (candle jar is satisfactory).

 Differential Diagnosis

Campylobacter enteritis may resemble viral gastroenteritis, salmonellosis, shigellosis, amebiasis, or other infectious diarrheas. Because it also mimics ulcerative colitis, Crohn disease, intussusception, and appendicitis, mistaken diagnosis can lead to unnecessary diagnostic testing or surgery.

 Complications

The most common complication is dehydration. Other uncommon complications include erythema nodosum, convulsions, reactive arthritis, bacteremia, urinary tract infection, and cholecystitis. Guillain-Barré syndrome may follow C jejuni infection by 1–3 weeks.

 Prevention

No vaccine is available. Hand washing and adherence to basic food sanitation practices help prevent disease. Hand washing and cleaning of kitchen utensils after contact with raw poultry are important.

 Treatment

Treatment of fluid and electrolyte disturbances is important. Antimicrobial treatment with erythromycin in children (30–50 mg/kg/d orally in four divided doses for 5 days), azithromycin (10 mg/kg/d orally once daily) for 3 days, or ciprofloxacin terminates fecal excretion. Fluoroquinolone-resistant C jejuni are now common worldwide. Therapy given early in the course of the illness will shorten the duration of symptoms but is unnecessary if given later. Antimicrobials used for shigellosis, such as TMP-SMX and ampicillin, are inactive against Campylobacter. Supportive therapy is sufficient in most cases.

 Prognosis

The outlook is excellent if dehydration is corrected and misdiagnosis does not lead to inappropriate diagnostic or surgical procedures.

Centers for Disease Control and Prevention (CDC): Campylobacter infections. Available at: http://www.cdc.gov/nczved/divisions/dfbmd/diseases/campylobacter

Kalra V et al: Association of Campylobacter jejuni infection with childhood Guillain-Barre syndrome: a case-control study. J Child Neuro 2009;24(6):664 [PMID: 19491112].

Scallan E: Estimates of illnesses, hospitalizations, and deaths caused by major bacterial enteric pathogens in young children in the United States. Pediatr Infect Dis J 2013;32(3):217 [PMID: 23249909].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 A cutaneous or mucous membrane lesion at the site of inoculation and regional lymph node enlargement.

 Sudden onset of fever, chills, and prostration.

 History of contact with infected animals, principally wild rabbits, or history of tick exposure.

 Positive culture or immunofluorescence from mucocutaneous ulcer or regional lymph nodes.

 High serum antibody titer.

 General Considerations

Tularemia is caused by Francisella tularensis, a gram- negative organism usually acquired directly from infected animals (principally wild rabbits) or by the bite of an infected tick. Occasionally infection is acquired from infected domestic dogs or cats; by contamination of the skin or mucous membranes with infected blood or tissues; by inhalation of infected material; by bites of fleas or deer flies that have been in contact with infected animals; or by ingestion of contaminated meat or water. The incubation period is short, usually 3–7 days, but may vary from 2 to 25 days.

Ticks are the most important vector of tularemia and rabbits are the classic vector. It is important to seek a history of rabbit hunting, skinning, or food preparation in any patient who has a febrile illness with tender lymphadenopathy, often in the region of a draining skin ulcer.

 Prevention

Children should be protected from insect bites, especially those of ticks, fleas, and deer flies, by the use of proper clothing and repellents. Because rabbits are the source of most human infections, the dressing and handling of such game should be performed with great care. Rubber gloves should be worn by hunters or food handlers when handling carcasses of wild rabbits. If contact occurs, thorough washing with soap and water is indicated. For postexposure prophylaxis from an intentional release of F tularensis (bioterrorism), a 14-day course of doxycycline or ciprofloxacin is recommended (children less than 8 years should not receive doxycycline unless benefits outweigh risks; in children less than 18 years ciprofloxacin is not approved for this indication—weigh benefits and risk).

 Clinical Findings

A. Symptoms and Signs

Several clinical types of tularemia occur in children. Sixty percent of infections are of the ulceroglandular form and start as a reddened papule that may be pruritic, quickly ulcerates, and is not very painful. Soon, the regional lymph nodes become large and tender. Fluctuance quickly follows. There may be marked systemic symptoms, including high fever, chills, weakness, and vomiting. Pneumonitis occasionally accompanies the ulceroglandular form or may be seen as the sole manifestation of infection (pneumonic form). A detectable skin lesion may be absent, and localized lymphoid enlargement may exist alone (glandular form). Oculoglandular and oropharyngeal forms also occur. The latter is characterized by tonsillitis, often with membrane formation, cervical adenopathy, and high fever. In the absence of a primary ulcer or localized lymphadenitis, a prolonged febrile disease reminiscent of typhoid fever can occur (typhoidal form). Splenomegaly is common in all forms.

B. Laboratory Findings

F tularensis can be recovered from ulcers, regional lymph nodes, and sputum of patients with the pneumonic form. However, the organism grows only on an enriched medium (blood-cystine-glucose agar), and laboratory handling is dangerous owing to the risk of airborne transmission to laboratory personnel. Immunofluorescent staining of biopsy material or aspirates of involved lymph nodes is diagnostic, although it is not widely available.

The WBC count is not remarkable. Agglutinins are present after the second week of illness, and in the absence of a positive culture their development confirms the diagnosis. A tube agglutination antibody titer of 1:160 or greater or a microagglutination titer of 1:128 or higher is considered presumptively positive for the diagnosis of tularemia. Confirmation of disease is established by demonstration of a fourfold antibody titer rise between acute and convalescent serum samples. PCR of blood, lymph node aspirate, or tissue may be available through State Health Departments.

 Differential Diagnosis

The typhoidal form of tularemia may mimic typhoid, brucellosis, miliary tuberculosis, Rocky Mountain spotted fever, and mononucleosis. Pneumonic tularemia resembles atypical or mycotic pneumonitis. The ulceroglandular type of tularemia resembles pyoderma caused by staphylococci or streptococci, plague, anthrax, and cat-scratch fever. The oropharyngeal type must be distinguished from streptococcal or diphtheritic pharyngitis, mononucleosis, herpangina, or other viral pharyngitides.

 Treatment

A. Specific Measures

Historically, streptomycin was the drug of choice. However, gentamicin is efficacious, more available, and familiar to clinicians. A 10-day course is usually sufficient, although more severe infections may need longer therapy. Doxycycline is effective, but relapse rates are higher. Doxycycline is not usually recommended for children younger than 8 years of age unless benefits of use outweigh the risk of dental staining. Doxycycline is a static (as opposed to cidal) agent and should be given for at least 14 days. Ciprofloxacin also can be used in patients with less severe disease. Ciprofloxacin is not approved for children younger than 18 years, and is not usually recommended in children unless benefits outweigh risks.

B. General Measures

Antipyretics and analgesics may be given as necessary. Skin lesions are best left open. Glandular lesions occasionally require incision and drainage.

 Prognosis

The prognosis is excellent in most cases of tularemia that are recognized early and treated appropriately.

Center for Disease Control (CDC) and Prevention: Tularemia. Available at: http://www.cdc.gov/tularemia/.

Ellis J, Oyston PCF, Green M, Titball RW: Tularemia. Clin Micro Rev 2002;15(4):61–646 [PMID: 12364373]. Available at: http://cmr.asm.org/cgi/content/full/15/4/631?view=long&p mid=12364373

Lieberman JM: North American zoonoses. Pediatr Ann 2009;38(4): 193–198 [PMID: 19455948].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Sudden onset of fever, chills, and prostration.

 Regional lymphadenitis with suppuration of nodes (bubonic form).

 Hemorrhage into skin and mucous membranes and shock (septicemia).

 Cough, dyspnea, cyanosis, and hemoptysis (pneumonia).

 History of exposure to infected animals.

 General Considerations

Plague is an extremely serious acute infection caused by a gram-negative bacillus, Yersinia pestis. It is a disease of rodents that is transmitted to humans by flea bites. Plague bacilli have been isolated from ground squirrels, prairie dogs, and other wild rodents in many of the western and southwestern states in the United States. Most cases have come from New Mexico, Arizona, Colorado, and California. Direct contact with rodents, rabbits, or domestic cats may transmit fleas infected with plague bacilli. Most cases occur from June through September. Human plague in the United States appears to occur in cycles that reflect cycles in wild animal reservoirs.

 Prevention

Proper disposal of household and commercial wastes and chemical control of rats are basic elements of plague prevention. Flea control is instituted and maintained with liberal use of insecticides. Children vacationing in remote camping areas should be warned not to handle dead or dying animals. Domestic cats that roam freely in suburban areas may contact infected wild animals and acquire infected fleas. There is no commercially available vaccine for plague.

All persons who have been exposed to plague in the previous 6 days (via personal contact with an infected person, contact with plague infected fleas, or exposure to infected tissues) should be given antimicrobial prophylaxis or be instructed to closely monitor themselves for fever or other symptoms and report any illness or any fever to their physician. Persons who have close personal contact (< 2 m) with a person with pneumonic plague should receive antimicrobial prophylaxis for 7 days from the last exposure. Doxycycline or ciprofloxacin are the recommended agents for prophylaxis. For children younger than 8 years, TMP-SMX is an alternative agent but the efficacy is unknown. Chloramphenicol is also an alternative agent. For persons who have had a known or suspected exposure to plague-infected fleas in the previous week, the same antimicrobial regimen can be used for prophylaxis. Patients on prophylaxis should still seek prompt medical care for onset of fever or other illness.

 Clinical Findings

A. Symptoms and Signs

Plague assumes several clinical forms; the two most common are bubonic and septicemic. Pneumonic plague, the form that occurs when organisms enter the body through the respiratory tract, is uncommon.

1. Bubonic plague—Bubonic plague begins after an incubation period of 2–8 days with a sudden onset of high fever, chills, headache, vomiting, and marked delirium or clouding of consciousness. A less severe form also exists, with a less precipitous onset, but with progression over several days to severe symptoms. Although the flea bite is rarely seen, the regional lymph node, usually inguinal and unilateral, is/are painful and tender, 1–5 cm in diameter. The node usually suppurates and drains spontaneously after 1 week. The plague bacillus produces endotoxin that causes vascular necrosis. Bacilli may overwhelm regional lymph nodes and enter the circulation to produce septicemia. Severe vascular necrosis results in widely disseminated hemorrhage in skin, mucous membranes, liver, and spleen. Myocarditis and circulatory collapse may result from damage by the endotoxin. Plague meningitis or pneumonia may occur following bacteremic spread from an infected lymph node.

2. Septicemic plague—Plague may initially present as septicemia without evidence of lymphadenopathy. In some series, 25% of cases are initially septicemic. Septicemic plague carries a worse prognosis than bubonic plague, largely because it is not recognized and treated early. Patients may present initially with a nonspecific febrile illness characterized by fever, myalgia, chills, and anorexia. Plague is frequently complicated by secondary seeding of the lung causing plague pneumonia.

3. Primary pneumonic plague—Inhalation of Y pestis bacilli causes primary plague pneumonia. This form of plague has been transmitted to humans from cats with pneumonic plague and would be the form of plague most likely seen after aerosolized release of Y pestis in a bioterrorist incident. After an incubation of 1–6 days, the patient develops fever, cough, shortness of breath, and the production of bloody, watery, or purulent sputum. Gastrointestinal symptoms are sometimes prominent. Because the initial focus of infection is the lung, buboes are usually absent; occasionally cervical buboes may be seen.

B. Laboratory Findings

Aspirate from a bubo contains bipolar-staining gram- negative bacilli. Pus, sputum, and blood all yield the organism. Rapid diagnosis can be made with fluorescent antibody detection or polymerase chain reaction (PCR) on clinical specimens. Confirmation is made by culture or serologic testing. Laboratory infections are common enough to make bacterial isolation dangerous. Cultures are usually positive within 48 hours. Paired acute and convalescent sera may be tested for a fourfold antibody rise in those cases with negative cultures.

 Differential Diagnosis

The septic phase of the disease may be confused with illnesses such as meningococcemia, sepsis caused by other bacteria, and rickettsioses. The bubonic form resembles tularemia, anthrax, cat-scratch fever, streptococcal adenitis, and cellulitis. Primary gastroenteritis and appendicitis may have to be distinguished.

 Treatment

A. Specific Measures

Streptomycin or gentamicin for 7–10 days (or until several days after defervescence) is effective. For patients not requiring parenteral therapy, doxycycline, ciprofloxacin or chloramphenicol may be given. Doxycycline is not usually recommended for children younger than 8 years of age and ciprofloxacin is not usually recommended for children less than 18 years of age unless benefits of use outweigh the risk. However, plague is a potentially life-threatening condition and benefits of use of these agents outweigh potential risks. Plague bacilli that are multiply resistant to antimicrobials are uncommon but of serious concern.

Mortality is extremely high in septicemic and pneumonic plague if specific antibiotic treatment is not started in the first 24 hours of the disease.

Every effort should be made to effect resolution of buboes without surgery. Pus from draining lymph nodes is infectious.

B. General Measures

State health officials should be notified immediately about suspected cases of plague. Pneumonic plague is highly infectious, and droplet isolation is required until the patient has been on effective antimicrobial therapy for 48 hours. All contacts of patients with pneumonic plague should receive antibiotic prophylaxis for 7 days after the last exposure. Contacts should see a physician immediately for any illness or fever.

 Prognosis

The mortality rate in untreated bubonic plague is about 50%. The mortality rate for treated pneumonic plague is 50%–60%. Recent mortality rates in New Mexico were 3% for bubonic plague and 71% for the septicemic form.

Centers for Disease Control and Prevention (CDC): Plague. Available at: http://www.cdc.gov/ncidod/dvbid/plague

Lieberman JM: North American zoonoses. Pediatr Ann 2009;38(4):193–198 [PMID: 19455948].

Prentice MB, Rahalison L: Plague. Lancet 2007;369:1196 [PMID: 17416264].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Purulent meningitis in children younger than age 4 years with direct smears of CSF showing gram-negative pleomorphic rods.

 Acute epiglottitis: high fever, drooling, dysphagia, aphonia, and stridor.

 Septic arthritis: fever, local redness, swelling, heat, and pain with active or passive motion of the involved joint in a child 4 months to 4 years of age.

 Cellulitis: sudden onset of fever and distinctive cellulitis in an infant, often involving the cheek or periorbital area.

 In all cases, a positive culture from the blood, CSF, or aspirated pus confirms the diagnosis.

 General Considerations

H influenzae type b (Hib) has become uncommon because of widespread immunization in early infancy. The 99% reduction in incidence seen in many parts of the United States is due to high rates of vaccine coverage and reduced nasopharyngeal carriage after vaccination. Forty percent of cases occur in children younger than 6 months who are too young to have completed a primary immunization series. Hib may cause meningitis, bacteremia, epiglottitis (supraglottic croup), septic arthritis, periorbital and facial cellulitis, pneumonia, and pericarditis.

Disease due to H influenzae types a, c, d, e, f, or unencapsulated strains is rare, but it now accounts for a larger proportion of positive culture results. Third-generation cephalosporins are preferred for initial therapy of Hib infections. Ampicillin is adequate for culture-proved Hib susceptible strains.

Unencapsulated, nontypeable H influenzae frequently colonize the mucous membranes and cause otitis media, sinusitis, bronchitis, and pneumonia in children and adults. Bacteremia is uncommon. Neonatal sepsis similar to early-onset GBS is recognized. Obstetric complications of chorioamnionitis and bacteremia are usually the source of neonatal cases.

Ampicillin resistance occurs in 25%–40% of nontypeable H influenzae. Beta-lactamase-negative, ampicillin-resistant (BLNAR) H influenzae has emerged as a clinically important pathogen in Europe, Japan, and Canada. In the United States, the prevalence of BLNAR strains currently remains low at around 3%.

 Prevention

Several carbohydrate protein conjugate Hib vaccines are currently available (see Chapter 10).

The risk of invasive Hib disease is highest in unimmunized, or partially immunized, household contacts who are younger than 4 years of age. The following situations require rifampin chemoprophylaxis of all household contacts (except pregnant women) to eradicate potential nasopharyngeal colonization with Hib and limit risk of invasive disease: (1) families where at least one household contact is younger than age 4 years and either unimmunized or incompletely immunized against Hib; (2) an immunocompromised child (of any age or immunization status) resides in the household; or (3) a child younger than age 12 months resides in the home and has not received the primary series of the Hib vaccine. Preschool and day care center contacts may need prophylaxis if more than one case has occurred in the center in the previous 60 days (discuss with state health officials). The index case also needs chemoprophylaxis in these situations to eradicate nasopharyngeal colonization unless treated with ceftriaxone or cefotaxime (both are effective in eradication of Hib from the nasopharynx). Household contacts and index cases older than 1 month of age who need chemoprophylaxis should be given rifampin, 20 mg/kg per dose (maximum adult dose, 600 mg) orally, once daily for 4 successive days. Infants who are younger than 1 month should be given oral rifampin (10 mg/kg per dose once daily for 4 days). Rifampin should not be used in pregnant females.

 Clinical Findings

A. Symptoms and Signs

1. Meningitis—Infants usually present with fever, irritability, lethargy, poor feeding with or without vomiting, and a high-pitched cry.

2. Acute epiglottitis—The most useful clinical finding in the early diagnosis of Hib epiglottitis is evidence of dysphagia, characterized by a refusal to eat or swallow saliva and by drooling. This finding, plus the presence of a high fever in a toxic child—even in the absence of a cherry-red epiglottis on direct examination—should strongly suggest the diagnosis and lead to prompt intubation. Stridor is a late sign (see Chapter 19).

3. Septic arthritis—Hib is a common cause of septic arthritis in unimmunized children younger than age 4 years in the United States. The child is febrile and refuses to move the involved joint and limb because of pain. Examination reveals swelling, warmth, redness, tenderness on palpation, and severe pain on attempted movement of the joint.

4. Cellulitis—Cellulitis due to Hib occurs almost exclusively in children between the ages of 3 months and 4 years but is now uncommon as a result of immunization. Fever is usually noted at the same time as the cellulitis, and many infants appear toxic. The cheek or periorbital (preseptal) area is usually involved.

B. Laboratory Findings

The WBC count in Hib infections may be high or normal with a shift to the left. Blood culture is frequently positive. Positive culture of aspirated pus or fluid from the involved site proves the diagnosis. In untreated meningitis, CSF smear may show the characteristic pleomorphic gram-negative rods.

C. Imaging

A lateral view of the neck may suggest the diagnosis in suspected acute epiglottitis, but misinterpretation is common. Intubation should not be delayed to obtain radiographs. Haziness of maxillary and ethmoid sinuses occurs with orbital cellulitis.

 Differential Diagnosis

A. Meningitis

Meningitis must be differentiated from head injury, brain abscess, tumor, lead encephalopathy, and other forms of meningoencephalitis, including mycobacterial, viral, fungal, and bacterial agents.

B. Acute Epiglottitis

In croup caused by viral agents (parainfluenza 1, 2, and 3, respiratory syncytial virus, influenza A, adenovirus), the child has more definite upper respiratory symptoms, cough, hoarseness, slower progression of obstructive signs, and lower fever. Spasmodic croup usually occurs at night in a child with a history of previous attacks. Sudden onset of choking and paroxysmal coughing suggests foreign body aspiration. Retropharyngeal abscess may have to be differentiated from epiglottitis.

C. Septic Arthritis

Differential diagnosis includes acute osteomyelitis, prepatellar bursitis, cellulitis, rheumatic fever, and fractures and sprains.

D. Cellulitis

Erysipelas, streptococcal cellulitis, insect bites, and trauma (including Popsicle panniculitis or other types of freezing injury) may mimic Hib cellulitis. Periorbital cellulitis must be differentiated from paranasal sinus disease without cellulitis, allergic inflammatory disease of the lids, conjunctivitis, and herpes zoster infection.

 Complications

A. Meningitis (See CHAPTER 25)

B. Acute Epiglottitis

The disease may rapidly progress to complete airway obstruction with complications owing to hypoxia. Mediastinal emphysema and pneumothorax may occur.

C. Septic Arthritis

Septic arthritis may result in rapid destruction of cartilage and ankylosis if diagnosis and treatment are delayed. Even with early treatment, the incidence of residual damage and disability after septic arthritis in weight-bearing joints may be as high as 25%.

D. Cellulitis

Bacteremia may lead to meningitis or pyarthrosis.

 Treatment

All patients with bacteremic or potentially bacteremic Hib diseases require hospitalization for treatment. The drugs of choice in hospitalized patients are a third-generation cephalosporin (cefotaxime or ceftriaxone) until the sensitivity of the organism is known. Meropenem is an alternative choice.

Persons with invasive Hib disease should be in droplet isolation for 24 hours after initiation of parenteral antibiotic therapy.

A. Meningitis

Therapy is begun as soon as bacterial meningitis has been identified and CSF, blood, and other appropriate cultures have been obtained. Empiric intravenous therapy recommended for meningitis (until organism identified) is vancomycin in combination with either cefotaxime or ceftriaxone. Once the organism has been identified as Haemophilus influenza and the susceptibilities are known, the antibiotic regimen can be tailored accordingly. Most isolates will be susceptible to ceftriaxone or cefotaxime. Meropenem is an alternative agent. Therapy should preferably be given intravenously for the entire course. Ceftriaxone may be given intramuscularly if venous access becomes difficult.

Duration of therapy is 10 days for uncomplicated meningitis. Longer treatment is reserved for children who respond slowly or in whom complications have occurred.

Dexamethasone given immediately after diagnosis and continued for 4 days may reduce the incidence of hearing loss in children with Hib meningitis. The use of dexamethasone is controversial, but when it is used the dosage is 0.6 mg/kg/d in four divided doses for 4 days. Starting dexamethasone more than 6 hours after antibiotics have been initiated is unlikely to provide benefits.

Repeated lumbar punctures are usually not necessary in Hib meningitis. They should be obtained in the following circumstances: unsatisfactory or questionable clinical response, seizure occurring after several days of therapy, and prolonged (7 days) or recurrent fever if the neurologic examination is abnormal or difficult to evaluate.

B. Acute Epiglottitis (See Chapter 19)

C. Septic Arthritis

Initial therapy should include an effective antistaphylococcal antibiotic and cefotaxime or ceftriaxone (dosage as for meningitis) until identification of the organism is made. Cefotaxime or ceftriaxone are the usual agents used once the isolate is known to be Haemophilus and susceptibilities are known. Ampicillin resistance is now common in the United States. Occasionally isolates are resistant to third generation cephalosporins. Meropenem, if the isolate is susceptible, can be used as an alternative. If a child is improved following initial intravenous therapy, transition to oral therapy based on susceptibilities can occur. Possible oral agents should be chosen based on susceptibilities but might include amoxicillin/clavulanate (90–100 mg/kg/d of amoxicillin component in four divided doses every 6 hours). Antibiotics should be administered under supervision to complete a 4-week course (longer if complications or signs and symptoms are unresolved). Alternative agents include second- or third-generation cephalosporins. Drainage of infected joint fluid is an essential part of treatment. In joints other than the hip, this can often be accomplished by one or more needle aspirations. In hip infections—and in arthritis of other joints when treatment is delayed or clinical response is slow—surgical drainage is advised. The joint should be immobilized.

D. Cellulitis, Including Orbital Cellulitis

Initial therapy for orbital cellulitis should be broad spectrum antibiotic therapy. The most likely pathogens may include Streptococcus pneumonia, Streptococcus anginosus, Group A Streptococcus, Staphylococcus aureus, Haemophilus influenzae, and anaerobes. Once the organism is known to be H influenzae orbital and susceptibilities are known, cefotaxime, ceftriaxone, or Meropenem can be used depending on susceptibilities for H influenzaecoverage. Mixed infections require additional agents. Therapy is given parenterally for at least 3–7 days (some clinicians treat up to 2 weeks intravenously) followed by oral treatment. There is usually marked improvement after 72 hours of treatment. The total antibiotic course will vary with the severity of the infection, response to therapy, whether or not an abscess was present, and whether or not drainage was performed. A minimum course of 21 days is reasonable in uncomplicated cases without abscess and good therapeutic response, assuming all signs of orbital cellulitis have completely resolved. In cases with severe ethmoid sinusitis and evidence of boney destruction at least a 4-week treatment course is advisable. Complicated cases may require longer treatment courses.

 Prognosis

The case fatality rate for Hib meningitis is less than 5%. Young infants have the highest mortality rate. One of the most common neurologic sequelae, developing in 5%–10% of patients with Hib meningitis, is sensorineural hearing loss. Patients with Hib meningitis should have their hearing checked during the course of the illness or shortly after recovery. Children in whom invasive Hib infection develops despite appropriate immunization should have tests to investigate immune function and to rule out HIV. The case fatality rate in acute epiglottitis is 2%–5%. Deaths are associated with bacteremia and the rapid development of airway obstruction. The prognosis for the other diseases requiring hospitalization is good with the institution of early and adequate antibiotic therapy.

Centers for Disease Control and Prevention: Epidemiology and prevention of vaccine-preventable diseases. The Pink Book: Course Textbook. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf

Centers for Disease Control and Prevention: Haemophilus influenzae. Available at: http://www.cdc.gov/hi-disease/index.html

Tristram S, Jacobs MR, Appelbaum AP: Antimicrobial resistance in Haemophilus influenzae. Clin Microbiol Rev 2007;20:368 [PMID: 17428889].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Prodromal catarrhal stage (1–3 weeks) characterized by mild cough and coryza, but without fever.

 Persistent staccato, paroxysmal cough ending with a high-pitched inspiratory “whoop.”

 Leukocytosis with absolute lymphocytosis.

 Diagnosis confirmed by PCR or culture of nasopharyngeal secretions.

 General Considerations

Pertussis is an acute, highly communicable infection of the respiratory tract caused by Bordetella pertussis and characterized by severe bronchitis. Children usually acquire the disease from symptomatic family contacts. Adults and adolescents who have mild respiratory illness, not recognized as pertussis, frequently are the source of infection. Asymptomatic carriage of B pertussis is not recognized. Infectivity is greatest during the catarrhal and early paroxysmal cough stage (for about 4 weeks after onset).

Pertussis cases have increased in the United States since 2000. In 2007, about 10,000 cases were reported; increased to more than 16,000 cases in 2009, and 27,000 cases in 2010. The morbidity and mortality of pertussis is greatest in young children. Fifty percent of children younger than age 1 year with a diagnosis of pertussis are hospitalized. Deaths occur primarily in children less than one year and are increasing in frequency.

The duration of active immunity following natural pertussis is not known. Reinfections are usually milder. Immunity following vaccination wanes in 5–10 years. The majority of young adults in the United States are susceptible to pertussis infection, and disease is probably common but unrecognized. Decreased efficacy of acellular vaccines compared to whole cell vaccines and low rates of immunization in some communities has led to increasing numbers of cases.

Bordetella parapertussis and Bordetella holmesii cause a similar but milder syndrome.

B pertussis organisms attach to the ciliated respiratory epithelium and multiply there; deeper invasion does not occur. Disease is due to several bacterial toxins, the most potent of which is pertussis toxin, which is responsible for the typical lymphocytosis.

 Clinical Findings

A. Symptoms and Signs

The onset of pertussis is insidious, with catarrhal upper respiratory tract symptoms (rhinitis, sneezing, and an irritating cough). Slight fever may be present; temperature greater than 38.3°C suggests bacterial superinfection or another cause of respiratory tract infection. After about 2 weeks, cough becomes paroxysmal, characterized by 10–30 forceful coughs ending with a loud inspiration (the whoop). Infants and adults with otherwise typical severe pertussis often lack characteristic whooping. Vomiting commonly follows a paroxysm. Coughing is accompanied by cyanosis, sweating, prostration, and exhaustion. This stage lasts for 2–4 weeks, with gradual improvement. Paroxysmal coughing may continue for some months and may worsen with intercurrent viral respiratory infection. In adults, older children, and partially immunized individuals, symptoms may consist only of irritating cough lasting 1–2 weeks. Clinical pertussis is milder in immunized children.

B. Laboratory Findings

WBC counts of 20,000–30,000/μL with 70%–80% lymphocytes typically appear near the end of the catarrhal stage; and the degree of lymphocytosis correlates with the severity of disease. Severe pulmonary hypertension and hyperleukocytosis (> 70,000/μL) are associated with severe disease and death in young children with pertussis. Many older children and adults with mild infections never demonstrate lymphocytosis. The blood picture may resemble lymphocytic leukemia or leukemoid reactions. Identification of B pertussis by culture or PCR from nasopharyngeal swabs or nasal wash specimens proves the diagnosis. The organism may be found in the respiratory tract in diminishing numbers beginning in the catarrhal stage and ending about 2 weeks after the beginning of the paroxysmal stage. After 4–5 weeks of symptoms, cultures are almost always negative. Culture requires specialized media and careful attention to specimen collection and transport. PCR detection has replaced culture in most pediatric centers because of improved sensitivity, decreased time to diagnosis, and cost. Enzyme-linked immunosorbent assays (ELISAs) for detection of antibody to pertussis toxin or filamentous hemagglutinin may be useful for diagnosis but interpretation of antibody titers may be difficult in previously immunized patients. The chest radiograph reveals thickened bronchi and sometimes shows a “shaggy” heart border.

 Differential Diagnosis

The differential diagnosis of pertussis includes bacterial, tuberculous, chlamydial, and viral pneumonia. The absence of fever in pertussis differentiates this disease from most bacterial infections. Cystic fibrosis and foreign body aspiration may be considerations. Adenoviruses and respiratory syncytial virus may cause paroxysmal coughing with an associated elevation of lymphocytes in the peripheral blood, mimicking pertussis.

 Complications

Bronchopneumonia due to superinfection is the most common serious complication. It is characterized by abrupt clinical deterioration during the paroxysmal stage, accompanied by high fever and sometimes a striking leukemoid reaction with a shift to predominantly polymorphonuclear neutrophils. Atelectasis is a second common pulmonary complication. Atelectasis may be patchy or extensive and may shift rapidly to involve different areas of lung. Intercurrent viral respiratory infection is also a common complication and may provoke worsening or recurrence of paroxysmal coughing. Otitis media is common. Residual chronic bronchiectasis is infrequent despite the severity of the illness. Apnea and sudden death may occur during a particularly severe paroxysm. Seizures complicate 1.5% of cases, and encephalopathy occurs in 0.1%. The encephalopathy frequently is fatal. Anoxic brain damage, cerebral hemorrhage, or pertussis neurotoxins are hypothesized, but anoxia is most likely the cause. Epistaxis and subconjunctival hemorrhages are common.

 Prevention

Active immunization (see Chapter 10) with DTaP vaccine should be given in early infancy. The occurrence and increased recognition of disease in adolescents and adults contributes to the increasing number of cases. A booster dose of vaccine in adolescents between the ages of 11 and 18 years is recommended. Subsequent booster doses of Tdap are recommended for adults aged 18–60 years to replace Td boosters. Immunization of pregnant women, new mothers, care givers of infants less than 6 months, and healthcare workers of young children is also recommended.

Chemoprophylaxis with azithromycin should be given to exposed family, household and hospital contacts, particularly those younger than age 2 years, although data to support the efficacy of such preventive therapy are not strong. Hospitalized children with pertussis should be isolated because of the great risk of transmission to patients and staff. Several large hospital outbreaks have been reported.

 Treatment

A. Specific Measures

Antibiotics may ameliorate early infections but have no effect on clinical symptoms in the paroxysmal stage. Azithromycin is the drug of choice because it promptly terminates respiratory tract carriage of B pertussis. Resistance to macrolides has been rarely reported. Clarithromycin may also be used. Erythromycin given 4 times daily for 14 days is acceptable but not preferred. Ampicillin (100 mg/kg/d in four divided doses) may also be used for erythromycin-intolerant patients. Azithromycin is often preferred due to ease of compliance and decreased gastrointestinal side effects. Erythromycin has been associated with pyloric stenosis in infants less than 1 month of age. Azithromycin is recommended for therapy or prophylaxis in infants less than 1 month.

Corticosteroids reduce the severity of disease but may mask signs of bacterial superinfection. Albuterol (0.3– 0.5 mg/kg/d in four doses) has reduced the severity of illness, but tachycardia is common when the drug is given orally, and aerosol administration may precipitate paroxysms.

B. General Measures

Nutritional support during the paroxysmal phase is important. Frequent small feedings, tube feeding, or parenteral fluid supplementation may be needed. Minimizing stimuli that trigger paroxysms is probably the best way of controlling cough. In general, cough suppressants are of little benefit.

C. Treatment of Complications

Respiratory insufficiency due to pneumonia or other pulmonary complications should be treated with oxygen and assisted ventilation if necessary. Convulsions are treated with oxygen and anticonvulsants. Bacterial pneumonia or otitis media requires additional antibiotics.

 Prognosis

The prognosis for patients with pertussis has improved in recent years because of excellent nursing care, treatment of complications, attention to nutrition, and modern intensive care. However, the disease is still very serious in infants younger than age 1 year; most deaths occur in this age group. Children with encephalopathy have a poor prognosis.

Centers for Disease Control and Prevention (CDC): Pertussis epidemic—Washington, 2012. MMWR Morb Mortal Wkly Rep 2012;61:517–522 [PMID: 22810264].

Cherry JD: Why do pertussis vaccines fail? Pediatrics 2012;129(5):968 [PMID: 22529282].

Committee on Infectious Diseases: Additional recommendations for use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (tdap). Pediatrics 2011;128(4):809 [PMID: 21949151].

Haberling DL et al: Infant and maternal risk factors for pertussis-related infant mortality in the United States, 1999–2004. Pediatr Infect Dis J 2009;28(3):194 [PMID: 19209089].

McIntyre PB, Sintchenko V: The “how” of polymerase chain reaction testing for Bordetella pertussis depends on the “why.” Clin Infect Dis 2013;56(3):332 [PMID: 23087394].

Munoz F, Englund J: Infant pertussis: is cocooning the answer? Clin Infect Dis 2011;53(9):893 [PMID: 21946188].

Nicholson CE: Early exchange and pheresis therapies in critical pertussis. Pediatr Crit Care Med 2011;12(2):240 [PMID: 21646959].

Rodgers L et al: Epidemiologic and laboratory features of a large outbreak of pertussis-like illnesses associated with cocirculating Bordetella holmesii and Bordetella pertussis—Ohio, 2010–2011. Clin Infect Dis 2013;56(3):322 [PMID: 23087388].

Rowlands HE et al: Impact of rapid leukodepletion on the outcome of severe clinical pertussis in young infants. Pediatrics 2010;126(4):e816 [PMID: 20819895].

Winter K et al: California pertussis epidemic, 2010. J Pediatr 2012;161(6):1091 [PMID: 22819634].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Early-onset neonatal disease:

 Signs of sepsis a few hours after birth in an infant born with fetal distress and hepatosplenomegaly; maternal fever.

 Late-onset neonatal disease:

 Meningitis, sometimes with monocytosis in the CSF and peripheral blood.

 Onset at age 9–30 days.

 General Considerations

Listeria monocytogenes is a gram-positive, non–spore-forming aerobic rod distributed widely in the animal kingdom and in food, dust, and soil. It causes systemic infections in newborn infants and immunosuppressed older children. In pregnant women, infection is relatively mild, with fever, aches, and chills, but is accompanied by bacteremia and sometimes results in intrauterine or perinatal infection with grave consequences for the fetus or newborn. One-fourth of cases occur in pregnant women, and 20% of their pregnancies end in stillbirth or neonatal death. Listeria is present in the stool of approximately 10% of the healthy population. Persons in contact with animals are at greater risk. Outbreaks of listeriosis have been traced to contaminated cabbage in coleslaw, soft cheese, hot dogs, luncheon meats, and milk. Listeria infections have decreased since the adoption of strict regulations for ready-to-eat foods; 821 cases were reported in 2010. A large multistate outbreak due to contaminated cantaloupe has caused more than 20 deaths in elderly and immunocompromised patients in 2011, and demonstrates the potential of this organism to cause serious illness.

Like GBS infections, Listeria infections in the newborn can be divided into early and late forms. Early infections are more common, leading to a severe congenital form of infection. Later infections are often characterized by meningitis.

 Clinical Findings

A. Symptoms and Signs

In the early neonatal form, symptoms of listeriosis usually appear on the first day of life and always by the third day. Fetal distress is common, and infants frequently have signs of severe disease at birth. Respiratory distress, diarrhea, and fever occur. On examination, hepatosplenomegaly and a papular rash are found. A history of maternal fever is common. Meningitis may accompany the septic course. The late neonatal form usually occurs after age 9 days and can occur as late as 5 weeks. Meningitis is common, characterized by irritability, fever, and poor feeding.

Listeria infections are rare in older children and usually are associated with immunodeficiency. Several recent cases were associated with tumor necrosis factor-α neutralizing agents. Signs and symptoms are those of meningitis, usually with insidious onset.

B. Laboratory Findings

In all patients except those receiving white cell depressant drugs, the WBC count is elevated, with 10%–20% monocytes. When meningitis is found, the characteristic CSF cell count is high (> 500/μL) with a predominance of polymorphonuclear neutrophils in 70% of cases. Monocytes may predominate in up to 30% of cases. Gram-stained smears of CSF are usually negative, but short gram-positive rods may be seen. The chief pathologic feature in severe neonatal sepsis is miliary granulomatosis with microabscesses in liver, spleen, CNS, lung, and bowel.

Culture results are frequently positive from multiple sites, including blood from the infant and the mother.

 Differential Diagnosis

Early-onset neonatal disease resembles hemolytic disease of the newborn, GBS sepsis or severe cytomegalovirus infection, rubella, or toxoplasmosis. Late-onset disease must be differentiated from meningitis due to echovirus and coxsackievirus, GBS, and gram-negative enteric bacteria.

 Prevention

Immunosuppressed, pregnant, and elderly patients can decrease the risk of Listeria infection by avoiding soft cheeses, by thoroughly reheating or avoiding delicatessen and ready-to-eat foods, by avoiding raw meat and milk, and by thoroughly washing fresh vegetables.

 Treatment

Ampicillin (150–300 mg/kg/d every 6 hours intravenously) is the drug of choice in most cases of listeriosis. Gentamicin (2.5 mg/kg every 8 hours intravenously) has a synergistic effect with ampicillin and should be given in serious infections and to patients with immune deficits. Vancomycin may be substituted for ampicillin when empirically treating meningitis. If ampicillin cannot be used, TMP-SMX also is effective. Cephalosporins are not effective. Treatment of severe disease should continue for at least 2 weeks; meningitis is treated 2–3 weeks.

 Prognosis

In a recent outbreak of early-onset neonatal disease, the mortality rate was 27% despite aggressive and appropriate management. Meningitis in older infants has a good prognosis. In immunosuppressed children, prognosis depends to a great extent on that of the underlying illness.

Centers for Disease Control and Prevention (CDC): Listeriosis. Available at: http://www.cdc.gov/listeria/index.html

Center for Disease Control and Prevention (CDC): Multistate outbreak of listeriosis associated with Jensen Farms Cantaloupe—United States, Aug–Sep 2011. MMWR 2011;60:1357 [PMID: 21976119].

Pouillot R et al: Relative risk of listeriosis in Foodborne Diseases Active Surveillance Network (FoodNet) sites according to age, pregnancy, and ethnicity. Clin Infect Dis 2012;54(Suppl 5):405 [PMID: 22572661].

Silk BJ et al: Invasive listeriosis in the Foodborne Diseases Active Surveillance Network (FoodNet), 2004–2009: further targeted prevention needed for higher-risk groups. Clin Infect Dis 2012;54(Suppl 5):396 [PMID: 22572660].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 All types: positive tuberculin test in patient or members of household, suggestive chest radiograph, history of contact, and demonstration of organism by stain and culture.

 Pulmonary: fatigue, irritability, and undernutrition, with or without fever and cough.

 Glandular: chronic cervical adenitis.

 Miliary: classic snowstorm appearance of chest radiograph.

 Meningitis: fever and manifestations of meningeal irritation and increased intracranial pressure. Characteristic CSF.

 General Considerations

Tuberculosis is a granulomatous disease caused by Mycobacterium tuberculosis. It is a leading cause of death throughout the world. Children younger than age 3 years are most susceptible. Lymphohematogenous dissemination through the lungs to extrapulmonary sites, including the brain and meninges, eyes, bones and joints, lymph nodes, kidneys, intestines, larynx, and skin, is more likely to occur in infants. Increased susceptibility occurs again in adolescence, particularly in girls within 2 years of menarche. Following substantial increases in disease during the 1980s, tuberculosis incidence has decreased since 1992 due to increased control measures. More than 10,465 new cases were reported in 2011; only 577 of these were in children less than 14 years old. High-risk groups include ethnic minorities, foreign-born persons, prisoners, residents of nursing homes, indigents, migrant workers, and healthcare providers. However, 50% of cases occurred in U.S.-born persons. HIV infection is an important risk factor for both development and spread of disease. Pediatric tuberculosis incidence mirrors the trends seen in adults.

Exposure to an infected adult is the most common risk factor in children. The primary complex in infancy and childhood consists of a small parenchymal lesion in any area of the lung with caseation of regional nodes and calcification. Postprimary tuberculosis in adolescents and adults commonly occurs in the apices of the lungs and is likely to cause chronic progressive cavitary pulmonary disease with less tendency for hematogenous dissemination. Mycobacterium bovis infection is clinically identical to M tuberculosis. M bovis may be acquired from unpasteurized dairy products obtained outside the United States.

 Clinical Findings

A. Symptoms and Signs

1. Pulmonary—(See Chapter 19.)

2. Miliary—Diagnosis is usually based on the classic “snowstorm” or “millet seed” appearance of lung fields on radiograph, although early in the course of disseminated tuberculosis the chest radiograph may show no or only subtle abnormalities. Choroidal tubercles are sometimes seen on funduscopic examination. Other lesions may be present and produce osteomyelitis, arthritis, meningitis, tuberculomas of the brain, enteritis, or infection of the kidneys and liver.

3. Meningitis—Symptoms include fever, vomiting, headache, lethargy, and irritability, with signs of meningeal irritation and increased intracranial pressure, cranial nerve palsies, convulsions, and coma.

4. Lymphatic—The primary complex may be associated with a skin lesion drained by regional nodes or chronic cervical node enlargement or infection of the tonsils. Involved nodes may become fixed to the overlying skin, suppurate, and drain.

B. Laboratory Findings

The tuberculin skin test (TST; 0.1 mL of intermediate-strength purified protein derivative inoculated intradermally) is positive at 48–72 hours if there is significant induration (Table 42–3). Parental reporting of skin test results is often inaccurate. All tests should be read by professionals trained to interpret TST. False-negative results occur in malnourished patients, in those with overwhelming disease, and in 10% of children with isolated pulmonary disease. Temporary suppression of tuberculin reactivity may be seen with viral infections (eg, measles, influenza, varicella, and mumps), after live virus immunization, and during corticosteroid or other immunosuppressive drug therapy. For these reasons, a negative TST test does not exclude the diagnosis of tuberculosis. When tuberculosis is suspected in a child, household members and adult contacts (eg, teachers and caregivers) also should be tested immediately. Multiple puncture tests (tine tests) should not be used because they are associated with false-negative and false-positive reactions, and because standards for interpretation of positive results do not exist. Interferon gamma release assays (IGRAs) are approved to replace TST tests in adults and older children. These assays have much higher specificity due to less common false-positive results from nontuberculosis mycobacteria and BCG. They are done on blood obtained by venipuncture and are further advantageous in requiring only a single visit. These tests are preferred in BCG-immunized children older than 4 years.

IGRA are reported as positive, negative or indeterminate. The ESR and CRP is usually elevated in symptomatic children. Cultures of pooled early morning gastric aspirates from three successive days will yield M tuberculosis in about 40% of cases. Biopsy may be necessary to establish the diagnosis. Therapy should not be delayed in suspected cases. The CSF in tuberculous meningitis shows slight to moderate pleocytosis (50–300 WBCs/μL, predominantly lymphocytes), decreased glucose, and increased protein.

The direct detection of mycobacteria in body fluids or discharges is best done by staining specimens with auramine-rhodamine and examining them with fluorescence microscopy; this method is superior to the Ziehl-Neelsen method.

C. Imaging

Chest radiograph should be obtained in all children with suspicion of tuberculosis at any site or with a positive skin test. Segmental consolidation with some volume loss and hilar adenopathy are common findings in children. Paratracheal adenopathy is a classic presentation. Pleural effusion also occurs with primary infection. Cavities and apical disease are unusual in children but are common in adolescents and adults.

 Differential Diagnosis

Pulmonary tuberculosis must be differentiated from fungal, parasitic, mycoplasmal, and bacterial pneumonias; lung abscess; foreign body aspiration; lipoid pneumonia; sarcoidosis; and mediastinal cancer. Cervical lymphadenitis is most likely due to streptococcal or staphylococcal infections. Cat-scratch fever and infection with atypical mycobacteria may need to be distinguished from tuberculous lymphadenitis. Viral meningoencephalitis, head trauma (child abuse), lead poisoning, brain abscess, acute bacterial meningitis, brain tumor, and disseminated fungal infections must be excluded in tuberculous meningitis. A positive TST or IGRA in the patient or family contacts is frequently valuable in suggesting the diagnosis of tuberculosis. A negative TST or IGRA does not exclude tuberculosis.

 Prevention

A. BCG Vaccine

Bacille Calmette–Guérin (BCG) vaccines are live-attenuated strains of M bovis. Although neonatal and childhood administration of BCG is carried out in countries with a high prevalence of tuberculosis, protective efficacy varies greatly with vaccine potency and method of delivery. BCG given to infants decreases disseminated tuberculosis but does not protect against pulmonary tuberculosis later in childhood or adolescence. Because the great majority of children who have received BCG still have negative TST tests, the past history of BCG vaccination should be ignored in interpreting the skin test. In the United States, BCG vaccination is not recommended. IGRAs give negative results in patients with false-positive PPDs due to BCG.

B. Isoniazid Chemoprophylaxis

Daily administration of isoniazid (10 mg/kg/d orally; maximum 300 mg) is advised for children who are exposed by prolonged close or household contact with adolescents or adults with active disease. Isoniazid is given until 8–10 weeks after last contact. At the end of this time, a TST or IGRA test should be done, and therapy should be continued for an additional 7 months if the test is positive.

C. Other Measures

Tuberculosis in infants and young children is evidence of recent exposure to active infection in an adult, usually a family member or household contact. The source contact (index case) should be identified, isolated, and given treatment to prevent other secondary cases. Reporting cases to local health departments is essential for contact tracing. Exposed tuberculin-negative children should usually receive isoniazid chemoprophylaxis. If a repeated skin test is negative 8– 10 weeks following the last exposure, isoniazid may be stopped. Routine tuberculin skin testing is not recommended for children without risk factors who reside in communities with a low incidence of tuberculosis. Children with no personal risk for tuberculosis but who reside in communities with a high incidence of tuberculosis should be given a skin test at school entry and then again at age 11–16 years. Children with a risk factor for acquiring tuberculosis should be tested every 2–3 years. Incarcerated adolescents and children living in a household with HIV-infected persons should have annual skin tests.

Children who immigrate into the United States from a country with a high incidence of infection should receive TST or IGRA on entry to the United States or upon presentation to healthcare providers. A past history of BCG vaccine should not delay testing.

 Treatment

A. Specific Measures

Most children with suspected active tuberculosis in the United States are hospitalized initially. If the infecting organism has not been isolated from the presumed source, reasonable attempts should be made to obtain it from the child using morning gastric aspirates, sputum, bronchoscopy, thoracentesis, or biopsy when appropriate. Unfortunately, cultures are frequently negative in children, and the risk of these procedures must be weighed against the yield.

Therapy is given daily for 14 days and then reduced to two to three times per week for the duration of the course. Directly observed administration of all doses of antituberculosis therapy by a trained healthcare professional is essential to ensure compliance with therapy.

Children with positive skin tests (see Table 42–3) without symptoms and a normal chest radiograph have latent tuberculosis and should receive 9 months of isoniazid (10 mg/kg/d orally; maximum 300 mg) therapy. Rifampin (10–15 mg/kg ld orally; maximum 600 mg) for 4 months is efficacious and compliance is easier with the shorter duration of therapy. A combination of isoniazid and rifapentine given once per week for 12 weeks is effective in adolescents older than 12 years and adults. In children with active pulmonary disease, therapy for 6 months using isoniazid (10 mg/kg/d), rifampin (15 mg/kg/d), and pyrazinamide (25–30 mg/kg/d) in a single daily oral dose for 2 months, followed by isoniazid plus rifampin (either in a daily or twice-weekly regimen) for 4 months appears effective for eliminating isoniazid-susceptible organisms. For more severe disease, such as miliary or CNS infection, duration is increased to 12 months or more, and a fourth drug (streptomycin or ethambutol) is added for the first 2 months. In communities with resistance rates greater than 4%, initial therapy should usually include four drugs.

1. Isoniazid—The hepatotoxicity from isoniazid seen in adults and some adolescents is rare in children. Transient elevation of aminotransferases (up to three times normal) may be seen at 6–12 weeks, but therapy is continued unless clinical illness occurs. Routine monitoring of liver function tests is unnecessary unless prior hepatic disease is known or the child is severely ill. Peripheral neuropathy associated with pyridoxine deficiency is rare in children, and it is not necessary to add pyridoxine unless significant malnutrition coexists or if the child is strictly breastfed.

2. Rifampin—Although it is an excellent bactericidal agent, rifampin is never used alone to treat active disease, owing to rapid development of resistance. Hepatotoxicity may occur but rarely with recommended doses. Rifampin causes an orange color of urine and secretions which is benign but may stain contact lenses or clothes. Rifampin interacts with many medications including anticonvulsants, some seizure medications, birth control pills, and Coumadin.

3. Pyrazinamide—This excellent sterilizing agent is most effective during the first 2 months of therapy. With the recommended duration and dosing, it is well tolerated. Although pyrazinamide elevates the uric acid level, it rarely causes symptoms of hyperuricemia in children. Use of this drug is now common for tuberculous disease in children, and resistance is uncommon. Oral acceptance and CNS penetration are good.

4. Ethambutol—Because optic neuritis is the major side effect in adults, ethambutol has usually been given only to children whose vision can be reliably tested for loss of color differentiation. Optic neuritis is rare and usually occurs in adults receiving more than the recommended dosage of 25 mg/kg/d. Documentation of optic toxicity in children is lacking despite considerable worldwide experience. Therefore, many four-drug regimens for children now include ethambutol.

5. Streptomycin—Streptomycin (20–30 mg/kg/d, given intramuscularly in one or two doses) should be given for 1 or 2 months in severe disease. The child’s hearing should be tested periodically during use as ototoxicity is common.

B. Chemotherapy for Drug-Resistant Tuberculosis

The incidence of drug resistance is increasing and reaches 10%–20% in some areas of the United States. Transmission of multiple drug-resistant and extensively drug-resistant strains to contacts has occurred in some epidemics. Consultation with local experts in treating tuberculosis is important in these difficult cases. Therapy should continue for 18 months or longer. Often, four to six first- and second-line medications are needed.

C. General Measures

Corticosteroids may be used for suppressing inflammatory reactions in meningeal, pleural, and pericardial tuberculosis and for the relief of bronchial obstruction due to hilar adenopathy. Prednisone is given orally, 1 mg/kg/d for 2 weeks, with gradual withdrawal over the next 4–6 weeks. The use of corticosteroids may mask progression of disease. Accordingly, the clinician needs to be sure that an effective regimen is being used.

 Prognosis

If bacteria are sensitive and treatment is completed, most children are cured with minimal sequelae. Repeat treatment is more difficult and less successful. With antituberculosis chemotherapy (especially isoniazid), there should now be nearly 100% recovery in miliary tuberculosis. Without treatment, the mortality rate in both miliary tuberculosis and tuberculous meningitis is almost 100%. In the latter form, about two-thirds of patients receiving treatment survive. There may be a high incidence of neurologic abnormalities among survivors if treatment is started late.

American Thoracic Society CDC: Infectious Diseases Society of America: Treatment of tuberculosis. MMWR Recomm Rep 2003;52(RR-11):1 [PMID: 12836625].

Lighter J: Latent tuberculosis diagnosis in children by using the QuantiFERON-TB Gold In-Tube test. Pediatrics 2009;123(1):30 [PMID: 19117857].

Mazurek GH et al: Centers for Disease Control and Prevention (CDC): updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep 2010;59(RR-5):1 [PMID: 20577159].

Perez-Velez CM, Marais BJ: Tuberculosis in children. N Engl J Med 2012;367(4):348 [PMID: 22830465].

Sterling TR et al: TB Trials Consortium PREVENT TB Study Team: three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365(23):2155 [PMID: 22150035].

Willis MD et al: Seasonality of tuberculosis in the United States, 1993–2008. Clin Infect Dis 2012 Jun;54(11):1553 [PMID: 22474225].

Winston CA, Menzies HJ. Pediatric and adolescent tuberculosis in the United States. Pediatrics 2012 Dec;130(6):e1425 [PMID: 23184110].

Zhao Y et al: National survey of drug-resistant tuberculosis in China. N Engl J Med 2012;366(23):2161 [PMID: 22670902].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Chronic unilateral cervical lymphadenitis.

 Granulomas of the skin.

 Chronic bone lesion with draining sinus (chronic osteomyelitis).

 Reaction to PPD-S (standard) of 5–8 mm, negative chest radiograph, and negative history of contact with tuberculosis.

 Diagnosis by positive acid-fast stain or culture.

 Disseminated infection in patients with AIDS.

 General Considerations

Many species of acid-fast mycobacteria other than M tuberculosis may cause subclinical infections and occasionally clinical disease resembling tuberculosis. Strains of nontuberculous mycobacteria are common in soil, food, and water. Organisms enter the host by small abrasions in skin, oral mucosa, or gastrointestinal mucosa. Strain cross-reactivity with M tuberculosis can be demonstrated by simultaneous skin testing (Mantoux) with PPD-S (standard) and PPD prepared from one of the atypical antigens. Unfortunately, reagents prepared for routine nontuberculosis skin testing are not available to clinicians.

Mycobacterium avium complex (MAC), Mycobacterium kansasii, Mycobacterium fortuitum, Mycobacterium abscessus, Mycobacterium marinum, and Mycobacterium chelonae are most commonly encountered. M fortuitum, M abscessus, and M chelonae are “rapid growers” requiring 3–7 days for recovery, whereas other mycobacteria require several weeks. After inoculation they form colonies closely resembling M tuberculosis morphologically.

 Clinical Findings

A. Symptoms and Signs

1. Lymphadenitis—In children, the most common form of infection due to mycobacteria other than M tuberculosis is cervical lymphadenitis. MAC is the most common organism. A submandibular or cervical node swells slowly and is firm and initially somewhat tender. Low-grade fever may occur. Over time, the node suppurates and may drain chronically. Nodes in other areas of the head and neck and elsewhere are sometimes involved.

2. Pulmonary disease—In the western United States, pulmonary disease is usually due to M kansasii. In the eastern United States, it may be due to MAC. In other countries, disease is usually caused by MAC. In adults, there is usually underlying chronic pulmonary disease. Immunologic deficiency may be present. Presentation is clinically indistinguishable from that of tuberculosis. Adolescents with cystic fibrosis may be infected with nontuberculous mycobacteria.

3. Swimming pool granuloma—This is due to M marinum. A solitary chronic granulomatous lesion with satellite lesions develops after minor trauma in infected swimming pools or other aquatic sources. Minor trauma in home aquariums or other aquatic environments may also lead to infection.

4. Chronic osteomyelitis—Osteomyelitis is caused by M kansasii, M fortuitum, or other rapid growers. Findings include swelling and pain over a distal extremity, radiolucent defects in bone, fever, and clinical and radiographic evidence of bronchopneumonia. Such cases are rare.

5. Meningitis—Disease is due to M kansasii and may be indistinguishable from tuberculous meningitis.

6. Disseminated infection—Rarely, apparently immunologically normal children develop disseminated infection due to nontuberculous mycobacteria. Children are ill, with fever and hepatosplenomegaly, and organisms are demonstrated in bone lesions, lymph nodes, or liver. Chest radiographs are usually normal. Between 60% and 80% of patients with AIDS will acquire MAC infection, characterized by fever, night sweats, weight loss, and diarrhea. Infection usually indicates severe immune dysfunction and is associated with CD4 lymphocyte counts less than 50/μL.

B. Laboratory Findings

In most cases, there is a small reaction (< 10 mm) when Mantoux testing is done. Larger reactions may be seen particularly with M marinum infection. The chest radiograph is negative, and there is no history of contact with a case of tuberculosis. Needle aspiration of the node excludes bacterial infection and may yield acid-fast bacilli on stain or culture. Fistulization should not be a problem because total excision is usually recommended for infection due to atypical mycobacteria. Cultures of any normally sterile body site may yield MAC in immunocompromised patients with disseminated disease. Blood cultures are positive, with a large density of bacteria.

 Differential Diagnosis

See section on differential diagnosis in the previous discussion of tuberculosis and in Chapter 19.

 Treatment

A. Specific Measures

The usual treatment of lymphadenitis is complete surgical excision. Occasionally excision is impossible because of proximity to branches of the facial or other nerves or the salivary glands. Chemotherapy may then be necessary. Response of extensive adenopathy or other forms of infection varies according to the infecting species and susceptibility. Usually, combinations of two to four medications administered for months are required. Isoniazid, rifampin, and ethambutol (depending on sensitivity to isoniazid) will result in a favorable response in almost all patients with M kansasii infection. Chemotherapeutic treatment of MAC is much less satisfactory because resistance to isoniazid, rifampin, and pyrazinamide is common. Susceptibility testing is necessary to optimize therapy. Most clinicians favor surgical excision of involved tissue if possible and treatment with at least three drugs to which the organism has been shown to be sensitive. Disseminated disease in patients with AIDS calls for a combination of three or more active drugs. Clarithromycin or azithromycin and ethambutol is started, in addition to one or more of the following drugs: ethionamide, capreomycin, amikacin, rifabutin, rifampin or ciprofloxacin. M fortuitum and M chelonei are usually susceptible to amikacin plus cefoxitin or meropenem followed by clarithromycin, azithromycin, or doxycycline, and may be successfully treated with such combinations. Swimming pool granuloma due to M marinum is usually treated with doxycycline (in children older than 9 years) or rifampin, plus ethambutol, clarithromycin, or TMP-SMX for a minimum of 3 months. Surgery may also be beneficial.

B. Chemoprophylaxis

Children with HIV are given chemoprophylaxis with azithromycin or clarithromycin to prevent disseminated MAC infection. Chemoprophylaxis is given when CD4⁺ T-lympocyte counts fall below age specific levels.

C. General Measures

Isolation of the patient is usually not necessary. General supportive care is indicated for the child with disseminated disease.

 Prognosis

The prognosis is good for patients with localized disease, although fatalities occur in immunocompromised patients with disseminated disease.

Blyth CC et al: Nontuberculosis mycobacterial infection in children. Pediatr Infect Dis J 2009;28(9):801 [PMID: 19636280].

Centers for Disease Control and Prevention (CDC): Mycobacterium avium complex. Available at: www.cdc.gov/ncidod/dbmd/diseaseinfo/mycobacteriumavium_t.htm

Cruz AT et al: Mycobacterial infections in Texas children: a 5-year case series. Pediatr Infect Dis J 2010;29(8):772–774 [PMID: 20661106].

Kennedy BS et al. Outbreak of Mycobacterium chelonae infection associated with tattoo ink. N Engl J Med 2012;367(11):1020 [PMID: 22913660].

Timmerman MK et al: Treatment of non-tuberculous mycobacterial cervicofacial lymphadenitis in children: critical appraisal of the literature. Clin Otolaryngol 2008;33(6):546 [PMID: 19126128].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Severe progressive pneumonia in a child with compromised immunity.

 Diarrhea and neurologic signs are common.

 Positive culture requires buffered charcoal yeast extract media and proves infection.

 Direct fluorescent antibody staining of respiratory secretions and urinary antigen tests are highly specific but do not identify all infections.

 General Considerations

Legionella pneumophila is a ubiquitous gram-negative bacillus that causes two distinct clinical syndromes: Legionnaires disease and Pontiac fever. Over 40 species of Legionella have been discovered, but not all cause disease in humans. L pneumophila causes most infections. Legionella is present in many natural water sources as well as domestic water supplies (faucets and showers), and fountains. Contaminated cooling towers and heat exchangers have been implicated in several large institutional outbreaks. Person-to-person transmission has not been documented.

Few cases of Legionnaires disease have been reported in children. Most were in children with compromised cellular immunity. In adults, risk factors include smoking, underlying cardiopulmonary or renal disease, alcoholism, and diabetes.

L pneumophila is thought to be acquired by inhalation of a contaminated aerosol. The bacteria are phagocytosed but proliferate within macrophages. Cell-mediated immunity is necessary to activate macrophages to kill intracellular bacteria.

 Prevention

No vaccine is available. Legionella is naturally found in water, so ensuring proper disinfectant and water temperature maintenance of water supplies will help prevent cases. Good cleaning, attention to pH, and proper disinfectants in hot tubs is important. Chlorine or monochloramine treatment of municipal water supplies has been shown to reduce the number of organisms and the risk of infection.

 Clinical Findings

A. Symptoms and Signs

In Legionnaires disease there is an abrupt onset of fever, chills, anorexia, and headache. Pulmonary symptoms appear within 2–3 days and progress rapidly. The cough is nonproductive early. Purulent sputum occurs late. Hemoptysis, diarrhea, and neurologic signs (including lethargy, irritability, tremors, and delirium) are seen.

B. Laboratory Findings

The WBC count is usually elevated in Legionnaires disease. Chest radiographs show rapidly progressive patchy consolidation. Cavitation and large pleural effusions are uncommon. Cultures from sputum, tracheal aspirates, or bronchoscopic specimens, when grown on specialized media are positive in 70%–80% of patients at 3–5 days. Direct fluorescent antibody staining of sputum or other respiratory specimens is only 50%–70% sensitive but 95% specific. A false-positive test can be seen in patients with tularemia. A negative result on culture or direct fluorescent antibody staining of sputum or tracheal secretions does not rule out disease due to Legionella. PCR detection of respiratory secretions for Legionella is available at some centers. Urine antigen tests for Legionella antigen are highly specific. These tests only detect L pneumophila serotype 1, but most community-acquired L pneumophilainfections are caused by this serotype. Performance of both culture and urine antigen testing should facilitate diagnosis. Serologic tests are available, but a maximum rise in titer may require 6–8 weeks.

 Differential Diagnosis

Legionnaires disease is usually a rapidly progressive pneumonia in a patient who appears very ill with unremitting fevers. Other bacterial pneumonias, viral pneumonias, Mycoplasma pneumonia, and fungal disease are all possibilities and may be difficult to differentiate clinically in an immunocompromised patient.

 Complications

In sporadic untreated cases, mortality rates are 5%–25%. The mortality rate is < 5% in normal hosts with early, appropriate therapy. In immunocompromised patients with untreated disease, mortality approaches 80%. Hematogenous dissemination may result in extrapulmonary foci of infection, including pericardium, myocardium, and kidneys. Legionella may be the cause of culture-negative endocarditis.

 Treatment

Intravenous azithromycin, 10 mg/kg/d given as a once-daily dose (maximum dose 500 mg), is the drug of choice in most children. In immunocompromised patients, levofloxacin is recommended (not approved for this indication in children < 18 years of age) because fluoroquinolones are cidal agents. Fluoroquinolones are not approved for use, doxycycline (not recommended for children < 8 years of age unless benefit exceeds risk) and TMP-SMX are alternative agents. Duration of therapy is 5–10 days if azithromycin is used; for other antibiotics a 14- to 21-day course is recommended. Oral therapy may be substituted for intravenous therapy as the patient’s condition improves.

 Prognosis

Mortality rate is high if treatment is delayed. Malaise, problems with memory, and fatigue are common after recovery.

Centers for Disease Control and Prevention: Legionella. Available at: http://www.cdc.gov/legionella/

Diederen BM: Legionella spp. and Legionnaires’ disease. J Infect 2008;56(1):1–12 [PMID: 17980914].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Psittacosis:

 Fever, cough, malaise, chills, headache.

 Diffuse rales; no consolidation.

 Long-lasting radiographic findings of bronchopneumonia.

 Isolation of the organism or rising titer of complement fixing antibodies.

 Exposure to infected birds (ornithosis).

 Neonatal Chlamydophila (Chlamydia) conjunctivitis:

 Watery, mucopurulent, to blood tinged discharge and conjunctival injection presenting from a few days of life until 16 weeks of age.

 May be associated with neonatal Chlamydophila pneumonia.

 Identification of Chlamydophila conjunctivitis or pneumonia in a neonate should prompt evaluation and treatment of the mother and her sexual partner.

 General Considerations

Psittacosis is caused by Chlamydophila psittaci. When the agent is transmitted to humans from psittacine birds (parrots, parakeets, cockatoos, and budgerigars), the disease is called psittacosis or parrot fever. However, other avian genera (eg, pigeons and turkeys) are common sources of infection in the United States, and the general term ornithosis often is used. The agent is an obligate intracellular parasite. Human-to-human spread rarely occurs. The incubation period is 5–14 days. The bird from which the disease was transmitted may not be clinically ill.

Chlamydophila pneumoniae (formerly Chlamydia pneumoniae) may cause atypical pneumonia similar to that due to M pneumoniae. Transmission is by respiratory spread. Infection appears to be most prevalent during the second decade; half of surveyed adults are seropositive. Only a small percentage of infections result in clinical pneumonia. Lower respiratory tract infection due to C pneumoniae is uncommon in infants and young children. C pneumoniaehas been associated with acute chest syndrome in children with sickle cell disease.

Chlamydophila trachomatis causes urogenital infections in adults including asymptomatic infections, lymphogranuloma venereum, nongonococcal urethritis, epididymitis, cervicitis, and pelvic inflammatory disease. Serovars D–K (and L1, L2, L3 in lymphogranuloma venereum) are responsible for most of these infections. In infants born to infected mothers, C trachomatis infection can be acquired through exposure in the birth canal, causing neonatal conjunctivitis and/or pneumonia. The risk of acquisition for a baby born vaginally to an infected mother is about 50%.

The disease called “trachoma” is unusual in the United States. Trachoma is caused by certain C trachomatis serovars (A–C). This chronic keratoconjunctivitis can cause inflammation and neovascularization of the cornea, leading to corneal scarring and blindness. It is the most common cause of acquired blindness worldwide. The peak incidence is seen at age 4–6, with scarring and blindness occurring in adulthood. Infections occur from direct contact with infected secretions (eye, nose, throat) or by direct contact with contaminated objects (secretions on towels, washcloths, handkerchiefs).

Sexually transmitted urogenital infections caused by Chlamydophila are discussed in Chapter 44.

 Prevention

Persons cleaning bird cages should use caution when cleaning cages or disposing of bird droppings to avoid aerosolization of C psittaci. C psittaci is susceptible to 1% Lysol or a 1:100 dilution of household bleach and one of these can be used to disinfect cages. Sick birds should be evaluated by a veterinarian and can be treated with antimicrobials. C pneumoniae is transmitted person to person by infected respiratory tract secretions. Prevention involves avoidance of known infected persons, using good hand hygiene (both infected persons and noninfected persons), and encouraging good respiratory hygiene (covering mouth with coughing, disposing of tissues contaminated with respiratory secretions).

The diagnosis and appropriate treatment of genital Chlamydophila (chlamydial) infections in pregnant women and their sexual partners is the most effective way to prevent neonatal conjunctivitis and pneumonia (see Chapter 44).

 Clinical Findings

A. Symptoms and Signs

1. C psittaci pneumonia—The disease is extremely variable but tends to be mild in children. The onset is rapid or insidious, with fever, chills, headache, backache, malaise, myalgia, and dry cough. Signs include pneumonitis, altered percussion notes and breath sounds, and rales. Pulmonary findings may be absent early. Dyspnea and cyanosis may occur later. Splenomegaly, epistaxis, prostration, and meningismus are occasionally seen. Delirium, constipation or diarrhea, and abdominal distress may occur.

2. C pneumoniae pneumonia—Clinically, C pneumoniae infection is similar to M pneumoniae infection. Most patients have mild upper respiratory infections. Lower respiratory tract infection is characterized by fever, sore throat (perhaps more severe with C pneumoniae), cough, and bilateral pulmonary findings and infiltrates.

3. C trachomatis neonatal conjunctivitis and pneumonia—Neonatal conjunctivitis caused by C trachomatis can occur from a few days until 12–16 weeks after birth. There may be mild to moderate swelling of the lids and watery or mucopurulent discharge. The conjunctivae may be friable and there may be some bloody discharge. Pneumonia may occur in babies with or without neonatal conjunctivitis. Pneumonia is most commonly seen between 2 and 12 weeks of age. Most babies are afebrile and have tachypnea and a staccato cough.

4. C trachomatis trachoma—Trachoma is unusual in the United States. It is seen in developing countries in Africa, Asia, Latin America, the Middle East, and some Pacific and East Pacific islands. This chronic keratoconjunctivitis can cause inflammation and neovascularization of the cornea, leading to corneal scarring and blindness. It is the most common cause of acquired blindness worldwide. The peak incidence is seen at 4–6 years of age, with scarring and blindness occurring in adulthood. Infections occur from direct contact with infected secretions (eye, nose, throat) or by direct contact with contaminated objects (secretions on towels, washcloths, handkerchiefs). Trachoma is caused by certain C trachomatis serovars (A–C).

B. Laboratory Findings

1. C psittaci—In psittacosis, the WBC count is normal or decreased, often with a shift to the left. Proteinuria is common. C psittaci is present in the blood and sputum during the first 2 weeks of illness but culture is avoided since it can represent a hazard to laboratory workers. A diagnosis can be made if, a culture (blood or respiratory tract specimen) is positive for the organism, or there is a fourfold rise in complement fixation titers in specimens obtained at least 2 weeks apart. Evidence of a probable case includes those where there is a single serum C psittaci IgM antibody titer above 1:32 (microimmunofluorescent or complement fixation assay). The titer rise may be blunted or delayed by therapy. Infection with C pneumoniae may lead to diagnostic confusion because cross-reactive antibody may cause false-positive C psittaci titers.

2. C pneumoniae—Eosinophilia is sometimes present. A fourfold rise in C pneumoniae IgG titer (microimmunofluorescence antibody test). IgG antibody peaks 6–8 weeks after infection. C pneumoniae can be isolated from nasal wash or throat swab specimens after inoculation into cell culture. A PCR is currently not commercially available.

3. C trachomatis—In infants with neonatal pneumonia or conjunctivitis, nucleic acid amplification tests (such as PCR) have not been FDA approved for testing conjunctival samples or respiratory samples (nasopharyngeal, tracheal aspirate) in infants. Culture or nonamplified direct detection methods are usually utilized.

C. Imaging

The radiographic findings in psittacosis are those of central pneumonia that later becomes widespread or migratory. Psittacosis is indistinguishable from viral pneumonias by radiograph. Signs of pneumonitis may appear on radiograph in the absence of clinical suspicion of pulmonary involvement.

In neonatal pneumonia from C trachomatis, infiltrates, and often hyperinflation, are seen on chest radiographs.

 Differential Diagnosis

Psittacosis can be differentiated from viral or mycoplasmal pneumonias only by the history of contact with potentially infected birds. In severe or prolonged cases with extrapulmonary involvement the differential diagnosis is broad, including typhoid fever, brucellosis, and rheumatic fever.

C pneumoniae pneumonia is not distinguishable clinically from Mycoplasma or viral pneumonia.

C trachomatis conjunctivitis must be differentiated from gonococcal conjunctivitis, chemical conjunctivitis, or viral conjunctivitis. Gonococcal conjunctivitis is often severe, with purulent drainage. A culture of the conjunctival discharge (plated on Thayer-Martin media) can aid in the diagnosis of gonococcal conjunctivitis.

 Complications

Complications of psittacosis include myocarditis, endocarditis, hepatitis, pancreatitis, and secondary bacterial pneumonia. C pneumoniae infection may be prolonged or may recur.

 Treatment

Psittacosis—Doxycycline should be given for 10–14 days after defervescence to patients older than 8 years with psittacosis. Alternatively, erythromycin or azithromycin may be used in younger children. Supportive oxygen may be needed.

Chlamydophila pneumonia—Most suspected infections are treated empirically. C pneumoniae responds to macrolides (azithromycin, erythromycin). Doxycycline is an alternative in those patients 8 years and older. A 10- to 14-day course is recommended for erythromycin or doxycycline; when using azithromycin the treatment length is 5 days.

Neonatal conjunctivitis or pneumonia—The American Academy of Pediatrics recommends a 10-day course of erythromycin base or ethylsuccinate (50 mg/kg/d given in four divided doses). Infants should have a follow-up visit because some infants have recrudescence of symptoms after the antibiotic course finishes or failure of symptoms to fully resolve. These infants can be retreated with a second course of erythromycin. Data on the use of azithromycin for these conditions in neonates is very limited, but azithromycin 20 mg/kg, given as an oral single dose once daily for 3 days, may be efficacious. An association with receipt of erythromycin and development of pyloric stenosis in infants less than 6 weeks of age has been reported. Parents should be informed of this potential risk and the symptoms of pyloric stenosis. There are case reports of pyloric stenosis occurring in infants who previously received azithromycin. The diagnosis of an infant with chlamydial conjunctivitis and/or pneumonia should prompt evaluation and treatment of the mother and her sexual partner for Chlamydia and other sexually transmitted diseases (see Chapter 44).

American Academy of Pediatrics: Chlamydial infections. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th ed. Pickering LK (ed), American Academy of Pediatrics, Elk Grove Village, IL 2012.

Centers for Disease Control and Prevention: Chlamydia pneumoniae. Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/chlamydiapneumonia_t.htm

Cunha BA: The atypical pneumonias: clinical diagnosis and importance. Clin Microbiol Infect 2006;12(Suppl 3):12–24 [PMID: 16669925].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 History of a cat scratch or cat contact.

 Primary lesion (papule, pustule, or conjunctivitis) at site of inoculation.

 Acute or subacute regional lymphadenopathy.

 Aspiration of sterile pus from a node.

 Laboratory studies excluding other causes.

 Biopsy of node or papule showing histopathologic findings consistent with cat-scratch disease and occasionally characteristic bacilli on Warthin-Starry stain.

 Positive cat-scratch serology (antibody to Bartonella henselae).

 General Considerations

The causative agent of cat-scratch disease is B henselae, a gram-negative bacillus that also causes bacillary angiomatosis. Cat-scratch disease is usually a benign, self-limited form of lymphadenitis. Patients often report a cat scratch (67%), bite (less common), or contact with a cat or kitten (90%). The cat almost invariably is healthy. Cats become infected via an infected flea; the flea becomes infected when feeding on a cat that is bacteremic with B henselae. Occasionally dogs can be infected and transmit disease. The clinical picture is that of a regional lymphadenitis associated with an erythematous papular skin lesion without intervening lymphangitis. The disease occurs worldwide and is more common in the fall and winter. It is estimated that more than 20,000 cases per year occur in the United States. The most common systemic complication is encephalitis.

 Prevention

Cat-scratch disease can be largely prevented by avoiding contact with cats, especially kittens. Flea control of animals will reduce cat-to-cat transmission.

 Clinical Findings

A. Symptoms and Signs

About 50% of patients with cat-scratch disease develop a primary lesion at the site of the wound. The lesion usually is a papule or pustule that appears 7–10 days after injury and is located most often on the arm or hand (50%), head or leg (30%), or trunk or neck (10%). The lesion may be conjunctival (10%). Regional lymphadenopathy appears 10–50 days later and may be accompanied by mild malaise, lassitude, headache, and fever. Multiple sites are seen in about 10% of cases. Involved nodes may be hard or soft and 1–6 cm in diameter. They are usually tender, warm, and erythematous and 10%–20% of them suppurate. Lymphadenopathy usually resolves in about 2 months but may persist for up to 8 months.

Unusual manifestations include erythema nodosum, thrombocytopenic purpura, conjunctivitis (Parinaud oculoglandular fever), parotid swelling, pneumonia, osteolytic lesions, mesenteric and mediastinal adenitis, neuroretinitis, peripheral neuritis, hepatitis, granulomata of the liver and spleen, and encephalopathy.

Immunocompetent patients may develop an atypical systemic form of cat-scratch disease. These patients have prolonged fever, fatigue, and malaise. Lymphadenopathy may be present. Hepatosplenomegaly or low-density hepatic or splenic lesions visualized by ultrasound or computed tomography scan are seen in some patients.

Infection in immunocompromised individuals may take the form of bacillary angiomatosis, presenting as vascular tumors of the skin and subcutaneous tissues. Immunocompromised patients may also have bacteremia or infection of the liver (peliosis hepatis).

B. Laboratory Findings

Serologic evidence of Bartonella infection by indirect immunofluorescent antibody with IgG titer of > 1:256 is strongly suggestive of recent infection. A positive IgM antibody is sometimes positive, the diagnosis. PCR assays are available. Cat-scratch skin test antigens are not recommended.

Histopathologic examination of involved tissue may show pyogenic granulomas or bacillary forms demonstrated by Warthin-Starry silver stain (but bacillary forms on stain are not specific for cat scratch disease). Later in the course necrotizing granulomas may be seen. There usually is some elevation in the ESR. In patients with CNS involvement, the CSF is usually normal but may show a slight pleocytosis and modest elevation of protein.

 Differential Diagnosis

Cat-scratch disease must be distinguished from pyogenic adenitis, tuberculosis (typical and atypical), tularemia, plague, brucellosis, lymphoma, primary toxoplasmosis, infectious mononucleosis, lymphogranuloma venereum, and fungal infections.

 Treatment

Treatment of cat-scratch disease adenopathy is controversial because the disease usually resolves without therapy and the patient is typically not exceedingly ill. Treatment of typical cat-scratch disease with a 5-day course of azithromycin has been shown to speed resolution of lymphadenopathy in some patients. The best therapy is reassurance that the adenopathy is benign and will subside spontaneously with time (mean duration of illness is 14 weeks). In cases of nodal suppuration, needle aspiration under local anesthesia relieves the pain. Excision of the involved node is indicated in cases of chronic adenitis. In some reports, azithromycin, ciprofloxacin, rifampin, or TMP-SMX have been useful. Azithromycin is used by many experts if treatment of adenopathy is desired because it is given once a day, is reasonably priced, and was studied in one randomized placebo-controlled trial. In that trial, lymph node volume decreased faster than placebo by 1 month; there was no difference in long-term resolution in the azithromycin and placebo groups.

Immunocompromised patients with evidence of infection should be treated with antibiotics: long-term therapy (months) in these patients with azithromycin or doxycycline often is needed to prevent relapses. Immunocompetent patients with more severe disease or evidence of systemic infection (eg, hepatic or splenic lesions) should also be treated with antibiotics.

 Prognosis

The prognosis is good if complications do not occur.

Centers for Disease Control and Prevention: Bartonella. Available at: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/bartonella-associated-infections.htm

English R: Cat-scratch disease. Pediatr Rev 2006;27:123 [PMID: 16581952].

SPIROCHETAL INFECTIONS

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Congenital:

 All types: history of untreated maternal syphilis, a positive serologic test, and a positive darkfield examination.

 Newborn: hepatosplenomegaly, characteristic radiographic bone changes, anemia, increased nucleated red cells, thrombocytopenia, abnormal spinal fluid, jaundice, edema.

 Young infant (3–12 weeks): snuffles, maculopapular skin rash, mucocutaneous lesions, pseudoparalysis (in addition to radiographic bone changes).

 Children: stigmata of early congenital syphilis, interstitial keratitis, saber shins, gummas of nose and palate.

 Acquired:

 Chancre of genitals, lip, or anus in child or adolescent.

 History of sexual contact.

 General Considerations

Syphilis is a chronic, generalized infectious disease caused by a spirochete, Treponema pallidum. In the acquired form, the disease is transmitted by sexual contact. Primary syphilis is characterized by the presence of an indurated painless chancre, which heals in 7–10 days. A secondary eruption involving the skin and mucous membranes appears in 4–6 weeks. After a long latency period, late lesions of tertiary syphilis involve the eyes, skin, bones, viscera, CNS, and cardiovascular system.

Congenital syphilis results from transplacental infection. Infection may result in stillbirth or produce illness in the newborn, in early infancy, or later in childhood. Syphilis occurring in the newborn and young infant is comparable to secondary disease in the adult but is more severe and life-threatening. Late congenital syphilis (developing in childhood) is comparable to tertiary disease.

The incidence of primary and secondary syphilis is increasing in the United States particularly among men. Nearly, 14,000 new cases of primary and secondary syphilis, 377 cases of congenital syphilis and nearly 45,000 total cases were reported in 2010.

 Prevention

A serologic test for syphilis should be performed at the initiation of prenatal care and repeated at delivery in women at increased risk for syphilis. Serologic tests may be negative on both the mother and infant at the time of birth if the mother acquires syphilis near term. Adequate treatment of mothers with secondary syphilis before the last month of pregnancy reduces the incidence of congenital syphilis from 90% to less than 2%. Examination and serologic testing of sexual partners and siblings should also be done.

 Clinical Findings

A. Symptoms and Signs

1. Congenital Syphilis

A. NEWBORNS—Most newborns with congenital syphilis are asymptomatic. If infection is not detected and treated, symptoms develop within weeks to months. When clinical signs are present, they usually consist of jaundice, anemia with or without thrombocytopenia, increase in nucleated red blood cells, hepatosplenomegaly, and edema. Overt signs of meningitis (bulging fontanelle or opisthotonos) may be present, but subclinical infection with CSF abnormalities is more common.

B. YOUNG INFANTS (3–12 weeks)—The infant may appear normal for the first few weeks of life only to develop mucocutaneous lesions and pseudoparalysis of the arms or legs. Shotty lymphadenopathy may be felt. Hepatomegaly is universal, with splenomegaly in 50% of patients. Other signs of disease similar to those seen in the newborn may be present. Anemia has been reported as the only presenting manifestation of congenital syphilis in this age group. “Snuffles” (syphilitic rhinitis), characterized by a profuse mucopurulent discharge, are present in 25% of patients. A syphilitic rash is common on the palms and soles but may occur anywhere on the body. The rash consists of bright red, raised maculopapular lesions that gradually fade. Moist lesions occur at the mucocutaneous junctions (nose, mouth, anus, and genitals) and lead to fissuring and bleeding.

Syphilis in the young infant may lead to stigmata recognizable in later childhood, such as rhagades (scars) around the mouth or nose, a depressed bridge of the nose (saddle nose), and a high forehead (secondary to mild hydrocephalus associated with low-grade meningitis and frontal periostitis). The permanent upper central incisors may be peg-shaped with a central notch (Hutchinson teeth), and the cusps of the sixth-year molars may have a lobulated mulberry appearance.

C. CHILDREN—Bilateral interstitial keratitis (at age 6– 12 years) is characterized by photophobia, increased lacrimation, and vascularization of the cornea associated with exudation. Chorioretinitis and optic atrophy may also be seen. Meningovascular syphilis (at age 2–10 years) is usually slowly progressive, with mental retardation, spasticity, abnormal pupillary response, speech defects, and abnormal CSF. Deafness sometimes occurs. Thickening of the periosteum of the anterior tibias produces saber shins. A bilateral effusion in the knee joints may occur but is not associated with sequelae. Soft inflammatory growths called gummas may develop in the nasal septum, palate, long bones, and subcutaneous tissues.

2. Acquired syphilis—The primary chancre of the genitals, mouth, or anus may occur from genital, anal, or oral sexual contact. If the chancre is missed, signs of secondary syphilis, such as rash, fever, headache, and malaise, may be the first manifestations.

B. Laboratory Findings

1. Darkfield microscopy—Treponemes can be seen in scrapings from a chancre and from moist lesions.

2. Serologic tests for syphilis—There are two general types of serologic tests for syphilis: treponemal and nontreponemal. There are two types of nontreponemal tests: Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR). The VDRL and RPR are inexpensive, rapid tests that are useful for screening and following disease activity or adequacy of therapy. These tests provide quantitative results if the test is positive. False-positive nontreponemal tests can occur in patient with measles, hepatitis, mononucleosis, lymphoma, tuberculosis, endocarditis, pregnancy, and intravenous drug abuse. When evaluating a newborn infant for potential syphilis, umbilical cord blood specimens should not be used for nontreponemal tests: a false-positive test may result from Wharton jelly contamination of the sample. Conversely, a false-negative test may be seen in the setting where maternal infection occurred late in pregnancy.

Positive nontreponemal tests should be confirmed with a more specific treponemal test such as the fluorescent treponemal antibody absorbed (FTA-ABS) test or the T pallidum particle agglutination (TP-PA) test. False-positive FTA-ABS tests are uncommon except with other spirochetal diseases such as leptospirosis, rat bite fever, and Lyme disease.

One or two weeks after the onset of primary syphilis (chancre), the FTA-ABS test becomes positive. The VDRL or a similar nontreponemal test usually turns positive a few days later. By the time the secondary stage has been reached, virtually all patients show both positive FTA-ABS and positive nontreponemal tests. During latent and tertiary syphilis, the VDRL may become negative, but the FTA-ABS test usually remains positive. The quantitative VDRL or a similar nontreponemal test should be used to follow-up treated cases (see following discussion).

EIA tests specific for T pallidun are available in many laboratories and are replacing FTA-ABS, TP-PA tests. As these are rapid, inexpensive tests with greater specificity, a different screening strategy is now often used. The initial screen is done with EIA test followed by the RPR or VDRL, if positive.

In infants, positive serologic tests in cord sera may represent passively transferred antibody rather than congenital infection and therefore must be supplemented by a combination of clinical and laboratory data. Elevated total cord IgM is a helpful but nonspecific finding. A specific IgM–FTA-ABS is available, but negative results are not conclusive and should not be relied on. Demonstration of characteristic treponemes by darkfield examination of material from a moist lesion (skin; nasal or other mucous membranes) is definitive. Mouth lesions would be best examined by direct fluorescent antibody to distinguish T pallidum from nonpathogenic treponemes commonly found in the mouth. Serial measurement of quantitative RPR or VDRL is also very useful, because passively transferred antibody in the absence of active infection should decay with a normal half-life of about 18 days (see discussion of evaluation of infants for congenital syphilis section on Initial Evaluation and Treatment).

For evaluation of possible neurosyphilis, the CSF should be examined for cell count, glucose, protein, and a CSF VDRL. A negative CSF VDRL does not rule out neurosyphilis.

C. Imaging

Radiographic abnormalities are present in 90% of infants with symptoms of congenital syphilis and in 20% of asymptomatic infants. Metaphyseal lucent bands, periostitis, and a widened zone of provisional calcification may be present. Bilateral symmetrical osteomyelitis with pathologic fractures of the medial tibial metaphyses (Wimberger sign) is almost pathognomonic.

 Differential Diagnosis

A. Congenital Syphilis

1. Newborns—Sepsis, congestive heart failure, congenital rubella, toxoplasmosis, disseminated herpes simplex, cytomegalovirus infection, and hemolytic disease of the newborn have to be differentiated. A positive Coombs test and blood group incompatibility distinguish hemolytic disease.

2. Young infants—Injury to the brachial plexus, poliomyelitis, acute osteomyelitis, and septic arthritis must be differentiated from pseudoparalysis. Coryza due to viral infection often responds to symptomatic treatment. Rash (ammoniacal diaper rash) and scabies may be confused with a syphilitic eruption.

3. Children—Interstitial keratitis and bone lesions of tuberculosis are distinguished by positive tuberculin reaction and chest radiograph. Arthritis associated with syphilis is unaccompanied by systemic signs, and joints are nontender. Mental retardation, spasticity, and hyperactivity are shown to be of syphilitic origin by strongly positive serologic tests.

B. Acquired Syphilis

Herpes genitalis, traumatic lesions, and other venereal diseases must be differentiated from primary chancers.

 Treatment

A. Specific Measures

Penicillin is the drug of choice for T pallidum infection. If the patient is allergic to penicillin, azithromycin, ceftriaxone or one of the tetracyclines may be used, but are of unknown efficacy.

1. Congenital syphilis

A. INITIAL EVALUATION AND TREATMENT—Newborns should not be discharged from the hospital until the mother’s serologic status for syphilis has been determined. Infants born to seropositive mothers require careful examination and quantitative nontreponemal (VDRL, RPR) syphilis testing. The same quantitative antitreponemal test used in evaluating the mother should be used in the infant so the titers can be compared. Maternal records regarding any prior diagnosis of syphilis, treatment, and follow-up titers should be reviewed. Infants should be further evaluated for congenital syphilis in any of the following circumstances:

• The maternal titer has increased fourfold.

• The infant’s titer is at least fourfold greater than the maternal titer.

• Signs of syphilis are found on examination.

• Maternal syphilis was not treated or was inadequately treated during pregnancy.

• Maternal syphilis was treated with a nonpenicillin regimen, or the regimen or dose of medication is undocumented.

• Maternal syphilis was treated during pregnancy, but therapy was completed less than 4 weeks prior to delivery.

• Maternal syphilis was treated appropriately during pregnancy, but without the appropriate decrease in maternal nontreponemal titers after treatment.

The complete evaluation of an infant for possible congenital syphilis includes complete blood count, liver function tests, long bone radiographs, CSF examination (cell counts, glucose, and protein), CSF VDRL, and quantitative serologic tests. In addition, the placenta and umbilical cord should be examined pathologically using fluorescent antitreponemal antibody, if available. An ophthalmologic examination may also be done.

Treatment for congenital syphilis is indicated for infants with physical signs; umbilical cord or placenta positive for DFA-TP staining or darkfield examination; abnormal radiographs; elevated CSF protein or cell counts; reactive CSF VDRL; or serum quantitative nontreponemal titer that is more than fourfold higher than the maternal titer (using same test). Newborns with proved or suspected congenital syphilis should receive either (1) aqueous crystalline penicillin G, 50,000 U/kg per dose intravenously every 12 hours (if < 1 week old) or (2) every 8 hours (if 1–4 weeks old) for 10 days. Procaine penicillin G, 50,000 U/kg in a single daily dose for 10 days is an alternative if compliance is assured. All infants diagnosed after age 4 weeks should receive 50,000 U/kg per dose aqueous crystalline penicillin intravenously every 4–6 hours for 10 days.

Additionally, treatment should be given to infants whose mothers have inadequately treated syphilis, to those whose mothers received treatment less than 1 month before delivery, to those whose mothers have undocumented or inadequate serologic response to therapy, and to those whose mothers were given nonpenicillin drugs to treat syphilis. In these instances, if the infant is asymptomatic, has a normal physical examination, normal CSF parameters, nonreactive CSF VDRL, normal bone films, quantitative nontreponemal titer less than fourfold of the mother’s titer, and good follow-up is certain, some experts would give a single dose of penicillin G benzathine, 50,000 U/kg intramuscularly. If there is any abnormality in the preceding evaluation or if the CSF testing is not interpretable, the full 10 days of intravenous penicillin should be given. Close clinical and serologic monthly follow-up is necessary.

Asymptomatic, seropositive infants with normal physical examinations born to mothers who received adequate syphilis treatment (completed > 4 weeks prior to delivery) and whose mothers have an appropriate serologic response (fourfold or greater decrease in titer) to treatment may be at lower risk for congenital syphilis. Some experts believe complete laboratory and radiographic evaluation in these infants (CSF and long bone films) is not necessary. Infants who meet the preceding criteria, who have nontreponemal titers less than fourfold higher than maternal titers, and for whom follow-ups are certain can be given benzathine penicillin G, 50,000 U/kg, administered intramuscularly in a single dose. Infants should be followed with quantitative serologic tests and physical examinations until the nontreponemal serologic test is negative (see discussion of follow-up, next). Rising titers or clinical signs usually occur within 4 months in infected infants, requiring a full evaluation (including CSF studies and long bone radiographs) and institution of intravenous penicillin therapy.

B. FOLLOW-UP FOR CONGENITAL SYPHILIS—Children treated for congenital syphilis need physical examinations every 2–3 months after completion of therapy, and both physical examinations and quantitative VDRL or RPR tests should be performed until the tests become nonreactive. Repeat CSF examination, including a CSF VDRL test, every 6 months until normal is indicated for infants with a positive CSF VDRL reaction or with abnormal cell counts or protein in the CSF. A reactive CSF VDRL test at the 6-month interval is an indication for retreatment. Titers decline with treatment and are usually negative by 6 months. Repeat treatment is indicated for children with rising titers or stable titers that do not decline.

2. Acquired syphilis of less than 1 year’s duration—Benzathine penicillin G (50,000 U/kg, given intramuscularly, to a maximum of 2.4 million units) is given to adolescents with primary, secondary, or latent disease of less than 1 year’s duration. All children should have a CSF examination (with CSF VDRL) prior to commencing therapy, to exclude neurosyphilis. Adolescents and adults need a CSF examination if clinical signs or symptoms suggest neurologic involvement or if they are HIV-infected.

3. Syphilis of more than 1 year’s duration (late latent disease)—Syphilis of more than 1 year’s duration (without evidence of neurosyphilis) requires weekly intramuscular benzathine penicillin G therapy for 3 weeks. CSF examination and VDRL test should be done on all children and patients with coexisting HIV infection or neurologic symptoms. In addition, patients who have failed treatment or who were previously treated with an agent other than penicillin need a CSF examination and CSF VDRL.

4. Neurosyphilis—Aqueous crystalline penicillin G is recommended, 200,000–300,000 U/kg/d in four to six divided doses, given intravenously for 10–14 days. The maximum adult dose is 4 million units per dose. Some experts recommend following this regimen with an intramuscular course of benzathine G penicillin, 50,000 U/kg given once a week for 3 consecutive weeks, to a maximum dose of 2.4 million units.

B. General Measures

Penicillin treatment of early congenital or secondary syphilis may result in a dramatic systemic febrile illness termed the Jarisch-Herxheimer reaction. Treatment is symptomatic, with careful follow-up. Transfusion may be necessary in infants with severe hemolytic anemia.

 Prognosis

Severe disease, if undiagnosed, may be fatal in the newborn. Complete cure can be expected if the young infant is given penicillin. Serologic reversal usually occurs within 1 year. Treatment of primary syphilis with penicillin is curative. Permanent neurologic sequelae may occur in meningovascular syphilis.

Centers for Disease Control and Prevention (CDC) et al: Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59(RR-12) [PMID: 21160459].

Pessoa L, Galvão V: Clinical aspects of congenital syphilis with Hutchinson’s triad. BMJ Case Rep 2011;2011 [PMID: 22670010].

Zhou Q: A case series of 130 neonates with congenital syphilis: preterm neonates had more clinical evidences of infection than term neonates. Neonatology 2012;102(2):152 [PMID: 22760016].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Episodes of fever, chills, malaise.

 Occasional rash, arthritis, cough, hepatosplenomegaly, conjunctivitis.

 Diagnosis suggested by direct microscopic identification of spirochetes in smears of peripheral blood. Diagnosis confirmed with serologic testing.

 Prevention

Measures that decrease exposures to soft ticks and body lice will prevent most cases. Soft-bodied ticks often are found in rodent burrows or nests, so decreasing rodent access to homes and eliminating rodents in the home is helpful. Body-louse infestation can be treated with hygiene and pediculicides.

 General Considerations

Relapsing fever is a vector-borne disease caused by spirochetes of the genus Borrelia. Epidemic relapsing fever is transmitted to humans by body lice (Pediculus humanus) and endemic relapsing fever by soft-bodied ticks (genus Ornithodoros). Tick-borne relapsing fever is endemic in the western United States. Although several hundred cases are reported per year, substantial underdiagnosis occurs. Transmission usually takes place during the warm months, when ticks are active and recreation or work brings people into contact with Ornithodoros ticks. B hermsii causes most tick-borne infection in the United States. Infection is often acquired in mountain camping areas and cabins. The ticks are nocturnal feeders and remain attached for only 5–20 minutes. Consequently, the patient seldom remembers a tick bite. Rarely, neonatal relapsing fever results from transplacental transmission of Borrelia. Both louse-borne and tick-borne relapsing fever may be acquired during foreign travel.

 Clinical Findings

A. Symptoms and Signs

The incubation period is 2–18 days. The attack is sudden, with high fever, chills, sweats, tachycardia, nausea and vomiting, headache, myalgia, and arthralgia. After 3–10 days, the fever falls. The disease is characterized by relapses at intervals of 1–2 weeks and lasting 3–5 days. The relapses duplicate the initial attack but become progressively less severe. In louse-borne relapsing fever, there is usually a single relapse. In tick-borne infection, two to six relapses occur.

Hepatomegaly, splenomegaly, pneumonitis, meningitis, and myocarditis may appear later in the course of the disease. An erythematous rash may be seen over the trunk and extremities, and petechiae may be present. Jaundice, iritis, conjunctivitis, cranial nerve palsies, and hemorrhage occur more commonly during relapses.

B. Laboratory Findings

During febrile episodes, the patient’s urine contains protein, casts, and occasionally erythrocytes; a marked polymorphonuclear leukocytosis is present; and about 25% of patients have a false-positive serologic test for syphilis. Spirochetes can be found in the peripheral blood by direct microscopy in approximately 70% of cases by darkfield examination or by Wright, Giemsa, or acridine orange staining of thick and thin smears. Spirochetes are not found during afebrile periods. Immunofluorescent antibody (or ELISA confirmed by Western blot) can help establish the diagnosis serologically. However, high titers of Borrelia hermsii can cross-react with Borrelia burgdorferi (the agent in Lyme disease) or Leptospira in immunofluorescent antibody assay, ELISA, and Western blots. Serologic specimens can be sent to the Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80522.

 Differential Diagnosis

Relapsing fever may be confused with malaria, leptospirosis, dengue, typhus, rat-bite fever, Colorado tick fever, Rocky Mountain spotted fever, collagen-vascular disease, or any fever of unknown origin.

 Complications

Complications include facial paralysis, iridocyclitis, optic atrophy, hypochromic anemia, pneumonia, nephritis, myocarditis, endocarditis, and seizures. CNS involvement occurs in 10%–30% of patients.

 Treatment

For children younger than age 8 years who have tick-borne relapsing fever, penicillin or erythromycin should be given for 10 days. Older children may be given doxycycline. Chloramphenicol is also efficacious and was often used in the past.

Severely ill patients should be hospitalized. Patients may experience a Jarisch-Herxheimer reaction (usually noted in the first few hours after commencing antibiotics). Isolation precautions are not necessary for relapsing fever. Contact precautions are recommended for patients with louse infestations.

 Prognosis

The mortality rate in treated cases of relapsing fever is very low, except in debilitated or very young children. With treatment, the initial attack is shortened and relapses prevented. The response to antimicrobial therapy is dramatic.

Centers for Disease Control: Relapsing fever. Available at: http://www.cdc.gov/ncidod/dvbid/relapsingfever/

Dworkin MS et al: Tick-borne relapsing fever. Infect Dis Clin North Am 2008;22(3):449–468 [PMID: 18755384].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Biphasic course lasting 2–3 weeks.

 Initial phase: high fever, headache, myalgia, and conjunctivitis.

 Apparent recovery for 2–3 days.

 Return of fever associated with meningitis.

 Jaundice, hemorrhages, and renal insufficiency (severe cases).

 Culture of organism from blood and CSF (early) and from urine (later), or direct microscopy of urine or CSF.

 Positive leptospiral agglutination test.

 General Considerations

Leptospirosis is a zoonosis caused by many antigenically distinct but morphologically similar spirochetes. The organism enters through the skin or respiratory tract. Classically the severe form (Weil disease), with jaundice and a high mortality rate, was associated with infection with Leptospira icterohaemorrhagiae after immersion in water contaminated with rat urine. It is now known that a variety of animals (eg, dogs, rats, and cattle) may serve as reservoirs for pathogenic Leptospira, that a given serogroup may have multiple animal species as hosts, and that severe disease may be caused by many different serogroups.

In the United States, leptospirosis usually occurs after contact with dogs. Cattle, swine, or rodents may transmit the organism. Sewer workers, farmers, slaughterhouse workers, animal handlers, and soldiers are at risk for occupational exposure. Outbreaks have resulted from swimming in contaminated streams and harvesting field crops. In the United States, about 100 cases are reported yearly, about one-third of them in children.

 Prevention

Preventive measures include avoidance of contaminated water and soil, rodent control, immunization of dogs and other domestic animals, and good sanitation. Gloves, boots, and other protective clothing can be worn when contact is unavoidable. Antimicrobial prophylaxis with doxycycline may be of value to certain high-risk occupational groups with short-term exposures. Doxycycline is not approved for use in children less than 8 years of age unless benefits exceed risk.

 Clinical Findings

A. Symptoms and Signs

1. Initial phase—The incubation period is 4–19 days (mean, 10 days). Chills, fever, headache, myalgia (especially lumbar area and calves), conjunctivitis without exudate, photophobia, cervical lymphadenopathy, and pharyngitis commonly occur. The initial leptospiremic phase lasts for 3–7 days.

2. Phase of apparent recovery—Symptoms typically (but not always) subside for 2–3 days.

3. Systemic phase—Fever reappears and is associated with headache, muscular pain, and tenderness in the abdomen and back, and nausea and vomiting. Conjunctivitis and uveitis are common. Lung, heart, and joint involvement occasionally occur. These manifestations are due to extensive vasculitis.

A. CNS INVOLVEMENT—The CNS is involved in 50%–90% of cases. Severe headache and mild nuchal rigidity are usual, but delirium, coma, and focal neurologic signs may be seen.

B. RENAL AND HEPATIC INVOLVEMENT—In about 50% of cases, the kidney or liver is affected. Gross hematuria and oliguria or anuria is sometimes seen. Jaundice may be associated with an enlarged and tender liver.

C. GALLBLADDER INVOLVEMENT—Leptospirosis may cause acalculous cholecystitis in children, demonstrable by abdominal ultrasound as a dilated, nonfunctioning gallbladder. Pancreatitis is unusual.

D. HEMORRHAGE—Petechiae, ecchymoses, and gastrointestinal bleeding may be severe.

E. RASH—A rash is seen in 10%–30% of cases. It may be maculopapular and generalized or may be petechial or purpuric. Occasionally erythema nodosum is seen. Peripheral desquamation of the rash may occur. Gangrenous areas are sometimes noted over the distal extremities. In such cases, skin biopsy demonstrates the presence of severe vasculitis involving both the arterial and the venous circulations.

B. Laboratory Findings

Leptospires are present in the blood and CSF only during the first 10 days of illness. They appear in the urine during the second week, where they may persist for 30 days or longer. Culture is difficult and requires specialized media and conditions. The WBC count often is elevated, especially when there is liver involvement. Serum bilirubin levels usually remain below 20 mg/dL. Other liver function tests may be abnormal, although the aspartate transaminase usually is elevated only slightly. An elevated serum creatine kinase is frequently found. CSF shows moderate pleocytosis (< 500/μL)—predominantly mononuclear cells—increased protein (50–100 mg/dL), and normal glucose. Urine often shows microscopic pyuria, hematuria, and, less often, moderate proteinuria (++ or greater). The ESR is elevated markedly. Chest radiograph may show pneumonitis.

Serologic antibodies measured by enzyme immunoassay may be demonstrated during or after the second week of illness. The confirmatory test of choice is a microscopic agglutination test, performed at the CDC. Leptospiral agglutinins generally reach peak levels by the third to fourth week. Fourfold or greater titer rise in acute and convalescent specimens is diagnostic. A PCR assay may be available at specialized research centers or through the CDC.

 Differential Diagnosis

Fever and myalgia associated with the characteristic conjunctival injection should suggest leptospirosis. During the prodrome, malaria, typhoid fever, typhus, rheumatoid arthritis, brucellosis, and influenza may be suspected. Later, depending on the organ systems involved, a variety of other diseases need to be distinguished, including encephalitis, viral or tuberculous meningitis, viral hepatitis, glomerulonephritis, viral or bacterial pneumonia, rheumatic fever, subacute infective endocarditis, acute surgical abdomen, and Kawasaki disease (see Table 40–3).

 Treatment

A. Specific Measures

Aqueous penicillin G (150,000 U/kg/d, given in four to six divided doses intravenously for 7–10 days) should be given when the diagnosis is suspected. Alternative agents include parenteral cefotaxime, ceftriaxone, or doxycycline. A Jarisch-Herxheimer reaction may occur. Oral doxycycline may be used for mildly ill patients. Doxycycline should not be used in children less than 8 years or pregnant women.

B. General Measures

Symptomatic and supportive care is indicated, particularly for renal and hepatic failure and hemorrhage. Contact isolation is recommended, due to potential transmission from contact with urine.

 Prognosis

Leptospirosis is usually self-limiting and not characterized by jaundice. The disease usually lasts 1–3 weeks but may be more prolonged. Relapse may occur. There are usually no permanent sequelae associated with CNS infection, although headache may persist. The mortality rate in the United States is 5%, usually from renal failure. The mortality rate may reach 20% or more in elderly patients who have severe kidney and hepatic involvement.

Centers for Disease Control and Prevention: Leptospirosis. Available at: http://www.cdc.gov/leptospirosis/

Levett P: Leptospirosis. Clin Microbiol Rev 2001;14(2):296–326 [PMID: 11292640]. Available at: http://cmr.asm.org/cgi/reprint/14/2/296

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 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Characteristic skin lesion (erythema migrans) 3–30 days after tick bite.

 Arthritis, usually pauciarticular, occurring about 4 weeks after appearance of skin lesion. Headache, chills, and fever.

 Residence or travel in an endemic area during the late spring to early fall.

 General Considerations

Lyme disease is a subacute or chronic spirochetal infection caused by B burgdorferi and transmitted by the bite of an infected deer tick (Ixodes species). The disease was known in Europe for many years as tick-borne encephalomyelitis, often associated with a characteristic rash (erythema migrans). Discovery of the agent and vector followed investigation of an outbreak of pauciarticular arthritis in Lyme, Connecticut, in 1977.

Although cases are reported from many countries, the most prominent endemic areas in the United States include the Northeast, upper Midwest, and West Coast. The northern European countries also have high rates of infection. Nearly 30,000 confirmed or probable cases were reported in the United States in 2010. Knowledge of the local epidemiology is important as Lyme disease is common in some areas of northeastern United States, but rare in the mountain states. The disease is spreading as a result of increased infection in and distribution of the tick vector. Most cases with rash are recognized in spring and summer, when most tick bites occur; however, because the incubation period for joint and neurologic disease may be months, cases may present at any time. Ixodes ticks are very small, and their bite is often unrecognized.

 Clinical Findings

A. Symptoms and Signs

Erythema chronicum migrans, the most characteristic feature of Lyme disease, is recognized in 60%–80% of patients. Between 3 and 30 days after the bite, a ring of erythema develops at the site and spreads over days. It may attain a diameter of 20 cm. The center of the lesion may clear (resembling tinea corporis), remain red, or become raised (suggesting a chemical or infectious cellulitis). Mild tenderness may occur. Many patients are otherwise asymptomatic. Some have fever (usually low-grade), headache, and myalgias. Multiple satellite skin lesions, urticaria, or diffuse erythema may occur. Untreated, the rash lasts days to 3 weeks.

In up to 50% of patients, arthritis develops several weeks to months after the bite. Recurrent attacks of migratory, monoarticular, or pauciarticular arthritis involving the knees and other large joints occur. Each attack lasts for days to a few weeks. Fever is common and may be high. Complete resolution between attacks is typical. Chronic arthritis develops in less than 10% of patients, more often in those with the DR4 haplotype.

Neurologic manifestations develop in up to 20% of patients and usually consist of Bell palsy, aseptic meningitis (which may be indistinguishable from viral meningitis), or polyradiculitis. Peripheral neuritis, Guillain-Barré syndrome, encephalitis, ataxia, chorea, and other cranial neuropathies are less common. Seizures suggest another diagnosis. Untreated, the neurologic symptoms are usually self-limited but may be chronic or permanent. Although fatigue and nonspecific neurologic symptoms may be prolonged in a few patients, Lyme disease is not a cause of chronic fatigue syndrome. Self-limited heart block or myocardial dysfunction occurs in about 5% of patients.

B. Laboratory Findings

Most patients with only rash have normal laboratory tests. Children with arthritis may have moderately elevated ESRs and WBC counts; the antinuclear antibodies and rheumatoid factor tests are negative or nonspecific; streptococcal antibodies are not elevated. Circulating IgM cryoglobulins may be present. Joint fluid may show up to 100,000 cells with a polymorphonuclear predominance, normal glucose, and elevated protein and immune complexes; Gram stain and culture are negative. In patients with CNS involvement, the CSF may show lymphocytic pleocytosis and elevated protein; the glucose and all cultures and stains are normal or negative. Abnormal nerve conduction may be present with peripheral neuropathy.

C. Diagnosis

Lyme disease is a clinical diagnosis. Local epidemiology, history of travel to endemic areas, physical examination, and laboratory features are important to consider. The causative organism is difficult to culture. Serologic testing may support the clinical diagnosis. Antibody testing should be performed in experienced laboratories. Serologic diagnosis of Lyme disease is based on a two-test approach: an ELISA and an immunoblot to confirm a positive or indeterminate ELISA. Antibodies may not be detectable until several weeks after infection has occurred; therefore, serologic testing in children with a typical rash is not recommended. Therapy early in disease may blunt antibody titers. Recent studies have shown considerable intralaboratory and interlaboratory variability in titers reported. Serologic testing of patients with nonspecific complaints from low prevalence areas results in falsely positive tests. Overdiagnosis of Lyme disease based on atypical symptoms and positive serology appears to be common. Sera from patients with syphilis, HIV, and leptospirosis may give false-positive results. Patients who receive appropriate treatment for Lyme disease may remain seropositive for years. Diagnosis of CNS disease requires objective abnormalities of the neurologic examination, laboratory or radiographic studies, and consistent positive serology.

 Differential Diagnosis

Aside from the disorders already mentioned, the rash may resemble pityriasis, erythema multiforme, a drug eruption, or erythema nodosum. Erythema chronicum migrans is nonscaly, minimally tender or nontender, and persists longer in the same place than many of the more common childhood erythematous rashes. The arthritis may resemble juvenile rheumatoid arthritis, reactive arthritis, septic arthritis, reactive effusion from a contiguous osteomyelitis, rheumatic fever, leukemic arthritis, systemic lupus erythematosus, and Henoch-Schönlein purpura. Spontaneous resolution in a few days to weeks helps differentiate Lyme disease from juvenile rheumatoid arthritis, in which arthritis lasting a minimum of 6 weeks is required for diagnosis. The neurologic signs may suggest idiopathic Bell palsy, viral or parainfectious meningitis or meningoencephalitis, lead poisoning, psychosomatic illness, and many other conditions.

 Prevention

Prevention consists of avoidance of endemic areas, wearing long sleeves and pants, frequent checks for ticks, and application of tick repellents. Ticks usually are attached for 24–48 hours before transmission of Lyme disease occurs. Ticks should be removed with a tweezer by pulling gently without twisting or excessive squeezing of the tick. Permethrin sprayed on clothing decreases tick attachment. Repellents containing high concentrations of N, N-Diethyl-meta-toluamide (DEET) may be neurotoxic and should be used cautiously in young children and infants and washed off when tick exposure ends. Prophylactic antibiotics for tick bites in asymptomatic individuals is not usually recommended.

 Treatment

Antimicrobial therapy is beneficial in most cases of Lyme disease. It is most effective if started early. Prolonged treatment is important for all forms. Relapses occur in some patients on all regimens.

A. Rash, Early Infections

Amoxicillin, 50 mg/kg/d orally in two divided doses (to a maximum of 2 g/d) for 14–21 days can be used for children of all ages. Doxycycline (100 mg orally twice a day) for 14–21 days may be used for children older than age 8 years. Erythromycin (30 mg/kg/d) or cefuroxime is used in penicillin-allergic children, although erythromycin may be less effective than amoxicillin.

B. Arthritis

The amoxicillin or doxycycline regimen (same dosage as for the rash) should be used, but treatment should continue for 4 weeks. Parenteral ceftriaxone (50–75 mg/kg/d) or penicillin G (300,000 U/kg/d, given intravenously in four divided doses for 2–4 weeks) is used for persistent arthritis.

C. Bell Palsy

The same oral drug regimens may be used for 3–4 weeks.

D. Other Neurologic Disease or Cardiac Disease

Parenteral therapy for 2–4 weeks is recommended with either ceftriaxone (50–75 kg/d in one daily dose) or penicillin G (300,000 U/kg/d intravenously in four divided doses).

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