Mark R. Schleiss and Arnold L. Smith
Although the types of infectious diseases caused by Haemophilus influenzae have changed considerably in recent years as a result of the widespread implementation of routine childhood immunization against type b organisms, this organism remains an important pathogen. There are two major categories of H influenzae: unencapsulated strains (untypeable, NTHi) and encapsulated strains (typeable). The unencapsulated strains are responsible chiefly for infections at mucosal surfaces, including conjunctivitis, otitis media, sinusitis, and bronchitis. In contrast, one of the six antigenically distinct encapsulated strains, strain type b, is associated with most invasive diseases such as septicemia, meningitis, cellulitis, septic arthritis, epiglottitis, and pneumonia. Prior to the availability of an effective vaccine, H influenzae type b (Hib) was the most common cause of pediatric bacterial meningitis in the United States.
Humans are the only natural host for H influenzae. Maintenance of the organism in the human population depends on person-to-person transmission, which appears to occur by the respiratory tract to hand to respiratory tract route. This mode of transmission was best documented during nosocomial outbreaks of NTHi pneumonia in the elderly. Nontypeable strains colonize the upper respiratory tract of as many as 75% of healthy adults. Type b H influenzae(Hib) strains colonize the nasopharynx of children at a rate of 3% to 5%; the effectiveness of the conjugate vaccines is related (in part) to their ability to diminish the incidence of nasopharyngeal colonization (see below). Although both nontypeable and type b strains of H influenzae are easily spread via person-to-person transmission, only the Hib strains have historically been associated with invasive disease in children. Nasopharyngeal colonization by Hib is for the most part asymptomatic, but breakthrough bacteremia with subsequent development of focal infection was at one time a common occurrence and a major pediatric public health problem in the United States.
In the prevaccine era, invasive Hib disease characteristically had a striking age-related incidence, with approximately 85% of disease occurring in children younger than 5 years. The peak incidence of the most serious form of invasive disease, meningitis, occurred between 6 and 12 months of age. Hib epiglottitis was, in contrast, predominantly a disease of older children, with more than 80% of the infections occurring in children older than 2 years. In the prevaccine era, approximately 20,000 instances of invasive Hib disease occurred annually in the United States, affecting about 1 in 200 children younger than 5 years.1
Chronic illnesses associated with increased risk for invasive Hib disease include sickle cell disease, asplenia, agammaglobulinemia, trisomy 21, Hodgkin disease, and complement deficiencies. Increased risk has also been associated with childcare attendance, the presence of siblings younger than 5 years, household crowding, lower socioeconomic status, and passive smoke exposure. Breast-feeding confers some protection against disease. A bimodal seasonal disease pattern has been described, with one peak of illness in the autumn between September and December, and a second peak in the spring between March and May.2 Although invasive Hib infection has historically been uncommon in adults, apparently due to the gradual development of protective antibodies over time in the context of asymptomatic nasopharyngeal colonization, Hib can occasionally cause invasive infection in adult patients.
The epidemiology of invasive Hib disease has changed dramatically in recent years as a consequence of the widespread administration of conjugate vaccines.
In populations with high rates of vaccine coverage, the incidence of Hib disease has been reduced by more than 95%.1 The protective efficacy of these vaccines exceeded initial expectations because of an unanticipated decrease in nasopharyngeal carriage, ultimately leading to a decreased environmental burden of Hib and a resultant protection even of unimmunized children, an effect of “herd immunity.” The conjugate vaccines are so effective in preventing Hib infection that the finding of invasive disease in a fully immunized child should prompt further diagnostic evaluation for the possibility of an underlying immunodeficiency.
An important aspect of Hib epidemiology is the risk it poses to contacts. Although the direct contagiousness of invasive Hib infection is limited, a significant risk for secondary disease exists among household contacts of a patient with invasive Hib disease, particularly in the 30 days following exposure to an index patient. This is a consequence of spread under conditions of continuous household exposure. Colonization rates higher than 70% have been noted following exposure in closed populations, such as within families or in daycare centers. This becomes the rationale for chemoprophylaxis following exposure to an invasive case of Hib disease (see below).
Another less common but recently recognized route of acquisition of H influenzae is vertical transmission via the birth canal. This phenomenon has been manifest in recent years as a “typical” cause of early onset pneumonia. These NTHi can cause neonatal bacteremia and meningitis after acquisition from the genital tract. These strains are genetically distinct from those colonizing the upper respiratory tract and are occasionally a cause of neonatal conjunctivitis.6
H influenzae is a small gram-negative coccobacillus that may show considerable microscopic pleomorphism, necessitating careful and cautious interpretation of Gram stains of clinical specimens (Fig. 263-1). Biochemical identification of H influenzae is based on the demonstration that growth on rich media (blood agar) is dependent on supplements, factors X and V, as found in chocolate agar. The growth of H influenzae is fastidious, and the viability of the organism is lost rapidly, necessitating expeditious handling of clinical specimens.
The polysaccharide capsule of H influenzae has a central role in the virulence of invasive H influenzae. Six antigenically and biochemically distinct capsular polysaccharide subtypes (a-f) have been identified. Although type b encapsulated strains have historically been of primary clinical and immunologic importance (because of the association with invasive infection, including meningitis), the other encapsulated strains are also capable of producing invasive disease.
FIGURE 263-1. Gram stain of Haemophilus influenzae. Arrows point to two small “cocco-bacillary” gram-negative rods. (Provider: Professor Shirley Lowe, University of California, San Francisco School of Medicine. With permission.)
Plasmid-mediated ampicillin resistance due to production of β-lactamase has become extremely common in Hib and NTHi, ranging from 5% to 50% of isolates in various parts of the world. Non-β-lactamase–mediated ampicillin resistance is increasing in the United States; thus, susceptibility testing should be performed on all isolates identified in invasive infections.8
Age-dependent susceptibility to Hib infections correlates with an age-dependent nature of immune response to Hib surface components. The bactericidal activity of children and adults against Hib and certain NTHi is directed against LPS and outer membrane proteins. Even after recovery from an invasive Hib illness, anticapsular antibody levels in infants remain low. As a consequence, instances of second or third episodes of invasive Hib disease are well described; thus, a previous episode of invasive infection does not obviate the need for Hib immunization. This failure to make serum anti-PRP antibodies is typical of the natural delay in immune response of infants to polysaccharide antigens. PRP stimulates B cells but does not adequately activate macrophages and appropriate T-helper cells, and therefore it is considered to be a T-cell-independent antigen. The characteristics of T-cell-independent antigens include limited immune responses, particularly in young infants; no booster response occurs with repeated antigenic stimulation, and production of antibody that is of low affinity and mostly consisting of IgM. The development of a Hib vaccine that was more immunogenic and protective for young infants required conversion of PRP from a T-cell-independent antigen to a T-cell-dependent antigen, using the principles of carrier-hapten linkage.10
CLINICAL MANIFESTATIONS OF DISEASE CAUSED BY TYPABLE STRAINS
Prior to Hib conjugate vaccines, meningitis was the most common and serious manifestation of invasive Hib disease. The differential diagnosis and clinical manifestations of meningitis are detailed in Chapter 231. The sequelae from Hib meningitis differ from other causes of bacterial meningitis. Approximately 30% of children will have seizures at some point in the course of Hib meningitis. Like patients with meningococcal disease, children with Hib bacteremia can have a petechial rash. They can also have a secondary site of infection, such as a septic arthritis or facial cellulitis (see below). Shock is present in approximately 20% of cases. Anemia is common, the result of a combination of accelerated red blood cell destruction and diminished erythropoiesis. Complications of H influenzae type b meningitis include subdural effusion or empyema, ischemic or hemorrhagic cortical infarction, cerebritis, ventriculitis, intracerebral abscess, and hydrocephalus. Intravenous antibiotics and supportive care are the mainstays of therapy, but the mortality from Hib meningitis remains approximately 5%, even with prompt diagnosis. Long-term sequelae occur in 15% to 30% of survivors and are manifest as sensorineural hearing loss, language disorders, mental retardation, and developmental disorders. A meta-analyses of randomized controlled clinical trials in children has shown that the incidence of severe hearing loss due to H influenzae was decreased by the administration of corticosteroids, an effect that was more evident in children in high-income countries.11
Acute upper airway obstruction caused by Hib infection of the epiglottis and supraglottic tissues is perhaps the most dramatic and rapidly progressive form of disease caused by this organism. In contrast to the peak incidence of meningitis in children younger than 1 year, epiglottitis occurs primarily in older children (2–7 years of age) and usually has an abrupt onset with high fever, dysphagia, drooling, and toxicity. Occasional cases of Hib epiglottitis are still observed in older children who were never fully immunized, and Hib is also an important cause of epiglottitis in adult patients.
Classically, the child with Hib epiglottitis will drool because of an inability to swallow oropharyngeal secretions. Progressive respiratory distress develops over a period of hours with tachypnea, stridor, cyanosis, and retractions. The patient may sit forward with the chin extended to maintain an open airway (“tripod” position). Few conditions produce such a striking constellation of symptoms and findings. A lateral neck radiograph is helpful if the clinical presentation is subtle, but the study should be performed cautiously and without undue delays, with a physician experienced in airway management in attendance (Fig. 263-2). Diagnostic studies should not delay the need for direct inspection of the epiglottis in the operating room and insertion of an endotracheal tube (Fig. 263-3). The mortality rate is 5% to 10% and is invariably related to poor control of the airway early in illness.
In the prevaccine era, Hib was the leading cause of septic arthritis in children younger than 2 years. Approximately 8% of H influenzae invasive disease presents as septic arthritis, typically affecting large joints, particularly knees, ankles, hips, or elbows. A contiguous osteomyelitis may be present, but isolated osteomyelitis without an adjacent septic joint is uncommon. Characteristically, there is a preceding nonspecific illness, followed by pain, swelling, and erythema of the involved joint. Clinical signs in children with a septic hip may be less prominent than for other joints, with findings limited to decreased range of motion of the joint, often with the leg abducted at the hip and externally rotated. In some cases, pain is referred from the hip to the lower leg. Septic arthritis of the hip joint requires surgical drainage; the majority of cases involving the shoulder also require open drainage. There is a strong association of septic arthritis with meningitis, necessitating lumbar puncture in these patients.
FIGURE 263-2. Lateral soft-tissue x-ray of the neck demonstrating thickening of aryepiglottic folds and thumbprint sign of epiglottis (arrow). (Courtesy of Richard M. Ruddy, MD.)
FIGURE 263-3. Epiglottitis: Endoscopic view of almost complete airway obstruction secondary to epiglottis. Note the slit-like opening of the airway. (Courtesy of Department of Otolaryngology, Childrens Hospital Medical Center, Cincinnati, OH.)
H influenzae type b cellulitis usually involves the face, head, or neck. The vast majority of cases occur in the first 2 years of life. Buccal cellulitis, seen almost exclusively in children during the first year of life, presents as a raised, warm, tender, and indurated area that progresses to a violaceous hue. The clinical presentation may mimic erysipelas. Periorbital (preseptal) cellulitis is similarly seen in young children and often occurs in the setting of contiguous sinus disease. It must be differentiated by appropriate imaging from the more serious orbital cellulitis. Hib cellulitis is a bacteremic disease, and meningitis must be excluded by lumbar puncture.
Although the vast majority of children with Hib bacteremia present with a focus of infection, occasionally bacteremia can be the sole manifestation of disease in the febrile child. These children are usually younger than 2 years and have temperatures of 39°C (102.2°F) or higher. In the prevaccine era, Hib was the second leading cause of occult bacteremia, behind Streptococcus pneumoniae. However, there is an important distinction between Hib and pneumococcal bacteremia, whereas most episodes of untreated occult pneumococcal bacteremia resolved spontaneously without sequelae, 30% to 50% of children with occult Hib bacteremia will develop focal infections, including meningitis. Hence, in any child with a positive blood culture for Hib, the possibility of meningitis must be seriously considered.
Hib pneumonia is clinically indistinguishable from other bacterial pneumonias. It was estimated to cause as many as one third of cases of documented bacterial pneumonias in the prevaccine era. Radiologically, it can appear as a segmental, subsegmental, interstitial, or lobar pattern. There is a strong association with pleural effusion; 50% of cases have evidence of pleural involvement on initial radiographic examination. The most useful diagnostic test is the blood culture, which is positive in almost 90% of cases. Complications of Hib pneumonia include pericarditis, meningitis, and pleural empyema often requiring decortication.
The classic presentation of H influenzae pericarditis is that of a toxic child with fever, respiratory distress, and a clear chest on examination. Associated conditions include pneumonia and meningitis. Hib pericarditis may become clinically manifest while a child is receiving antibiotic therapy and should be considered in the differential diagnosis of the child with persistent fever while receiving therapy for H influenzae meningitis. Although the diagnosis may be suggested after careful inspection of the cardiac silhouette and jugular veins, echocardiography is the best modality for establishing the diagnosis of pericardial effusion. Pericardiocentesis is the diagnostic procedure of choice. Early pericardectomy, in conjunction with antibiotics, is the treatment of choice.
In recent years, H influenzae has been increasingly recognized as a cause of bacteremia and meningitis in the neonatal period. Neonatal infections are usually caused by nontypeable H influenzae, which can also be cultured from the maternal genital tract, the presumed source of the infection. The disease is one of early onset sepsis, with more than 80% of cases occurring during the first day of life. Maternal-to-fetal transmission probably occurs in utero because the infection is associated with prematurity, low birth weight, and maternal complications such as premature rupture of membranes and chorioamnionitis.12Routine therapy with ampicillin and gentamicin for presumptive neonatal sepsis may not be effective if an ampicillin-resistant strain of H influenzae has caused the infection.
Brazilian Purpuric Fever
A nonserotypeable H influenzae, biogroup III (which has characteristics identical to the Haemophilus aegyptius group), is the etiology of Brazilian purpuric fever (BPF), first recognized in children in southern Brazil. Following an antecedent episode of purulent conjunctivitis, children with BPF become bacteremic and present with fever, shock, and purpura indistinguishable from that caused by meningococci. The disease has not been reported in the United States.
Other Invasive Infections
Hib bacteremic disease has also been rarely associated with seeding of other body sites. Endophthalmitis, glossitis, uvulitis, thyroiditis, endocarditis, lung abscess, epididymitis, peritonitis, pericarditis, intraperitoneal abscesses, hepatobiliary disease, and brain abscesses have been reported.
CLINICAL MANIFESTATIONS CAUSED BY NONTYPEABLE STRAINS
Nontypeable strains of H influenzae frequently cause otitis media, sinusitis, conjunctivitis, and bronchitis, the latter in adults. Conjunctivitis is usually bilateral and purulent, and is often associated with acute otitis media (“conjunctivitis-otitis” syndrome). Although these respiratory tract infections are common, they are rarely life threatening and are not associated with bacteremia. Prematurity, cerebrospinal fluid (CSF) leak, congenital heart disease, and immunoglobulin deficiency may predispose to invasive disease with nontypeable strains of H influenzae. In the absence of these predisposing conditions, nontypeable H influenzae systemic infection should prompt an immunologic investigation. Importantly, immunization with conjugate Hib vaccines does not confer protection against nontypeable strains: nontypeable H influenzae remains a major cause of otitis media in children and appears to be increasing in prevalence since the introduction of pneumococcal conjugate vaccines. Encapsulated non-Hib strains of H influenzae are increasingly identified as causes of invasive disease.13 An apparent increase in reports of H influenzae types a and f meningitis suggest that these organisms could conceivably “emerge” as important causes of invasive disease in children in the post-Hib vaccine era, although this trend has not yet become widespread.
The primary criterion for the diagnosis of H influenzae infection is isolation of the organism from the infectious focus (blood, CSF, or any other site of infection, such as joint, pericardial, or empyema fluid). Patients with epiglottitis usually have positive blood cultures; cultures from the inflamed epiglottis should be obtained only after the airway has been secured. Whenever invasive disease is encountered, or meningitis is suspected on clinical grounds, lumbar puncture should be performed. Because the organism is fastidious, specimens should be processed immediately after they are acquired. Gram stain should be performed on any body fluid possibly infected with H influenzae. Organisms are seen in about 90% of stained CSF smears in patients with meningitis, and the Gram stain appearance of CSF has important implications in the management of pediatric meningitis. The appearance of gram-positive cocci suggests the possibility of pneumococcal meningitis, and the possible need for empiric vancomycin therapy, whereas the appearance of organisms consistent with H influenzae suggests that antibiotic administration should consider local resistance patterns. The CSF of a child with Hib meningitis characteristically has a marked pleocytosis, a low glucose concentration, and an elevated protein concentration, but these findings are not specific for the diagnosis of Hib meningitis.
The type b capsular polysaccharide (PRP) can be detected in body fluids (serum, urine, joint fluid, CSF) from children with invasive disease. The three most commonly used assays are countercurrent immunoelectrophoresis (CIE), latex particle agglutination (LPA), and coagglutination (CoA). The tests are most useful when performed on CSF from children with meningitis who have been pretreated with antibiotics because cultures may be unrevealing in this setting. Unfortunately, immunization with the Hib conjugate vaccines often results in urinary excretion of antigen for days to weeks, and such false-positive results limit the usefulness of these assays in that fluid. False-positive reactions are unusual in the CSF.
For infections caused by nontypeable strains of H influenzae, antigen detection and blood cultures are of little diagnostic value because bacteremia is rare. The diagnosis is usually clinical, although a microbiological diagnosis can be established for pneumonia/bronchitis by culture of sputum, for otitis media by diagnostic tympanocentesis, for sinusitis by culture of sinus aspirate, and for conjunctivitis by vigorous culture of the eye exudate containing epithelial cells with adherent bacteria.
Because bacteremia is central in invasive H influenzae type b disease, therapy must anticipate the need for adequate central nervous system (CNS) penetration and be of sufficient duration to sterilize the primary and any secondary foci. The emergence of antibiotic resistance further necessitates that therapy of invasive infections includes β-lactamase–stable agents. The antibiotic susceptibility of H influenzaeisolated from the nasopharynx should not be used to guide therapy. Although a correlation may exist between the specific nasopharyngeal strain and that present in the middle ear, the correlation cannot be used to guide therapy. In addition, the nasopharynx may yield nonhemolytic Haemophilus haemolyticus, which is an avirulent commensal.
Because of the emergence of ampicillin-resistant isolates of H influenzae in the setting of proven or suspected Hib meningitis, cefotaxime or ceftriaxone are recommended until the antibiotic susceptibility of the organism is known, or an alternative diagnosis is established. Both antibiotics have bactericidal activity against Hib, including β-lactamase-producing strains, and both penetrate well into infected CSF. Ceftriaxone is approved for once-daily therapy of meningitis at a dose of 100 mg/kg/d and can be administered by daily intramuscular injections if intravenous access is difficult, or used to complete a course of outpatient therapy in the patient who is clinically stable. Empiric therapy with ampicillin alone is not justified because approximately 50% of Hib isolates in the United States are resistant, although it is effective for isolates that are documented to be susceptible. Other extended-generation cephalosporins with indications for meningitis include ceftazidime and cefepime, but because of their overly broad spectrum they are not desirable choices for therapy of documented Hib meningitis.
Meropenem is an acceptable alternative to third-generation cephalosporins with a well-established track record of efficacy for pediatric meningitis, including meningitis caused by Hib. However, meropenem does not appear to have activity for strains of S pneumoniae with high-level resistance to penicillins, and therefore should not be used as single-agent therapy when pneumococcal meningitis is suspected.
Cefuroxime has good activity against H influenzae and Staphylococcal aureus, and is a reasonable choice for empiric therapy of some infections when H influenzae is in the differential diagnosis, such as pneumonia, cellulitis, or bone and joint infections. However, caution must be taken with this agent if the diagnosis of meningitis has not been excluded because cefuroxime is associated with delayed sterilization of the CSF.14
Although chloramphenicol became the drug of choice for Hib infections shortly after the appearance of ampicillin-resistant strains in the 1970s, with the emergence of the third-generation cephalosporins, chloramphenicol is now rarely used because of the need to monitor serum levels to prevent toxicity. In addition, chloramphenicol-resistant strains are becoming increasingly prevalent in some parts of the world, so local resistance patterns must be considered. However, ampicillin in combination with chloramphenicol remains a reasonable option for treatment of invasive Hib disease in the United States. Although adequate blood levels of chloramphenicol can be achieved with oral administration, it is usually advisable to initiate therapy intravenously. Oral chloramphenicol has been used successfully to complete the course of antibiotic therapy in invasive Hib disease, but the current lack of availability of formulations of oral chloramphenicol in the United States limits the usefulness of this option. Serum levels should be monitored and maintained between 10 and 20 mg/L in all patients receiving chloramphenicol. Although chloramphenicol has dose-related and reversible bone marrow toxicity, this is usually evident only in the neonate, the child with liver disease, or after prolonged treatment. Idiosyncratic aplastic anemia in young children is very rare.
The duration of antibiotic therapy is determined by the site of infection and the clinical response. Children with uncomplicated Hib meningitis can be treated for 7 to 10 days. Children with cellulitis can be changed to oral therapy after several days of parenteral therapy, provided they have had a satisfactory clinical response and do not have meningitis. Patients with septic arthritis should receive at least 14 to 21 days of therapy, in conjunction with appropriate surgical care. Children with pericarditis, empyema, or osteomyelitis may require longer courses of intravenous antibiotic treatment (3–6 weeks) followed by a course of oral therapy. Children with occult Hib bacteremia should be treated initially with parenteral antibiotics, given the risk for focal infection.
Supportive therapy is also vital in the management of children with invasive Hib disease. The recommended dose of dexamethasone is 0.6 mg/kg/d divided every 6 hours for 4 days, with the first dose given just before or with the first antibiotic dose. Management of the child with meningitis requires anticipation of complications such as shock, SIADH, subdural empyema, and secondary foci of infection. Prolonged fever during treatment of Hib meningitis is common and does not imply failure of the antibiotic regimen, but should prompt consideration of additional foci of infection (pericarditis, subdural effusion, etc). Children treated with dexamethasone have a shorter duration of fever acutely, but are still at risk to develop secondary fevers late in the course of illness.
In children with epiglottitis, the first priority is airway management. Endotracheal intubation is optimally performed in the operating room by an experienced anesthesiologist. If it can be done safely, cultures of the epiglottis may be obtained at this time, and blood cultures should be obtained once the airway is secure. Intravenous antibiotics should be provided as soon as possible.
For patients with joint infections, subdural empyema, pericarditis, or pleural empyema, surgical consultation is required. Infected joint fluid should be aspirated from the child with septic arthritis, particularly with septic arthritis of the hip joint, to reduce pressure and to prevent avascular necrosis of the femoral head. Most orthopedic surgeons prefer open drainage of the hip.
Numerous orally administered antimicrobials are available to treat respiratory tract infections caused by nontypeable H influenzae. Generally, therapy in this setting is empiric, without specific culture confirmation of H influenzaeas the etiology.
Two modalities are available to prevent Hib disease: chemoprophylaxis to prevent secondary disease and active immunization to prevent endemic disease. The widespread success of immunization has rendered chemoprophylaxis largely of historical interest only.
Many studies have documented the increased risk of invasive disease among household contacts in the month following onset of disease in the index case. The attack rate is a function of age, approaching 4% in children younger than 2 years. Rifampin is the most effective antibiotic for eradicating Hib from the nasopharynx, primarily because of its exquisite ability to penetrate respiratory secretions. Children younger than 12 years should receive 20 mg/kg once daily for 4 days, and adults should receive 600 mg once daily for 4 days. The quinolones may also be effective, although they are not approved for this use in children. Prophylaxis should be instituted as soon as possible because the risk of secondary disease is greatest during the few days after disease onset in the index patient. Prophylaxis is recommended only if it can be given within 2 weeks of disease onset. Because therapeutic antibiotics do not consistently eradicate Hib from the nasopharynx, rifampin should also be given to the index patient prior to hospital discharge. Although there have been daycare-associated outbreaks of invasive Hib disease, the use of rifampin chemoprophylaxis in childcare settings remains controversial, primarily because the risk of secondary disease in this setting is not well defined. Coordination with the local health department and consultation with an expert is warranted. Fortunately, most childcare attendees are now immunized and therefore at low risk of secondary disease.
Recommendations for Hib vaccination are detailed in Chapter 244.