Adolescent Health Care: A Practical Guide
Infectious Respiratory Illnesses
Emmanuel B. Walter
Infectious mononucleosis (IM) is usually an acute, self-limited, and benign lymphoproliferative disease caused by the Epstein-Barr virus (EBV) and commonly occurs in adolescence or young adulthood. Although EBV is responsible for IM in approximately 90% of cases, the syndrome may also be caused by other infectious agents, such as cytomegalovirus (CMV), toxoplasmosis, human herpes virus 6, and adenovirus. EBV is most often transmitted through direct saliva contact, hence its reputation among adolescents as “the kissing disease.” The virus replicates in the lymphoreticular system, where it provokes an intense immunological response frequently involving lymph nodes, spleen, liver, and bone marrow. It is this immune response that is responsible for the clinical symptomatology.
EBV is a fragile, enveloped DNA herpes virus. Humans and a few other primates are the only known reservoirs, and the virus cannot survive long outside of the host. Transmission occurs primarily through exposure to oropharyngeal secretions, and the incubation time is 30 to 50 days. The virus initially infects oral epithelial cells, and then spreads to B lymphocytes which disseminate the infection throughout the lymphoreticular system. During this time, there is a polyclonal B-cell proliferation and a vigorous T-cell response. In reaction to infected and transformed B cells, atypical lymphocytes appear in the peripheral blood. These atypical cells are mainly cytotoxic or suppressor (CD8) cells. This immunological response is responsible for many of the clinical manifestations of IM, including lymphadenopathy, hepatomegaly, and splenomegaly.
Acute infection with EBV stimulates production of antibodies directed against EBV antigens as well as non-EBV–specific antibodies that react with antigens found on sheep and horse erythrocytes. These heterophil antibodies form the basis of rapid diagnostic tests for IM. Antibodies to EBV viral capsid antigen (VCA-IgM, and VCA-IgG) are produced slightly earlier than the heterophil antibody, and are more specific for EBV infection. VGA-IgG antibodies persist after acute infection, and represent the development of immunity.
During an acute infection, approximately 0.001% to 0.01% of circulating B cells are infected. Over the next 3 to 4 months, this rate declines to 0.00001%, which persists indefinitely. EBV remains in the body for life, replicating as an extrachromosomal plasmid in a subset of B cells. Virus is shed by 70% to 90% of individuals for 8 to 24 weeks after resolution of the clinical syndrome. After this, 60% to 100% of normal, asymptomatic EBV seropositive individuals shed virus intermittently.
More than 90% of adults have serological evidence of past EBV infection. The highest rates of acute infection in the United States are in older adolescents and young adults, particularly those living in close proximity to one another, such as in college or the military. EBV is present in the oropharyngeal secretions of up to 20% of asymptomatic adults in the United States.
- Age: In developing countries, tropical areas, and areas of high population density in industrialized countries, infection usually occurs early in life and is usually subclinical. In these areas, up to 90% of children seroconvert by the age of 6. However, if infection does not occur in childhood, infection with EBV in adolescents and young adults results in the clinical syndrome of IM in 30% to 75% of cases. In one study of first-year university students, 13% of those susceptible had developed EBV antibodies within 9 months of starting classes, and IM developed in 75% of the seroconverters. In the United States, the annual incidence of IM for those between the ages of 15 and 19 is between 345 and 671 cases per 100,000 person-years. In contrast, the incidence for those aged 35 years and older is only two to four cases per 100,000 person-years.
- Gender: There are no gender differences in prevalence.
- Race: IM is more prevalent among whites than blacks in the United States. This may be a reflection of earlier subclinical infection in black children living in areas of higher population density.
- Season: There is no seasonal variation, although there may be an increased incidence in spring and fall among college students, and in summer in military personnel, but these variations are likely population specific.
- Contagiousness: Because the virus is shed in oropharyngeal secretions, and cannot live outside the host for long, direct contact with saliva is the main vehicle for transmission of EBV. Hence, kissing is an important
modality of transmission in adolescents and young adults. In families, 10% to 40% of susceptible members will develop EBV infection from a household contact. EBV is also detectable in the genital tracts of men and women; therefore the possibility of sexual transmission exists, although salivary contact likely plays a much more prominent role. Because EBV resides in the B lymphocytes, transmission through blood products has also been reported.
The majority of EBV infections are either asymptomatic or associated with mild, nonspecific symptoms such as malaise, fever and chills, and anorexia. Even in adolescents and young adults in whom classic IM is common, a significant number of EBV infections are subclinical.
The traditional triad of IM includes:
- Fever, lymphadenopathy, and pharyngitis
- Lymphocytosis with atypical lymphocytes
- Antibody response demonstrated by the presence of heterophil antibodies or EBV-specific antibodies
In those who develop clinical symptoms, there is often a prodromal period of 3 to 5 days of malaise, headache, anorexia, myalgia, and fatigue, followed by more severe symptoms and signs as the immune response mounts.
Signs and Symptoms
The common presentation includes fever, which may persist for several weeks. A prominent symptom is sore throat, which can be severe, and may include an exudative pharyngitis in up to 50% of individuals. Palatal petechiae may be seen at the junction of the hard and soft palate. Periorbital or facial edema occurs in approximately 25% of teens with IM. Adenopathy is usually significant and is most commonly symmetrical, with posterior cervical lymph nodes more prominent than anterior ones. Splenomegaly and hepatomegaly may occur by the second week of the illness. Approximately 10% of individuals have a rash that may take on a number of different appearances—erythematous, maculopapular, morbilliform, urticarial, or erythema multiforme. Approximately 90% of patients who receive ampicillin or amoxicillin will develop an erythematous maculopapular rash, which typically does not appear until approximately 1 week after antibiotic therapy has been initiated. Although the exact mechanism for the development of this rash is unknown, it appears that a true drug sensitization does occur in these patients. Whether this sensitization persists following resolution of IM is unknown.
Occasionally, patients will present with a major complication of IM as their only manifestation of the disease, and the typical clinical symptoms may not appear until later in the course of the illness. Overall, the complication rate is approximately 1% to 2%.
- Splenic rupture: Splenic rupture is seen in approximately 0.1% to 0.2% of cases, and at least half of cases are spontaneous without any history of trauma or unusual physical exertion. Typically, there is abrupt abdominal pain in the left upper quadrant that radiates to the top of the left shoulder, known as Kehr sign. This is followed by generalized abdominal pain, pleuritic chest pain, and signs and symptoms of hypovolemia. However, the onset may be insidious. Splenic rupture occurs between the 4th and 21st days of the illness, with approximately half of cases occurring during the height of the acute illness, and the other half in the early convalescent phase. Only approximately 50% of cases of splenic rupture have clinically significant splenomegaly noted before the rupture. All patients with IM should be considered at risk for splenic rupture, because clinical severity, laboratory results, and physical examination are not reliable predictors of risk. Because of this, as well as the morbidity and mortality risk associated with splenic rupture, patients should refrain from vigorous physical activity for at least 1 month after the onset of symptoms, or until palpable splenomegaly resolves, whichever is later. Some have advocated using ultrasound to assess for splenomegaly before allowing patients to return to contact sports such as football or hockey, but there is little evidence to support this.
- Airway obstruction: Airway obstruction is an uncommon but life-threatening complication of IM related to massive lymphoid hyperplasia and mucosal edema. This tends to be more common in younger teens and typically occurs approximately 1 week after the initial symptoms begin. Corticosteroids have been used in an attempt to reduce the edema and hypertrophy of the lymphoid tissue. In more severe cases, acute tonsillectomy may be indicated, and, in emergency situations, intubation or tracheostomy may be necessary.
- Streptococcal pharyngitis: Although EBV infection may potentiate the ability of β-hemolytic streptococci to adhere to epithelial cells membranes, there are widely varying reported rates of coinfection. Studies from 30 to 40 years ago reported coinfection rates as high as 33%. The most recent studies available are from approximately 20 years ago, and noted a coinfection rate of 4%.
There are a number of distinctive hematological abnormalities observed with IM. Generally, the total white blood cell count is elevated, in the range of 10,000 to 20,000/mm3. Approximately 95% of patients will demonstrate a lymphocytosis, with >50% of the leukocytes being lymphocytes, and 10% or more being atypical lymphocytes. The atypical lymphocytes are usually activated CD8 T lymphocytes, or occasionally EBV-transformed B lymphocytes. Although atypical lymphocytes may be seen in a variety of other viral illnesses, including human immunodeficiency virus (HIV), acute viral hepatitis, rubella, mumps, and rubeola, they typically do not comprise >10% of the total leukocyte count. However, this level of atypical lymphocytosis may also be seen with CMV and toxoplasmosis infections. Other common hematological abnormalities include a mild granulocytopenia and thrombocytopenia (usually in the range of 100,000 to 140,000/mm3) in approximately half of individuals with IM. Anemia is uncommon, although a mild hemolytic anemia may occur in up to 3% of cases.
Other Laboratory Findings
Evidence of mild hepatitis is very common, and is seen in approximately 90% of individuals. Transaminase levels may be as high as 2 to 3 times the normal, and alkaline phosphatase and lactate dehydrogenase levels may also be elevated. Less commonly, bilirubin levels may be mildly elevated, to the range of 1 to 3 mg/dL. These liver function test abnormalities peak at approximately the second or third week of symptoms, and usually resolve by the end of the fourth week. Entirely normal findings from liver chemistries may suggest a diagnosis other than EBV infection.
The classic test for EBV-associated IM is the presence of heterophil antibodies. These tests detect immunoglobulin M (IgM) antibodies induced by EBV infections that cross-react with phylogenetically unrelated antigens, typically sheep, horse, or bovine erythrocytes. Although the presence of heterophil antibodies is the hallmark of IM, heterophil antibodies can be found in normal human serum in low titers, as well as in higher titers in individuals with malignant disease, serum sickness, or a variety of other viral infections. Additionally, some patients with IM, particularly young children, may be heterophil antibody negative.
Slide and card tests, such as MonoSpot®, exploit the fact that IM heterophil antibodies agglutinate sheep and horse erythrocytes after preabsorption with guinea pig kidney, but not after preabsorption with bovine erythrocytes. These tests are rapid, simple to perform,
and inexpensive. The MonoSpot test has a sensitivity of 86% and a specificity of 88% to 99%, but the sensitivity is lower during the first week of illness, and is lower (~80%) in adolescents younger than 16 years. Children younger than 4 years with EBV-associated IM are even less likely to produce heterophil antibodies—only approximately 30% will test positive for heterophil antibody. Individuals who do test positive will have a persistently positive heterophil antibody result for approximately 3 to 6 months following the acute infection and sometimes even longer in low titers.
If EBV-associated IM is suspected, but the heterophil antibody result is negative, one may perform EBV-specific antibody tests.
Specific Epstein-Barr Virus Antibodies
Antibody responses to several EBV antigens have been well studied. These antibodies include viral capsid antigen (VCA), early antigen (EA), and Epstein-Barr nuclear antigen (EBNA). Commercially-available enzyme immunoassay (EIA) tests are readily available. Figure 29.1 shows the characteristic EBV antibody responses to various EBV antigens. Table 29.1 shows the pattern of serological results in various EBV stages.
FIGURE 29.1 The evolution of antibodies to various Epstein-Barr virus (EBV) antigens in patients with infectious mononucleosis (IM) is shown in the figure. The titers are geometric mean values expressed as reciprocals of the serum dilution. Immunoglobulin M (IgM) and IgG antibody responses to EBV capsid antigen develop during the acute phase, as does an IgG response to EBV early antigen in most cases. The IgG response lasts for life, but the IgM response is transient and is shortest in very young children. Antibody response to nuclear antigen lasts for life and is typically quite late in onset. (From Sumaya CV. Epstein-Barr serologic testing: diagnostic indications and interpretations. Pediatr Infect Dis 1986;5:337.)
- VCA antibody: Antibodies against VCA are composed of both IgG and IgM. Antibody levels for both peak at approximately 3 to 4 weeks after the clinical onset of the disease. IgM declines rapidly and is undetectable by 3 months. IgG declines somewhat with time but persists for life. High persistent levels of IgG antibodies against VCA can indicate remote EBV infection as well as systemic lupus, chronic renal failure, lymphoma, nasopharyngeal carcinoma, leukemia, sarcoidosis, rheumatoid arthritis, or any other immunodeficiency state.
- EA antibody: Antibodies against EA are induced in 70% to 90% of individuals with acute EBV IM. The antibodies are produced very early in the infection and usually persist for 8 to 12 weeks. However, as many as 30% of individuals with past infections have positive titers for EA. These antibodies have been divided into two patterns of staining—diffuse and restricted. Most adolescents and young adults with IM have antibodies against the D (diffuse) component.
- Nuclear antigen antibody: Antibodies against EBNA develop 2 to 3 months after the onset of infection and tend to persist indefinitely. Positive titers usually indicate an infection at least 1 to 2 months in the past. Absent EBNA titers in patients with an EBV infection are associated with immunodeficiency states and rheumatoid arthritis.
Acute EBV-associated IM is characterized by the presence of both IgM and IgG VCA and EA antibodies. Older and remote infections are characterized by the absence of IgM VCA antibodies and the appearance of IgG EBNA antibodies (Table 29.1). EBV serology is best reserved for measurement in adolescents when (a) clinical IM is present and a heterophil test result is negative; or (b) the clinician is investigating clinical situations such as thrombocytopenia, pneumonia, or a neurological condition to exclude the diagnosis of acute EBV disease.
Epstein-Barr Viral Detection
Specific polymerase chain reaction (PCR) assays that quantify EBV DNA in serum have been developed. The assays are specific for EBV DNA, have high sensitivity early in the course of illness including in young children, and the magnitude of the viral load has been correlated with the severity of illness. However, EBV PCR tests are not yet readily available for clinical use.
- Causes of EBV-negative mononucleosis-like syndrome include:
- Toxoplasma gondii
- Herpes simplex virus 6
- Drug side effects
- Acute HIV infection
- Other considerations include:
- Group A β-hemolytic streptococcal pharyngitis
- Viral tonsillitis
- Mycoplasma pneumonia
- Vincent angina (necrotizing ulcerative gingivitis)
- Viral hepatitis
- Lymphoproliferative disorder or leukemia
The diagnosis is based on the following considerations:
- Clinical symptoms: IM should be suspected in an adolescent with fatigue, fever, splenomegaly, adenopathy, and pharyngitis.
- Abnormal white blood cell count: Patients will usually have the following:
- Relative lymphocytosis >50%.
- Absolute lymphocytosis >4,000/mm3.
- Relative atypical lymphocytosis >10%.
- Positive serology: Almost all adolescents with IM have positive heterophil antibodies. If a patient continues to be symptomatic and heterophil antibodies are negative, titers for EBV (including VCA and EBNA) should be evaluated.
- A throat culture is indicated in patients with pharyngitis or tonsillitis, but a positive result does not exclude IM.
Only supportive care is required for most patients with IM.
- Symptomatic care
- Rest as needed should be provided during the acute phase. Adolescents and their parents should be made aware that the acute symptoms usually resolve over 1 to 2 weeks, although the associated fatigue may persist for 2 to 4 weeks, or sometimes longer. Many patients require up to 2 months to achieve a stable level of recovery. Between 9% and 22% of those with IM have reported persistent fatigue 6 months after the onset of symptoms.
- Nonsteroidal anti-inflammatory agents or acetaminophen may be used as needed for fever and pain. Aspirin should be avoided, because there is a rare association between EBV and Reye syndrome.
- Antimicrobials: In the absence of coinfection with group A streptococcus or Mycoplasma pneumoniae, antibiotics serve no purpose. Acyclovir is not indicated; although it may reduce viral shedding, it does not impact the clinical syndrome.
- Corticosteroids: Steroids have not been shown to be effective and are not indicated for routine cases. However, corticosteroids are recommended in patients with significant pharyngeal edema that threatens or causes respiratory compromise. Prednisone, initially 40 to 60 mg daily, then tapered over 1 to 2 weeks may be used in these situations.
- Return to activity
- Light, nonimpact activities may be resumed after 3 weeks of illness, as symptoms permit. Full participation in nonimpact activities may be resumed after 4 weeks of illness.
- Contact sports should be delayed for 4 to 6 weeks, even in the absence of splenomegaly. If there is a concern for persistent splenomegaly, ultrasound may be used to assess and monitor splenic size. However, data on the utility of splenic ultrasound to prevent rupture is lacking.
Chronic Epstein-Barr Virus Infection
The vast majority of patients with EBV-associated IM develop lifelong immunity. There are rare individuals who have very high titers of EBV antibodies and have chronic persistent active EBV infection. This is characterized by the following:
- Severe illness lasting >6 months
- Histological evidence of end-organ disease, such as hepatitis, uveitis, or pneumonitis
- Evidence of EBV antigen or DNA in tissue
Despite some clinical similarities, there is little evidence that EBV causes chronic fatigue syndrome, and a positive IgG test for EBV does not imply a causal relationship.
EBV infections can be associated with lymphoproliferative disorders, particularly in individuals with underlying abnormal immune responses. For example, patients with acquired immunodeficiency syndrome (AIDS) have a 10- to 20-fold increase in circulatory EBV-infected B cells as compared with persons without HIV infection. This has implications for such disorders as virus-associated hemophagocytic syndrome, lymphomatoid granulomatosis, and the X-linked lymphoproliferative syndrome in which affected males die from EBV disease, sometimes in a matter of days. When EBV leaves the latent state and becomes chronically active, it can potentially trigger lymphoid malignancies, such as Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma.
- pneumoniaeis a common cause of upper respiratory infections and pneumonia in adolescents that is often referred to as walking pneumonia. It may also cause pharyngitis, tracheobronchitis, and otitis media, but at other times the infection may be asymptomatic.
Mycoplasma are approximately 150 to 250 nm, or about the same size as large viruses. More than 100 species have been identified, with at least 13 infecting humans. Mycoplasma are prokaryotes that do have not cell walls, rather, they are bounded by cell membranes containing sterols. Because they lack cell walls, they are resistant to β-lactam antimicrobials. However, they are sensitive to antibiotics that interfere with protein synthesis, such as macrolides and tetracyclines. They appear to cause infection primarily as extracellular parasites, but may also contaminate cell cultures as intracellular parasites.
By means of attachment proteins, M. pneumoniae adheres to ciliated and nonciliated respiratory epithelium, causing cellular damage to the trachea, bronchi, and bronchioles. The organism also causes ciliostasis, which may lead to prolonged cough. Transmission to the respiratory tract is through aerosolized inhalation. There is a high rate of transmission to family members and other close contacts, with an incubation period of 3 to 4 weeks.
Each year there are approximately 2 million cases of Mycoplasma pneumonia in the United States, resulting in 100,000 hospitalizations. M. pneumoniae infects patients of all ages, but lower respiratory disease is of particular importance in adolescents and young adults. Highest rates of infection are in those between the ages of 5 and 20 years. The illness is responsible for up to 20% of all pneumonias in middle and high school, and up to 50% among college students and military recruits. Epidemic infection occurs at 3 to 7 year intervals in the United States, with low-level endemic disease in the intervals. These epidemics typically occur in the fall, and can persist for months.
- Symptoms: The onset of symptoms can be insidious.
- General: Malaise, fever, chills, and headache occur early in the course
- A cough develops 3 to 5 days after the onset of general symptoms. It usually starts as nonproductive, but may lead to the production of frothy white sputum. Sputum production is not as copious as in typical bacterial pneumonias. The cough may become paroxysmal, and occasionally chest pain and hemoptysis occur.
- Dyspnea is common
- In those who are predisposed, infection may lead to reactive airway disease
- Nasal congestion and rhinorrhea are uncommon
- Bilateral bullous myringitis is highly suggestive, but rare
- Signs: Patients do not generally appear very ill.
- Pharyngitis: 75%
- Conjunctivitis: 50%
- Lymphadenopathy: 25% to 50%
- Chest examination: Findings are often minimal. If pneumonia is present, there may be isolated crackles or areas of wheezing over one or both of the lower lobes. Wheezing may be present in those with reactive airway disease. Signs of pleural effusion are occasionally present.
Nonrespiratory infections and complications may occur 1 to 21 days after initial symptoms. One must use caution in the diagnosis of an M. pneumoniae infection in individuals with extrapulmonary manifestations and no respiratory tract symptoms. In the past, the failure to isolate M. pneumoniae from nonrespiratory clinical specimens led to the conclusion that extrapulmonary complications were due to cross-reacting antibodies or by an unidentified toxin. However, through the use of PCR testing, M. pneumoniae has been identified in cerebrospinal fluid and serum, both of which are indicative of dissemination. Cross-reacting antibodies may still be the cause for hemolysis and cutaneous manifestations.
- Musculoskeletal Arthralgias, myalgias, arthritis, and rhabdomyolysis. The arthritis is usually monoarticular, but may be migratory and polyarticular.
- Gastrointestinal Gastroenteritis, hepatitis, and pancreatitis.
- Dermatological Most common are erythematous maculopapular lesions or vesicular exanthemas. Other rashes may be vesicular-pustular, petechial, or urticarial. Stevens-Johnson syndrome can occur.
- Hematological Hemolytic anemia, splenomegaly, thrombocytopenia, and disseminated intravascular coagulopathy.
- Cardiovascular Myocarditis, pericarditis, heart block, congestive heart failure, and acute myocardial infarction.
- Central nervous system (CNS): Meningitis, Guillain-Barré syndrome (GBS), cranial nerve involvement, sensorineural hearing loss, transverse myelitis, focal encephalitis, cerebellar involvement, and psychosis.
- Renal: Acute glomerulonephritis and interstitial nephritis.
- Ophthalmologic: Conjunctivitis, anterior uveitis, optic papillitis, and rarely optic neuropathy.
- Serological testing, although not routine, is the most useful of the laboratory tests.
- Cold agglutinins—cold agglutinins are elevated to a titer of >1:32 in 75% of cases. This test is nonspecific, and cold agglutinins may be elevated in patients with other disorders such as infection with EBV, or CMV, lymphoma, or hemolytic anemias. For patients younger than 12 years, cold agglutinins are insensitive and nonspecific.
- Complement-fixation serology—this test is more specific than cold agglutinins, but requires paired acute and convalescent titers and so is of little value in the acute setting.
- Enzyme-linked immunoassay (EIA) detects IgM and IgG antibodies against M. pneumoniae. The IgM test does not become positive until 7 to 10 days after the onset of symptoms, so may not be useful in guiding initial therapy.
- Direct antigen testing is increasingly available.
- Direct antigen testing in sputum may be performed using antigen-capture indirect EIA.
- Detection of M. pneumoniaeribosomal RNA using radioactive iodine–labeled complementary DNA.
- PCR assays are the most promising, being rapid with high sensitivity and specificity.
- White blood cell count—this is usually normal, although a mild leukocytosis may be present.
- Chest x-ray examination—variable; appearance is usually a non-lobar, patchy or interstitial pattern; occasionally a pleural effusion is present. Major consolidation is rare. The radiographic findings often appear worse than the clinical findings.
- Bacterial cultures—these are of little use, because M. pneumoniaemust be grown in cell culture, has fastidious growth requirements, and growth takes at least 3 weeks.
- Streptococcal pneumonia
- Viral pneumonia, including adenoviral infections, parainfluenza, and influenza
- Chlamydia pneumoniaeis a gram-negative intracellular pathogen that is a relatively common cause of pneumonia in adolescents and young adults. Between 35% and 45% of adolescents have been previously infected. Clinical symptoms are quite similar to those of M. pneumoniae. Diagnosis is based on serological testing, but specific testing for C. pneumoniae is difficult to obtain and requires acute and convalescent sera. Culture is even more difficult for C. trachomatis than for M. pneumoniae, and direct antigen detection does not appear to work well. Various PCR assays have been investigated, but none are as of yet standard. Treatment is with erythromycin, doxycycline, clarithromycin, or azithromycin.
- Legionellapneumonia—more than 40 Legionella species have been identified, but L. pneumophila accounts for approximately 2% to 6% of community-acquired pneumonias in adults. Pneumonic illness usually begins abruptly with malaise, headache, myalgia, and weakness. Approximately 24 hours later, a high fever develops in more than half of infected individuals. Nonproductive cough is most common. Other symptoms include pleuritic chest pain, dyspnea, nausea, vomiting, and abdominal pain. Diarrhea is common. Physical findings on chest examination are mild compared with the radiographic findings, but in general, patients appear quite ill. There are numerous pulmonary and extrapulmonary complications including lung abscesses, hypotension, disseminated intravascular coagulation, and renal failure.
- Less common causes of pneumonia in adolescents include tuberculosis infection, Q fever (Coxiella),rickettsial infections, and fungal infections. Other causes of pneumonia are rare in nonimmunosuppressed teenagers.
The diagnosis of Mycoplasma infections is most often presumptive and based on the patient's clinical presentation. In some instances, a more precise diagnosis may be required, and cold agglutinin tests may be performed quickly, even at the bedside. To perform the rapid test, add approximately 0.3 to 0.4 mL of blood to a standard laboratory collection tube containing 3.8% sodium citrate (a blue-stoppered Protime [PT] tube). Place the tube in ice-cold water for 15 to 30 minutes. Tilt on one side and examine for agglutination. The presence of coarse, floccular agglutination is a positive sign that correlates with a cold agglutinin titer of >1:64. Between 66% and 85% of adolescent patients with a positive cold agglutinin test result have M. pneumoniae infection. Other tests are described in the preceding text. PCR assays will likely become the diagnostic test of choice once they become more available.
Although most infections with M. pneumoniae are self-limited and resolve without treatment, antibiotic therapy has been shown to decrease the length and severity of illness.
- Rest, supportive care, and appropriate management of underlying or exacerbated reactive airway disease are important.
- Azithromycin: 500 mg on day 1, then 250 mg daily on days 2 through 5.
- Clarithromycin: 500 mg twice a day for 7 days.
- Erythromycin: 500 mg four times a day for 7 days.
- Tetracycline: 500 mg four times a day for 7 days.
- Doxycycline: 100 mg twice a day for 7 days
Pertussis, meaning “intense cough,” is widely unrecognized and under diagnosed in adolescents and young adults. The term pertussis is more appropriate than “whooping cough,” because many patients, particularly adolescents
and adults, do not “whoop.” Pertussis infection continues to cause fatal illness in vulnerable neonates and incompletely immunized infants, and adolescents and young adults are likely a major source of infection for these vulnerable populations.
Bordetella organisms are small gram-negative coccobacilli. Bordetella pertussis is the sole cause of epidemic pertussis, and the usual cause of sporadic pertussis. Only B. pertussisproduces pertussis toxin (PT). B. parapertussis may occasionally cause pertussis, but accounts for fewer than 5% of Bordetella isolates in the United States.
Pertussis is primarily a toxin-mediated disease with PT playing a major virulence role. Besides PT, B. pertussis produces other biologically active products and cytotoxins that impact the severity of the illness and induce protective immune responses. Transmission is through close contact with respiratory secretions, and intrafamilial spread is quite common in both immunized and nonimmunized individuals. The incubation period is commonly 5 to 10 days but may be as long as 21 days. Pertussis is primarily a mucosal disease, and although the organism may invade alveolar macrophages, there is no systemic invasion nor bacteremic phase of the illness.
Each year approximately 60 million cases of pertussis occur worldwide, resulting in >500,000 deaths. The incidence of pertussis demonstrates a cyclic pattern, with peaks occurring every 2 to 5 years—this was true in the prevaccine era, as well as today. Over the past decade, pertussis has increased significantly, even in highly immunized populations. Before widespread vaccine use, pertussis was the leading cause of death due to infectious disease in children younger than 14 years. Routine childhood vaccination resulted in a significant decrease in disease burden, and the rate of pertussis infection reached its lowest level in 1976. Since that time, there have been numerous epidemic outbreaks in the United States, and even the interepidemic rates have not returned to the low levels of 1976. The number of reported cases in the United States went from 4,570 in 1990, to 7,796 in 1996, 9,971 in 2001, 11,647 in 2003, and 25,827 in 2004. Most of the recent increase in pertussis illness has been attributed to disease in adolescents and adults, who now account for approximately half of all cases in the United States. From 1990 to 2004, there has been an 18.8-fold increase in the diagnosis of pertussis in 10- to 19-year olds and 15.5-fold increase in those 20 years and older. Seventy-six percent of illness in infants (who are most at risk for serious illness) is contracted from adolescents and adults (Bisgard et al., 2004). The increase in rate is thought to be a combination of waning immunity (immunity to whole cell pertussis and acellular pertussis is approximately 6 years or perhaps slightly longer) and improved recognition and diagnosis of the illness. In adolescents with prolonged cough illness, between 13% and 20% are due to B. pertussis infection.
The clinical severity of pertussis varies widely, and may be influenced by patient age, immunization history, degree of exposure, past antibiotic administration, and concomitant infections. Classic pertussis is divided into three stages:
- Catarrhal: This begins after the incubation period with nasal congestion and rhinorrhea that are sometimes accompanied by low-grade fever, sneezing, and watery eyes. Patients are most contagious at this time, but the symptoms are indistinguishable from a routine upper respiratory tract infection. These symptoms begin to wane after 1 to 2 weeks, as the paroxysmal stage begins.
- Paroxysmal: The onset of cough marks the beginning of the paroxysmal stage. The cough begins as dry and intermittent, which then evolves into the coughing paroxysms that are characteristic of pertussis. An otherwise well-appearing patient will have episodic coughing fits with choking, gasping, and feelings of strangulation and suffocation. A forceful inspiratory gasp sounding like a “whoop” is most frequently seen in young infants. Posttussive emesis is common. At its peak, these episodes may occur hourly.
- Convalescent: During this stage, the number, severity, and duration of the coughing paroxysms diminish.
The duration of classic pertussis is 6 to 10 weeks. Adolescents, particularly those who have been immunized, are unlikely to show distinct stages of illness. The adolescent may complain only of coughing episodes, with no history of fever or upper respiratory congestion, but the illness often leads to days or weeks of interrupted sleep and time away from school. The physical examination in between coughing episodes may be completely normal.
Pertussis is most contagious from approximately 1 to 2 weeks before the onset of cough and for 2 to 3 weeks after coughing begins. Therefore, in most cases, the person may have transmitted the disease to others before they are diagnosed and treated.
Complications are primarily seen in infants and young children and may include seizures, pneumonia, apnea, encephalopathy, and death. Adolescents rarely develop serious complications, but secondary bacterial pneumonia and adult-respiratory distress syndrome have been reported. Adolescents may develop subconjunctival hemorrhages due to increased intraabdominal and intrathoracic pressures when coughing.
- Profound leukocytosis: Profound leukocytosis with white blood cell counts from 15,000 to as high as 100,000/mm3due to an absolute lymphocytosis may be seen, particularly in the catarrhal phase. The platelet count may also be elevated, and significant thrombocytosis as well as extreme leukocytosis have been correlated with a more severe clinical course.
- Culture: Culture requires nasopharyngeal secretions obtained either by aspiration or with a Dacron (polyethylene terephthalate) or calcium alginate swab that are then plated on special media. The incubation period is 10 to 14 days, and so culture rarely guides treatment decisions. False-negative cultures may occur after the second week of illness, or if antibiotics have been administered.
- Direct immunofluorescence assay (DFA): DFA of nasopharyngeal secretions may help guide early treatment decisions, but the test is unreliable due to variable sensitivity and low specificity, and culture confirmation of the test should be attempted.
- Serology: Pertussis infection elicits a heterogeneous antibody response that differs between individuals depending on immune status, age, and history of previous infection. No single test is diagnostic, and to achieve acceptable sensitivity and specificity, acute and convalescent titers must be obtained.
- DNA amplification: If available, the PCR for the diagnosis of pertussis has shown great promise, being rapid, and having a sensitivity of 97% and specificity of 93%.
- Adenoviral infection
- Mycoplasma pneumonia
- Chlamydia pneumonia
Pertussis should be suspected in any adolescent with a complaint of a cough lasting >1 to 2 weeks, regardless of immunization status. A history of posttussive vomiting and a lymphocytosis on laboratory evaluation support the diagnosis, as do the absence of other symptoms, such as fever, and lack of findings on physical examination. Because laboratory confirmation of pertussis may be delayed or unavailable, the diagnosis is often made based on clinical evaluation. Increasing use of PCR as a diagnostic tool may change the ability of health care providers to make a more timely diagnosis.
All cases of suspected or confirmed pertussis should receive appropriate antibiotic therapy. Treatment may provide some clinical benefit, and clearly decreases the spread of infection.
- Erythromycin 500 mg 4 times daily for 14 days has been the traditional treatment.
- Azithromycin has been shown to be as effective as erythromycin and is better tolerated. Dose is given daily for 5 days; 500 mg on day 1 and 250 mg on days 2 to 5.
- Clarithromycin 500 mg twice daily for 7 days is another alternative.
- Trimethoprim-sulfamethoxazole is an alternative for those who are unable to tolerate treatment with macrolides. Dose is 1 double-strength tablet twice daily for 14 days.
- Treatment with a full course of antibiotics is indicated for all household contacts regardless of immunization status. Prompt treatment can limit secondary transmission, because pertussis immunity is not absolute and even those with subclinical disease may be able to transmit the illness to others. Treatment is particularly important for those who have close contact with infants and other young children.
- Close contacts younger than 7 years who have received fewer than four doses of pertussis vaccine should be immunized appropriately.
- Others who have been in contact with the infected individual should be monitored for symptoms for 21 days after the most recent contact.
- Students with pertussis should be excluded from school. Patients are considered no longer infectious after 5 days of antibiotic therapy, and may return to school at that time. If they are unable to take antibiotics, they are considered infectious for 21 days after the onset of cough.
Universal pertussis immunization is recommended for children starting at 2 months of age and has been widely used in combination with diphtheria and tetanus toxoids (diphtheria, tetanus, pertussis [DTP]) since the 1940s. Whole cell pertussis vaccines (DTwP) were utilized in the United States until the mid-1990s. These vaccines frequently caused local reactions as well as significant fever and were uncommonly associated with more severe systemic effects such as convulsions and hypotonic and hyporesponsive episodes. Less reactogenic acellular pertussis vaccines (DTaP), containing purified inactivated components of the B. pertussis organism, are highly effective and they have replaced the use of the whole cell vaccine in the United States. The primary series of four doses of DTaP are administered at 2, 4, 6, and 15 to 18 months of age. A fifth dose of DTaP vaccine is recommended before school entry to assure protection of school-aged children.
Natural and vaccine-induced immunity to pertussis wane over time, leaving adolescents and adults susceptible to infection. Two acellular pertussis vaccines have recently been licensed for use in adolescents (Tdap). In order to decrease vaccine reactogenicity, the adolescent pertussis formulations are combined with lower concentrations of tetanus toxoid, diphtheria toxoid, and PT than are present in the infant formulations. Acellular pertussis vaccine in adolescents induces comparable levels of tetanus and diphtheria antibody as the tetanus and diphtheria toxoids (Td) booster as well as antibody responses to pertussis that are higher than those seen in infants who were shown to be protected from pertussis in previous efficacy studies. Tdap has demonstrated effectiveness at reducing pertussis disease in adolescents and adults. Tdap is indicated for:
- Routine use in adolescents at 11 to 12 years replacing the standard Td booster previously administered at this age.
- Older adolescents, young adults, and older adults up to 64 years, who have not received a dose of Tdap provided that it has been at least 2 years since a previous dose of Td vaccine.
Tdap should not be administered to those with a severe allergic reaction or an immediate life-threatening reaction after receipt of a prior dose of a vaccine containing the same substances (DTaP, DTP, DT, Td), or to those with encephalopathy not attributable to another identifiable cause within 7 days of a prior dose of a pertussis-containing vaccine.
Influenza is an acute respiratory illness that is highly contagious, affects all age-groups, and has caused epidemics for hundreds of years. Although most influenza infections in adolescents are self-limited, those patients with chronic illness such as asthma or cardiac disease may develop a serious life-threatening infection.
Influenza viruses are orthomyxoviruses that are enveloped with two important surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). Influenza viruses are classified as A, B, or C. Influenza A and B viruses are responsible for seasonal epidemics, whereas C virus is responsible for mild, common cold–like illnesses. Influenza A viruses are further categorized into subtypes on the basis of HA and NA. Since 1977 there have been two predominant circulating subtypes, influenza A (H1N1) and influenza A (H3N2). Influenza B is not subtyped. Influenza A and B are indistinguishable clinically, but influenza A (H3N2) viruses are generally associated with the most severe epidemics.
Influenza viruses are negative-sense RNA viruses that contain eight separate gene segments. During virus replication, point mutations in the gene segments can lead to minor antigenic virus variants. Minor antigenic changes occur frequently and lead to yearly epidemics of influenza illness. Novel influenza subtypes are due to genetic reassortment and lead to episodic influenza pandemics. Reassortment between animal and human influenza viruses may occur if a suitable host such as a pig is coinfected by human and animal influenza viruses. Occasionally, an animal virus may begin infecting humans, such as in Hong Kong in 1997 when avian influenza A (H5N1) seen in poultry began infecting humans.
Transmission is person to person through respiratory droplets or by direct contact with articles recently contaminated by nasopharyngeal secretions. The incubation period is only 1 to 4 days, and a single infected person may transmit the virus to a large number of susceptible individuals. Patients are most infectious during the 24 hours before and through the peak of symptoms. Viral shedding continues for approximately 7 days after the onset of symptoms. Seasonal epidemics typically occur during the winter. Local outbreaks can peak within 2 weeks of onset and last 4 to 8 weeks.
Although influenza may be sporadically identified through the year, epidemics typically occur annually during the winter months. Influenza A generally occurs annually, whereas influenza B recurs every 3 or 4 years. Changes in viral HA and, to a lesser extent, NA account for ability of influenza to cause regular epidemics. Different strains of influenza are associated with varying severities of illness—H3N2 appears to be more virulent than the H1N1-associated illness, and both strains of influenza A appear to be more virulent than influenza B. Despite this, there is no way to clinically differentiate between the various strains.
Local epidemics are maintained by high infection rates in young children. During these outbreaks, infection rates may be as high as 40% for school-aged and preschool children, as opposed to infection rates in young adults of 10% to 20%. Although for most adolescents, influenza may be nothing more than a bad cold, it is a cause of morbidity, particularly for younger children and those with underlying medical conditions. Among those aged 5 to 14 years, influenza accounts for a hospitalization rate of 20 to 40 per 100,000 population, but 200 per 100,000 in those with high-risk conditions such as asthma or heart disease.
- Sudden onset of fever and chills
- Nonproductive cough
- Sore throat
- Nausea, vomiting, diarrhea are more common in younger patients
- Patient appears unwell
- Hyperemic mucous membranes
- Injected conjunctiva
- Clear rhinorrhea
The fever is often as high as 40°C, peaks within 24 hours of the onset of symptoms, and may last up to 5 days. The dry, hacking cough may persist for up to 1 week after the other symptoms have resolved.
- Primary viral pneumonia
- Guillian-Barre Syndrome
- Reye syndrome
- White blood cell count is usually normal, although there may be a relative neutrophilia and lymphopenia.
- Viral culture: The time needed for this test renders it impractical for use in clinical care.
- DFA and indirect fluorescent antibody (IFA) staining.
- Viral antigen detection.
- Antibodies are either directly or indirectly conjugated to a fluorescein compound. These antibodies bind to influenza antigen, and are then detected under a fluorescent microscope.
- Must be performed at a hospital or reference laboratory.
- Results are available in 2 to 4 hours.
- Tests have low sensitivity (62%–74%), but high specificity (97%–98%). Therefore, it is unusual to have false-positive test results, but false-negative results are more common.
- Rapid diagnostic test: Immunoassay
- Viral nucleoprotein detection
- Antibodies bind to the viral nucleoprotein, and are detected by visualizing a color change.
- May be performed in the hospital or reference laboratory, or in a medical office.
- Results are available in approximately 15 minutes.
- Sensitivity varies widely, from 40% to 100%, as does specificity, ranging from 63% to 100%.
- Rapid diagnostic test: Viral NA detection
- Viral NA catalyzes a chemical reaction that is detected by visualizing a color change.
- May be performed in the hospital or reference laboratory, or in a medical office.
- Results are available in approximately 30 minutes.
- Sensitivity varies from 48% to 96%, and specificity ranges from 63% to 93%.
- Bacterial infections
- Streptococcal pneumonia
- Chlamydia pneumonia
- Mycoplasma pneumonia
- Other viral infections
- Respiratory syncytial virus
The clinical diagnosis of influenza can be difficult, even during peak influenza activity, because many other circulating respiratory viruses exhibit similar symptoms. During episodes of peak disease activity it is impractical to test every patient with signs and symptoms of influenza. Therefore, the diagnosis is often made based on the clinical presentation of the patients, as well as the prior probability of influenza based on local rates of influenza activity. There is little data examining the validity of the clinical diagnosis of influenza in adolescents, but the reported positive predictive value of the clinical diagnosis in adults varies widely, from 18% to 87% as compared with laboratory-confirmed influenza. During a seasonal outbreak, the diagnosis should be considered in any adolescent who presents with the sudden onset of fever and a dry, nonproductive cough.
Most adolescents who contract influenza will require supportive care only. Ibuprofen or acetaminophen may be used for fever, headache, and myalgia. Patient should be cautioned against the use of aspirin because of the potential for the development of Reye syndrome. Patients who have underlying illness or otherwise healthy patients who present for treatment within 48 hours of the onset of symptoms may benefit from treatment with antiviral medications. These medications have been shown to decrease the time to symptom resolution to 1 to 2 days.
- Approved for treatment of influenza A in children 1 year and older
- Interferes with M2 protein function
- May cause CNS disturbance
- Adolescent treatment dose: 100 mg by mouth twice a day for 5 days
- May be unhelpful in the treatment of resistant strains; it is important to be aware of local patterns of resistance
- Approved for treatment of influenza A in adults; approved for chemoprophylaxis of influenza A in children 1 year and older
- Interferes with M2 protein function
- Causes less CNS disturbance than amantadine
- Adolescent treatment dose: 100 mg b.i.d. by mouth twice a day for 5 days
- May be unhelpful in the treatment of resistant strains; it is important to be aware of local patterns of resistance
- Approved for treatment of influenza A and B in children 1 year and older; approved for chemoprophylaxis of influenza A and B in adolescents 13 years and older
- Inhibits viral NA
- Adolescent treatment dose: 75 mg by mouth twice a day for 5 days
- Approved for treatment of influenza A and B in children 7 years and older
- Inhibits viral NA
- Orally inhaled powder
- Should not be used in patients with underlying respiratory diseases such as asthma because bronchospasm may occur
- Adolescent dose: Two inhalations (5 mg each inhalation) twice a day for 5 days
Although antiviral agents may be used for the prevention of influenza, the primary means is through immunization. Vaccines are currently trivalent, containing two A antigens (representing both the H1N1 and H3N2 subtypes) and a B antigen. In years when there is an ample vaccine supply, influenza vaccine should be given to any adolescent and young adult requesting vaccination. Vaccine should be prioritized for adolescents who are at increased risk of developing severe complications due to influenza including:
- Those with chronic disorders of the pulmonary or cardiovascular systems, including asthma
- Those who had required regular medical follow-up or hospitalization during the preceding year for the following conditions:
- Chronic metabolic diseases (including diabetes mellitus)
- Renal dysfunction
- Those who have any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration
- Those who are receiving long-term aspirin therapy and, therefore, might be at risk for experiencing Reye syndrome after influenza infection
- Those who will be pregnant during the influenza season
There are two options for immunization—trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV). Both vaccines are trivalent and both vaccine viruses are grown in chicken eggs. TIV is a killed virus product administered by intramuscular injection, whereas LAIV is a live attenuated virus product administered using an intranasal sprayer. Neither vaccine should be given to those with a history of an anaphylactic hypersensitivity to eggs or to other specific vaccine components. TIV can be used for both healthy adolescents as well as those with high-risk medical conditions. Use of LAIV should be restricted to healthy adolescents only and should not be administered to those with the high-risk medical conditions noted in the preceding text. In addition,
LAIV should not be administered to those with a history of Guillian-Barre Syndrome (GBS). The decision to use TIV in patients with a history of GBS should be made on an individual basis. For those at low risk of complications due to influenza and for those who experienced GBS within 6 weeks of receipt of a prior influenza vaccine, TIV should be avoided.
For Parents and Teens
www.cdc.gov/flu. Mass of information available for both adolescents, parents and health care providers.
www.familydoctor.org. The American Academy of Family Practice has a number of patient-education handouts available including mononucleosis and influenza, and Spanish translations are available.
www.aap.org/parents.html. The American Academy of Pediatrics has patient education information primarily listed by symptom rather than condition.
For Health Care Providers
www.cdc.gov/flu/weekly. Every week from October through mid-May, the Centers for Disease Control and Prevention publishes weekly influenza surveillance reports.
www.cdc.gov/flu. Mass of information available for both adolescents, parents and health care providers.
There are a variety of commercial Web sites available that offer patient handouts, as well as information for clinicians. Two of these include Up to Date, available at http://uptodate.com, and MDConsult, available at http://mdconsult.com. Many academic institutions have subscriptions, but they are subscription services for individuals.
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