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.
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:
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%.
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.)
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.
The diagnosis is based on the following considerations:
Only supportive care is required for most patients with IM.
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:
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.
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.
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.
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.
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:
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.
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.
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:
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.
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.
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.
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:
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.
References and Additional Readings
Ambinder RF. Epstein-Barr virus-associated lymphoproliferative disorders. Rev Clin Exp Hematol 2003;7(4):362.
Anikster Y, Glustein JZ, Weill M, et al. Extrapulmonary manifestations of Mycoplasma pneumoniae infections. Isr J Med Sci 1994;30:412.
Auwaerter PG. Infectious mononucleosis in middle age. JAMA 1999;281(5):454.
Baum SG. Introduction to mycoplasma diseases. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases, 5th ed. New York: Churchill Livingstone, 2000:2015.
Baum SG. Mycoplasma pneumoniaae and atypical pneumonia. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases, 5th ed. New York: Churchill Livingstone, 2000:2018.
Biscardi S, Lorrot M, Marc E, et al. Mycoplasma pneumoniae and asthma in children. Clin Infect Dis 2004;38:1341.
Bisgard KM, Pascual FB, Ehresmann KR, et al. Infant pertussis: Who was the source? Pediatr Infect Dis J 2004;23:985.
Boivin G, Hardy I, Tellier G, et al. Predicting influenza infections during epidemics with use of a clinical case definition. Clin Infect Dis 2000;31:1166.
Burroughs KE. Athletes resuming activity after infectious mononucleosis. Arch Fam Med 2000;9(10):1122.
Candy B, Chalder T, Cleare AJ, et al. Recovery from infectious mononucleosis: a case for more than symptomatic therapy? A systematic review. Br J Gen Pract 2002;52:844.
Carrat F, Tachet A, Rouzioux C, et al. Evaluation of clinical case definitions of influenza: detailed investigation of patients during the 1995–1996 epidemic in France. Clin Infect Dis 1999;28:283.
Centers for Disease Control and Prevention. Pertussis: United States, 1997–2000. MMWR Morb Mortal Wkly Rep 2002;51:73.
Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2005;54(RR-8):1.
Chan SC, Dawes PJ. The management of severe infectious mononucleosis tonsillitis and upper airway obstruction. J Laryngol Otol 2001;115(12):973.
Chatterjee A. Mycoplasma infections. eMedicine. August 1, 2002. Available at www.emedicine.com/ped/topic1524.htm. accessed November 19, 2005.
Chen CJ, Huang YC, Jaing TH, et al. Hemophagocytic syndrome: a review of 18 pediatric cases. J Microbiol Immunol Infect 2004;37(3):157.
Cherry JD. The epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of bordetella pertussis infection. Pediatrics2005;115:1422.
Cherry JD, Grimprel E, Guiso N, et al. Defining pertussis epidemiology: clinical, microbiologic, and serologic perspectives. Pediatr Infect Dis J 2005;24(5):S25.
Cherry JD, Heininger U. Pertussis. In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases, 5th ed. Philadelphia: WB Saunders, 2003.
Cimolai N. Mycoplasma pneumoniae respiratory infection. Pediatr Rev 1998;19(10):327.
Collins M, Fleisher GR, Fager SS. Incidence of beta hemolytic streptococcal pharyngitis in adolescents with infectious mononucleosis. J Adolesc Health 1984;5(2):96.
Cooper MJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomized controlled trials. Brit Med J 2003;326:1235.
Cox NJ, Subbarao K. Influenza. Lancet 1999;354:1277.
Cromer BA, Goydos J, Hackell J, et al. Unrecognized pertussis infection in adolescents. Am J Dis Child 1993;147:575.
Cunha BA. Influenza: historical aspects of epidemics and pandemics. Infect Dis Clin North Am 2004;18(1):141.
Dragsted DM, Dohn B, Madsen J, et al. Comparison of culture and PCR for detection of Bordetella pertussis and Bordetella parapertussis under routine laboratory conditions. J Med Microbiol 2004;53(Pt 8):749.
Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician 2004;70(7):1279.
Edwards KM. Is pertussis a frequent cause of cough in adolescents and adults? Should routine pertussis immunization be recommended? Clin Infect Dis 2001;32:1698.
Epstein MA. Reflections of Epstein-Barr virus: some recently resolved old uncertainties. J Infect 2001;43(2):111.
Esposito S, Bosis S, Faelli N, et al. Role of atypical bacteria and azithormycin therapy for children with recurrent respiratory tract infections. Pediatr Infect Dis J 2005;24(5):438.
Foreman BH, Mackler L. Can we prevent splenic rupture for patients with infectious mononucleosis? J Fam Pract 2005;54(6):547.
Ginevra C, Barranger C, Ros A, et al. Development and evaluation of Chlamylege, an new commercial test allowing simultaneous detection and identification of Legionella, Chlamydophila pneumoniae, and mycolasma pneumoniae in clinical respiratory specimens by multiplex PCR. J Clin Microbiol 2005;43(7):3247.
Glezen WP, Greenberg SB, Atmar RL, et al. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000;283:499.
Godshall SE, Kirchner JT. Infectious mononucleosis: complexities of a common syndrome. Postgrad Med 2000;107(7):175.
Goetz MB, Rhew DC, Torres A. Pyogenic bacterial pneumonia, lung abscess, and empyema. In: Mason RJ, Murray JF, Broaddus VC et al., eds. Murray & Nadel's textbook of respiratory medicine, 4th ed. Philadelphia: Elsevier Science, WB Saunders, 2005:920.
Grayston JT, Campbell La, Kuo CC, et al. A new respiratory tact pathogen: Chlamydia pneumoniae strain TWAR. J Infect Dis 1990;161:618.
Grotto I, Mimouni D, Huerta M, et al. Clinical and laboratory presentation of EBV positive infectious mononucleosis in young adults. Epidemiol Infect 2003;131:683.
Halperin SA, Bortolussi R, Langley JM, et al. A randomized, placebo-controlled trial of erythromycin estolate chemoprophylaxis for household contacts of children with culture-positive Bordetella perussis infection. Pediatrics 1999;104:e42.
Hammerschlag MR. Pneumonia due to Chlamydia pneumoniae in children: epidemiology, diagnosis, and treatment. Pediatr Pulmonol 2003;36:384.
Hardegger D, Nadal D, Bossrt W, et al. Rapid detection of Mycoplasma pneumoniae in clinical samples by real-time PCR. J Microbiol Methods 2000;41(1):45.
Hijazi Z, Pacsa A, Eisa S, et al. Laboratory diagnosis of acute lower respiratory tract viral infectious in children. J Trop Pediatr 1996;42:276.
van der Horst C, Joncas J, Ahronheim G, et al. Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis. J Infect Dis 1991;164(4):788.
Jefferson T, Smith S, Demicheli V, et al. Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet 2005;365:773.
Kindernecht JJ. Infectious mononucleosis and the spleen. Curr Sports Med Rep 2002;1(2):116.
Lahat E, Berkovitch M, Barr J, et al. Abnormal visual evoked potentials in children with “Alice in Wonderland” syndrome due to infectious mononucleosis. J Child Neurol1999;14(11):732.
Langly JM, Halperin SA, Boucher FD, et al. Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics 2004;114:96.
Long SS. Pertussis (Bordetella pertussis and B. Parapertussis). In: Behrman RE, Kliegman R, Jenson HM, eds. Nelson's textbook of pediatrics, 17th ed. Philadelphia: WB Saunders, 2004.
Long SS, Welkin CJ, Clark JL. Widespread silent transmission of pertussis in families: antibody correlates of infection and symptomatology. J Infect Dis 1990;161:473.
Lorenzo CV, Robertson WS. Genital ulcerations as presenting symptom of infectious mononucleosis. J Am Board Fam Pract 2005;18(1):67.
Merriam SC, Keeling RP. Beta-hemolytic streptococcal pharyngitis: uncommon in infectious mononucleosis. South Med J 1983;76(5):575.
Monto AS, Gravenstein S, Elliot M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000;160:3243.
Morais-Almeida M, Marinho S, Gaspar A, et al. Cold urticaria and infectious mononucleosis in children. Allergol Immunopathol (Madr) 2004;32(6):368.
Morozumi M, Hasegawa K, Chiba N, et al. Application of PCR for Mycoplasma pneumoniae detection in children with community-acquired pneumonia. J Infect Chemother2004;10(5):274.
Morris MC, Edmunds WJ. The changing epidemiology of infectious mononucleosis. J Infect 2002;45:107.
Mullooly JP, Barker WH. Impact of type A influenza on children: a retrospective study. Am J Public Health 1982;72:1008.
Murray BJ. Medical complications of infectious mononucleosis. Am Fam Physician 1984;30(5):195.
Nicholson AG, Wotherspoon AC, Diss TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology1996;29(4):317.
Niesters HGM, van Esser J, Fries E, et al. Development of a realtime quantitative assay for detection of Epstein-Barr virus. J Clin Microbiol 2000;38:712.
Pichichero ME, Casey JR. Acellular pertussis vaccines for adolescents. Pediatr Infect Dis J 2005;24(6):S117.
Pickering LK, ed. American Academy of Pediatrics. Red Book: 2003 report of the committee on infectious diseases, 26th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2003.
Pitetti RD, Laus S, Wadowsky RM. Clinical evaluation of a quantitative real time polymerase chain reaction assay for diagnosis of primary Epstein-Barr virus infection in children.Pediatr Infect Dis J 2003;22(8):736.
Rea TD, Russo JE, Katon W, et al. Prospective study of the natural history of infectious mononucleosis caused by Epstein-Barr virus. J Am Board Fam Pract 2001;14:234.
Renn CN, Straff W, Dorfmuller A, et al. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Br J Dermatol 2002;147:1166.
Rennels MB, Meissner HC. Technical report: reduction of the influenza burden in children. Pediatrics 2002;110:e80.
Rodriguez WJ, Schwartz RH, Thorne MM. Evaluation of diagnostic tests for influenza in a pediatric practice. Pediatr Infect Dis J 2002;21:193.
Stenfors LE, Bye HM, Raisanen S, et al. Bacterial penetration into tonsillar surface epithelium during infectious mononucleosis. J Laryngol Otol 2000;114(11):848.
Strebel P, Nordin J, Edwards K, et al. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995–1996. J Infect Dis 2001;183:1353.
Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children: part I. Clinical and general laboratory findings. Pediatrics 1985;75(6):1003.
Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children: part II. Heterophil antibody and viral-specific responses. Pediatrics 1985;75(6):1011.
Teo SSS, Nguyen-Van-Tam JS, Booy R. Influenza burden of illness, diagnosis, treatment, and prevention: what is the evidence in children and where are the gaps? Arch Dis Child2005;90:532.
Terebuh P, Uyeki T, Fukuda K. Impact of influenza on young children and the shaping of United States influenza vaccine policy. Pediatr Infect Dis J 2003;22:S231.
Torre D, Tambini R. Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis 1999;31:543.
Tozzi AE, Celentano LP, degli Atti ALC, et al. Diagnosis and management of pertussis. Can Med Assoc J 2005;172(4):509.
Tsai HP, Kuo PJ, Liu CC, et al. Respiratory viral infections among pediatric inpatients and outpatients in Taiwan from 1997 to 1999. J Clin Microbiol 2001;39:111.
Uyeki TM Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J 2003;22:164.
Vincent MT, Celestin N, Hussain A. Pharyngitis. Am Fam Physician 2004;69(6):1465.
Waits KB, Talkington DF. Mycoplasma pneumonia and its role as a human pathogen. Clin Microbiol Rev 2004;17(4):697.
Ward JI, Cherry JD, Chang S, et al. Efficacy of acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555.
Weiner LB, McMillan JA. Mycoplasma pneumoniae. In: Long SS, Pickering LK, Prober CG, eds. Principles and practice of pediatric infectious diseases, 2nd ed. Philadelphia: Churchill Livingstone, 2003.
Yuen KY, Chan PKS, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1. Lancet 1998;351:467.
Zambon M, Hays J, Webster A, et al. Diagnosis of influenza in the community: relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza. Arch Intern Med 2001;161:2116.
Zambon MC, Stockton JD, Clewley JP, et al. Contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study. Lancet2001;358:1410.