Afebrile Pneumonia Syndrome

Although many organisms can cause afebrile pneumonia syndrome (APS), this article focuses on Chlamydia trachomatis, cytomegalovirus (CMV), and Ureaplasma urealyticum, which are vertically transmitted to newborns during passage through the birth canal or, in the case of CMV, also during breastfeeding. In a series, C trachomatis was identified as the causative agent in 5-90% of patients, CMV was identified in 0-23%, and U urealyticum was identified in 0-21%.

Chlamydia trachomatis

C trachomatis colonizes the genital tracts of 2-13% of pregnant women (with higher rates among unmarried women with lower socioeconomic status, a greater number of sexual partners, and younger age) and is transmitted to more than 50% of their infants. Portals of entry include the eyes, nasopharynx, respiratory tract, and vagina. If left untreated, 5-13% of infants colonized by C trachomatis develop pneumonia.

Cytomegalovirus infection

CMV has been identified in the genital tracts of 11-28% of women close to term and in breast milk of 10-20% of mothers who are breastfeeding. More than 50% of exposed infants become infected, but development of pneumonia is uncommon.

Ureaplasma urealyticum

U urealyticum colonizes the genital tract of 40-80% of pregnant women (with risk factors similar to those for C trachomatis) and the mucous membranes of 16% of newborns with low birthweight and 8-11% of infants who weigh more than 2500 g at birth. How frequently U urealyticum causes pneumonia remains unclear.

Other pathogens

Other common causative agents associated with seasonal or epidemic occurrences include respiratory syncytial virus (RSV), parainfluenza, human bocavirus, human metapneumovirus, and adenovirus. These organisms cause APS, as well as more typical bronchiolitis, pneumonia, pneumonitis, laryngotracheobronchitis, and conjunctivitis/pharyngitis. In contrast to the vertically transmitted etiologies, these viruses cause highly contagious infections that are horizontally transmitted. RSV infection is the most commonly identified cause of pneumonia (typically febrile) in neonates and infants younger than 6 months (79% of cases) in the United States. This frequency may be artificially elevated because of the ease with which this diagnosis can be made.

P jiroveci is increasingly being recognized as a cause of APS. Among newborns and infants, P jiroveci appears to cause asymptomatic infection more commonly than it causes any recognizable disease. The extent to which human bocavirus, human metapneumovirus, and S negevensis (a Chlamydia -like organism) cause APS will be determined as they become more easily identified in the clinical setting.

Risk factors

Factors that are associated with increased risk of contracting APS in infants include the following:

• Low socioeconomic status

• Young maternal age

• Multiple maternal sex partners

• Unmarried maternal status

• Exposure to other children at home or in daycare

• Exposure to secondhand smoke

The frequency of APS is unknown. Vertically transmitted APS is more common among children of lower socioeconomic status and those who have the risk factors listed above. All APS infections tend to be more common in regions where crowding and poor hygiene predominate.

APS is generally a benign and self-limiting disease. However, one long-term follow-up study showed a 3.4% mortality rate among 205 infants younger than 3 months who had APS.[9] In the study, 46% of infants who survived experienced one or more episodes of wheezing by age 4 years, and 15% of infants had persistently abnormal chest radiographic findings for at least 12 months.

Of children with APS who were monitored for 5 years, 60% had abnormal pulmonary function test results. Abnormal results occurred irrespective of prematurity, atopy, or the etiologic agent associated with the APS. Evidence indicates that respiratory infections in infancy predispose patients to obstructive airway disease later in life.

Immediate prognosis is good for more than 95% of affected infants, although long-term prognosis for significant morbidity is high. Following a 5-year follow-up period, 60% of infants have abnormal pulmonary function test findings. More than one half of infants with chlamydial pneumonitis have obstructive airway disease and physician-diagnosed asthma by age 7 years.

Complications

Secondary bacterial infection may occur, particularly with viral disease.

Early symptoms of respiratory disease in neonates and infants are frequently nonspecific and include changes in feeding status, listlessness, irritability, and poor color. Onset may be acute or subacute. Typically, infants are afebrile or have only a low-grade fever (< 102°F).

Viral afebrile pneumonia syndrome (APS) typically has a more rapid onset, with a 1- to 2-day history of rhinorrhea and, often, a brassy cough. Nonspecific findings of poor feeding, lethargy, and irritability may be accompanied by congestion, apnea (uncommon), and cyanosis (rare).

Symptoms of APS from Chlamydia trachomatis typically begin at age 2-19 weeks. Onset is insidious, often occurring over several days to weeks. No signs of systemic illness are apparent, but infants with mild-to-moderate illness often have a repetitive staccato cough (inspiration between each single cough).[1, 10]  In one study, most of the infants with C trachomatis lower respiratory tract infection were afebrile, and 47% had wheezing.[3] A history of conjunctivitis (which may be concurrent) increases the possibility of chlamydial infection.[11]

Ureaplasma urealyticum

U urealyticum is typically associated with prematurity and chronic lung disease. U urealyticum has been routinely isolated from the lower respiratory tract and lung biopsy specimens from infants with low birthweight, premature infants with pneumonia, and infants younger than 3 months who have chronic lung disease. Nevertheless, the role of this organism in development of lower respiratory tract infections in other infants remains unclear. Infection may manifest in this population as chronic lung disease, acute deterioration, or subacute deterioration in lung function.

Cytomegalovirus

Clinical manifestations of disease from CMV vary with the age and immunologic status of the child. Although infection following vertical transmission is usually not associated with clinical illness, maternal cervical colonization commonly occurs; therefore, many infants are exposed at birth. Cervical excretion rates are highest among young mothers in lower socioeconomic groups. Most infants infected are asymptomatic, but some may develop interstitial pneumonitis in early infancy. Because CMV infection is common in newborns, its association with afebrile pneumonia has been questioned. Symptoms are typically not distinguishable from those in APS from other causes.

Respiratory syncytial virus

RSV is likely the most common cause of afebrile pneumonia in young infants, although it more frequently causes febrile pneumonia or bronchiolitis, since the incidence of chlamydial APS seems to be decreasing. Peak age of onset is 2-5 months. Infection during the first few weeks of life may produce minimal respiratory signs. Lethargy, irritability, and poor feeding (which signal a possible illness in any young infant) accompanied by periods of apnea may be the major manifestations of infection. Most infants do not require hospitalization. However, the illness can be severe or fatal in some infants, particularly if associated with cyanotic or congenital heart disease, prematurity, or immunodeficiency due to disease or immunosuppressive therapy.

RSV infection is usually epidemic during the winter and early spring months, primarily affects children in the first 3 years of life, and is spread horizontally by household or childcare center contacts. Although wheezing and typical bronchiolitis may be noted, nonspecific symptoms more typical of APS may predominate.

Adenovirus

Adenovirus is an infrequent cause of croup and bronchiolitis. In infancy, adenovirus can cause severe pneumonia, which may disseminate, resulting in death. Infants may present with conjunctivitis, pharyngitis, respiratory tract symptoms, and, possibly, gastrointestinal tract disturbances. Less commonly, adenoviral disease may result in more typical APS.

Parainfluenza virus

Parainfluenza virus infections may be epidemic or sporadic. Type 1 occurs every other fall and manifests as croup. Type 2 also occurs in the fall, but disease is typically less severe than that caused by type 1. Type 3 infection occurs in the spring and summer and is usually acquired during the first 2 years of life; it is also a major cause of lower respiratory tract infection. Repeat infection may occur at any age and is usually milder, resulting in upper respiratory tract infections. Individuals with immunodeficiency can develop severe lower respiratory tract infection with prolonged viral shedding. Secondary bacterial infections are common after viral disease. Rarely, apnea may occur in infants younger than 6 months and may necessitate short-term apnea monitoring. Otherwise, APS secondary to infection by parainfluenza virus may be clinically indistinguishable from APS that results from other causes.

Pneumocystis jiroveci

P jiroveci, a pathogen related to fungi, is best known as a cause of opportunistic disease in immunocompromised individuals. Recently, it has also been associated with afebrile pneumonia in immunocompetent infants. Approximately 75% of healthy persons acquire antibody to P jiroveci by age 4 years. Onset of symptoms during the first month of life is rare; peak incidence of infection is from age 2-6 months. The mode of transmission of P jiroveci is unknown. Typically, infection is asymptomatic, but it may cause APS in a small percentage of infants who are exposed to the pathogen.

Signs of APS are typically nonspecific, and considerable overlap occurs among the various causes. Rarely, infants may display lethargy or irritability and poor color.

Respiratory findings may include cough, tachypnea, and crackles. Cough, which may be staccato (particularly in C trachomatis infection), is nearly universal. Tachypnea and crackles are usually present. In APS caused by C trachomatis, auscultatory findings may be out of proportion to the overall healthy appearance of the infant.

Respiratory distress is typically only mild to moderate and may include the following:

• Retractions

• Grunting

• Flaring

Apnea is uncommon. Cyanosis is rare.

Other pulmonary findings are possible but uncommon and may include the following:

• Decreased aeration

• Dullness to percussion

• Wheezing[12]

Conjunctivitis suggests C trachomatis infection (present concurrently or in the history in half of cases). GI tract, conjunctival, or pharyngeal involvement may suggest adenovirus infection. Concomitant hepatosplenomegaly or lymphadenopathy may suggest CMV infection.

Knowledge of the likely pathogens in afebrile pneumonia syndrome (APS) can guide the selection of laboratory studies. However, detection of one of these organisms is not conclusive evidence of causation because all of them may colonize infants without producing disease.

Complete blood cell count

In patients with APS, the complete blood cell count may reveal a mild eosinophilia, with or without mild leukocytosis.

Serology

Serum immunoglobulin levels are typically moderately elevated.

Tests for Chlamydia trachomatis

Tissue culture isolation of the organism from nasopharyngeal specimens is the most useful test for C trachomatis. If conjunctivitis is present, conjunctival specimens are also helpful. Nonculture techniques include direct fluorescent antibody (DFA) tests and enzyme-linked immunoassays (EIAs).

Polymerase chain reaction (PCR), ligase chain reaction (LCR), and other nucleic acid probe techniques are routinely becoming more widely available.[13, 14]

Serology is useful but takes longer than the above-named tests.

Tests for Cytomegalovirus

Cell culture is the definitive test for CMV. Urine, respiratory secretions, or blood buffy coat (including the shell-vial centrifugation technique) may be used. Polymerase chain reaction and nucleic acid hybridization are becoming more readily available.[15]  Serology is often useful, although it takes longer than more direct methods.

Tests for Ureaplasma urealyticum

U urealyticum can be cultured from respiratory secretions. PCR and serology are not routinely available.

Tests for other pathogens

RSV, parainfluenza virus, and adenovirus can be cultured from respiratory secretions, although DFA, EIA, and polymerase chain reaction (PCR) are more rapid and more readily available. P jiroveci is diagnosed using DFA on secretions or biopsy material from the lungs.

Chest radiographs may reveal the following[16] :

• Air trapping

• Bronchial wall thickening

• Diffuse interstitial infiltrates (which may be out of proportion to the clinical condition, especially in infants with C trachomatis infection)

• Atelectasis

• Reticulonodular or miliary pattern (rare)

Go to Imaging in Pediatric Pneumonia for more complete information on this topic.

Pulmonary function testing

Results of infant pulmonary function testing (when available) are frequently abnormal in both the acute phase of infection and the long term.

Bronchoalveolar lavage

Bronchoalveolar lavage with or without transbronchial biopsy may be used to collect specimens for diagnosis if the clinical severity warrants.

Histologic findings

Special stains of biopsy material may reveal evidence of particular etiologies. More commonly, direct or indirect fluorescent antibody staining helps identify viral antigens in respiratory secretions (RSV, adenovirus, and parainfluenza).

Usually, the degree of afebrile pneumonia syndrome (APS) is mild, although clinical and radiographic findings may appear out of proportion (particularly in infants with Chlamydia trachomatis infection); most infants do not require extensive diagnostic evaluation or hospitalization.

Infants who present with more severe illness may need prompt institution of empiric treatment, forgoing the risk of delay and expense of an extensive diagnostic evaluation. These infants often have viral illness, which does not respond to antibiotic therapy, but differentiating bacterial from viral illness is often difficult. Consider empiric antibiotic therapy if the potential benefits of early intervention outweigh the risks of unnecessary treatment.

Consultation with specialists in pulmonary and infectious diseases may be helpful for more serious disease or in difficult cases.

Go to Pneumonia, Pediatric for more complete information on this topic.

Infants in whom the clinical picture suggests afebrile pneumonia syndrome (APS) may benefit from a 10- to 14-day course of erythromycin. Newer macrolides and azalides are also effective and may be tolerated better (particularly azithromycin).

Reports suggest an association between early receipt of erythromycin and the development of hypertrophic pyloric stenosis. Whether such an association will be substantiated or whether the effect will extend to clarithromycin or azithromycin is unclear. Thus, antimicrobial therapy for APS should be considered in the light of this potential adverse outcome.

Macrolides are the first line of treatment for atypical pneumonia in children because of their low minimum inhibitory concentration and good safety profile; however, the increasing incidence of macrolide resistance is becoming a global concern.[17]

Antiviral therapy is used in the treatment of cytomegalovirus (CMV), but only when unusually severe disease or immunocompromise is present. Severe CMV pneumonitis may require CMV hyperimmunoglobulin and antiviral therapy.

Although ribavirin is available for the treatment of RSV, disease sufficiently severe enough to merit treatment would not be APS and is beyond the scope of this discussion.

Detection and treatment of maternal C trachomatis infection prevents vertical transmission of the pathogen.[18]  An estimated 10-20% of infants whose mothers have active, untreated C trachomatis infection will develop pneumonia. Studies have shown significantly reduced rates of chlamydial infection among infants born to women who received erythromycin compared with mothers who received no treatment.[2]

Avoidance of other risk factors for APS is prudent. Institute appropriate isolation of all patients who are hospitalized.

Infants in whom the clinical picture suggests afebrile pneumonia syndrome (APS) may benefit from a 10- to 14-day course of erythromycin. Newer macrolides and azalides are also effective and may be tolerated better (particularly azithromycin).

Antiviral therapy is used in the treatment of cytomegalovirus (CMV), but only when unusually severe disease or immunocompromise is present. Severe CMV pneumonitis may require CMV hyperimmunoglobulin and antiviral therapy.

Although ribavirin is available for the treatment of respiratory syncytial virus (RSV), disease sufficiently severe enough to merit treatment would not be APS and is beyond the scope of this discussion.

Class Summary

In patients with APS, antibiotics are used for treatment of presumptive C trachomatis and U urealyticum infection. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Whenever feasible, antibiotic selection should be guided by sensitivity testing of organisms isolated on blood cultures (although this occurs rarely in APS).

Erythromycin (E.E.S., E-Mycin, Eryc)

Erythromycin is a macrolide antibiotic, and cost, safety, and experience make erythromycin the drug of choice for APS. Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Azithromycin (Zithromax)

Azithromycin is a macrolide antibiotic and may become the drug of choice for APS because of its safety profile, ease of use, and improved GI tract tolerability relative to erythromycin. The dose for infants younger than 6 months has not been established.

Clarithromycin (Biaxin)

Clarithromycin is a macrolide antibiotic that inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It may be used as a substitute for erythromycin if compliance is a likely problem, as it is given qid rather than bid.

Class Summary

These agents are used to treat CMV infection. Ganciclovir is the drug of choice for documented CMV pneumonitis. Use foscarnet if a ganciclovir-resistant virus is identified or if adverse effects prevent ongoing use. Oral valganciclovir is under investigation for use in the treatment of congenital or neonatal CMV and recently has been approved for the prophylaxis of CMV disease in renal and/or heart transplant patients older than 3 months.[19]

Ganciclovir (Cytovene)

Ganciclovir is a synthetic guanine derivative that is the drug of choice for CMV infections, although experience with use in children is limited. An acyclic nucleoside analog of 2'-deoxyguanosine, ganciclovir inhibits replication of herpes viruses both in vitro and in vivo.

Levels of ganciclovir-triphosphate are as much as 100-fold higher in CMV-infected cells than in uninfected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells.

Foscarnet (Foscavir)

Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at the pyrophosphate-binding site on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance.

Patients who can tolerate foscarnet well may benefit from initiation of maintenance treatment at 120 mg/kg/d early in treatment. Individualize dosing based on renal function status.