AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Afebrile pneumonia syndrome (APS) is a relatively uncommon disease of neonates and infants younger than 6 months. APS was first described as a vertically transmitted infection of newborns and young infants by the female genital tract pathogens Chlamydia trachomatis, cytomegalovirus (CMV), and Ureaplasma urealyticum.

More recently, other potential causes of the syndrome have been recognized, including respiratory syncytial virus (RSV), parainfluenza virus, adenovirus, and Pneumocystis jiroveci.¹ Please refer to the particular articles devoted to these pathogens (Chlamydial Infections, Cytomegalovirus Infection, Parainfluenza Virus Infections, Pneumocystis Carinii Pneumonia, and Respiratory Syncytial Virus Infection) for specific details.

APS is typified by chlamydial pneumonitis, with acute or subacute onset of a chronic, afebrile or minimally febrile, diffuse pulmonary process associated with mild peripheral eosinophilia and elevated serum immunoglobulin levels. Symptoms are usually nonspecific and include cough, tachypnea, irritability, poor feeding, and low-grade fever or lack of fever, making differentiating among the above etiologies of APS and among APS and other pulmonary processes difficult. A correlation has been noted between low birthweight, prematurity, and low socioeconomic status and the incidence of APS. Affected individuals have a high incidence of obstructive airway disease later in life.

Pathophysiology

Although many organisms can cause APS, this article focuses on C trachomatis, CMV, and U urealyticum, which are vertically transmitted to newborns during passage through the birth canal or during breastfeeding (CMV). In recent 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%.

C trachomatis colonizes the genital tracts of 2-13% of women who are pregnant (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. If untreated, 5-13% of infants colonized by C trachomatis develop pneumonia. Similarly, 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. Finally, 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 common causative agents associated with seasonal or epidemic occurrences include RSV, parainfluenza, 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. Human transmission of P jiroveci remains unclear, although the organism is increasingly 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. Whether human metapneumovirus causes APS will be determined as it becomes more easily identified.

Frequency

United States

Frequency of APS is unknown, although identifiable RSV infection is the most common cause of pneumonia in neonates and infants younger than 6 months (79% of cases). This frequency may be artificially elevated because of the ease with which this diagnosis can be made.

International

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

Mortality/Morbidity

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.²

• 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 radiograph 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 initial etiologic agent associated with the pneumonitis. Evidence indicates that respiratory infections in infancy predispose patients to obstructive airway disease later in life.

Race

No racial predilection has been reported.

Sex

APS affects male and female newborns and infants in equal numbers.

Age

Afebrile pneumonia can occur in children at any age, but APS is considered to occur almost exclusively in the first 6 months of life.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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). Fever is often absent in very young infants.

• C trachomatis: Portals of entry include the eyes, nasopharynx, respiratory tract, and vagina. Symptoms typically begin at age 2-19 weeks with insidious onset, often 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).³ A history of conjunctivitis (which may be concurrent) increases the possibility of chlamydial infection.⁴
• U urealyticum: This pathogen 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. The role of the pathogen 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.
• CMV: Clinical manifestations of disease 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 that result from other causes of APS.
• RSV: RSV is likely the most common cause of afebrile pneumonia in young infants. Peak age of onset is 2-5 months. Infection during the first few weeks of life may manifest with 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: 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: 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 children younger than 6 months and may require short-term apnea monitoring. Otherwise, APS secondary to infection by parainfluenza virus may be clinically indistinguishable from APS that results from other causes.
• P jiroveci: A pathogen related to fungi, P jiroveci has typically been recognized to cause illness among individuals who are immunocompromised. Recently, it has also been associated with afebrile pneumonia in infants who are not immunocompromised. 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 because peak incidence of infection usually occurs in infants aged 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.

Physical

Signs of APS are typically nonspecific and considerable overlap occurs.

• Cough, which may be staccato (particularly in C trachomatis infection), is nearly universal.
• Tachypnea is usually present.
• Crackles are typically present. In APS caused by C trachomatis, auscultatory findings may be out of proportion to the overall healthy appearance of the infant.
• Nonspecific findings are often noted and may include the following:
• • Poor feeding
  • Lethargy or irritability
  • Poor color
• 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
• Conjunctivitis suggests C trachomatis infection (present concurrently or in the history one half of the time).
• GI tract, conjunctival, or pharyngeal involvement may suggest adenovirus infection.
• Concomitant hepatosplenomegaly or lymphadenopathy may suggest CMV infection.

Causes

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count may reveal a mild eosinophilia, with or without mild leukocytosis.
• Serum immunoglobulin levels are typically moderately elevated.
• C trachomatis
• • Tissue culture isolation of the organism from nasopharyngeal specimens is the most useful test. 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 available.
  • Serology is useful but takes longer than the above-named tests.
• CMV
• • Cell culture of urine, respiratory secretions, or blood buffy coat (including the shell-vial centrifugation technique) is the definitive test.
  • PCR and nucleic acid hybridization are becoming more readily available.
  • Serology is often useful, although it takes longer than more direct methods.
• U urealyticum
• • The organism can be cultured from respiratory secretions.
  • PCR and serology are not routinely available.
• RSV, parainfluenza virus, and adenovirus can be cultured from respiratory secretions, although DFA and EIA are more rapid and more readily available.
• P jiroveci is diagnosed using DFA on secretions or biopsy material from the lungs.
• Detection of the agents listed is not conclusive evidence of causation because all agents may colonize infants without producing disease.

Imaging Studies

Chest radiographs may reveal the following:⁵

• 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)

Other Tests

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

Procedures

• Bronchoalveolar lavage with or without transbronchial biopsy may provide 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).

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Usually, the degree of illness is mild, although clinical and radiographic findings may appear out of proportion (particularly in infants with C trachomatis infection); most infants do not require diagnostic evaluation or hospitalization. Infants who present with more severe illness may need empiric treatment to be instituted promptly, foregoing 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.

Consultations

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

Diet

No particular diet is required.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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). Recent reports suggest an association of early receipt of erythromycin and 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 light of this potential adverse outcome. Antiviral therapy is used in the treatment of CMV, but only when unusually severe disease or immunocompromise is present. 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.

Drug Category: Antibiotics

These are used for presumptive treatment of 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. Guide antibiotic selection by blood culture sensitivity whenever feasible.

Drug Category: Antivirals

These are used to treat CMV. Ganciclovir is the DOC for documented CMV pneumonitis. Use foscarnet if 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Supportive therapy is required as dictated by the clinical manifestations of the disease.
• Severe CMV pneumonitis may require CMV hyperimmunoglobulin therapy.

Transfer

• Transfer may be necessary if the required services are not locally available.

Deterrence/Prevention

• Detection and treatment of maternal C trachomatis infection prevents vertical transmission of the pathogen.⁶
• Avoidance of other risk factors for afebrile pneumonia syndrome (APS) is prudent.
• Institute appropriate isolation of all patients who are hospitalized.

Complications

• Secondary bacterial infection may occur, particularly with viral disease.
• Following a 5-year follow-up period, 60% of infants had abnormal pulmonary function test findings.
• More than one half of infants with chlamydial pneumonitis had obstructive airway disease and physician-diagnosed asthma starting at age 7 years.

Prognosis

• Immediate prognosis is good for more than 95% of affected infants, although long-term prognosis for significant morbidity is high.

Patient Education

• Discuss risk factors for APS with prospective mothers.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to make the diagnosis in the appropriate clinical context
• Failure to counsel mothers of the need to seek appropriate diagnostic and treatment services in the presence of chlamydial infections in infants

Special Concerns

• All of these infections tend to be more severe in hosts who have underlying medical abnormalities.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 7, 2008