Part 1 of a look at community-acquired pnemunia, the various bacteria that cause it, and how to diagnose it.
Pneumonia is one of the most common infections physicians encounter in outpatient practice. Despite this fact, pneumonia can be challenging to diagnose or even define. The World Health Organization defines pneumonia as cough and fast or difficult breathing, with a respiratory rate greater than 50 bpm for children 2 to 12 months old, and greater than 40 bpm for children 1 to 5 years old.1 Other definitions require fever or abnormalities on chest x-ray. This article focuses on pediatric community-acquired pneumonia (CAP) as defined by all infections of the pulmonary parenchyma acquired outside a hospital setting.
(ILLUSTRATION BY ALEX BAKER)
The annual incidence of CAP ranges from 36 to 54.7 for every 1,000 children age 1 and under, and decreases to 16.2 for every 1,000 children age 5 to 14.2,3 Children with CAP often require hospitalization, but mortality is rare: fewer than 1% of children hospitalized with CAP in the US die.4 CAP, nevertheless, still accounts for almost 20% of deaths in children under age 5 in the developing world.5
Children with CAP typically present with fever, cough, and tachypnea. However, the manifestations of CAP are diverse, and few physical examination findings permit reliable distinction among viral, bacterial, and atypical causes. Viral upper-respiratory-tract infections often precede CAP.
Tachypnea alone has a sensitivity of up to 74% in identifying children with radiographically confirmed pneumonia.6 However, tachypnea has a low specificity (67%) in pneumonia; while most patients with pneumonia will have tachypnea (accounting for its high sensitivity), most patients with tachypnea will not have pneumonia (accounting for its low specificity). Combining criteria of tachypnea, rales, and increased respiratory effort raises the specificity for a clinical diagnosis of pneumonia to 84%, but lowers the sensitivity to only 43%, thus missing a significant portion of patients with pneumonia, since the majority of patients do not have all three findings on exam.6 Similarly, the absence of rales does not preclude the diagnosis of pneumonia.
Vomiting and abdominal pain are also common complaints in children with pneumonia. Vomiting typically follows episodes of severe coughing (ie, post-tussive). Abdominal pain may occur in patients with basilar pneumonia, and at times is the most prominent complaint. Wheezing and exacerbation of underlying asthma are symptoms more typically encountered in patients with CAP caused by viruses and atypical bacteria such as Mycoplasma pneumoniae and Chlamydophila pneumoniae (formerly Chlamydia pneumoniae). In children with infections caused by atypical bacteria, symptoms such as headache, low-grade fever, pharyngitis, and cough usually precede signs of lower-respiratory-tract infection by five to seven days.
While the complete list of pathogens that can cause CAP is extensive, the most common causes among healthy outpatient children in the developed world are more limited, and vary by age (Table 1).7,8
VIRAL ETIOLOGY. Viruses can be identified in up to half of patients hospitalized for CAP, occasionally as part of a co-infection with bacteria.9,10 Common respiratory viruses that cause CAP include respiratory syncytial virus (RSV); influenza A and B; parainfluenza 1, 2, and 3; adenovirus; and human metapneumovirus. Human metapneumovirus was initially described in 2001, and causes a spectrum of respiratory disease in young children similar to that of RSV, ranging from mild bronchiolitis to severe pneumonia.11
BACTERIAL ETIOLOGY.Streptococcus pneumonia (pneumococcus) is the most common bacterial cause of childhood CAP.3,9,10 In randomized trials of the heptavalent pneumococcal conjugate vaccine, the incidence of radiographically confirmed pneumonia was reduced by 20% in vaccine recipients compared with placebo recipients. This finding suggests that S pneumoniae is responsible for at least 20% of CAP cases in children 2 years of age and younger.12 Moreover, post-licensure epidemiologic studies show that all-cause pneumonia hospitalizations in children under age 2 in the US have decreased by 39%, providing further evidence of pneumococcus's role as a major cause of childhood CAP.12-14
Haemophilus influenzae type b (Hib) was a common cause of CAP prior to the creation of the conjugate Hib vaccine, and likely now plays a smaller role.8,10 In countries or areas in which the adoption of the Hib vaccine is low, Hib should still be considered as a common cause of CAP.
Staphylococcus aureus, and particularly community-associated methicillin-resistant S aureus (MRSA), is increasingly recognized as a cause of severe CAP, even in previously healthy children.15
M pneumoniae had previously been felt to be a pathogen primarily in adolescents and young adults, but is now known to be common in school-age children and toddlers. In a study of hospitalized asthmatic children (ages 2 and older), Biscardi et al proposed an association between M pneumoniae and wheezing, identifying M pneumoniae in half of patients with a first episode of wheezing, and 20% of patients admitted for an exacerbation of their known prior asthma.16
Chlamydophila pneumoniae is identified in approximately 10% of children of all ages with CAP.Non-typable H influenzae can occasionally cause CAP in children under age 5, while enteric gram-negative pathogens can be causes in neonates or patients with aspiration or neurologic compromise.
Less common causes of CAP include Mycobacterium tuberculosis, herpes simplex virus (in newborns), varicella-zoster virus, Legionella pneumophila, and endemic mycoses such as Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatiditis.
Preceding viral illness is thought to play a part in the pathogenesis of bacterial pneumonia. Ampofo et al recently showed a strong temporal association between confirmed viral respiratory illnesses (RSV, influenza, and human metapneumovirus) and invasive pneumococcal disease over six winter seasons.17 Though their data do not prove causation, rates of invasive pneumococcal disease rose in close association with diagnosis of respiratory viral illnesses each winter season.
A randomized trial of children receiving a nonavalent pneumococcal vaccine found that vaccine recipients had fewer admissions for both pneumococcal pneumonia and pneumonia with human metapneumovirus compared with placebo recipients. These results suggest that hospitalizations for human metapneumovirus involve co-infection with pneumococcus.18
Identifying the causative agent in childhood CAP cases is often difficult. Studies that included an intensive search for etiology in hospitalized children identified a likely cause in up to 85% of cases, but an etiologic diagnosis may be made in a much smaller proportion of routine outpatient cases.8,10 This is partly due to a reluctance to perform invasive diagnostic procedures in young children such as broncho-alveolar lavage or needle thoracentesis.
SPUTUM SAMPLES.Children may be incapable of providing adequate sputum specimens, although those older than 8 with a productive cough may be more capable of providing adequate specimens. These cultures must be interpreted cautiously, however ,due to potential capture of colonizing oropharyngeal flora. A high-quality sputum specimen should have few squamous epithelial cells (≤10 per high power field) and numerous white blood cells (WBC) (≥25 per high power field). Specimens should be transported within two hours to a microbiology lab for culture.
Sputum culture should be considered for hospitalized patients capable of submitting an adequate specimen, but may not be routinely helpful in the outpatient setting.
NASOPHARYNGEAL SAMPLES. Polymerase chain reaction (PCR) or immunfluorescence studies using nasopharyngeal aspirates are more reliable means for determining certain causes of outpatient CAP. Both methods detect respiratory viruses, such as RSV and influenza A and B, with high sensitivity. Likewise, PCR from a nasopharyngeal aspirate is the diagnostic method of choice for Bordetella pertussis during the first four weeks of illness. After that time serology may be necessary to make the diagnosis, given the clearance of organisms from the nasopharynx over time.19 Culture can also still be used for the diagnosis of B pertussis in the first three weeks of illness, but results may not be available for five to seven days.
In contrast, detection of S pneumoniae in the nasopharynx by any method likely represents colonization; therefore, diagnosis of pneumococcal pneumonia can only be made by isolation of the organism from sputum or normally sterile sites such as blood or pleural fluid.
C trachomatis (in neonates) and C pneumoniae can also be detected via PCR, though prolonged shedding can occur, causing PCR tests to remain positive outside a period of active disease.20 Both of these pathogens can otherwise be diagnosed by acute and convalescent serologies; for neonates and young infants, direct fluorescent antibody testing can also be used on conjunctival and respiratory specimens for the diagnosis of C trachomatis.
M pneumoniae is most reliably detected by serologic testing of paired specimens obtained two to three weeks apart; a fourfold or greater rise in the antibody titer indicates a recent or current infection. Unfortunately, such testing rarely provides information in a timeframe to influence clinical practice meaningfully.
PCR testing is also available for the diagnosis of M pneumoniae. The sensitivity of PCR tests for M pneumoniae are approximately 80% for pharyngeal specimens, and 90% for nasopharyngeal specimens compared with results of acute and convalescent serologic testing. The specificity is >95%, so false-positive results are uncommon, but may occasionally occur in cases of prolonged shedding. 21
CXR, BLOOD CULTURES, URINE ANTIGENS. Chest x-ray (CXR) should be considered in highly febrile patients without another identifiable source, especially those with tachypnea or a peripheral leukocytosis.22 Confirmatory CXR is not necessary, however, in patients with classic findings of CAP such as high fever, tachypnea, and rales on exam.
Certain CXR findings in patients with pneumonia can suggest a particular etiology (Table 2). Bacterial pneumonia tends to be lobar (Figures 1A, 1B), though S aureus can cause a patchy bronchopneumonia. Viral and atypical bacterial pathogens, such as M pneumoniae or L pneumophila, tend to cause interstitial infiltrates on CXR, but atypical bacterial pathogens occasionally cause lobar infiltrates. Simple parapneumonic effusions can be seen with bacterial, viral, or atypical pneumonia. Severe bacterial pneumonias can also be complicated by complex effusions or empyemas (Figure 2). Hilar lymphadenopathy and nodular disease suggest M tuberculosis, P jiroveci (PCP), and endemic mycoses such as Histoplasma, Coccidiodes, or Blastomyces. Pneumatoceles are air-filled cavities caused by alveolar rupture that can be visualized on CXR, and are often seen in pneumonias caused by S aureus (and occasionally those caused by enteric gram-negative bacilli).23
With the advent of the Hib and pneumococcus vaccines, blood cultures are now positive in less than 3% of outpatients with CAP, and are therefore unnecessary in well-appearing patients without hypoxia.24,25 The rate of positive blood cultures is somewhat higher in those requiring admission (up to 10%), and may be even higher in patients with pneumonia complicated by empyema. Blood cultures therefore may provide useful microbiologic data, including antibiotic sensitivities, for these patients.
Children with uncomplicated pneumonia and small pleural effusions treated as outpatients do not necessarily require pleural effusion drainage. Drainage should, however, be considered for patients with large or loculated effusions. Gram stain and bacterial culture of pleural fluid should always be performed on patients with pneumonia complicated by pleural effusion and who have received pleural fluid drainage.
Urine antigen testing for S pneumoniae should not be routinely performed, given its high false positive rate (up to 18%) in some patient groups.26 In immunocompromised children at greater risk for atypical pathogens, a urine antigen assay for L pneumophila can be obtained. Consider tuberculin skin testing for patients with appropriate tuberculosis risk factors and CXR findings, bearing in mind that children under 2 years of age are more likely to have nonspecific CXR findings or miliary disease. In patients with an appropriate travel history and CXR, Histoplasma serology or urine antigen testing are indicated. Paired acute and convalescent serologies can also be used to diagnose pneumonia caused by Coccidioides immitis and Blastomyces dermatiditis.
WBC AND CRP COUNTS. Studies differ in terms of the utility of serum WBC count and inflammatory markers in differentiating viral from bacterial pneumonia.27,28 Very high circulating neutrophil and C-reactive protein (CRP) levels may be found more frequently in patients with bacterial pneumonia, but normal neutrophil and CRP levels do not exclude the possibility of bacterial pneumonia. Therefore, these serum inflammatory markers are best used as infrequent supportive measures of disease resolution when tracking the course of severe pneumonia.
FURTHER EVALUATION. Follow-up CXR is seldom warranted in patients who have recovered uneventfully, since the results of these scans are often abnormal even in the face of complete recovery. Patients who have not improved on empiric treatment should have CXR to confirm the diagnosis of pneumonia if no prior CXR has been obtained, and to look for the presence of pleural effusion, empyema, or worsening disease in those who have had a prior CXR. Patients with increasing effusions and worsening symptoms should be referred for diagnostic and therapeutic drainage of the effusion. Further diagnostic procedures are indicated for patients with hilar lymphadenopathy (to consider tuberculosis, endemic mycoses, and certain autoimmune conditions), cystic or nodular disease (to consider underlying immune deficiencies and atypical pathogens), or pulmonary anatomic abnormalities.
Based on his history, fevers, tachypnea, and focal findings on chest exam, you diagnose your 2-year-old patient with CAP. You forego chest imaging and blood work, as he appears nontoxic. Given his history of a viral upper-respiratory infection one week prior, you feel that his current pneumonia may have a secondary bacterial cause, and recognize that S pneumoniae is the likeliest agent.
Editor's note- Look for "Pediatric community-acquired pneumonia, Part 2: Current challenges in outpatient treatment" in the September 2009 issue of Contemporary Pediatrics.
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