The atypical pneumonias: clinical diagnosis and importance

Copyright © 2006 European Society of Clinical Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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Abstract

The most common atypical pneumonias are caused by three zoonotic pathogens, Chlamydia psittaci (psittacosis), Francisella tularensis (tularemia), and Coxiella burnetii (Q fever), and three non-zoonotic pathogens, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella. These atypical agents, unlike the typical pathogens, often cause extrapulmonary manifestations. Atypical CAPs are systemic infectious diseases with a pulmonary component and may be differentiated clinically from typical CAPs by the pattern of extrapulmonary organ involvement which is characteristic for each atypical CAP. Zoonotic pneumonias may be eliminated from diagnostic consideration with a negative contact history. The commonest clinical problem is to differentiate legionnaire's disease from typical CAP as well as from C. pneumoniae or M. pneumonia infection. Legionella is the most important atypical pathogen in terms of severity. It may be clinically differentiated from typical CAP and other atypical pathogens by the use of a weighted point system of syndromic diagnosis based on the characteristic pattern of extrapulmonary features. Because legionnaire's disease often presents as severe CAP, a presumptive diagnosis of Legionella should prompt specific testing and empirical anti-Legionella therapy such as the Winthrop-University Hospital Infectious Disease Division's weighted point score system. Most atypical pathogens are difficult or dangerous to isolate and a definitive laboratory diagnosis is usually based on indirect, i.e., direct flourescent antibody (DFA), indirect flourescent antibody (IFA). Atypical CAP is virtually always monomicrobial; increased IFA IgG tests indicate past exposure and not concurrent infection. Anti-Legionella antibiotics include macrolides, doxycycline, rifampin, quinolones, and telithromycin. The drugs with the highest level of anti-Legionella activity are quinolones and telithromycin. Therapy is usually continued for 2 weeks if potent anti-Legionella drugs are used. In adults, M. pneumoniae and C. pneumoniae my exacerbate or cause asthma. The importance of the atypical pneumonias is not related to their frequency (~15% of CAPs), but to difficulties in their diagnosis, and their nonresponsiveness to β-lactam therapy. Because of the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis (MS), and the role of M. pneumoniae and C. pneumoniae in causing or exacerbating asthma, atypical CAPs also have public health importance.

Keywords: Atypical pneumonias, clinical diagnosis of legionnaire's disease, community-acquired pneumonia, doxycycline, legionnaire's disease, Mycoplasma pneumonia, Chlamydia pneumonia, quinolones, review, telithromycin, therapy of Legionella

INTRODUCTION

The term ‘atypical pneumonia’ was first applied to viral community-aquired pneumonias (CAP) that were clinically and radiologically distinct from bacterial CAPs. Over the past decades, atypical pneumonia has come to mean lower respiratory tract infections due to specific respiratory pathogens, i.e., Chlamydia psittaci (psittacosis), Francisella tularensis (tularemia), Coxiella burnetii (Q fever), Chlamydia pneumoniae, Mycoplasma pneumoniae or Legionella species [1, 2, 3, 4, 5]. The newly recognised causes of CAP, i.e., severe acute respiratory syndrome (SARS), hantavirus, and avian influenza, are not considered ‘atypical pneumonias', but should be regarded as viral CAPs [5, 6].

Atypical CAPs represent approximately 15% of all CAPs. While outbreaks due to atypical pneumonia pathogens occur in the community, most cases of atypical CAP are sporadic. Atypical pulmonary pathogens causing pneumonia may also cause outbreaks of nursing home-acquired pneumonia (NHAP) or nosocomial pneumonia (NP). Atypical pneumonia as a cause of NHAP or NP is rare. Atypical pathogens are more common than typical bacterial pathogens in mild or ambulatory CAP in adults. Legionella is an important cause of severe CAP in hospitalised patients [4, 5, 7, 8, 9, 10].

The atypical pneumonias may be classified clinically as those that are zoonotically transmitted and those that are not. The zoonotic atypical pneumonias include psittacosis, Q fever, and tularaemia, and the non-zoonotic atypical pneumonias include Mycoplasma, Chlamydia pneumoniae, and Legionella CAPs. Both the zoonotic and non-zoonotic atypical pneumonias differ fundamentally from bacterial CAPs. However, the main feature differentiating atypical from typical CAP pathogens is the presence or absence of extrapulmonary findings. All atypical pulmonary pathogens, both zoonotic and non-zoonotic, cause systemic infectious disease with a pulmonary component, i.e., pneumonia. Pneumonias caused by Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis are typical CAPs with clinical and laboratory findings limited to the lungs. Once this distinction is made in CAP with extrapulmonary findings, the clinician can then determine the characteristic pattern of organ involvement and narrow down the diagnostic possibilities [4, 5, 6, 7, 8, 9, 10].

Each atypical pulmonary pathogen has a predilection for certain extrapulmonary organ systems. It is the characteristic pattern of organ involvement rather than individual clinical or laboratory findings, that distinguishes the atypical pneumonias from each other. The extrapulmonary pattern of organ involvement of Legionella, for example, is very different and distinct from C. pneumoniae or Mycoplasma CAP, and provides the basis for a presumptive clinical diagnosis. If the distinctive patterns of extrapulmonary organ involvement associated with each atypical pathogen are recognised, a presumptive clinical diagnosis is usually straightforward and accurate. Presumptive clinical diagnosis is not definitive but should prompt specific diagnostic testing to confirm or rule out specific pathogens [1, 2, 3, 4, 7, 8, 9, 10].

In the literature, most studies have been unable to clearly differentiate typical from atypical pneumonias. The main difficulty with such studies is that they have compared individual clinical and laboratory findings of atypical and typical pathogens. These studies correctly concluded that there are few, if any, discernible differences in isolated findings. Only rarely have studies used a syndromic diagnosis, and only one has used a weighted syndromic point system of diagnosis. Using a weighted syndromic approach based on the relative clinical specificity of characteristic clinical findings, it is clear that with good sensitivity and specificity, clinicians can not only differentiate typical from atypical pneumonias, but can accurately presumptively diagnose legionnaire's disease [11, 12, 13, 14].

The importance of the atypical pneumonias is not based on their clinical incidence per se, which is important enough, but rather on other clinical and public health aspects. The atypical pneumonias require a different therapeutic approach than that for typical CAPs [1, 2, 15]. Atypical CAP pathogens, particularly M. pneumoniae and C. pneumoniae constitute the majority of CAPs in young adults in the ambulatory or outpatient setting. The outpatient setting is the area where atypical pathogens are quantitatively more important than their typical CAP counterparts. Atypical pathogens, particularly Legionella, also are an important cause of severe CAP. Typical bacterial pathogens have classically responded to β-lactam antimicrobial therapy because they have a cell wall amenable to β-lactam disruption. In contrast, most of the atypical pathogens do not have a bacterial cell wall and some are intracellular, e.g., Legionella, and still others are paracellular, e.g., M. pneumoniae [1, 2, 9, 10].

Antimicrobials that inhibit or eradicate microorganisms by interfering with intracellular protein synthesis enzymes are effective against atypical pathogens. Macrolides and tetracyclines interfere with intracellular bacterial protein synthesis. Quinolones, and most recently ketolides, have been shown to be the most highly effective antimicrobials against atypical pathogens, particularly Legionella. Because some of the atypical pathogens are intracellular, e.g., Legionella, intracellular antibiotic penetration into alveolar macrophages (AM), is also important. Macrolides, tetracyclines, quinolones and ketolides concentrate in AMs [12, 16, 17, 18, 19].

Atypical CAP pathogens are quantitatively more important in the outpatient setting, and qualitatively important in hospitalised patients with severe CAP. There are also public health considerations that add to the importance of some atypical CAP pathogens. Aside from the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis, it is clear that C. pneumoniae and M. pneumoniae infection may be complicated by asthma. M. pneumoniae and C. pneumoniae infection are also important causes of Non-exudative pharyngitis [21, 22, 23, 24, 25, 26, 27, 28].

Zoonotic atypical pneumonias have always been important causes of CAP in areas endemic for these infectious diseases. Psittacosis remains an important cause of CAP among those in contact with psittacine birds. Q fever occurs sporadically in those in close contact with parturient cats, or in sheep-raising areas. Endocarditis is an infrequent but important problem in endemic Q fever areas. Tularemia has six clinical presentations, any of which may be accompanied by pneumonia. In endemic areas tularaemia remains an important and potentially serious infectious disease [4, 7, 10, 29, 30, 31, 32].

Atypical pathogens are thus more important than estimates of their relative incidence would suggest in terms of diagnostic difficulties, nonβlactam susceptibility and their severity/complications.

CLINICAL DIAGNOSIS OF ATYPICAL PNEUMONIAS

If a patient presents with pneumonia, and in addition there are extrapulmonary findings, the patient has an atypical pneumonia. Patients with CAP plus extrapulmonary findings should, for clinical purposes, be further subdivided into those with zoonotic or non-zoonotic CAP. Zoonotic atypical CAPs due to Q fever, psittacosis, or tularaemia occur after contact with the respective vectors. Psittacosis is an exception and may be contracted after contact with well or ill psittacine birds. Tularemia and Q fever CAP are not random occurrences and a recent epidemiological contact history is required before considering the diagnosis. If a patient with an atypical pneumonia has a negative epidemiological contact history for psittacosis, Q fever, or tularaemia, it is extremely unlikely that the patient has a zoonotic atypical CAP, [6, 7, 21, 22, 23, 24] and it may be correctly assumed that the patient has a non-zoonotic atypical pneumonia due to Legionella, M. pneumoniae, or C. pneumoniae ( Table 1 ) [33, 34, 35, 36, 37, 38].

Table 1

Diagnostic features of the non-zoonotic atypical pneumonias. Adapted from Cunha, 2006 [6]

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CF, complement fixation; DFA/IFA, direct/indirect fluorescent antibody test; N, normal; WBC, white blood cell; +, usually present; ±, sometimes present; –, usually absent; ↑, increased; ↓, decreased; ↑↑↑, markedly increased