10 cosentini

Monaldi Arch Chest Dis2001; 56: 6, 527–534 REVIEW
Community-acquired pneumonia:
role of atypical organisms
R. Cosentini, P. Tarsia, F. Blasi*, E. Roma*, L. Allegra* ABSTRACT: Community-acquired pneumonia: role of
nary radioimmunoassay (RIA) antigen detection is the
atypical organisms. R. Cosentini, P. Tarsia, F. Blasi, E. Roma,
method of choice for L. pneumophila serogroup 1. The best
L. Allegra.
treatment regimen is a full three-week treatment with a
M. pneumoniae infection occurs world-wide and is the
macrolide (erythromycin, clarithromycin, azithromycin).
most common cause of community-acquired pneumonia
An alternative treatment regimen may be the association
(CAP) in the 5 to 20 year-old age group. The most reliable
of second generation fluoroquinolones with tetracyclines.
diagnostic test is enzyme immunoassay that allows im-
A notable improvement in most of the new fluoro-
munoglobulin (Ig)G and IgM titration and presents 92%
quinolones is their activity against Legionella, so that their
sensitivity and 95% specificity on paired samples. Poten-
use as single agent may be hypothesised even if clinical da-
tially active drugs are tetracyclines, macrolides, ketolides,
ta are still insufficient for a definitive indication. Chlamy-
lincosamides, streptogamines, chloramphenicol, and fluo-
dia pneumoniae account for 6-20% of CAP depending on
roquinolones. The incidence of Legionella infection, in
several factors such as setting of the studied population,
spite of its world-wide diffusion, is highly variable in dif-
age group examined, and diagnostic methods used. The
ferent studies, ranging from 1% to 27% of CAP. The most
current gold standard for serological diagnosis of acute in-
likely mode of transmission is direct inhalation from Le-
fection is microimmunofluorescence testing. Tetracyclines
gionella-contaminated water-supply systems. Extrapul-
and erythromycin show good in vitro activity and so far
monary manifestations are relatively common but non-
have been the most commonly employed drugs in the
specific. However, some signs and symptoms may raise the
treatment of C. pneumoniae infection. New macrolides, ke-
suspicion of Legionella infection: a sputum Gram stain
tolides, and new fluoroquinolones are other potentially ef-
with a high number of neutrophils without any organism,
fective drugs.
hyponatremia, and diarrhea in a critically ill patient. Uri-
Monaldi Arch Chest Dis 2001; 56: 6, 527–534.
Keywords: Community-acquired pneumonia, atypical micro-organisms, Mycoplasma pneumoniae, Chlamydia pneumoniae,
Legionella spp.
Department of Emergency Medicine, IRCCS Ospedale Maggiore di Milano. *Institute of Respiratory Diseases, University ofMilan, IRCCS Ospedale Maggiore di Milano, Italy. Correspondence: Dr Roberto Cosentini; IRCCS Ospedale Maggiore; Divisione Medicina d’Urgenza; Via F. Sforza, 35; 20122 Milan,Italy; e-mail: medurg3@polic.cilea.it Atypical pneumonia is a clinical syndrome Mycoplasma pneumoniae
without a precise definition, first described byReimann in 1938 [1], who realised that in some pa- M. pneumoniae is a slowly growing, pleiomor- tients with pneumonia the clinical picture and the phic, nonmotile bacteria that lacks a cell wall. It natural history differed from that seen in patients was first identified by Eaton et al. and then cul- with pneumococcal infection. The syndrome in- tured by Chanock et al. and eventually classified as cludes a subacute onset with low-moderate grade Mycoplasma pneumoniae in 1963 [4–6]. M. pneu- fever, dry cough, prominent constitutional symp- moniae is bound by a single triple-layered mem- toms, absent or moderate leukocytosis, with a more brane, stains Gram negative, appears filamentous, extensive radiographic involvement than physicalexamination would suggest. The term “atypicalpathogens” indicates a number of micro-organisms Table 1. – Microbial causes of community-acquiredpneumonia (CAP) in adults (%) that can cause so-called “atypical pneumonia” andother respiratory and probably non-respiratory dis- eases. For the past decade, the frequency of pneu- monia due to atypical pathogens has varied consid-erably in different clinical series, but these pathogens as a group have become accepted as rel- atively common causes of pneumonia in both out- patient and inpatient settings (table 1) [2, 3].
The most important bacteria included in this group are Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp. measures 10 x 200 nm in size, and displays a neu-raminic acid receptor site for attachment to host Table 2. – Extrapulmonary manifestations of M.
pneumoniae infection cell membranes [7]. The absence of a cell wall hasbeen associated with atypical biochemical, sero- logical and cultural behaviour, marked pleiomor- phism, and, from a clinical point of view, resis- tance to antibiotics that exert antibacterial activity by interfering with cell wall synthesis.
Gastrointestinal Anorexia, nausea, vomiting, diarrhea, Epidemiology
Myocarditis, pericarditis, endocarditis,congestive heart failure, pericardial effu- M. pneumoniae infection occurs world-wide throughout the year without significant seasonal fluctuations and is both endemic and epidemic.
Peaks of incidence occur every 5-7 years and epi- Muscolo-skeletal Arthralgias, myalgias, migratory pol- demics of Mycoplasma infection last 6 to 8 months [8]. Children and young adults are the individuals most often involved in M. pneumoniae infections, and this agent is the most common cause of com- munity-acquired pneumonia (CAP) in the 5 to 20 year-old age group (9). M. pneumoniae infection has however also been identified in 11 to 17% cas- palsies, cerebellar ataxia, polyradiculitis es of pneumonia in patients over 40 years of age [10]. Epidemics have been described in enclosed populations such as college students, prisoners, nephritis, renal failure, generalised lym- military garrisons, and even hospital workers [11].
Simultaneous cases within single households are Infection is transmitted from person to person by inhalation of droplet nuclei after exposure to anacutely ill coughing individual. There is no pro- prognostic factor [13]. The exact mechanisms un- longed carrier state, although a temporary carrier derlying the onset of extrapulmonary involvement condition occurs following natural human infec- are poorly understood. Immunopathogenetic fac- tion. After attaching to epithelial cells by means of tors are probably involved given the cross-reactiv- its neuraminic differentiated terminal unit, M. ity between human and M. pneumoniae antigens.
pneumoniae interrupts cell RNA and protein syn- The principal hematologic manifestations as- thesis, resulting in ciliostasis, inflammatory cell sociated with M. pneumoniae pneumonia are he- recruitment, denudation of cilia and extensive ep- molytic anemia and cold hemagglutination. The ithelial cell injury [12]. Immunopathological dam- latter has been found in 33-76% of patients with age is mediated by mimicry between M. pneumo- pneumonia and is determined by IgM antibodies niae and host antigens. Typical manifestations are that bind to red cell wall antigens and activate the extrapulmonary manifestations of infection complement. Hemolytic anemia often appears such as hemolytic anemia. The organism does not during the second or third week following infec- generally penetrate into the lung parenchyma or tion, is associated with high cold hemoagglutinin the bloodstream. Airway inflammation extends titres and may result in paroxysmal cold hemo- from the trachea and bronchi to the bronchioles.
globinuria, thrombocytopenic purpura, intravas- The most common pathological finding is an acute cular coagulation, and renal failure (metahe- and chronic bronchiolitis and peribronchiolitis.
Host defence to M. pneumoniae infection may Maculopapular, measle-like, urticarial, bul- be mediated by cellular rather than humoral mech- lous, and petecchial skin rashes have been report- anisms. Infection stimulates an initial specific im- ed in approximately 20% of M. pneumoniae infec- munoglobulin (Ig)-M antibody response present in tions and are sometimes interpreted as allergic up to 78% of patients within 2 weeks, followed by drug reactions. Further important extrapulmonary an IgG antibody response. Although the IgM re- manifestations are central nervous system symp- sponse peaks at about one month, IgG antibodies toms that are however present in a limited number persist for very long periods. Cold hemagglutinins and rheumatoid factor have been identified in pa-tients with M. pneumoniae infection.
Legionella pneumophila
Extrapulmonary complications
Legionella is a small, pleiomorphic, Gram- negative bacillus. It is a strict aerobic bacterium Extrapulmonary involvement during M. pneu- rich in ramified fatty acids. Legionella is a fastidi- moniae infection may sometimes overshadow the ous organism that needs a specific growth medi- respiratory picture (table 2). Presence of multiple um. Water reservoirs are the micro-organism’s nat- extrapulmonary manifestations is an ominous In 1976, an outbreak of pneumonia that caused toms including headache, rigor, myalgia and 34 deaths in Philadelphia at an American Legion arthralgia. In most studies C. burnetii is identified convention led to the clinical definition of Legion- in 1-3% of pneumonia cases. Fever may be high naires’ disease [14]. A previously unknown bac- but the disease is usually self-limited. Radiograph- terium was isolated and identified as the etiologic ic resolution is slow and may take up to 70 days agent and named Legionella pneumophila. Retro- [19]. A common complication of pneumonia is spective analysis of stored sera of patients with granulomatous hepatitis. Other extrapulmonary previously unexplained pneumonia reveals that complications include hemolytic anemia, thyroidi- outbreaks may be traced back to at least the 1950s. tis, pericarditis and myocarditis, and glomeru-lonephritis.
Epidemiology
Chlamydia pneumoniae
The bacteria have been consistently isolated form a variety of man-made water reservoirs in In 1989, the previously labeled Chlamydia nosocomial outbreaks and community-acquired strain TWAR was recognised as a third species of cases [15]. Available data indicate that the most the Chlamydia genus on the basis of ultrastructur- likely mode of transmission is direct inhalation from Legionella-contaminated water supply-sys- tems. Patient isolation is not mandatory as no evi- Like other Chlamydia, this agent is an obligate dence of person-to-person transmission has been intracellular, Gram negative bacterium present in two developmental forms: infective elementary The incidence of Legionella infection, in spite bodies (EB) and reproductive reticulate bodies of its world-wide diffusion, is highly variable in (RB). Chlamydia possess a specific replication cy- different studies, ranging from 1 to 27% of com- cle which differs from conventional bacteria. They munity-acquired pneumonia [16]. The clinical multiply within membrane-bound vacuoles in eu- severity of Legionella pneumonia ranges from caryotic host cells but are unable to generate mild respiratory disease to fulminating pneumo- adenosine triphosphate (ATP) and are therefore de- nia. The incubation period ranges from 2 to 10 pendent on the host cell ATP deposits for all ener- days. Most patients report dry cough, and high gy requirements. Moreover, they are incapable of fever (>40°C) is reported in about 20% of cases.
de novo nucleotide biosynthesis and are dependent Extrapulmonary manifestations such as neurologic complaints, abnormal liver enzymes, diarrhea, hy-pophosphatemia, hematuria and hematologic ab- Epidemiology
normalities are relatively common but non-specif-ic [17]. However, some signs and symptoms may Chlamydia pneumoniae has been recognised as raise the suspicion of Legionella infection: a spu- a cause of respiratory tract infections and is consid- tum Gram stain with a high number of neutrophils ered the most common non-viral intracellular human without any organism, hyponatremia, and diarrhea respiratory pathogen. C. pneumoniae is involved in a wide spectrum of respiratory infections of the upper Initial radiological involvement is usually uni- respiratory tract (pharyngitis, sinusitis and otitis) and lateral with a frequent spread to multilobar consol- lower respiratory tract (acute bronchitis, exacerba- idation. Pleural effusion is present in about 50% of tions of chronic bronchitis and asthma, and commu- nity-acquired pneumonia) in both immunocompe-tent and immunocompromised hosts. Coxiella burnetii
C. pneumoniae accounts for 6-20% of commu- nity-acquired pneumonia (CAP) depending on Coxiella burnetii is the agent of Q fever, a several factors such as setting of the studied popu- zoonotic infection [18]. It is a strictly intracellular lation, age group examined, and diagnostic meth- Gram negative, pleiomorphic, coccobacillary or- The clinical course may vary from a mild, self- limiting illness to a severe form of pneumonia, par- Epidemiology
ticularly in elderly patients, and in patients with co-existing cardiopulmonary diseases. This agent is The infection is widely present in animals in- present as part of a coinfection involving other bac- cluding cattle, sheep, goat, pets such as cats and terial agents in approximately 30% of cases [21].
dogs, and arthropods, mainly ticks. Transmission Presenting symptoms most frequently reported occurs by aerosolised particles. Infection may oc- by patients with C. pneumoniae pneumonia are cur from inhalation of contaminated aerosols from sore throat and hoarseness [22] (table 3). After a amniotic fluid or placenta of contaminated wool, period of up to a week, dry persistent cough often making Q fever an occupational hazard. Person-to- sets in [23]. Body temperature is generally slightly person transmission is unusual but may occur via increased, seldom going higher than 38-39°C.
droplet nuclei, transplacental transmission, intra- Fever may be often missed if the patient is not seen dermal inoculation and blood transfusions. Incuba- tion time is around 3 weeks and the disease begins Physical examination does not often show ab- as a flu-like syndrome with extrapulmonary symp- normalities and, if present, physical findings are generally not specific. Pulmonary rales, ronchi or Table 3. – Common signs and symptoms of Chlamy- signs of pulmonary consolidation are sometimes dia pneumoniae pneumonia and frequency of pre- monary infiltrates, sublobar or segmental at pre- sentation (table 4). Multiple infiltrates may some-times be seen and are often bilateral. Extensive lo- bar involvement is uncommon, whereas pleural ef- fusion may be present in up to 20% of cases.
Diagnostic methods (table 5)
Mycoplasma pneumoniae
M. pneumoniae culture is time consuming and requires specialised media. M. pneumoniae anti-gen may be detected by several methods. Poly-clonal antiserum in respiratory secretions hasyielded very low specificity since many subjects Table 4. – Most commonly occurring radiographic presentations of Chlamydia pneumoniae pneumonia Antigen capture enzyme immunoassay in spu- tum has shown variable sensitivity (40-81%) and specificity (64-100%) depending on the referencemethod (culture/serology) [25]. Caution is manda- tory if negative results are found. Monoclonal an- tibody immunoblot A has been used in research samples for M. pneumoniae antigen detection in respiratory specimens [26]. DNA and RNA probeshave been developed and are commercially avail- Table 5. – Summary of clinical relevance of diagnostic techniques for identification of Mycoplasma pneumoniae, Legionella spp, Coxiella burnetii and Chlamydia pneumoniae Mycoplasma pneumoniae
EIA test: sensitivity 92% and specificity 95% on paired serumsamples. Cold agglutinin test: sensitivity 50-75% suitable as a rapidbedside test Legionella spp
Difficult and variable sensitivity (11-80%) Variable sensitivity (18-80%) good specificity (94%). Bettersensitivity on BALF than sputum Sub-optimal sensitivity (50-69%) optimal specificity (99%) Method of choice for sero-group 1 infection diagnosis IFA and ELISA tests show good sensitivity (80-85%) and specificity (95%). However, worse performance for strains other than sero-group 1 Coxiella burnetii
Need for cell cultures in high biosafety labs Chlamydia pneumoniae
Sub-optimal sensitivity (20-60%), good specificity (95%).
Little clinical value MIF is still the gold standard for acute infection diagnosis.
Paired serum samples are required Variable sensitivity and specificity. No commercial kitsavailable. Still under evaluation Abbreviations: PCR = polymerase chain reaction; EIA = enzyme immunoassay; BALF = bronchalveolar lavage fluid;
IFA = immunofluorescent antibody; ELISA = enzyme-linked immunosorbent assay; MIF = microimmunofluoresnence assay.
able, and show high specificity but low sensitivity Coxiella burnetii
(22-100%) in pharyngeal specimens [27]. Thepolymerase chain reaction (PCR) has been applied Culture of this organism must be performed in to clinical specimens showing the suitability of high biosafety laboratories only, due to its ex- this technique for the detection of M. pneumoniae treme infectivity. C. burnetii may be isolated by [28, 29]. However, a serological test should always inoculation in conventional cell cultures, yolk be performed in order to distinguish between acute sacs, or laboratory animals. The recent develop- ment of a commercially available cell microcul- Serological cold agglutinin testing is seldom ture system allows better isolation of this bacteri- employed in clinical practice; however, approxi- um. Serological tests include indirect immunoflu- mately 50-75% of patients with pneumonia due to orescence, complement fixation, ELISA, and mi- M. pneumoniae have a positive test. Even if the croagglutination. The immunofluorescence assay sensitivity is suboptimal, this bedside test is still (IgG, IgM, and IgA fractions) is currently the ref- attractive since it is simple and rapid. Complement erence method for the diagnosis of Q fever (18).
fixation (CF) yields a variable sensitivity (50- Seroconversion is usually detected 7-15 days after 90%) and suboptimal specificity. The most reliable the onset of clinical symptoms. PCR has been suc- test is enzyme immunoassay (EIA) that allows IgG cessfully employed both on clinical specimens and IgM titration and presents 92% sensitivity and 95% specificity on paired samples. Seroconver-sion timing is from 3 to 8 weeks [30].
Chlamydia pneumoniae
Legionella pneumophila
Laboratory methods for the diagnosis of C. pneumoniae infection include culture, antigen de- This difficult-to-culture pathogen, with culture sensitivity ranging from 11 to 80% (31), has been The procedure for culturing C. pneumoniae studied extensively by antigen detection. Buffered has been adapted from that for C. trachomatis.
charcoal yeast extract agar added with α-ketoglu- Different cell lines have been evaluated and HL tarate (BCYEα) is the primary medium for the iso- and Hep-2 have been found to yield best results.
lation of this organism. Specimens should always So far successful culture of C. pneumoniae has be cultured on selective and semi-selective media been obtained in a limited number of laboratories.
since some strains of L. pneumophila are inhibited The main problems encountered with culture are easy inactivation during transport, collection from The direct fluorescence antibody (DFA) stain anatomical sites devoid of active colonisation, low is used on clinical samples with variable sensitivi- yield often requiring repeated blind passages. ty (18-80%) and good specificity (94%). Sensitiv- The sensitivity of antigen detection using direct ity appears to be greater on bronchoalveolar lavage fluorescent antibodies on respiratory specimen smears is estimated to be 20-60% compared to culture, and the specificity should approach 95% but is highly op- sputum samples with a 50-69% sensitivity and erator-dependent. This technique is of little clinical 99% specificity. The test is rapid, not operator- use and is mostly employed as culture confirmation.
dependent, but still very expensive and experi- brought major advantages to the diagnosis of C. Serologic test, immunofluorescent antibody pneumoniae infection. It has been successfully (IFA) detection, enzyme-linked immunosorbent employed on respiratory specimens, lung and vas- assay (ELISA), and microagglutination are readi- cular bioptical specimens, and blood. A number of ly available techniques for the diagnosis of L. studies have found PCR to be a more sensitive pneumophila infection [34]. Seroconversion technique than culture, and nested PCR is proba- commonly requires 4 to 8 weeks, but may take up bly the best technology now available [36]. Fur- to 14 weeks in elderly patients. In addition, as thermore, two recent studies suggest that C. pneu- many as 30% of patients with acute L. pneu- moniae DNA detection by PCR on peripheral mophila infection do not show an antibody rise.
blood mononuclear cells may provide useful infor- IFA has a high specificity (95%) and a sensitivity mation on the presence of chronic C. pneumoniae of about 85% (joint IgG and IgM determination), infection [37, 38]. However, the overall diagnostic although cross-reactivity with other bacteria has utility of PCR techniques is currently hampered by been described. ELISA and microagglutination the lack of standardisation of extraction proce- present an 80% sensitivity and 96% specificity, which however decreases for strains other than Serology testing for C. pneumoniae currently includes only microimmunofluorescence assay L. pneumophila antigen may also be detected (MIF) and enzyme immunoassay (EIA), given that in urinary specimens by radioimmunoassay (RIA), complement fixation is genus-specific, has a 60% ELISA, and latex agglutination [35]. These are sensitivity in acute primary infection, but a sensi- simple, noninvasive, rapid, sensitive, and highly tivity below 10% in re-infection. Several EIA kits are commercially available, all giving qualitative Urinary RIA antigen detection is the method of but not quantitative information on C. pneumoniae choice for L. pneumophila serogroup 1.
antibody levels. Experience with these kits is lim- ited and sensitivity and/or specificity are currentlyunsatisfactory. The current gold standard for sero- Table 6. – In vitro susceptibility of C. pneumoniae logical diagnosis is MIF testing. MIF may be em- ployed to detect IgG, IgM, IgA antibodies and, when performed by an experienced reader, pos-sesses high sensitivity and specificity.
On the basis of available techniques, the most convincing evidence of acute infection is given when IgM antibodies or a fourfold rise in IgG an- tibodies can be shown. However, the need for paired sera to show a fourfold rise in antibody titres is a limitation of the MIF technique. More- over, positive findings on PCR, DFA or culture specimens from the upper respiratory tract in the presence of clinical symptoms of infection strong- ly support the presence of C. pneumoniae infection given that asymptomatic carriage has been shown Treatment
Considering the distinctive pathogenic charac- MIC, minimal inhibitory concentration; MCC, minimal teristics of Mycoplasma, Legionella and Chlamy- chlamydicidal concentration: ranges of values reported in dia infections the best therapy should combine literature (values are given as range against clinical high levels of drug intrinsic activity with the abili- isolates or against type strains of Chlamydia pneumoniae). ty to reach high intracellular concentrations.
The specific characteristics of Mycoplasma pneumoniae determine the complete inactivity ofsome antibiotics: betalactams, glycopeptides, Ketolides are a new class of macrolide antibi- sulphonamides, and rifampicin. Potentially active otics with a 3-keto function instead of the cladi- drugs are tetracyclines, macrolides, lincosamides, nose sugar, endowed with good activity against a streptogamines, chloramphenicol, and fluoro- broad range of respiratory pathogens [45].
quinolones. Exceptional cases of acquired resis- Fluoroquinolones show good activity (table 3).
tance to the macrolide-lincosamide-streptogamine Levofloxacin is more active than ofloxacin [46, 47]. Chlamydia pneumoniae susceptibility to Many antibiotics that present high in vitro ac- ciprofloxacin and fleroxacin is lower than that to tivity against Legionella spp., including imipenem other tested derivatives. The most recent and amoxicillin/clavulanic acid, are not clinically quinolone derivatives show good activity against useful in vivo due to their inability to reach the tar- Chlamydia pneumoniae. The minimal inhibitory get intracellularly, accounting for the in vitro-in vi- concentration (MIC) of moxifloxacin against three strains of Chlamydia pneumoniae were 0.6 µg/ml The best treatment regimen is a full three-week and the minimal chlamydicidal concentration treatment with a macrolide (erythromycin, clar- ithromycin) combined with rifampicin. Baker et al.
Beta-lactams and aminoglycosides show poor reported the possible induction of resistant strains or absent cell penetration. The beta-lactam target is using rifampicin as sole therapy [40]. An alterna- the bacterial cell wall, a structure lacking in tive treatment regimen may be the association of chlamydiae. However, Kuo and Grayston ob- second generation fluoroquinolones with tetracy- served that penicillin and ampicillin, while show- clines. A notable improvement in most of the new ing no effect on Chlamydia viability, could inhibit fluoroquinolones (levofloxacin, moxifloxacin, gat- infectivity (48). Rifampicin seems to have a high ifloxacin, and gemifloxacin) is their activity activity against Chlamydia pneumoniae showing against Legionella, so that their use as a single MIC and MCC values ranging from 0.005 to 0.01.
agent may be hypothesised even if clinical data are Clindamycin, chloramphenicol and co-trimoxa- still insufficient for a definitive indication.
zole, which show some in vitro activity against Data on the in vitro activity of antibiotics C. trachomatis and C. psittaci, might also be active against Chlamydia pneumoniae are relatively lim- against Chlamydia pneumoniae, but no data are ited, due to the difficulty in isolating the agent and in performing the susceptibility test (table 6). It appears that the eradication of Chlamydia Tetracyclines and erythromycin show good in pneumoniae during first infection may be obtained vitro activity and so far have been the most com- by prolonged (up to 3-4 weeks) use of macrolides.
The length of treatment may be associated with Chlamydia pneumoniae infection. Doxycycline Chlamydia’s long life cycle, and with the possibil- and minocycline are apparently slightly more ac- ity of a quiescence phase in the replication of the tive than tetracycline. The most active macrolide bacterium. Much more complex is the eradication seems to be clarithromycin [41–44].
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