• Chlamydophila;
  • Mycoplasma;
  • outcome;
  • pneumonia;
  • severity


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Background and objective:  Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community-acquired pneumonia (CAP) worldwide. This study examined the role of these ‘atypical pathogens’ (AP) among adult hospitalized patients with CAP.

Methods:  A prospective, observational study of consecutive adult CAP (clinico-radiological diagnosis) patients hospitalized during 2004–2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed.

Results:  There were 1193 patients studied (mean age 70.8 ± 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: ‘bacterial’ (48.7%), ‘viral’ (26.9%), ‘AP’ (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co-infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one-third of patients were classified as ‘intermediate’ or ‘high’ risk CAP on presentation (pneumonia severity index IV–V (35.1%); CURB-65 2–5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8%; non-invasive ventilation 3.7% vs 3.3%; admission to the intensive care unit 4.5% vs 2.7%; length of hospitalization 6 day vs 7 day; 30-day mortality: 2.2% vs 6.0%; overall P > 0.05). Age <65 years, female gender, fever ≥38.0°C, respiratory rate <25/min, pulse rate <100/min, serum sodium >130 mmol/L, leucocyte count <11 × 109/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75).

Conclusions: M. pneumoniae and C. pneumoniae as single/co-pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.


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This study assessed the clinical significance and outcome of Mycoplasma pneumoniae and Chlamydophila pneumoniae infection in adults hospitalized with community-acquired pneumonia (CAP). A prediction rule based on clinical and routine laboratory parameters could not reliably distinguish the underlying aetiology or guide therapy in CAP patients, so empirical antibiotic coverage for atypical pathogens should be considered in all patients hospitalized with CAP.


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Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community-acquired pneumonia (CAP) worldwide.1,2 These organisms, frequently referred as ‘atypical pathogens’ (AP), do not respond to beta-lactam therapy alone. While M. pneumoniae and C. pneumoniae are often implicated as the causes of mild CAP in young ambulatory patients,3,4 their roles among the older and sicker hospitalized patients remain uncertain, particularly in the Asia–Pacific region.3,5 In certain regions including Hong Kong, empirical β-lactam mono-therapy is recommended, while the use of a macrolide is optional.6 However, recent studies have suggested that treatment of AP may be associated with faster clinical recovery and lower mortality.2

This study reports the epidemiology, disease severity and clinical outcomes of patients with AP infection in a large cohort of adults hospitalized with CAP. The study investigated whether there are any useful clinical, laboratory and radiological indicators of AP infection, and developed a score-based clinical prediction rule to assist clinicians to decide on empirical antibiotic coverage for AP.


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Study design, patients and setting

This prospective observational study was conducted at a Hong Kong teaching hospital.7 Consecutive patients, aged 18 years or above, admitted to hospital between 1 January 2004 and 30 June 2005 (18 months) with a diagnosis of CAP were enrolled. In Hong Kong, older CAP patients with severe symptoms are usually treated in hospital.7 The diagnosis of pneumonia in our cohort was made by the attending physician, based on the presence of symptoms and signs compatible with acute lower respiratory tract infection and new pulmonary infiltrates on CXR.8,9 Patients who had been hospitalized within 14 days of the current admission, and those with severe immunosuppression (defined as HIV infection, neutropaenia <1 × 109/L, on long-term immunosuppressants or steroids, or solid organ transplant recipients) were excluded from the study.7

A standard protocol was used for the microbiological investigation of CAP patients regardless of the presenting clinical features and disease severity: (i) nasopharyngeal aspiration for respiratory viruses; (ii) expectorated sputum for bacterial culture; (iii) blood culture; and (iv) paired serology for AP (IgM and IgG assays, see below). In the first 200 consecutive patients, urinary antigen testing for L. pneumophila serogroup 1 was also performed.10,11 The first blood sample for serological assay was collected at presentation, and the convalescent-phase blood sample was taken in hospital if the patient remained hospitalized beyond 2 weeks, or arranged during a review visit in our outpatient clinic if discharged. Serology results for AP were not available to clinicians during the period of hospitalization. All patients with the diagnosis of CAP were treated with empirical antibiotics according to standard hospital guidelines, which included the use of a beta-lactam (amoxicillin-clavulanate, cefotaxime or ceftriaxone) ± clarithromycin/azithromycin, or a respiratory fluoroquinolone.6

Data collection

Clinical data were recorded according to a standard questionnaire administered by a trained research nurse. Variables collected included age, gender, admission from home or a nursing home, coexisting illness, symptoms and clinical parameters (blood pressure, pulse rate, respiratory rate, SaO2, tympanic temperature and mental confusion), and laboratory findings on presentation (full blood count, arterial blood gases, glucose, electrolytes, liver and renal function).7 The requirement for supplemental oxygen therapy to maintain SaO2 >95%, intensive care unit (ICU) admission, invasive/non-invasive ventilatory support, length of stay (LOS) in hospital, and all-cause 30-day mortality were also recorded. Severity of pneumonia was graded according to the Pneumonia Severity Index (PSI)12 and CURB-65 score.13 Patients with PSI class IV–V, and a CURB-65 score of 2–5 were considered as intermediate and high risk.7,12,13 Every patient had a CXR performed at presentation. Images were assessed using a picture archiving and communication system, viewer workstation with a 2048 × 2048-pixel monitor (Magicview, version VA22E; Siemens, Erlangen, Germany). For patients recruited in year 2004, the CXRs were reviewed by senior radiologists to determine the presence of new infiltrates and the pattern of abnormality (n = 789). The reviewers were blinded to the clinical information except for being aware that this was a study aiming to include patients with CAP. Ethics approval for the study was obtained from the Institutional Review Boards of the Hospital Authority of Hong Kong. Authorization was granted by the Board to access, use and publish patient records, and confidentiality was maintained.

Microbiological investigations

A combined approach was used to investigate the cause of pneumonia, as previously described.10,11 Patients were considered to have an aetiologic diagnosis established if significant pathogens were isolated from their respiratory specimens (e.g. sputum, BAL fluid), peripheral blood and nasopharyngeal aspirates (for respiratory viruses); if serology testing showed definitive evidence of acute infection by an ‘atypical pathogen’ (a fourfold rise in titre, or positive IgM); or if rapid antigen tests were positive in nasopharyngeal aspirates for respiratory viruses and urine specimens for L. pneumophila serogroup 1 respectively (see below). All patients whose investigation results did not meet these criteria were classified as ‘aetiology uncertain’ (including patients with ‘probable’ or ‘presumptive’ aetiologies).4,14,15

Respiratory specimens were processed and interpreted according to standard procedures as described.11,16 Isolates with greater than 105 colony forming units were reported as positive growth. Potential pathogens (including Pseudomonas spp., Klebsiella and other Enterobacteriaceae spp., Staphylococcus aureus, Pasteurella spp., β-haemolytic streptococci, etc.) were reported as significant only when they were present in heavy or predominant growth, or as pure culture.17 Acid fast staining and culture for Mycobacterium species onto Lowenstein–Jensen medium after decontamination of sputum specimens were performed according to standard procedures.16 Blood cultures were performed using the BacT/Alert Microbial Detection System (BioMerieux SA, Marcy l'Etoile, France). Both aerobic and anaerobic cultures were inoculated and incubated for 6 days before a negative culture was reported. Positive cultures were isolated and identified as per standard procedures and antibiotic susceptibilities performed according to CLSI.16,17

Acute and convalescent-phase sera collected more than 2 weeks apart were used for serological assays. Serology for influenza virus types A and B, respiratory syncytial virus (RSV), parainfluenza virus types 1, 2 and 3, adenovirus, Chlamydia spp. (incl. C. psittaci and C. pneumoniae), M. pneumoniae and Coxiella burnetii were performed by complement fixation tests.5 A fourfold rise in titre was considered definitive evidence for acute infection by these pathogens. In addition, IgM and IgG antibody levels were detected for M. pneumoniae by commercial enzyme immunoassays (PLATELIA M. pneumoniae IgG and IgM EIAs, Bio-Rad, USA). IgM, IgG and IgA antibody levels to C. pneumoniae were detected using the commercial EIAs (SeroCP IgM, SeroCP Quant IgG and IgA, Savyon Diagnostics Ltd, Israel). These tests were performed and interpreted according to the manufacturers' recommendations. For M. pneumoniae, only a positive IgM, a twofold rise in antibody titre and/or a markedly raised IgG titre (>40 AU/mL), were regarded as definitive evidence for acute M. pneumoniae infection.18,19 For C. pneumoniae, all the second sera were tested in parallel with the patients' first sera. An equivalent micro-immunofluorescent test (MIF) end point titre for IgG was calculated based on the IgG values of the test, according to the instructions of the manufacturer. Only a positive IgM and/or a fourfold difference in IgG level were regarded as definitive evidence for acute C. pneumoniae infection.20,21

Immunofluorescent assays for viral antigen detection and viral isolation were performed on nasopharyngeal aspirates as described previously.10,11 Briefly, immunofluorescent antigens to influenza virus types A and B, and RSV were detected by direct immunofluorescence. A positive result by immunofluorescence and/or isolation of a respiratory virus was considered as definitive aetiology.

L. pneumophila serogroup 1 antigens were tested on 200 consecutive urinary samples using the NOW Legionella Urinary Antigen Test (Binax, Portland, USA), according to the manufacturer's instructions. Urine specimens were stored at −20°C until use. A positive result was considered as acute infection due to L. pneumophila serogroup 1. All but one sample was negative.

Statistical analysis

Community-acquired pneumonia patients with an established causative organism were further analysed. Clinical, laboratory, radiological and outcome variables (including 30-day mortality and LOS among survivors) were compared between groups with different CAP aetiologies using chi-square test, the Student's t-test, or the Mann–Whitney U-test as appropriate. Variables with P value <0.1 in the univariate analyses were included in multivariate backward stepwise logistic regression models to determine independent variables. A score-based prediction rule for a final diagnosis of AP infection was developed from the logistic regression equations using a regression coefficient-based scoring method.22 To generate a simple integer-based point score for each predictor variable, scores were assigned by dividing β-coefficients by the absolute value of the smallest coefficient in the model and rounding up to the nearest integer. The overall risk score was calculated by adding each component together. A receiver operating characteristics (ROC) curve was used to evaluate the sensitivity and specificity of the risk scores, with the area under the curve (AUC) indicating its discriminatory ability. All probabilities were two-tailed, with a P value <0.05 indicating statistical significance. All statistical analyses were performed by SPSS (version 13.0; SPSS, Inc., Chicago, IL, USA).


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The study analysed 1193 patients who completed the protocol. Patients were mostly elderly (73.4% were >65 years of age), 49.2% had an underlying comorbid illness and at presentation their pneumonia was frequently classified as ‘intermediate’ and ‘high’ risk (PSI class IV–V in 47.3%; CURB-65 score 2–5 in 50.8%) (Table 1).7 Aetiologic diagnoses were established in 468 (39.2%) patients (‘aetiology uncertain’, n = 725). Among these, 134 (28.6%) patients had AP infections, including M. pneumoniae (n = 78), C. pneumoniae (n = 55), L. pneumophila (n = 1) and C. burnetii (n = 2). Two patients had dual mycoplasma/chlamydophila infections. Co-infections were observed in 41 (30.6%) of the 134 patients with AP infections, with concomitant pathogens being bacterial (n = 31), viral (n = 8) or another AP (n = 2). Mycoplasma or Chlamydophila pneumoniae (28.0%), influenza virus (21.8%), S. pneumoniae (21.6%) and H. influenzae (13.2%) together were responsible for pneumonia in 85% of CAP patients in whom the infectious agent was identified.

Table 1.  Clinical characteristics and aetiologic diagnoses of community-acquired pneumonia (CAP) in 1193 patients
Clinical characteristicsWhole cohort n = 1193Aetiologies established n = 468
  • Numbers are % unless otherwise indicated.

  • Classification based on the Pneumonia PORT Severity Index scoring system (congestive heart failure, cerebrovascular, neoplastic, chronic liver and renal disease);12 other significant comorbidities recorded include diabetes, ischemic heart disease, autoimmune, endocrine and neurological diseases. Supplemental oxygen therapy was used in patients with dyspnoea to maintain oxygen saturation >95%.

  • Proportion of patients with various samples collected: sera 100%, sputum 72.3%, nasopharyngeal aspirate 82.6%. Overall, mixed infections with ≥2 organisms identified were present in 74/468 (15.8%) of the CAP patients (e.g. dual bacterial infections = 17; concomitant M. pneumoniae and C. pneumoniae infections = 2). Patients with bacterial infection = 228 (bacterial alone = 183; bacterial + AP/virus = 45); among these, eight had positive blood culture results (S. pneumoniae = 3, S. aureus = 2, Gram-negative bacilli = 2, Streptococcus species = 1). Other bacterial pathogens: M. catarrhalis (n = 11), S. aureus (n = 11), Gram-negative bacilli (n = 60). Other viral pathogens: respiratory syncytial virus (n = 12), parainfluenza (n = 9), adenovirus (n = 3).

  • ICU, intensive care unit ± intubation; LOS, length of stay in hospital among survivors; Non-invasive ventilation, BIPAP in medical wards; PSI, pneumonia severity index.

Age (mean ± SD)70.8 ± 18.069.6 ± 18.6
Gender, male59.360.5
Nursing home resident22.617.7
Major comorbidity34.429.7
Comorbidity, any49.246.4
PSI class IV-V47.342.1
CURB-65 score 2–550.850.0
Supplemental O2 therapy29.029.6
Non-invasive ventilation3.03.4
ICU admission3.93.2
30-day mortality6.54.9
LOS in hospital (median, IQR)7 (5–10)7 (5–10)
Aetiological agents, by patient (%)
Atypical pathogens, AP (n = 134)11.228.6
 Mycoplasma pneumoniae (n = 78)6.516.7
 Chlamydophila pneumoniae (n = 55)4.611.8
 Coxiella burnettii (n = 2)0.20.4
 Legionella pneumophila (n = 1)0.10.2
 Mixed AP and bacteria (n = 31)2.66.6
 Mixed AP and virus (n = 8)0.71.7
Bacterial pathogens (n = 228)19.148.7
 Streptococcus pneumoniae (n = 101)8.521.6
 Haemophilus influenzae (n = 62)5.213.2
 Others (n = 82)6.917.5
Viral pathogens (n = 126)10.626.9
 Influenza virus (n = 102)8.521.8
 Others (n = 24)2.05.1
Mycobacterium. Tuberculosis (n = 38)3.28.1

Of the 134 patients with AP infections, the majority (63.4%) were aged >65 years (with >16% being nursing home residents) and 35.1% and 42.5% were classified at presentation as ‘intermediate’ and ‘high’ risks according to the PSI (class IV–V) and CURB-65 (score 2–5) rules respectively. Compared with patients with other causes of pneumonia (Table 2), patients with AP infection had comparable disease severity and clinical outcomes, including the need for oxygen therapy, non-invasive ventilation, ICU admission and total LOS (P > 0.05). The 30-day mortality tended to be lower in these patients (n = 3, 2.2%), but this reduction was not statistically significant (P = 0.09).

Table 2.  Clinical characteristics and outcomes of 134 patients infected with atypical pathogens, compared with patients with other confirmed aetiologies of community-acquired pneumonia, and statistical significance of the difference
CharacteristicsAtypical pathogen (n = 134)Other aetiologies (n = 334)P value
  • Numbers are %s unless otherwise indicated.

  • Including mono-infections and mixed infections with a bacteria/virus; 97.8% were due to M. pneumoniae or C. pneumonia.

  • 30-day mortality for patients with bacterial and viral causes of pneumonia was 6.6% and 4.0% respectively (e.g. S. pneumoniae 3.0%; H. influenzae 4.8%; influenza virus 3.9%).

  • §

    Median LOS (interquartile range) for patients with bacterial and viral causes of pneumonia was 7 days (5–10) and 6 days (5–9) respectively (e.g. S. pneumoniae 7 days (5–10); H. influenzae 7 days (5–9); influenza virus 6 days (5–9)).

  • Also refer to Table 1 footnotes for the explanation of variables.

  • ICU, intensive care unit; LOS, length of stay.

Age (mean ± SD)66.4 ± 20.670.9 ± 17.70.027
Gender (male)57.561.70.399
Nursing home residents16.418.30.637
Major comorbidity26.930.80.395
Comorbidity, any41.848.20.209
PSI class IV-V35.144.90.051
CURB-65 score 2–542.553.00.041
Supplemental O2 therapy29.129.80.878
Non-invasive ventilation3.73.30.814
ICU admission4.52.70.322
30-day mortality2.26.00.090
LOS in hospital, median (IQR)6 (5–10)7 (5–10)§0.877

Patient demographics, clinical, routine laboratory and radiological variables were compared between patients with AP (n = 95) and bacterial (n = 183) mono-infections (Table 3). Patients with mixed AP and bacterial/viral infections were excluded from these comparisons. When compared with bacterial pneumonia, age <65 years (OR 2.5, 95% CI: 1.4–4.6; P = 0.003), female gender (OR 1.9, 95% CI: 1.1–3.4; P = 0.024), fever ≥38.0°C (OR 2.7, 95% CI: 1.5–4.9; P = 0.001), respiratory rate <25/min (OR 1.9, 95% CI: 1.0–3.6; P = 0.039), pulse rate <100/min (OR 1.8, 95% CI: 1.0–3.3; P =  0.047), absence of hyponatraemia with serum sodium >130 mmol/L (OR 12.5, 95% CI: 1.5–100.9; P = 0.018), leucocyte count <11 × 109/L (OR 2.0, 95% CI: 1.1–3.5; P = 0.021) and Hb < 11 g/dL (OR 2.2, 95% CI: 1.1–4.5; P = 0.024) at presentation were independent indicators of AP infection as shown by multivariate analysis. However, a score-based prediction rule derived from these variables could not reliably discriminate patients with pneumonia caused by AP from patients with bacterial pneumonia (AUC = 0.75, 95% CI: 0.69–0.81) (Fig. 1). No specific cut-off value could be identified that provided reasonable sensitivity or specificity. For instance, to obtain a specificity of 80%, the cut-off value provided a sensitivity of only 54%. When compared with viral pneumonia, only respiratory rate <25/min (OR 2.7, 95% CI: 1.3–5.9; P = 0.009) and absence of runny nose (OR 2.5, 95% CI: 1.1–5.7; P = 0.025), but no laboratory variables, were independently associated with AP infection. Comparison of patients with AP mono-infection to patients with bacterial or viral pneumonia, respectively, showed no significant differences in PSI class, CURB-65 score, requirement for oxygen therapy, non-invasive ventilation and ICU care, and hospital LOS even when mixed infections were excluded from these comparisons (all P > 0.05) (see Table 2 footnotes). The only exception was a lower all-cause 30-day mortality (AP 1.1% vs bacterial 6.6%; P = 0.04) in patients with AP mono-infection compared with patients with bacterial infection.

Table 3.  Clinical, laboratory and radiological features of patients with atypical pneumonia (AP) at presentation compared with patients with bacterial pneumonia
Clinical variablesAP pneumonia (n = 95)Bacterial pneumonia (n = 183)P value
  • Numbers are %s unless otherwise indicated.

  • This included only patients with AP mono-infections; cases with mixed AP and bacterial/viral infections were excluded from these comparisons for clinical features.

  • Normal reference ranges of laboratory variables: sodium (134–145 mmol/L), urea (3.4–8.9 mmol/L), Hb (11.5–14.3 g/dL), platelets (140–380 × 109/L), WCC (4.0–10.8 × 109/L), bilirubin (<15 µmol/L), alanine aminotransferase (<58 IU/L).

  • NS, no statistical significance.

Age >65 years57.974.90.004
Gender, male53.771.00.004
Major comorbidity29.531.7NS
Comorbidity, any44.247.5NS
Travel history18.915.3NS
Nursing home resident20.019.1NS
Onset >3 days before admission43.236.1NS
Sputum production82.187.4NS
Chest pain15.822.4NS
Sore throat13.710.9NS
Runny nose15.823.0NS
Systolic BP, mm Hg (mean ± SD)140.1 ± 24.1144.0 ± 31.3NS
Tachycardia (pulse rate ≥100)48.460.10.063
Temperature ≥38°C64.244.80.002
Tachypnoea (resp. rate ≥25)
Oxygen desaturation31.632.8NS
Glasgow Coma score <159.512.0NS
Radiological changes (%)   
 Airspace consolidation83.782.6NS
 Reticular or ground-glass16.317.4NS
 Pleural effusion19.611.3NS
Laboratory variables (mean ± SD)   
 Sodium (mmol/L)136.3 ± 3.4134.9 ± 5.30.007
 Urea (mmol/L)6.9 ± 4.67.7 ± 4.0NS
 Hb (g/dL)11.9 ± 1.912.6 ± 1.70.004
 Platelet (×109/L)248 ± 91238 ± 107NS
 WCC (×109/L)11.6 ± 5.713.9 ± 6.50.006
 Bilirubin (µmol/L)15.7 ± 13.616.6 ± 17.0NS
 Alanine aminotransferase (IU/L)43.9 ± 54.036.9 ± 51.2NS

Figure 1. Receiver operator characteristic (ROC) curve for discriminating pneumonia caused by atypical pathogens from bacterial pneumonia, using a score-based clinical prediction rule. Area under ROC curve (AUC) = 0.75; 95% CI: 0.69–0.81. In general, the discriminatory ability of AUC can be interpreted as follows: AUC ≥ 0.90 as ‘excellent’, 0.80 to <0.90 ‘good’, 0.70 to <0.80 ‘fair’ and <0.70 ‘poor’. Intersection of the two lines indicates the corresponding sensitivity (54%) and specificity (80%) to diagnose pneumonia due to atypical pathogens (refer to text).

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This is one of the largest Asian studies to report on the clinical significance and outcomes of adults hospitalized with CAP due to AP. M. pneumoniae and C. pneumoniae, as single or co-pathogens, can cause severe diseases in older patients, resulting in hospitalization. Our results concur with data from other Asia–Pacific studies, which showed that mycoplasma and chlamydophila are responsible for 9–12% and 6–13% of CAP respectively,2,14,23–26 whereas L. pneumophila infection remains uncommon (∼5%).2,23,24,26

In contrast to some early studies which described mild or ‘walking’ pneumonia due to APs in children and younger adults,3,4 our results and more recent reports have shown that these organisms are important causes of CAP in elderly community-dwellers and nursing home residents.27–31 Very often these patients have comorbid medical conditions; and many of them would be sick enough to warrant hospitalization.2,5,23,31–34 Some may even require intensive care because of severe sepsis and/or respiratory failure.8,23,33–35 In fact, based on the clinical prediction rules of PSI and CURB-65, >35–40% of the patients with AP infection in our cohort were classified as ‘intermediate’ and ‘high’ risk on presentation. About 30% of these patients had required oxygen therapy, >8% received ventilatory support (non-invasive ventilation in ward/mechanical ventilation in ICU), and the total hospital LOS was 5–10 days. These outcomes were generally comparable with CAP patients with aetiologies other than AP.28,32,34,36 Although there was a lower overall mortality in patients with AP infection, the reduction was statistically insignificant. Co-infection (with a bacteria/virus), which occurred commonly (>30%), might have contributed to the overall disease severity and outcome.5,9,24,27,33,34,36 We observed that two out of the three deaths in the AP infection group were patients who had a concomitant bacterial pathogen isolated. Either as a sole or a co-pathogen, our results suggested that AP infection can be associated with severe CAP in older adults, and their treatment may need to be considered. This suggestion is supported by a recent analysis which showed that treating hospitalized CAP patients with dual β-lactam and macrolide therapies is associated with decreased time to clinical stability, decreased LOS and reduced mortality.2

Laboratory diagnosis of acute M. pneumoniae and C. pneumoniae infections remains difficult.9,37 Therefore we attempted to develop a ‘clinical prediction rule’, based on the results of routine assessments, to assist clinicians in identifying AP infections and to indicate the requirement for treatment other than a beta-lactam (such as a macrolide). In other studies/regions, prediction rules for AP infection in adult CAP have provided sensitivities ranging from 48% to 77%, and specificities 89–93%.5,38,39 Consistent with other reports, younger age, high fever, normal WCC, mild anaemia, absence of significant hyponatraemia and lack of tachypnoea/tachycardia were found to be indicators of AP infection.5,36,38 Despite its ‘fair’ discriminatory ability (AUC 0.75), our prediction rule did not seem to provide a cut-off point with reasonable sensitivity and specificity for AP infection. It is possible that the heterogeneous clinical features of the various ‘atypical pathogens’, and their different relative compositions in each studied cohort (e.g. L. pneumophila) limited the generalizability of these prediction rules.5,39 Further studies to include certain surrogate markers may be warranted.5

Because reliable clinical indictors are lacking, our data support the latest recommendations from the Infectious Diseases Society of America and the American Thoracic Society to use an empirical antibiotic regime that covers APs in all hospitalized CAP patients in our region. In addition to an anti-pneumococcal β-lactam, a macrolide (or doxycycline) should be considered; respiratory fluoroquinolone is another option. Recent analyses (which included studies from the Asia–Pacific region) show that lack of specific treatment for AP may be associated with poorer clinical outcomes.2,14,40,41 However, well-conducted randomized controlled trials (e.g. β-lactam vs β-lactam + macrolide) are necessary to resolve this issue,2,42 and the diagnosis of viral (influenza) infections in the remaining 20–30% of hospitalized CAP patients may help to reduce antibiotic prescriptions.43,44

Our study is limited by the fact that acute infections caused by M. pneumoniae and C. pneumoniae were diagnosed based on serological assays, and not culture or PCR;1,9,37 and urinary antigen tests for legionella were performed in only 200 patients.26 Cultures, although specific, are insensitive; and PCR assays for these infections have not been standardized/validated.1,9,37 To avoid exaggeration, we have adopted the more stringent criteria for serological diagnosis; patients with results indicating a ‘probable’/‘presumptive’ aetiology (e.g. a single, moderately high titre) were classified as ‘aetiology uncertain’ and not included in the detailed analysis.5,14,15,23 The sensitivities and specificities of the serology assays used to detect M. pneumoniae infection (complement fixation; IgM and IgG EIA, PLATELIA) have been shown to be reasonably accurate when performed on adult acute/convalescent-phase sera samples collected 2 weeks apart (AUC 0.87–0.94; PCR assay as the ‘gold standard’).18,19,26 Although the serological diagnosis of acute C. pneumoniae was not based on the MIF test, the SeroCP-EIA (Savyon)(using preserved specific LPS of C. pneumoniae as antigens), when evaluated against the MIF ‘gold standard’, gave a sensitivity, specificity and an overall agreement of >90% (n = 240).20,21 Since the MIF test lacks standardization (e.g. use of different strains), and studies have shown poor inter-observer consistency on the interpretation of endpoints, a well-evaluated commercial EIA method was chosen for this study.14,26,37 Finally, it is possible that patients who had died early during admission would not have had the convalescent-phase sera available for study. Together with the more stringent diagnostic criteria adopted, the prevalence and severity of APs in adult CAP might have been underestimated.

In conclusion, M. pneumoniae and C. pneumoniae as single/co-pathogens are important causes of severe pneumonia in older adults. As reliable clinical indicators are lacking, their empirical coverage among hospitalized CAP patients may need to be considered.


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We would like to thank Ms Jenny Ho for her excellent clerical support.


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