Geography and the aetiology of community‐acquired pneumonia

Community acquired pneumonia (CAP) is one of the commonest severe and potentially life-threatening infections worldwide. Due to the limitations of microbiological diagnosis initial treatment of CAP is usually empirical, and remains so for a substantial proportion of patients. It is therefore essential that empirical therapy covers all the likely pathogens, which in hospitalized patients in Europe and North America are viral infections (mainly influenza), Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae Haemophilus influenzae or Staphylococcus aureus (Table 1). As a consequence European and American guidelines for CAP emphasize empirical treatment with a combination of a β lactam (active against S. pneumoniae, H. influenzae and S. aureus) with a macrolide (active against S. pneumoniae, M. pneumoniae and C. pneumoniae, although S. pneumoniae resistance is an increasing problem), or single-agent therapy with a respiratory fluoroquinolone (active against all the above pathogens). However given the immense variation in climate, geography and social conditions across the world the aetiology of CAP may vary between (and even within) countries, and guidelines suitable for one country may not be suitable for another. Two studies in this issue of Respirology provide further information on the aetiology of CAP in Asia that could influence empirical antibiotic therapy.1,2 C. pneumoniae and M. pneumoniae, along with Legionella pneumophila, Chlamydia psittaci and Coxiella burnetii, are often described as ‘atypical’ organisms due to their intracellular life cycle, the difficulty in culturing them, and because they are not sensitive to β lactams. With the exception of L. pneumophila, atypical organisms are generally considered to cause milder disease than other bacterial causes of CAP, and there has been some controversy whether empirical treatment for CAP should always include cover against atypical organisms. Lui et al. demonstrate that the incidence of CAP due to atypical organisms in a large series of patients admitted to a teaching hospital in Hong Kong was 24%, with the vast majority of infections due to M. pneumoniae and C. pneumoniae.1 The results support other studies from Asia that consistently demonstrate that atypical organisms cause over 20% of cases of CAP admitted to hospital, similar to the incidence in the rest of the world (Table 1). Patients with CAP due to atypical organisms were younger, had less dyspnoea and a lower mortality compared with other bacteria, but nonetheless over 35% had high severity scores (PSI IV or V) and the incidence of admission to intensive care was similar to patients with CAP not caused by atypical organisms.1 In common with other authors, Lui et al. found that clinical parameters could not reliably distinguish CAP caused by atypical organisms from CAP due to other bacteria. Overall this study provides additional data demonstrating CAP due to atypical organisms is common and can be severe, but is difficult to identify clinically. As treatment with empirical antibiotics against atypical organisms is associated with a faster recovery and a 4.1% fall in all cause mortality,3 this suggests empirical therapy for atypical organisms is important in Hong Kong and other Asian centres, as well as in Europe and North America. Although the incidence of CAP due to atypical organisms is remarkably similar across the word, studies in Asian countries clearly indicate that there are often significant differences in the aetiology of CAP to Europe and North America (Table 1). One immediate difference is the significant incidence of pulmonary tuberculosis (TB) presenting as CAP in some Asian countries, which is up to 29% in Hong Kong, Malaysia and Singapore. There are only limited data on viruses as a cause of CAP in Asia, but at least in Japan viral CAP is much less common than in European studies. CAP caused by non-H. influenzae Gram-negative bacteria such as coliforms and Pseudomonas aeruginosa is rare in European studies although causes up to 16% of cases in North America, probably due to a greater preponderance of elderly debilitated patients. In contrast, Gram-negative bacteria are a common cause of CAP in some Asian studies, and are even the predominant cause in Malaysia and Singapore (Table 1), mainly due to a much greater incidence of Klebsiella pneumoniae CAP. The incidence of K. pneumoniae CAP ranges from 4% in Japan to 23% of cases in Malaya, with an average of 15% in a pan-Asian study, compared with <1% in the United Kingdom (Table 1). As well as the high incidence of K. pneumoniae CAP, additional unusual bacterial pathogens can account for a significant proportion of cases of CAP in specific geographic areas. For example, Burkholderia pseudomallei, the cause of meliodosis, accounts for 1–2% of cases of CAP in urban centres in South East Asia, increasing to 32% in rural Thailand. As well as these differences in the endemic causes of CAP, epidemics of less common causes of CAP such as SARS, pneumonic plague (currently active in parts of China) and avian flu often originate in Asia and will be major causes of CAP on occasions. The above data demonstrate that the pathogens causing CAP in Asia can differ to those in Europe and North America, and this is reinforced by the second study published in this edition of Respirology.2 Leo et al. present a case series of eight patients in Singapore presenting with CAP and positive cultures for Acinetobacter baumannii.2A. baumannii is a Gram-negative pathogen that is often considered a skin contaminant and is usually associated only with nosocomial infections, but has also recently been described in US military personnel returning from Iraq and Afghanistan. However, A. baumannii was cultured from both blood and sputum in the majority of patients described by Leo et al., strongly suggesting it was the cause of the infection and supporting epidemiological studies that have shown Acinetobacter causes up to 2% of cases of CAP in several Asian countries (Table 1). Patients with A. baumannii CAP were relatively young and presented in a similar way to severe S. pneumoniae CAP, with a rapid onset of disease, purulent phlegm and lobar infection.2 Most patients had shock and respiratory failure, and the mortality was over 60%. Although this clinical presentation may be skewed by the unreliability of making a diagnosis of A. baumannii infection in the absence of septicaemia, these data suggest it is a cause of severe CAP. Despite its relatively low incidence, the severity of infection combined with the organisms' resistance to first line antibiotics make A. baumannii an important consideration when managing CAP in certain Asian countries. Why should there be a wider range of pathogens causing CAP in Asia? The increased incidence of TB as a cause of CAP in Asia reflects the overall higher incidence of TB compared with Europe and North America, so is perhaps predictable. The reasons causing the increase in K. pneumoniae CAP and occurrence of pathogens such as A. baumannii are less clear. In Europe K. pneumoniae pneumonia is classically associated with alcoholism but this is unlikely to explain the high incidence in some Asian countries. The prevalence of particularly virulent strains of K. pneumoniae may be higher in Asia, and this is supported by the observation that 94% of K. pneumoniae isolates from patients with CAP are mucoid and these strains are more virulent in mouse models of infection.18 Alternatively the increased incidence of K. pneumoniae CAP in Asia may reflect the effects of different environmental conditions on transmission, or possibly an increased frequency of host factors such as abnormal nutritional status, comorbidities or genetic background that may favour K. pneumoniae infection. Similar considerations could also apply to A. baumannii, but this is an environmental organism and the increased incidence of infection in Asia suggests exposure to an environmental reservoir of A. baumannii analogous to the situation with B. pseudomallei CAP. If an environmental source can be identified this may allow preventative measures. Overall, considerably more research is required to characterize why certain organisms are prevalent causes of CAP in some Asian countries. The more immediately practical question is whether the data on aetiology of CAP in Asia should affect management? The high incidence of TB suggests there should be a low threshold for specific microbiological investigations for TB, especially in patients who have had symptoms for longer than 2 weeks, upper lobe disease or cavitation.13 The increased range of bacterial causes of CAP, and in particular the higher incidence of infections with Gram-negative organisms, should probably also influence empirical therapy for CAP in some parts of Asia. For example, K. pneumoniae is often resistant to β lactams and macrolides, and Acinetobacter species are even resistant to some β lactam-stable agents (e.g. coamoxiclav) as well as second generation cephalosporins. CAP due to Gram-negative organisms tends to be more severe than other causes of CAP,19 emphasizing the importance of appropriate empirical therapy. Furthermore, in 25–70% of cases of CAP no microbiological diagnosis can be found, and in Europe these cases are assumed to be mainly due to S. pneumoniae. However, in Asia the larger range of organisms that can cause CAP suggests cases with no microbiological diagnosis will have a more varied aetiology than in Europe, and broader empirical therapy could therefore be necessary. Unfortunately this is likely to have a negative impact on antibiotic resistance and the costs of health care. Differences in the aetiology of CAP between countries could also have additional implications. First, CAP severity scores developed in Europe and North America may not be as useful in Asian patients infected with a different range of organisms. Second, vaccination programmes against S. pneumoniae might be less effective at reducing the incidence of CAP, and could even make empirical treatment more difficult by increasing the relative prevalence of unusual organisms as causes of CAP. The papers in this addition of Respirology shed more light on the causes of CAP in Asia, and how this might affect management. Although primary of importance to Asian countries, in the globalized world of today doctors treating an Asian patient visiting another country need to be aware that CAP could be due to a relatively unusual pathogen. These and other studies demonstrate the importance of each country having local data on the causes of infectious diseases to inform local guidelines, and so avoid potentially sub-optimal empirical therapy.