This study is notable in many ways. To our knowledge, it is the first report of a comprehensive picture of radiographically confirmed pneumonia and other ALRI that resulted in hospitalization in a low-income tropical country of Southeast Asia. In addition, only a few studies have been conducted in semi-rural hospitals in a population of all ages using a wide range of diagnostic tools to identify viruses and bacteria causing ALRI [5
The primary finding relates to categorizing various forms of ALRI based on radiographic patterns combined with the identification of pathogens. Indeed, bacterial etiologies varied significantly from one form of ALRI to another. Pneumonia, which is mainly caused by bacteria in hospitalized persons aged ≥5 years, accounted for most of the ALRI cases. However, a large proportion of the ALRI patients had radiographic imaging of lung sequelae, most probably caused by tuberculosis or undertreated pneumonia.
Depending on the immune response of the host, TB generally evolves slowly (3–8 weeks) before the onset of symptoms [17
]. However, in this study, we were surprised to have found AFB to be the most common pathogen in hospitalized patients with acute pneumonia. Although Cambodia is known as one of the countries with the highest TB prevalence and incidence reported in the world (http://www.who.int/tb/country/en/index.html
), the interpretation of these results is unclear. It is possible that the history of illness was poorly recalled by the patient or a mixed infection existed with a non-TB respiratory pathogen which may have led to hospitalization. On the other hand, there is emerging evidence across the world and particularly shown in African studies, that M. tuberculosis
is commonly present in acute community-acquired pneumonia in children [15
] and adults [20
], particularly in settings of high TB prevalence. One suggested explanation is the increased susceptibility to bacterial infection (particularly pneumococcal infection) by prior M. tuberculosis
infection as demonstrated by experimental studies [21
]. In the present study, 21% of tuberculosis cases were co-infected with other bacteria, of which S. pneumoniae
was the main (43%) pathogen identified. Our findings imply that expanding the TB screening criteria to include acute pneumonia might be considered. Of note, Cambodia is planning to develop a multi-symptoms approach to increase cost-effective routine screening for TB.
Our second main finding also indicates that a non-negligible proportion of patients presenting with cavitary lung imaging suggestive of TB were affected by other abscess-associated bacteria (e.g. K. pneumoniae, B. pseudomallei, S. aureus
, etc.…). Prior to this study, these bacteria tended not to be recognized by local clinicians who empirically treated patients with a penicillin A-based therapy, an antibiotic that is not effective on some naturally resistant strains of Gram-negative bacteria such as B. pseudomallei
]. In adult patients with non-cavitary pneumonia, common pathogens causing community-acquired pneumonia in West and Far-East Asia include S. pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae
and Legionella pneumoniae
]. First, atypical pathogens (i.e. C. pneumoniae
and M. pneumoniae
) were rarely detected in our hospitalized patients: of a subgroup of sputum specimens from a group of 304 randomly selected study patients, only 3 tested positive by PCR: 2 for M. pneumoniae
and 1 for C. pneumoniae
(IPC, unpublished data). This result was also observed elsewhere [20
] and was consistent with another recent study of community-acquired pneumonia among immuno-compromised adults in Cambodia [27
]. Secondly, we found a lower frequency of S. pneumoniae
compared with other bacteria.
Because S. pneumoniae
is known to be fragile, some related infections might have gone undetected as cultures were performed at IPC after a certain delay due to transportation of specimens [29
]. The extent of undetected S. pneumoniae
infection may be suggested by the following sub-study: of a random sample of 24 ALRI cases (median 58 years of age, range 18 – 78) for which we also collected urine samples, three (13%, 95% confidence interval 3% - 32%) patients tested positive for S. pneumoniae
antigen by Binax NOW® rapid immunochromatographic assay (Scarborough, ME). (IPC, unpublished data). Accounting for this underestimation, one might expect S. pneumoniae
or H. influenzae
–related respiratory infections to reach ~60% of the bacterial etiology of acute pneumonia. As a Global Alliance Vaccine Initiative or GAVI - eligible country, Cambodia introduced H. influenzae b
vaccines in 2010 and will probably do so in the near future for pneumococcal conjugate vaccine.
RSV and influenza viruses have been recognized as the leading causes of severe ALRI in infants and young children [30
]. These viruses can also cause severe ALRI in certain at-risk groups. In our study, viral pathogens, especially rhinoviruses and RSV were not only limited to these high risk groups but were common in older children. Moreover, age was determined as a major confounding factor when identifying risks associated with viral etiologies. Only time-to-admission was independently associated with the viral identification rate, a finding that suggests that viral infections were under-detected in many bacterial ALRI patients who were admitted late in the course of illness [32
The extent to which these viruses cause direct and severe ALRI is difficult to assess in our study, particularly in absence of a control group. Indeed, certain viruses were demonstrated to be associated with severe pneumonia [33
]; however, detection of some respiratory viruses, especially rhinoviruses, was frequently found in non-ill or non-respiratory infected control groups when using highly sensitive molecular diagnostic techniques [13
]. Interestingly we identified viruses in ALRI patients with little evidence of associated bacterial infection. Further virologic analyses would be worthwhile to determine the factors comparing pneumonia cases with no evidence of bacterial infection to those associated with superinfection.
Symptoms associated with severity as defined by the parameters of the study were highly prevalent in children; the reasons are unclear or potentially explained by several factors such as having acute pneumonia and/or underlying asthma. Interestingly, wheezing was also independently associated with viral respiratory infection. This relationship between viral infection, asthma (wheezing as its surrogate), and disease severity have been observed more recently. Indeed, recent studies suggest that respiratory infections caused by rhinoviruses or RSV in infancy can lead to the development of asthma at an older age [40
], which could be exacerbated by viral infections [34
]. Recognizing the high frequency of wheezing in children with pneumonia (~62%) and its association with hyperleucocytosis in our study, it is possible that asthma could either directly cause a severe case or lead indirectly to signs of severity via superinfection and subsequent pneumonia. Education programs designed to recognize asthmatic symptoms, teach management strategies, and encourage the prevention of asthma should be urgently implemented.
These preceding findings need to be interpreted in light of some major limitations. First, the rate of bacteria identification in this study was low compared to other studies using routine clinical diagnostic techniques [15
]. Approximately 17% of bacterial diagnoses were achieved through the use of blood or sputum cultures. This relatively low yield contrasted with a much higher proportion of pneumonia-related patients (~40%) who had an elevated blood neutrophil count, a parameter that is indicative of bacterial infection. Various factors contributed to this low yield, including the probable high intake of antibiotics, which can be bought without a prescription and frequently are administered irrespective of the proper dosage and length in Cambodia [45
]. Since there was only a one-time collection of sputum and blood for each patient, a high bacterial yield was not expected. Moreover, sputum tests, which are commonly used to diagnose pneumonia, may lack specificity without evocative clinical information, have poor sensitivity or are frequently contaminated by saliva or upper respiratory tract colonization. This resulted in having to discard numerous sputum specimens prior to culture in our study. The use of invasive procedures such as brochioalveolar lavage or sputum induction was difficult to introduce, particularly in children. Second, the burden of TB in this study was probably largely underestimated as cultures for M. tuberculosis
were not performed [46