Respiratory virus infection as a cause of severe acute respiratory distress syndrome is well-established in literature [16,17,18]. However, its significance as a contributory pathogen in the outcomes of severe CAP is uncertain. In this study, we showed that respiratory viruses were as commonly found as bacteria (42.7% vs 38.5%), as an aetiological pathogen. Mixed viral-bacterial co-infections occurred in 15.4% of patients and was associated with an adjusted odds ratio of 13.99 for hospital mortality.
The impact of respiratory viruses on the prognosis of severe CAP remains unclear with recent studies demonstrating contradictory results. Fisher et al., in a prospective 1-year microbiologic survey of nosocomial pneumonia and CAP complicated by respiratory failure, showed that 21.7% of patients had viral infections, which was associated with a hospital mortality of 36.7% . However, Siow et al., found that viral infections were independently associated with lower hospital mortality compared to other microbial aetiologies, with an adjusted odds ratio of 0.12 (CI 0.2–0.99; p = 0.049) .
In light of these findings, accurate characterisation of the impact of microbial aetiology on the outcomes of severe CAP is required to influence future development of rapid molecular diagnostics assays and novel antimicrobial therapies that would target both viruses and bacteria [21, 22].
Piralla et al. reviewed the microbiological data of severe CAP in Northern Italy during winter-spring seasons over 7 years and found that 54.6% of patients had one or more respiratory viruses identified . The 2 most common viruses isolated were Influenza A and Rhinovirus, similar with our findings. While our study was performed in a tropical country, local microbiological surveillance has shown that influenza epidemics occur twice annually . This would mean that 3 influenza seasons occurred over the course of this study.
The molecular mechanisms in the viral pathogenesis of severe pneumonia are most well studied in Influenza A and Streptococcus pneumoniae co-infections. Viral infections alter host immune responses that increase susceptibility to bacterial infection through viral-induced interferons [25,26,27]. On clinical suspicion alone, only 35.7% (n = 10) of patients with Influenza A in this study received empirical oseltamivir. The authors postulate that incorporation of early Influenza A diagnostic tests may decrease the time to effective anti-viral therapies.
The second most common virus detected in our study was Rhinovirus (n = 6). The association of Rhinovirus with severe pneumonia has previously been shown in a surveillance program for Middle East respiratory syndrome Coronavirus in Saudi Arabia . Its genotypes A to C are associated with severe pneumonia, with in-hospital mortality rates from 10.7 to 15.5% . Patients who are immunocompromised or who have chronic lung disease are most at risk .
There are several reasons why viral infections may have been less prominent as a cause of severe CAP in prior decades. Firstly, Grève et al. performed a prospective observational study on physician practices in the use of respiratory virus diagnostics demonstrating that despite clinical guideline recommendations on testing of respiratory viruses during influenza season, less than half of patients admitted to the intensive care unit with pneumonia were tested for viral pathogens . This may have led to under-recognition of the true significance of viral pathogens and mixed viral-bacterial infections, on outcomes in severe pneumonia.
Other factors which may have contributed to under-diagnosis of viral pneumonias include the unavailability or cost of molecular diagnostic assays, and the lack of effective anti-viral therapies . However, the authors argue that in this age of globalisation, highly virulent respiratory viruses have the potential to spread rapidly. Constant surveillance is required to detect outbreaks and for the implementation of isolation precautions in a timely manner [32, 33]. Understanding the significance of respiratory viruses in the pathogenesis of severe CAP would guide administrators with resource allocation when implementing vaccination programs for at-risk populations.
The high rates of compliance with performing respiratory aerobic cultures, blood aerobic and anaerobic cultures in this study, were in accordance with sepsis guidelines . The most common bacterial pathogen found was Streptococcus pneumoniae (16.3%), which is consistent with the known epidemiology of CAP globally [35,36,37]. Gadsby et al., in a prior study, was able to demonstrate a bacterial yield of 81.1% when respiratory specimens from patients with CAP were tested with bacterial multiplex PCR . Incorporating the use of bacterial multiplex PCR in future studies, may increase the rate of bacteria detection, and shed light on potential molecular synergisms between specific viruses and bacteria in the pathogenesis of severe CAP.
Pulmonary tuberculosis is endemic in the region where this study was performed. In our study, 3 patients had tuberculosis, one of whom had concomitant Adenovirus infection while another had Streptococcus pneumoniae. The initial presentation of pulmonary tuberculosis with clinical features consistent with severe CAP has been described by Tseng et al. , where 4% of patients with pulmonary tuberculosis presented with respiratory failure or septic shock. The authors postulate that pulmonary tuberculosis may play a role in increasing host susceptibility to severe infection with CAP organisms.
The authors recognise that there were several limitations to this study. Firstly, while first-dose antibiotics would have been administered as soon as sepsis is identified, we are unable to accurately define the time between administration of antibiotics and collection of specimens for microbiological assessment. This may affect the yield of bacterial pathogens recovered from blood and respiratory cultures despite bacterial sampling occurring within 24 h of intensive care admission. The yield of bacterial pathogens of this study, however, was similar with other prospective studies in severe CAP that have been performed and is therefore likely representative of the true bacterial epidemiology [37, 40, 41].
Secondly, the inherent retrospective nature of this study increases the risk of bias in data collection. However, as part of pre-established intensive care unit clinical audits and with the availability of national health records, clinical data such as participant demographics, co-morbid illnesses and severity indicators such as APACHE II were established at the time of intensive care admission and stored prospectively.
Thirdly, given the high population density of the country (3rd in the world) where this study was performed, the microbial epidemiology of severe CAP may only be extrapolated to urban settings. The study is a single-centre survey conducted in 1 of the 6 acute general hospitals serving a population of 5.6 million in a land area of 721.5 Km2. Hence, the epidemiology may lack generalisability when extrapolated to other tropical countries.
The fourth limitation is that we included 5 patients who were immunocompromised with typical CAP organisms and survived. They may potentially have had opportunistic infections that were not detected, however, as they did not contribute to the mortality outcomes, we felt that the microbiological data contributed by these patients were useful in the understanding of the prevalence of various classes of CAP organisms. Lastly, another potential limitation was that vaccination records could not be retrieved, and we were unable to ascertain its influences on microbial aetiologies of severe pneumonia in our study population.
The main strength of the study is the characterisation of the epidemiology of microbial pathogens in severe CAP. We were able to show that in a tropical environment, the viral and bacterial pathogens associated with severe CAP were similar with regions with a seasonal climate. Despite a lower-than-expected mortality rate for severe CAP in our study (13.7%) compared with international data [41,42,43,44], we were able to demonstrate that mixed viral-bacterial co-infections were independently associated with hospital mortality.