Diversity of infectious aetiologies of acute undifferentiated febrile illnesses in south and Southeast Asia: a systematic review

During the past 20 years, there has been a dramatic emergence and re-emergence of viruses, bacteria and parasitic infections, including novel pathogens as well as those previously believed to be under control. Many of these pathogens cause acute undifferentiated febrile illness (AUFI, or acute febrile illness, AFI). The common causes of AUFI include malaria, dengue fever, enteric fever, leptospirosis, rickettsiosis, hantavirus and Japanese encephalitis [1‐3]. AUFI contributes to substantial morbidity and death among children and adults worldwide [4, 5]. Many preventable deaths occur because of incorrect or delayed diagnosis, largely due to limited access to medical care and laboratory diagnostic facilities in the developing countries [6‐9]. The majority of patients present with non-specific symptoms such as low-grade fever, general malaise, headache, arthralgia, myalgia, and rash; and usually without a focal point of infection. The symptoms and differential diagnoses of these diseases are similar, making accurate clinical diagnosis difficult without laboratory confirmation [10‐12].

In recent decades, dengue has rapidly emerged as a major cause of AUFI in tropical Asia particularly in the World Health Organization (WHO) Southeast Asia (SEA) region [13, 14]. However, many other infectious diseases can cause a dengue-like illness with thrombocytopaenia, including scrub typhus, chikungunya, infectious mononucleosis, malaria, typhoid fever, leptospirosis and acute human immuno-deficiency virus conversion disease [15]. Presumptive diagnosis and reporting of AUFI with thrombocytopaenia as dengue infection would lead to over-reporting of this infection and under-reporting of other illnesses.

Evidence-based decision-making in health requires the availability of sound data, but good quality information on the occurrence of infectious diseases is unavailable for most countries in Asia [16]. The provision of accurate epidemiological data for common pathogens will enable identification of changing patterns of disease aetiology and burden, allowing informed priority setting, and optimal allocation of resources to key areas. Understanding the common causes of AUFI in resource-poor settings in tropical and subtropical countries will help improve case management. In areas where there is limited access to laboratory diagnosis, the local epidemiology of AUFI and validated clinical predictors may help guide presumptive diagnosis and therapeutic interventions. Such information is also crucial for developing appropriate diagnostic tests and guidelines, and informing resource mobilization and public health interventions. Therefore, the objective of this review was to synthesise information on the diversity and relative importance of common infectious aetiologies of AUFI in recent history in South and Southeast Asia given it is a melting point of tropical infectious diseases and a hotspot for disease emergence [14, 17, 18].

The findings of this review illustrate that in tropical and subtropical South and Southeast Asian countries, the most common causes of AUFI were viruses, followed by bacteria and malaria. Generally, dengue fever was the commonest cause followed by leptospirosis and typhoid. Consistent with our findings, the decline in malaria cases in Asia and Africa has resulted in a relative increase in non-malarial AUFIs in these continents [58]. Non-malarial fever was responsible for 20–50% of all fevers in Asia and Africa in children over 5 years of age and adults [59]. While dengue was mostly frequently reported febrile illness in Latin America [60].

Leptospirosis was the leading cause of AUFI in the Southeast region similar to other reported studies from that region [61‐65], in agricultural workers [66, 67] and mostly in males [68]. The ability of all countries in the region to accurately report and monitor leptospirosis hinges strongly on their respective capacity to provide accurate and reliable laboratory diagnosis, and robust reporting and surveillance systems [69, 70]. While the microscopic agglutination test (MAT) is considered to be the gold standard serological test [71], there are limitations to the test including a need for live cultures of Leptospira of different serogroups, cross-reactions between serogroups and serovars, poor sensitivity in the first week of illness, and persistence of high titres for many years after an infection. Conversely, treatment with antibiotics can blunt the immune response in leptospirosis, reducing the number of cases detectable by serology [72]. Hence, the number of leptospirosis patients reported in this review could be under or overestimated.

Dengue was the commonest cause of AUFI in South Asia contrary to Southeast Asia. It is generally a childhood disease and our results are consistent with that trend because it was the commonest cause of AUFI among children [73‐75]. In the past, dengue cases were mostly hospitalized irrespective of the severity of the disease. However, with the new admission criteria which includes clinical, laboratory, and dengue haemorrhage fever (DHF) predictive parameters [76], only severe cases of dengue: DHF and dengue shock syndrome (DSS) are admitted. The admission criteria were not clear in our study since most of the cases were from both OPD and IPD.

This review confirms that influenza is also an important cause of AUFI in the region, being the fourth commonest cause. Persistence of influenza virus especially in Southeast Asia is thought to be mediated by domestic ducks and large live poultry markets acting as a virus reservoir [77, 78]. Seasonal influenza is a highly transmissible, abrupt, and usually a self-limiting febrile infection of the respiratory tract and the majority of patients would present to outpatient departments [79, 80]. In many countries, the disease burden from influenza is underestimated because many cases are undiagnosed.

Typhoid fever was also identified as one of the major causes of AUFI. Previous reports have indicated that children are most at risk of developing typhoid fever [81]. The disease remains an important public health problem in developing countries. Similarly, rickettsial diseases including scrub typhus (Orientia tsutsugamushi) and murine typhus (Rickettsia typhi) were responsible for a small fraction of AUFI in this review. However, it is important to note that rickettsial diseases are an important cause of febrile illness worldwide but are often undiagnosed, sometimes leading to life-threatening conditions [82‐85]. Given rickettsial infections are treatable causes of AUFI, greater recognition of scrub typhus and murine typhus is important to increase the index of suspicion amongst the physicians so that cases are not missed.

Protozoal infection particularly malaria was responsible for 3.7% of all AUFI cases. This figure is likely to have been an underestimate because four studies excluded malaria patients in their analysis as their inclusion criteria were non-malarial patients. Of the 11 member countries in the WHO SEA Region, 10 are endemic for malaria. Six countries (Bhutan, Democratic People’s Republic of Korea, Indonesia, Nepal, Sri Lanka, and Thailand) are aiming for malaria elimination as a longer-term goal [86], and Sri Lanka has already eliminated malaria [87].

We found that 1.0% of AUFIs were associated with co-infections, the majority being in inpatients. Patients not responding to treatment for a particular infection or those in whom the presentation was atypical or severe should be suspected of harbouring a second infectious agent. The possibility of co-infections of leptospirosis with hepatitis E virus (HEV) [88] has been described as water is the vehicle of transmission for both pathogens. The under-diagnosis of mixed infections is very likely due to the overlapping clinical spectrum [89]. The relatively high morbidity and mortality in mixed infections underscores the need for greater awareness of the possibility of mixed infections as well as the need for optimal use of microbiological laboratory services to reach a specific diagnosis [88].

Causes of fever remained unknown in more than half of patients with AUFI in this review. Similar findings have been reported in other studies, including a review of AUFI in South Asian countries [90]. A lack of an established diagnosis could be partly due to the fact that laboratory confirmations were not done in many studies of acute self-limiting viral infections. In addition, commercial serological rapid diagnostic tests used are semi-quantitative ELISAs that detect antibodies and are not conclusive of the present or past infection [91, 92]. For some pathogens, definitive diagnosis requires demonstration of a serial rise in antibody titres over a specific time period. Noncompliance of patients to report for repeat serological tests following improvement of the illness remains a major drawback in serology-based diagnostics [10, 93]. Moreover, ELISAs have poor specification and cross reactions are common [94]. Antigen-based or PCR-based diagnostics have been increasingly introduced to overcome these problems. However, their availability and affordability in resource-poor countries are limited, and the fact that they are not freely available in most government-run health institutions means that accessibility to such tests is limited to those in the private sector who can afford to pay from their own pocket [93].

This review has several limitations. Interpretation of data in this study should take into consideration the heterogeneity of the reviewed studies including study design, patient sampling and diagnostic testing. In addition, many of these studies were descriptive studies. Furthermore, there is no reliable way to judge the quality of heterogeneous descriptive studies included in this review. Some articles failed to report duration of fever and definition of AUFI varied widely between the studies. Aetiologies of AUFI of less than one-week duration would likely differ from those of a minimum of three weeks. Therefore, adherence to a common case definition between studies is important to make comparisons more reliable. Seasonal variation of diseases such as influenza, changes in disease patterns due to economic development, urbanization, environmental changes and changes in population densities during the last 15 years could have affected observed aetiologies and disease patterns. In addition, data from some countries including Bhutan and Timor-Leste were not available and results were also dominated by studies from India and Thailand. Since English is not the primary language in most of these countries, restricting the studies included in this review to studies published in English may have affected the findings.

Algorithms for the management of fevers at the community level as well as for inpatients have been developed by WHO [59]. A lack of knowledge of the geographical heterogeneity in AUFI aetiology prevents local adaptation of generic protocols, and thus precludes better targeting of drugs and implementation of early, effective management [95]. Therefore, it is necessary that data on pathogen presence collected incidentally in various studies and data collected by surveillance mechanisms be analysed systematically and mapped to provide information on the distribution and prevalence of infectious aetiologies of AFIs. Clinical algorithms could then be adapted, greatly improving targeting of treatment. Strengthening of notification systems (including sentinel systems) and sharing of data between clinical research communities will be important to construct more comprehensive information on geographically specific aetiologies of AUFI.

In this study the most common causes of AUFI were viral, followed by bacterial and protozoal (malaria) infections. Dengue was the commonest virus that caused AUFI while leptospirosis and typhoid were important bacterial infectious causes. The challenges of unidentified causes of AUFI can be partly overcome by roll-out of affordable serological tests. It is imperative that data on pathogen presence collected incidentally in various studies and data collected by surveillance systems be analysed systematically and mapped to provide information on the distribution and prevalence of infectious aetiologies of AFIs for improving treatment and prevention programmes.