The database search identified a total of 29,558 articles, with 20,442 and 9116 articles for SA and SEA, respectively. Of these, 2410 unique articles were selected for the final synthesis (Fig. 1). Among these, 1181 (49.0%) were case series, 585 (24.3%) were seroprevalence studies, 512 (21.2%) were fever series, and 132 (5.5%) articles comprised combinations of the aforementioned study types. Of 711 articles describing seroprevalence studies, 468 were in symptomatic patients, 67 were in asymptomatic participants, and 174 comprised of both groups (133 were conducted during outbreaks).
Data were collected from 2075 unique study sites, 1880 (90.6%) of which were within a radius of 50 km of the nearest city (Fig. 2). There were 1675 (69.5%) unique articles from SA, 732 (30.4%) from SEA, and three (0.1%) reported from both regions (Fig. 3). In SA, most reports were from India (n = 1207) followed by Pakistan (n = 194), Nepal (n = 102), Bangladesh (n = 92), and Sri Lanka (n = 80). Most reports from SEA were from Thailand (n = 301), followed by Malaysia (n = 154), Singapore (n = 98), Indonesia (n = 58), and Vietnam (n = 52). There were fewer than 10 reports from each of Afghanistan, Bhutan, Brunei Darussalam, Maldives, Myanmar, and Timor-Leste.
Studies reporting on neonates were found in 176 (7.3%) articles, infants in 47 (2.0%), children aged 1 to < 13 years in 408 (16.9%), and older children and adults (≥ 13 years) in 764 (31.7%). There were 757 (31.4%) articles that included participants of all ages, while the age group studied was not reported in 258 (10.7%) articles (Fig. 4; upper panel).
Samples collected and diagnostic methods
Blood was the main specimen analysed in 2068 (85.8%) reports included in this review. Cerebrospinal fluid (CSF) samples were analysed in 101 (4.2%) articles; both CSF and blood in 60 (2.5%); bone marrow, joint, lymph, or liver aspirates in 63 (2.6%); peritoneal, pericardial, or pleural fluids in 23 (1.0%); spleen samples in 10 (0.4%); and vitreous humour samples in 10 (0.4%). Multiple sample sources were analysed in 73 (3.0%) articles, and the specimen analysed was not specified in two (0.1%) (Supplemental file 1; section 1.3).
Bacterial infections were detected using culture methods in 920 (66.8%) articles, serological assays in 340 (24.7%), PCR in 30 (2.2%), and microscopy and staining in seven (0.5%), and multiple diagnostic methods were reported in 89 (5.8%) articles. For viruses, 680 (75.5%) articles reported serological testing, and 90 (10.0%) PCR methods, 14 (1.6%) culture methods, and multiple diagnostic methods were reported in 117 (13.0%) articles. Fungal infections were identified using culture methods in 125 (87.4%) articles while parasites were detected using microscopy methods in 70 (51.1%) articles and serological tests in 39 (5.6%) articles. Further details are presented in Supplemental file 1; section 1.3.
Bacterial infections were reported in 1235 (51.2%) articles, viral infections in 846 (35.1%), parasitic infections in 132 (5.5%), and fungal infections in 54 (2.2%), and 143 (6.0%) articles reported more than one pathogen group (Fig. 4; lower panel). The median number of pathogen species reported in a study was one [range 1–46, interquartile range 1–2]. Among 2410 articles, 1774 (73.6%) reported one species of microorganisms while 2 to < 5 microorganisms were reported in 319 (13.2%) articles, between 5 to < 10 in 192 (8.0%) articles, and ≥ 10 microorganisms in 125 (5.2%) articles.
Salmonella Typhi (n = 285 articles), Escherichia coli (n = 270), Staphylococcus aureus (n = 255), Klebsiella pneumoniae (n = 169), and coagulase negative Staphylococci (n = 160) were the top five commonly reported bacteria (Fig. 5). Salmonella Typhi (n = 236) was the most commonly reported bacterium in Southern Asia (Fig. 5; left panel), whereas in South-eastern Asia, Burkholderia pseudomallei (n = 86) was the most commonly reported (Fig. 5; right panel).
Vector-borne bacterial infections
Orientia tsutsugamushi was the most commonly reported vector-borne bacterium (n = 151 articles) followed by Rickettsia typhi (n = 48); Rickettsia, spotted fever group (n = 37); and Rickettsia spp. (n = 34) (Fig. 5). Orientia tsutsugamushi was reported in 104 (6.2%) articles from Southern Asia and 47 (6.4%) from South-eastern Asia. There was a single report of Borrelia burgdorferi from India in 2010.
Food- and/or water-borne bacterial infections
Salmonella Typhi (n = 285 articles) was the most common cause of food- and/or water-borne bacterial infections, followed by Leptospira spp. (n = 125) and Burkholderia pseudomallei (n = 108). Among neonates, Salmonella spp. were reported in seven articles followed by Burkholderia pseudomallei (n = 6) and Listeria monocytogenes (n = 4); this was similar among children aged 1 to < 13 years. Among adolescent children and adults (≥ 13 years), Burkholderia pseudomallei (n = 58), Leptospira spp. (n = 44), and Salmonella Typhi (n = 37) were the most common reported pathogens. Burkholderia pseudomallei was reported in 86 articles from SEA and 22 from SA. Streptococcus suis was reported in SEA from Cambodia (n = 1; 2013), Lao PDR (n = 2; 2013–2015), Vietnam (n = 1; 2008), and Thailand (n = 11; 2003–2015).
Bacterial infections that spread through contact
Escherichia coli (n = 270 articles), Staphylococcus aureus (n = 255), and Klebsiella pneumoniae (n = 169) were the most commonly identified bacteria which spread through contact. Among neonates, Klebsiella pneumoniae was reported in 60 articles, while among children aged 1 to < 13 years, Streptococcus pneumoniae (n = 54), Staphylococcus aureus (n = 50), Escherichia coli (n = 45), Haemophilus influenzae (n = 31), and Pseudomonas aeruginosa (n = 27) were the top five commonly reported bacteria (Fig. 5).
Airborne bacterial infections
Coxiella burnetii was reported in 13 articles and Legionella pneumophila in two articles, and Mycobacterium chelonae and Legionella spp. were reported in an article each. Among neonates, Coxiella burnetii (n = 1) was the only description of airborne bacterial infection, while there were no reports among older children.
Dengue virus infection was the most commonly reported viral infection (n = 593) followed by chikungunya virus (n = 102), Japanese encephalitis virus (n = 71), hepatitis B virus (n = 35), and hepatitis C virus (n = 33) (Fig. 6). Among neonates, the distribution of viral infections differs with 13 articles reporting dengue virus infections (n = 13), herpes simplex virus (n = 3), chikungunya virus (n = 2), enterovirus (n = 2), Japanese encephalitis virus (n = 1), and flavivirus (n = 1). Among infants, dengue virus (n = 8), rubella virus (n = 2), and an article each reported: chikungunya virus, Coxsackie B virus, hepatitis B virus, human herpesvirus 6, and B19 virus. Among children, dengue virus (n = 118), Japanese encephalitis virus (n = 28), measles virus (n = 9), hepatitis A virus (n = 7), and human herpes simplex virus (n = 7) were the top five commonly reported viruses. Among adults, dengue virus (n = 184), chikungunya virus (n = 28), Crimean-Congo haemorrhagic fever virus (n = 16), hepatitis B virus (n = 15), and Japanese encephalitis virus (n = 12) were the top five reported viruses. The age-stratified distribution of the reports on viral infections is presented in Supplemental file 1; section 1.3.
Dengue virus was the most commonly reported arbovirus (n = 593) followed by chikungunya virus (n = 102), Japanese encephalitis virus (n = 71), Crimean-Congo haemorrhagic fever virus (n = 31), and West Nile virus (n = 17). Zika virus was reported in an article each from Indonesia (1981), Pakistan (1983), and the Philippines (2015).
Food- and/or water-borne viral infections
Hepatitis A virus was reported in 17 articles and hepatitis E virus in 16. Human poliovirus was reported in an article from India (1991), and there was one report describing Coxsackie B virus from Thailand (1991). There were no other descriptions of food- and/or water-borne viral infections.
Airborne viral infections
Hantaan virus (n = 14), measles virus (n = 13), hantavirus (n = 7), human respiratory syncytial virus (n = 2 articles), and Sin Nombre virus (n = 1) were the airborne viral infections reported. Hantavirus was reported in an article each from Cambodia, Indonesia, and Thailand and in two articles each from India and Singapore.
Viral infections spreading through contact
Hepatitis B virus (n = 35), hepatitis C virus (n = 33), rubella virus (n = 16), and human herpes simplex virus (n = 12) were the most commonly reported viruses spreading through contact. Nipah virus was reported from Malaysia (n = 3, 1999–2002), Singapore (n = 2, 1999–2001), India (n = 1, 2006), and Bangladesh (n = 4, 2006–2012).
Parasitic and fungal infections
Leishmania donovani was the most reported parasite (n = 50 articles) followed by Leishmania spp. (n = 31), Wuchereria bancrofti (n = 7), Naegleria fowleri (n = 6), and Trichinella spp. (n = 6). All of the reported Leishmania donovani were from Southern Asia (Fig. 7). Among fungi, Candida spp. (n = 90) were the most commonly reported, with 31 articles describing Candida albicans, followed by Cryptococcus neoformans (n = 24) and Candida tropicalis (n = 12) (Fig. 7). The majority of the reported C. neoformans were in HIV-uninfected patients.
Spatial and temporal trends in infectious causes of fever
The temporal trend in most commonly reported fever-causing pathogens over the different time periods is presented in Tables 1, 2, and 3. In SA, the leading reported bacterial cause of NMFI was Salmonella Typhi whereas Burkholderia pseudomallei was the most commonly reported cause of NMFI in SEA (Fig. 5). Dengue virus was the most commonly reported viral cause across different time periods in both SA and SEA (Fig. 6). Among parasites, Leishmania spp. were the most commonly reported parasites in SA, but were not commonly reported in SEA (Fig. 7). Literature on fungi mostly reported Candida spp. and Cryptococcus spp. (mostly from HIV-uninfected patients) across the time periods and regions (Fig. 7).
Pathogens of regional interest or considered as emerging
The distribution of the study sites for some of the pathogens (Nipah virus, Borrelia burgdorferi, Zika virus) considered as emerging or of regional interest is presented in Fig. 8. Streptococcus suis was reported only in SEA, from Cambodia (n = 1; 2013), Lao PDR (n = 2; 2013–2015), Vietnam (n = 1; 2008), and Thailand (n = 11; 2003–2015). Nipah virus was reported from Malaysia (n = 3; 1999–2002), Singapore (n = 2; 1999–2001), India (n = 1; 2006), and Bangladesh (n = 4; 2006–2012).
Assessment of risk of bias
Of 2410 included articles, the risk of bias was considered to be moderate or high in 1181 (49.0%) and low in 1229 (51.0%). Of 2075 studies where it could be ascertained, 1880 (90.6%) were from urban settings or located within a radius of 50 km of the capital city or another major city (Supplemental file 2).