Background
Scrub typhus is a vector-borne acute febrile illness caused by
Orientia tsutsugamushi and transmitted to humans and rodents by infected chigger mites (larval stage of Trombiculidae mites) [
1,
2]. Historically, scrub typhus had been endemic in Asia, Australia and islands in the Indian and Pacific Oceans, known as the “tsutsugamushi triangle” [
1]. However, there have been recent reports of scrub typhus from Africa, the Middle East, and South America suggesting the disease is no longer restricted to this triangle [
2] but no autochthonous cases have been reported from north America and Europe. Scrub typhus is frequently reported from many Asian countries and is endemic in Nepal’s neighboring countries including India (Sub-Himalayan belt) and Bhutan, where it is considered an emerging infectious disease [
3‐
6]. In Bhutan, one in six undifferentiated febrile patients had rickettsial infections, with scrub typhus being the most common [
6]. However, the disease situation in Nepal remained unexplored until 2015, likely due to the high burden of other febrile illnesses with indistinguishable clinical signs and limited availability of diagnostics.
There have been a few previous attempts to investigate the incidence of scrub typhus in Nepal. As early as 1981, a study showed the high possibility of scrub typhus in Nepal when it demonstrated elevated antibody titers in 10% of healthy adults [
7]. Unfortunately, additional surveillance studies in the country were not conducted for next 23 years until 2004. A serological investigation of scrub typhus at Patan Hospital, Kathmandu found a small number of febrile patients (28/876) positive for scrub typhus antibodies [
8]. The investigation was performed using a multi-test assay without further confirmation for scrub typhus by immuno-fluorescent assay (IFA), gold standard for scrub typhus diagnosis. It was inconclusive whether scrub typhus or another rickettsial illness, such as murine typhus, was present. Another report in 2007 also indicated the presence of scrub typhus in Nepal [
9]. However, no outbreak investigations of scrub typhus (with fatality information) were reported in Nepal before 2015 and no systematic investigations by the government had been conducted. As a consequence, scrub typhus cases had not been reported to the Epidemiology and Disease Control Division (EDCD) of the Ministry of Health and Population before 2014 [
10].
In April 2015, Nepal experienced a mega-earthquake claiming thousands of lives, massive destruction, and huge economic losses followed by an upsurge in febrile illnesses [
11,
12]. Three months after this devastating earthquake in Nepal (August 2015), a tertiary care teaching hospital in Nepal alerted EDCD that children with fever and severe respiratory features were not responding to the usual course of antibiotic treatment, leading to high mortality rates (8%) [
10,
11]. The clinicians had used cefexime or ceftraiaxone and imipenem in intensive care. After the initially suspected aetiologies (hantavirus and other viral diseases) were ruled out, the samples were screened with M- Enzyme Linked Immunosorbent Assay (ELISA) for scrub typhus and found positive. This was the first and most significant fatal scrub typhus outbreak in the country [
11]. Since then, scrub typhus has been increasingly reported in Nepal but no clear epidemiological picture is available.
In this study, a systematic investigation was carried out in Nepal to investigate the ongoing transmission ecology of Scrub typhus which included patient, vector, and animal studies employing both serological and molecular tools.
Discussion
Our study demonstrates that scrub typhus is an emerging public health problem in Nepal with several outbreaks since 2015. Scrub typhus is an under studied neglected tropical disease and a leading cause of undifferentiated treatable fever in Asia [
1,
17]. This study uncovered the firmly established nature of scrub typhus outbreaks in Nepal through evidence of the causative agent
O. tsutsugamushi in human (patients), animals and vector/reservoir hosts (chigger mites) during the recent fatal outbreaks.
Despite the frequent reports of outbreaks from neighbouring countries, particularly India [
3‐
6,
18‐
21], scrub typhus was undetected in Nepal for decades after its first indication in 1981 [
7]. This has resulted in a significant lack of understanding when it comes to epidemiological features, treatment response and severity, and its ecological niche. This type of baseline information is required for a country to formulate appropriate guidelines and pave strategies for scrub typhus control. Apart from a handful of reports discussing the human cases [
7‐
10,
22,
23], no study has explored whether the human-host-vector/reservoir-pathogen cycle is maintained in Nepal. This ecological chain is essential to understand a sudden outbreak of any magnitude [
24]. The present study has contributed by providing solid evidence of the ongoing circulation of the scrub typhus pathogen
O. tsutsugamushi among human, animals, and chigger mites in areas affected by recent large outbreaks.
The scrub typhus outbreaks that occurred in Nepal during 2015 to 2017 may be linked to the devastating earthquake of 2015. The outbreaks could have been triggered as a result of intimate contact between humans and mite infested rats that might have come out of their usual underground habitat with the demolition of many houses [
25], and this would provide people increased exposure to
O. tsutsugamushi infected mites which are both the vectors and the reservoirs. However, there is no evidence to support this hypothesis. Close proximity while living in temporary shelters [
12] due to overcrowding and unsanitary conditions could have contributed to increased contact between vectors, pathogens and humans [
25]. A weakened health system due to the massive earthquake compromised the availability of diagnostic and treatment facilities, which further affected the control program resulting in the large outbreak in 2016.
A large scrub typhus outbreak during 2015 to 2017 initiated in 2015 with 141 cases and nine deaths, which was an unforeseen eruption of this disease after the years of silence in the country. The apparent disappearance of the disease in a territory for a long period before a sudden re-emergence in an epidemic form is symptomatic of scrub typhus. For example, scrub typhus re-emerged in the Maldives as a fatal epidemic in 2002–2003 after 58 years of its disappearance [
26,
27], and it also resembles the scenario in India where the re-emergence was observed during 1990s after World War II [
4]. There was no strong evidence of persistent scrub typhus in Nepal after the initial indication in 1981, although we cannot totally exclude this possibility considering the lack of diagnostic facilities, endemicity, and inadequate clinical suspicion/precision in Nepal. In peripheral settings of Nepal, widal test is exclusively used for enteric fever due to the lack of blood cultures facilities. This may lead to misdiagnosis of enteric fever [
12], one of the most common AUFI [
28], when the actual etiology might be other febrile diseases like scrub typhus, leptospirosis, dengue, etc. Such misdiagnosis [
12] and the minimal clinical interest (due to effective treatment) could be other factors for no visible infections [
26]. Nevertheless, we cannot overlook the serologically positive cases reported in 2004 and 2007 in the Kathmandu valley [
8,
9] while considering such absence of the overt disease in this location.
Among those infected with scrub typhus, the majority were females aged below 40 years, with a significant proportion of children. Younger and reproductive females in rural areas are mostly involved in outdoor or agriculture activities in Nepal,and this could be one reason for increased scrub typhus infection. India, South Korea and China have also reported higher incidence among females [
18,
29,
30]. Similarly, we observed a clear seasonality with the majority of cases being detected in August and September, which is quite similar to what was reported from the Indian states [
18,
21]. The overall pattern of scrub typhus in Nepal resembles that in neighbouring countries including India, indicating potential cross-border transmission due to massive trade and transport activities (woods, trucks) and lack of physical barrier probably provide ample opportunity for chiggers’ migration across the borders .
In Nepal, scrub typhus cases were reported nationwide (52 of 75 districts) in just 3 years, and the disease may expand very rapidly as seen in other parts of the world [
31,
32]. In this study, the majority of cases were reported from lowland terai districts where other febrile illnesses including Japanese encephalitis (JE) [
33,
34], leptospirosis [
35], and dengue [
33,
34,
36,
37] have been frequently reported. Even before the initiation of JE vaccination in Nepal, only one-third of the acute encephalitis syndrome (AES) cases were due to JE, which declined with immunization. However the AES remains persistent, clearly indicating other aetiologies of AES in the country. From the same areas of Nepal, cases of leptospirosis and dengue were identified among AES population [
34,
35]. Looking at the severity and high fatality (up to 6%) of scrub typhus during 2015 to 2017, it is logical to consider that a fraction of AES cases could be due to scrub typhus and vice-versa in Nepal. This is further supported by the contemporaneous outbreaks occurring in some states of India (along the Nepal border) where scrub typhus was identified as one of the significant causes of AES [
20,
24]. Interestingly, six out of eight fatal cases reported in that Indian state had evidence of
O. tsutsugamushi infection [
20]. In addition to AES cases, rodents and mites were also positive for
O. tsutsugamushi in those AES-reported areas [
24]. This is similar to what we found in Nepal, suggesting the need to include scrub typhus in the differential diagnosis in AES and other acute undifferentiated febrile illness (AUFI) which are common in Nepal [
38].
Despite the high fatality rate (6%) observed during the first wave of scrub typhus in Nepal in 2015, CFR successfully declined to approximately 1% in 2017, which is quite encouraging for the disease control program. This rate is within the wide range of reported fatality (median, 6 and 1.4% for untreated and treated cases, respectively) [
1]. The government initiatives that may have reduced the CFR [
10,
11] include distribution of guidelines, public awareness, and training and orientation of health workers for prompt treatment of scrub typhus with available drugs (doxycycline, azithromycin, and chloramphenicol or their appropriate combinations). Infection with resistant or reduced drug-susceptible
O. tsutsugamushi strains often yield very high mortality (up to 24%), miscarriage and poor neonatal outcomes [
1]; it may be speculated that these strains are yet to emerge in Nepal. Since there was no definitive evidence for this, careful monitoring for drug resistance (including potential resistance genes) should be in place. Poor response with doxycycline in some countries suggested the potential emergence of resistant strains [
26]. Early administration of doxycycline/azithromycin reduced the progression to AES in India [
3], and so treatment delay should be avoided.
This study has some limitations. The detailed individual level data were not available for cases of 2015 and 2017, and even all cases of 2016 was not available for analysis which suggest the need of sustainable integrated surveillance system. The IFA and PCR confirmation tests were limited to representative samples, and further genetic characterization of the pathogenic strain of
O. tsutsugamushi that circulated in Nepal was not performed. Although a total of 104 animal traps were set in the suspected areas, a relatively small number of animals were captured as well as a low number of chigger mites (
L. imphalum). We cannot discount the possibility of other animal species associated with scrub typhus in Nepal. Although we did not cover other rickettsial diseases, cases of spotted fever group, typhus group and Q Fever rickettsia in scrub typhus endemic areas of neighbouring countries like India [
19] and Bhutan [
6] warrant further investigation of these aetiologies in Nepal. Recent indications of Q fever in some acute undifferentiated febrile cases in Nepal also underscores this [
22]
. Apart from humans, very high rickettsial
seropositivity was reported among domestic animals in Bhutan suggesting that a One Health approach could be useful in understaning the prevalence of
O. tsutsugamushi through serological sentinel surveys that may aid in rickettsial diseases control programs [
39]. Therefore, the need for domestic animal studies is also key in the context of Nepal.
Acknowledgements
Authors thank Dr. Baburam Marasini, then Director of EDCD and Dr. Krishna Kumar Aryal, former Research Officer of NHRC for their contribution in research design. Similarly, we applaud the efforts of Mr. Resham Lamichhane, Mr. Uttam Raj Pyakurel and Mr. Bijay Rimal from EDCD, Mr. Shishir Kumar Pant from Vector Borne Disease Research and Training Centre (VBDRTC), Hetauda, Mr. Pramod Kumar Mehta from Shukraraj Tropical & Infectious Disease Hospital-Teku, Mr. Laxman Maharjan, and Mr. Buddha Ratna Maharajan from NPHL and Mr. Bijay Kumar Jha, Mr. Ram K.C. from District Public Health Office, Chitawan, Dr. Dayaram Lamsal, Dr. Santosh Pathak & Mr. Sanjay Yadav from CMC Hospital, Bharatpur for their co-operation to conduct this study.
We are very grateful Dr. Wuttikon Rodk Vamtook, Mr. Surachai Leepita Krat and Ms. Maneerat Somsri of AFRIMS, Thailand as WHO Collaborating Centre for Diagnostic Reference, Training and Investigation of Emerging Infectious Diseases for SEARO and Ms. `Jasmine Shrestha, Mr. Pashupati Khanal, Mr. Ashish Shrestha, Mr. Bishnu Bahadur Rayamajhi, Ms. Samita Bajracharya & Ms. Bina Sakha of WARUN for their technical support in confirmatory diagnosis of human samples and rodent/mite investigations. We woud also thank Ms. Anna Durcane Bagale of London School of Hygiene and Tropical Medicine for reviewing the manuscript.
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