Journal of Medical Evidence

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 1  |  Issue : 1  |  Page : 8--14

Scrub typhus in the Himalayan ranges and sub-Himalayan plains: Recognising an expanding clinical syndrome


Augustine Jose1, Apoorva Chaudhary1, Prasan Kumar Panda1, Deepjyoti Kalita2,  
1 Department of Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Correspondence Address:
Dr. Prasan Kumar Panda
Department of Medicine, Sixth Floor, College Block, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India

Abstract

Background: Scrub typhus, a rickettsial zoonosis, is endemic in the Indian sub-continent but is rare in the Himalayan region due to natural geographic barriers to both organism and vector. Aims: To study the clinical profile of scrub typhus cases admitted in a tertiary care center. Patients and Methods: We did a retrospective observational study of the positive cases from July 2018 to June 2019 in a tertiary care center. All possible risk factors, demographic details, clinical presentations, laboratory parameters, treatment, and outcomes were analyzed. Results: A total of 80 cases were analyzed. The maximum number of cases was observed in September. Major symptoms noted were fever, abdominal pain, headache, cough, breathlessness, and myalgia. Atypical presentations including capillary syndrome and demyelinating polyneuropathy were observed. The eschar detection rate was low. Among organ involvement, hematology system (70%) was most commonly involved followed by liver, kidney, brain, lungs, and heart respectively. The case fatality rate was 6.82%. Himalayan and non-Himalayan cohorts (n = 32 vs 48 respectively) did not show any statistically significant differences in clinical profile, although one could observe that Himalayan cohorts had higher incidences of leukopenia, splenomegaly, and myocarditis, while fever for >7days at admission, hepatomegaly, acute respiratory distress syndrome, major organ involvement resulting admission in high dependency unit (HDU), and mortality were higher in non-Himalayan cohorts. Conclusion: The current study reveals few atypical presentations and complications differing from the classical scrub typhus. Raised ALP is noticed in majority of cases which can be established as a diagnostic marker in acute undifferentiated febrile illnesses in further study. The presence of leukocytosis has high predictive association with major organ involvement and complications.



How to cite this article:
Jose A, Chaudhary A, Panda PK, Kalita D. Scrub typhus in the Himalayan ranges and sub-Himalayan plains: Recognising an expanding clinical syndrome.J Med Evid 2020;1:8-14


How to cite this URL:
Jose A, Chaudhary A, Panda PK, Kalita D. Scrub typhus in the Himalayan ranges and sub-Himalayan plains: Recognising an expanding clinical syndrome. J Med Evid [serial online] 2020 [cited 2021 Sep 19 ];1:8-14
Available from: http://www.journaljme.org/text.asp?2020/1/1/8/290135


Full Text



 Introduction



Scrub typhus is a rickettsial zoonosis spread by the bite of the larval stage (chigger) of Trombiculid mite. Apart from Orientia tsutsugamushi, other rickettsial species such as Orientia chuto have been identified to cause this tropical infection. It is endemic to the Asia-Pacific region, but the disease has been found recently to extend beyond the classically described 'tsutsugamushi triangle'.[1] Recently, a hospital-based study showed 11.2% prevalence of scrub typhus among acute febrile illness (AFI) cases in the Himalayan and sub-Himalayan regions of the state of Uttarakhand (previously categorised under non-endemic area), India.[2] Cases in this region present predominantly with a respiratory syndrome resembling community-acquired pneumonia with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), and these have been identified also as important predictors for mortality. Because the underlying pathophysiology of this infection involves vasculitis, widespread organ involvement is observed in this clinical syndrome in the form of hepatitis, peritonitis, meningitis, pneumonitis and atypical manifestations such as myocarditis, or systemic or cutaneous vasculitis. The pattern of organ involvement shows significant heterogeneity, probably due to the difference in infecting strain and patient profile.[3] Thus, it becomes imperative to define the variations in the clinical spectrum of this infection.

Improved availability of serological tests with satisfactory performance in detecting Orientia infection has enabled early detection of typhus cases in the endemic areas. This empowers the clinician in early diagnosis and initiation of treatment, which is helpful especially because the disease shows good response to the currently available therapy, when instituted early.[4] Treatment-resistant cases observed during various outbreaks have raised the question of an emerging resistance to the existing drugs such as doxycycline.[5] In the Himalayan cohort, however, satisfactory response (85.2% cure rate) to doxycycline and azithromycin has been reported.[2]

The current retrospective study was undertaken at a tertiary care centre (a recently established medical institution) in North India (Uttarakhand), to describe the demographical, clinical, laboratory, treatment and outcome details of scrub typhus cases presenting to our centre, to identify the Himalayan and sub-Himalayan variation, and to determine the predictors of morbidity and mortality, if any.

 Patients and Methods



The study was conducted over 12 months from July 2018 to June 2019. All adult (>18 years) cases of scrub typhus, tested positive at our centre (in the department of microbiology), were traced retrospectively by viewing their hospital records. The cases from the outpatient department for which no follow-up of laboratory and clinical parameters were available were excluded. The cases of co-infection in which the clinical features were consistent with the alternate diagnosis were also excluded. Laboratory testing method used in the study was IgM ELISA, performed on serum samples using Scrub Typhus Detect (InBios International, Inc., Seattle, WA, USA) as per the manufacturer's instructions. An optical density > 0.5 was considered positive. This was a second-generation lateral-flow-format product using a mixture of four recombinant 56-kDa antigens from Karp, Kato, Gilliam and TA763 strains of O. tsutsugamushi, which has shown sensitivity for IgM detection of 99.25% and 100% among Indian and Thailand patients, respectively.[6],[7]

Diagnosis of ARDS and AKI was made based on the Berlin definition and KDIGO definitions, respectively.[8],[9] New-onset pulmonary congestion, hypotension and elevated cardiac markers (excluding cases with AKI) were used to define myocarditis, as per the description of clinically suspected myocarditis by the European Society of Cardiology Position statement in 2013.[10] Either or both hyperbilirubinaemia (total bilirubin >2.5 mg/dL) and transaminase elevation (more than twice the upper limit of normal) were used to classify as acute liver injury after excluding the prior history of liver diseases. Headache with features of raised intracranial pressure and altered sensorium indicated encephalopathy due to the infection, after the exclusion of uraemia, fulminant liver failure, electrolyte imbalance and intracranial bleeding following thrombocytopenia. Any atypical presentations attributable to be a consequence of the infection, including neuropathy, cutaneous manifestations and features of vasculitis, observed during the review of cases were noted.

The characteristics of the study population were described, and mean values were determined. All possible risk factors and independent variables including demographic details, clinical presentations and laboratory parameters were described. A comparison of the clinical profile of cases from the Himalayan ranges and the sub-Himalayan plains in India was attempted. The main outcomes considered for subgroup analysis were complications with significant major end-organ involvement, prolonged hospital stay (defined as more than 5 days), the requirement of care in a high-dependency unit, shock with ventilator requirement, need for mechanical ventilatory support and mortality. The decision for admission to a high-dependency unit was based on specific criteria including haemodynamic instability, poor sensorium, respiratory distress and progressive organ injury, but was often limited by the availability of resources and high load of patients. The complications did not include mild elevations of liver enzymes and asymptomatic thrombocytopenia as both have been reported as frequently associated with scrub typhus with no major clinical implication. The odds ratio for various risk variables was determined. Chi-square test was used for determining the association between qualitative variables with P < 0.05 (95% confidence interval) considered statistically significant. All analyses were done using SPSS version 23 (for Windows, Armonk, NY: IBM Corp). The study was done after approval of institutional ethical committee.

 Results



A total of 96 cases were screened, among which 16 were excluded due to inconsistencies in clinical features, association with a co-infection and non-availability of complete clinical profile, leaving a final sample size of eighty patients [Figure 1]. The study population had a mean age of 44.16 years (47.5% of males and 52.5% of females). Among comorbidities, five patients had diabetes mellitus, four patients were hypertensive, two cases had chronic liver disease and one had chronic kidney disease. The geographical distribution of cases is depicted in [Figure 2]. More cases were from plain areas than the Himalayan region (n = 48 vs. 32, respectively). Most cases were reported in September with the rapid transition to winter [Figure 3]a.{Figure 1}{Figure 2}{Figure 3}

Fever was the most common symptom at presentation [Figure 3]b. Among the two cases without fever, one was hospitalised for neuropathy, whereas the other presented with headache and myalgia alone. The mean duration of fever was 9 days (ranging from 1 to 25 days). Most cases had a high-grade intermittent (54%)-type fever. Fever >7 days was found in 42 cases (52.5%) and >14 days was found in 14 cases (18%). Abdominal pain was mostly a periumbilical and colicky type. Headache was bi-frontal and of non-throbbing type in two-thirds of cases. Hepatosplenomegaly was seen in 18 cases (22.5%), evidence of capillary leak and serositis in 10 cases (12.5%), bleeding manifestations in 2 cases and a maculopapular rash in a single case. An eschar, consistent with the typical description [Figure 4], was found only in three cases.{Figure 4}

Among organ involvement, haematology system was most commonly involved followed by liver, kidney, brain, lungs and heart [Table 1].{Table 1}

A comparison of the disease profile of the hilly population (Himalayan) and patients from the plains was made [Table 2]. None of the parameters showed a statistically significant difference between the two groups, although one could observe that the frequency of fever for >7 days at admission, hepatomegaly, ARDS, requirement of mechanical ventilation, major organ involvement resulting admission in high-dependency unit and mortality were higher in the plain population, whereas the Himalayan patients had higher incidences of splenomegaly, leucopaenia and myocarditis.{Table 2}

The presence of uncontrolled diabetes, leucocytosis, hepatitis, marked transaminitis (>10× transaminase elevation) and ARDS was found to be a predictor of hospital stay of >5 days among scrub typhus patients [Table 3]. The presence of leucocytosis, AKI, hepatitis, marked transaminitis (>10×) and encephalopathy was found to be a significant predictor for admission to a high-dependency unit. The presence of leucocytosis was found to have a significant association with major organ involvement or complications. The presence of hepatitis, AKI, myocarditis and ARDS was significantly associated with the development of shock with the inotropic requirement. Smoking > 40 pack-years and the presence of leucocytosis, AKI and encephalopathy were significantly associated with mortality.{Table 3}

 Discussion



Scrub typhus has re-emerged as an important tropical disease in the past. Various authors have attributed this trend to be the result of an expanding urban population and changes in the land usage pattern.[11] Chiggers have been observed to prevail abundantly in a cooler season with high relative humidity and low sunlight in a dense vegetative canopy.[12] The Himalayan subset of the current study population, who live close to the forest region, are occupationally exposed to dense scrub vegetations.[13] However, in the plain regions, compromise in sanitation and increase in rodent population which are possible reservoirs for the chiggers may be responsible for the reported outbreaks. Thus, the absence of scrub vegetation in the locale does not reduce the probability of the diagnosis of scrub typhus.[14]

The tertiary level healthcare centre, where the current study was undertaken, is located near the foothills of the Himalayas and caters to the healthcare needs of people of North India (two states mainly). The study population, hence, was composed of an almost balanced distribution of patients from both the hilly regions and the plains. The state of Uttarakhand forms two international borders, with China and Nepal [Figure 4]. The study population, hence, becomes unique, in probably a mixture of ethnic makeups and of different environmental mechanisms for vector survival. In a retrospective study of 2524 cases of AFI attending a tertiary care centre in the sub-Himalayan region, from areas of Uttarakhand and the adjoining areas of Uttar Pradesh, 284 (11.2%) cases were diagnosed to have scrub typhus.[2] However, scrub typhus cases are highly underdiagnosed in our country due to poor suspicion, lack of availability of tests and early initiation of empirical treatment.

The WHO provides the clinical description of scrub typhus as follows: 'disease with a primary “punched out” skin ulcer (eschar) where the bite occurred, followed by acute onset fever after several days, along with headache, profuse sweating, conjunctival injection, and lymphadenopathy. Within a week, a dull maculopapular rash appears on the trunk, extends to the extremities and disappears in a few days. Cough is also common. Defervescence within 48 h strongly suggests a rickettsial etiology'. From the classical description provided by the WHO, scrub typhus has progressed to demonstrate a more expanded clinical spectrum during its re-emergence, especially in the Indian subcontinent, as seen also in the current study. Majority of patients present with features suggestive of a viral prodrome, respiratory involvement, acute encephalitis syndrome, hepatitis or gastrointestinal issues at the first point of contact with physicians. The notable atypical features observed in the study are cutaneous small-vessel vasculitis and polyneuropathy, suggesting the potential for rickettsia as an important antigenic trigger. The possibility of the widespread organ involvement of scrub typhus to be having more of an immunologic basis is yet to be explored in detail. As expected from the previous studies from the North Indian cohorts, the incidence of detecting an eschar at the site of the bite was low. The observations of the WHO during the formulation of surveillance standards in 1999 suggest that the incidence of eschar may be low in highly endemic areas with frequent re-infections.[15] Another characteristic feature was raised alkaline phosphatase (ALP) (>2 times upper limit), observed in 75.2% of cases which is notable similar to few recent studies documenting the same fact, needs further study to determine its importance for a clinician.[16],[17]

Leucocytosis in a case of scrub typhus was found to have a significant predictive association with major organ involvement and complications.[18] Procalcitonin levels were not uniformly available in all our cases. However, none of the cases with leucocytosis revealed any isolate in various cultures. In addition, leucocytosis was observed at <5 days into the illness i.e., from the onset of the first symptom, in most cases. Thus, it could be assumed that the leucocytosis observed is attributable to the typhus itself, rather than a superadded bacterial infection. However, it needs a future prospective study to confirm the predictivity of leucocyte response. In contrast to this, data provided by Gupta et al. in the paediatric population indicate a higher incidence of complications in patients with leucopaenia rather than leucocytosis.[19]

The incidence of ARDS and ventilator requirement was observed to be lower in patients residing at high altitude, though not statistically significant. One possible explanation for this trend would be the acclimatisation of the patients to the high-altitude environment with consequent development of resilience to a hypoxic injury. In an exclusive study of Himalayan patients by Mahajan et al., the frequency of symptoms and clinical features was comparable to that of the current study, except for a high incidence of lymphadenopathy (52.3% vs. 0.0%) and lower rates of ARDS (9.5% vs. 18.7%).[16],[20],[21],[22]

The incidence of eschar, shock, ARDS and ventilator requirements was lower compared to the findings of Varghese et al. from Vellore in South India, whereas the incidence of myalgia, cough, AKI and encephalopathy was higher. A comparison of clinical profile with other North Indian states is also described, which shows a similar contrasting difference in the rates of ARDS, encephalopathy and shock [Table 4].[23]{Table 4}

Limitations

One can observe certain limitations in the current study, which include the study's retrospective observational nature and its intrinsic deficiency in important clinical details, limiting the exploration of questions arising during the description of the profile of the infection. The sample size was limited, disabling a statistically significant prediction of severity and mortality. The cases from the outpatient departments were not included as the complete laboratory profile and clinical description were not available from them. This would alter the actual incidence of organ involvement and complications. This can be solved by prospective studies and consideration of cumulative data of expected outbreaks. Another important fact that needs to be considered is the possibility of co-infections as the seasonality of most parasite/viral outbreaks coincides in this region. The serological studies should be backed by polymerase chain reaction-based assays, which can authentically conclude the diagnosis. However, clinical diagnosis is more important than laboratory diagnosis, which was taken care of in this study.

 Conclusions



The current study reveals few atypical presentations and complications differing from the classical description, calling for redefining the clinical profile of scrub typhus. Raised ALP was noticed in >75% of cases. The presence of leucocytosis was found to have a predictive association with major organ involvement and complications. ARDS was observed to be lesser in the Himalayan population compared to the plains. CNS involvement and AKI were found to have a higher incidence in the study population compared to other North Indian data, and respiratory complications showed a lower overall incidence compared to South Indian studies. The mechanism of raised ALP in North Indian cases and lesser incidence of ARDS in Himalayan cases need a prospective study for better characterisation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Izzard L, Fuller A, Blacksell SD, Paris DH, Richards AL, Aukkanit N, et al. Isolation of a novel Orientia species (O. chuto sp. nov.) from a patient infected in Dubai. J Clin Microbiol 2010;48:4404-9.
2Bhargava A, Kaushik R, Kaushik RM, Sharma A, Ahmad S, Dhar M, et al. Scrub typhus in Uttarakhand & adjoining Uttar Pradesh: Seasonality, clinical presentations &amp; amp; predictors of mortality. Indian J Med Res 2016;144:901-9.
3Peter JV, Sudarsan TI, Prakash JA, Varghese GM. Severe scrub typhus infection: Clinical features, diagnostic challenges and management. World J Crit Care Med 2015;4:244-50.
4Rajapakse S, Rodrigo C, Fernando SD. Drug treatment of scrub typhus. Trop Doct 2011;41:1-4.
5Watt G, Chouriyagune C, Ruangweerayud R, Watcharapichat P, Phulsuksombati D, Jongsakul K, et al. Scrub typhus infections poorly responsive to antibiotics in northern Thailand. Lancet 1996;348:86-9.
6Anitharaj V, Stephen S, Pradeep J, Park S, Kim SH, Kim YJ, et al. Serological diagnosis of acute scrub typhus in Southern India: Evaluation of InBios scrub typhus detect IgM rapid test and comparison with other serological tests. J Clin Diagn Res 2016;10:DC07-10.
7Chao CC, Zhangm Z, Weissenberger G, Chen HW, Ching WM. Lateral flow rapid test for accurate and early diagnosis of scrub typhus: A febrile illness of historically military importance in the pacific rim. Mil Med 2017;182:369-75.
8ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012;307:2526-33.
9KDIGO clinical practice guideline for acute kidney injury. Kidney Internat Suppl 2012;2:8-12.
10Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, et al. European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636-48, 2648a-2648d.
11Kuo CC, Huang JL, Shu PY, Lee PL, Kelt DA, Wang HC. Cascading effect of economic globalization on human risks of scrub typhus and tick-borne rickettsial diseases. Ecol Appl 2012;22:1803-16.
12Tsai PJ, Yeh HC. Scrub typhus islands in the Taiwan area and the association between scrub typhus disease and forest land use and farmer population density: Geographically weighted regression. BMC Infect Dis 2013;13:191.
13Elliott I, Pearson I, Dahal P, Thomas NV, Roberts T, Newton PN. Scrub typhus ecology: A systematic review of Orientia in vectors and hosts. Parasit Vectors 2019;12:513.
14Lindahl JF, Grace D. The consequences of human actions on risks for infectious diseases: A review. Infect Ecol Epidemiol 2015;5:30048.
15World Health Organization. WHO Recommended Surveillance Standards. 2nd ed.. Geneva: World Health Organization. Available from: http://www.who.int/iris/handle/10665/65517. [Last accessed on 2020 Jul 04].
16Pathania M, Amisha, Malik P, Rathaur VK. Scrub typhus: Overview of demographic variables, clinical profile, and diagnostic issues in the sub-Himalayan region of India and its comparison to other Indian and Asian studies. J Family Med Prim Care 2019;8:1189-95.
17Jain D, Nand N, Giri K, Bhutani J. Scrub typhus infection, not a benign disease: An experience from a tertiary care center in Northern India. Med Pharm Rep 2019;92:36-42.
18Lee N, Ip M, Wong B, Lui G, Tsang OT, Lai JY, et al. Risk factors associated with life-threatening rickettsial infections. Am J Trop Med Hyg 2008;78:973-8.
19Gupta P, Gurjar U, Sharma BS, Gupta ML. Complication profile of scrub typhus and its associations with total leucocyte count. Int J Contemp Pediatr 2017;9:96-9.
20Mahajan SK, Rolain JM, Kashyap R, Bakshi D, Sharma V, Prasher BS, et al. Scrub typhus in Himalayas. Emerg Infect Dis 2006;12:1590-2.
21Takhar RP, Bunkar ML, Arya S, Mirdha N, Mohd A. Scrub typhus: A prospective, observational study during an outbreak in Rajasthan, India. Natl Med J India 2017;30:69-72.
22Sethi S, Prasad A, Biswal M, Hallur VK, Mewara A, Gupta N, et al. Outbreak of scrub typhus in North India: A re-emerging epidemic. Trop Doct 2014;44:156-9.
23Varghese GM, Abraham OC, Mathai D, Thomas K, Aaron R, Kavitha ML, et al. Scrub typhus among hospitalised patients with febrile illness in South India: Magnitude and clinical predictors. J Infect 2006;52:56-60.