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 Table of Contents 
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 1362-1369  

Rising visceral leishmaniasis in Holy Himalayas (Uttarakhand, India) – A cross-sectional hospital-based study


Department of General Medicine, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission17-Dec-2019
Date of Decision03-Feb-2020
Date of Acceptance12-Feb-2020
Date of Web Publication26-Mar-2020

Correspondence Address:
Dr. Prasan Kumar Panda
Asst. Professor, Dept. of General Medicine, Sixth Floor, College Block, All India Institute of Medical Sciences (AIIMS), Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jfmpc.jfmpc_1174_19

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  Abstract 


Background: Apart from the rarity of the visceral leishmaniasis (VL) cases in high altitude (>2000 ft), the combination triad of VL, hemophagocytic lymphohistiocytosis (HLH) syndrome, and Himalayas is rarely being reported. Here, we studied the triad in the Himalayan region, attending a single tertiary care hospital over a period of 2 years. Methods: The study was a cross-sectional analysis of case records of seven confirmed VL patients. A systematic master chart review analyzed the demographic, clinical, laboratory, treatment, and outcome details of these patients. Results: These cases were diagnosed as VL by clinical findings and confirmed by rk-39 anti-body and demonstration of LD bodies in bone marrow smears. All cases without any travel history to endemic regions presented with prolonged fever (>1 months duration), anorexia, weight loss, and having hepatosplenomegaly and bi-or pan-cytopenia. All cases were having HLH, confirmed based on the HScore system (online calculation), and liver injury having transaminitis. Kidney involvement was seen in 27% cases. All cases improved with liposomal amphotericin-B, but one had cardiac arrest after blood transfusion reaction. Conclusion: Clinician of the non-endemic zone should suspect VL in patients with fever of unknown origin and have a high suspicion in cases of HLH and liver involvement and vice versa. Kidney involvement is seen in one-third of the VL cases. Liposomal amphotericin-B is recommended in this region. The leishmaniasis prevalent in these areas should further be subject to comparison with endemic parts, and a large-scale study is needed to find the reason of the rising vector from the holy Himalayas.

Keywords: Endemicity, Hemophagocytic lymphohistiocytosis (HLH) syndrome, High altitude, Kala-azar, LD bodies, Liver injury


How to cite this article:
Kumari S, Dhawan P, Panda PK, Bairwa M, Pai VS. Rising visceral leishmaniasis in Holy Himalayas (Uttarakhand, India) – A cross-sectional hospital-based study. J Family Med Prim Care 2020;9:1362-9

How to cite this URL:
Kumari S, Dhawan P, Panda PK, Bairwa M, Pai VS. Rising visceral leishmaniasis in Holy Himalayas (Uttarakhand, India) – A cross-sectional hospital-based study. J Family Med Prim Care [serial online] 2020 [cited 2020 Apr 8];9:1362-9. Available from: http://www.jfmpc.com/text.asp?2020/9/3/1362/281194




  Introduction Top


Visceral leishmaniasis (VL), a systemic parasitic vector borne disease, is prevalent in low-altitude areas having river belts attributing to preferential habitat of its vector, i.e. sand fly. It does rarely occur in altitudes over 2000 ft (600 m).[1] However, in the last quarter of the twentieth century, migration of disease has been noticed and new niches being reported from previous non-endemic regions. One of them is across the Himalayas (Southern) from Pakistan to Bhutan through India. Considering Uttarakhand Himalayas of India, sporadic cases have been reported from the natives of Himalayan region such as Kumaon (350–900 m above mean sea level) and Garhwal (1500–2500 m above mean sea level) region.[2],[3] This phenomenon of migrations of the disease from Indian endemic locality such as Bihar and West Bangel towards the hilly regions of Himalayas points towards the new endemicity of the disease.

The disease pattern of this region also varies slightly from rest of the world as documented in the few published case reports/series. Almost all cases present as VL rather than cutaneous leishmaniasis, and the common association of VL and hemophagocytic lympho-histiocytosis (HLH) syndrome is being found.[4] HLH-associated VL is more malignant and difficult to diagnose as features of both overlap and lead to delayed treatment. Both require aggressive and early treatment for better outcomes in terms of morbidity and mortality.

This needs a study to know the demography and clinical details of VL patients in this so-called non-endemic area. Thereby, we do a cross-sectional hospital-based study of all adult VL cases who are coming from Uttarakhand state of India and admitted in our hospital (General Medicine Department) during the last two years.


  Materials and Methods Top


This cross-sectional study was conducted during July 2017 to June 2019 in a referral 1000-bedded tertiary health center in Rishikesh, located in the base of Uttarakhand (state full of Himalayas), India.

Case records of all patients (n = 10) with VL (confirmed diagnosis), admitted to the Department of General Medicine of the hospital in the last two years, were scrutinized. Seven patients were included in the study after the inclusion criteria of Uttarakhand residential address.

The demographic, clinical, laboratory, treatment, and outcome details of all seven patients were entered in a systematic master chart excel. HLH was diagnosed based on diagnostic criteria and HScore calculated by online software http://saintantoine.aphp.fr/score predicted the percentage of possibility of HLH [Table 1].[5],[6] Diagnosis of acute kidney injury (AKI) was made based on the KDIGO definition. Either or both hyperbilirubinemia (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 (ALI) after excluding the prior history of liver diseases.
Table 1: HLH diagnostic criteria and online software version to predict HLH[5],[6]

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  Results Top


During the last two years, we found seven cases of VL proven by rk-39 (point of care test for leishmaniasis) and later confirmed by bone marrow examination. Majority of them (except few having atypical features) presented with prolonged (>1 months) high-grade fever with chills, rigors, malaise, anorexia, and unintentional weight loss without the history of any localizing symptoms [Table 2]. None of them gave any history of IV drug abuse, exposure to STDs, or travel to endemic region of VL (within a period of 1 year). Most of them had pancytopenia and hepato-splenomegaly.
Table 2: Clinical characteristics of seven cases of visceral leishmaniasis

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Other local causes of prolonged fever like malaria, enteric fever, scrub typhus, tuberculosis, HIV, HCV, and HBV were ruled out except case 7 that had HBsAg positive. Bone marrow examinations showed LD bodies confirming VL [Table 3]. During further evaluation, serum ferritin and triglyceride were found to be raised, so possibility of HLH syndrome was suspected and HScore calculated. All had >90% probability of HLH (secondary to VL). However, NK cell activity and sCD25 level could not be done due to unavailability. Final diagnosis of VL with secondary HLH was considered. All cases except one improved after treatment with either plain amphotericin-B (never alone) and or liposomal amphotericin-B depending upon affordability and preferences. Positive response was considered to have informed of absence of fever, decrease in spleen size, and improving hematological parameters. All were discharged on due course and doing well on follow up except one who died during hospital course.
Table 3: Laboratory (initial) characteristics of seven cases diagnosed as visceral leishmaniasis

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Few atypical findings were observed. All cases had liver involvement in the form of transaminitis and three had jaundice. Two cases had anasarca and kidney injury. One had gastrointestinal manifestation. Although case 6 had been diagnosed as VL 4- 5 months before by haematology department, but she deferred treatment and after 2 months she presented with intermittent bleeding lips and progressive anasarca. She developed transfusion reaction after the transfusion of packed RBC with acute lung injury and suddenly went to irreversible cardiac arrest.


  Discussion Top


The present study focuses on cases, presenting as fever of unknown origin (FUO) from hilly regions of Southern Indian Himalayas, and later on unexpectedly proven to be VL. These cases were native of Uttarakhand (mainly areas near the river belts, especially Ganga), neither visited to endemic zone nor having any contacts with people of that zone except case 3 and 7 having h/o contact with Bengali and Bihari laborers, suggesting the possibility of expansion of endemicity [Figure 1]. All cases were proven to have HLH (>95% chance based on Hscore) and liver involvement. Hence, expansion of disease territory and variation in disease manifestations are more concern.
Figure 1: Terrain map showing distribution of seven visceral leishmaniasis cases (in orange colored) and previous published studies (in blue colored) in Uttarakhand Himalayas and trace of river Ganga along with endemic locations (inlet, Indian map having colored states: Uttar Pradesh, Bihar, Jharkhand, and West Bengal) of leishmaniasis. Map courtesy: Terrain map scaled down from Google MapR – modified in compliance with in-app permissions and policies

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Previous case reports of VL from different regions of Uttarakhand are mainly distributed along the banks of river Ganges [Table 4].[2], 3, [7],[8],[9],[10],[11],[12] But there is lack of data and research regarding whether the parasite and its vector have developed as a new species in these areas or introduced de novo by migrant population. Although the latter appears more likely, as one study suggests the possibility of ecological changes causing an environmental shift in favor of vector proliferation, due to the development of Tehri dam reservoir and migration of laborers from endemic areas.[3] Also, the possibility of the upstream move of sandflies along the Ganges from endemic zone cannot be excluded as has been suspected in our study in the map. Each primary care physicians should consider this possibility now in this non-endemic region.
Table 4: Summary of published articles on leishmaniasis in Uttarakhand Himalayas[2],[3],[7],[8],[9],[10],[11],[12]

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Clinical presentation of cases varies compared to endemic cases. For example, most of the cases till now, reported from this area, are of VL rather than cutaneous leishmaniasis similar to our study. Liver function derangement is infrequent in VL although the parasite primarily infects the reticuloendothelial system and hepatomegaly is common. In previous Indian studies, biochemical evidence of hepatitis was found in 25%, 17%, and 51% of VL patients, respectively.[13],[14] In our study, 43% had direct hyperbilirubinemia, 70% had hypoalbuminemia, and all had transaminitis (100%), although none had evidence of other causes of hepatitis except case 7 having positive HBsAg. This 100% liver involvement could be a part of HLH since all of our cases had the same. This supports HLH goes hand in hand with VL in this region.

VL is one of the major infective causes of HLH. The clinical picture of both is often overlapping and bone marrow may fail to reveal LD bodies. Consequently, VL might be missed and intense immunosuppression for HLH without specific antimicrobial therapy may be administered with disastrous consequences. Till date only few cases have been reported to have this combination.[4] In our study, all cases have strong association with HLH. If it comes true, we need aggressive approach for VL in these areas since the main treatment of secondary HLH is the treatment of primary cause. This will help all clinicians in this region to work up for HLH in the suspected cases of VL and vice versa. The common association is yet to be studied on large database so as to conclude the exact relationship and association between the two.

Kidney involvement is also unusual in VL. According to a prospective study, kidney impairment found in 11% cases of VL, but in our study, two cases (27%) had AKI (case 4 and 7).[15] We could not find out the exact cause of AKI, but case 4 had diarrhea (pre-renal AKI). We need further detail study and more data to conclude the cause. VL-associated lymphadenopathy is seen in hilly area as per one study, but our study could not establish this relationship.[16] Case no 6 had epistaxis and bleeding lips, mostly due to thrombocytopenia or deficient clotting factor as suggested by Sigdel et al.[17] Bilateral pleural effusion is also a very rare finding in immunocompetent VL cases and has been reported only in few cases from endemic cases.[18]

Treatment for VL and associated HLH is mainly amphotericin-B either as a single dose of liposomal one or multiple doses of plain one.[19]An efficacy of 95.7% is seen with a single-dose regimen of liposomal amphotericin B at a dose of 10 mg/kg, along with the lower toxicity and shorter duration of therapy. However, multiple doses of 18–21 mg/kg plain amphotericin-B have 90%–100% efficacy in southern Europe with many adverse effects, which necessitate close monitoring and hospitalization for 4–5 weeks, which ultimately increases the cost of therapy. Amphotericin-B may inhibit macrophage function, cytokine expression, antigen-induced proliferation of T and B cells in vitro, and the function of cytotoxic T cells. Therefore, it may have exerted a dual effect on both HLH and VL in our study. All our cases respond to liposomal molecule including one case that failed from plain amphotericin-B. This suggests importance of liposomal over plain amphotericin-B, especially a note for physicians in this community.

Our study had its own set of limitations. First, this study was of small sample size and short follow up. However, in a non-endemic area, this may be significant. Second, the data collected were dependent on medical records. Third, our work is based on the characteristics of the study population, which was from a tertiary care center and most likely represents a more severe disease spectrum. Therefore, the disease prevalence might have been underestimated. Lastly, the study did not account negative diagnostic test results during the study period. Since pointers to think for VL/HLH depend upon experiences of concerned doctors of this study, good documentation quality and knowledge capacity of the doctors are to be taken care in future studies to answer this question. Findings in our study are similar to few studies done before, adding validity to the data.[20] Since this study was done in non-endemic zone for VL, the result is valid to whole Himalayas where VL may be a rising threat. This may serve as a benchmark for further epidemiological study for case detection.

In summary, in cases presenting with FUO from hilly regions of Uttarakhand, VL should be considered as one of the differentials. It is alarming that so-called non-endemic areas for VL are converting to endemic zone. The possible reason may be migration of vectors along the upstream belts of Gange. High index of suspicion of VL is to be kept in cases of HLH and vice versa. Similarly, liver involvement is to be considered in VL/HLH cases and vice versa. Kidney involvement is seen in one-third of the VL cases. Liposomal amphotericin-B is recommended over plain one in VL cases in this region. Furthermore, VL cases should further be subject to comparison with those found in other endemic parts of India so as answer and fill the gap of knowledge about increasing prevalence and variances of VL in this region.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Authors' contribution

Sweety Kumari and Piyush Dhawan searched the literature, collected the data, drafted, reviewed, and approved the study. Prasan K. Panda, Mukesh Bairwa, and Venkatesh S. Pai searched the literature, drafted statistically, critically reviewed, and approved the study.



 
  References Top

1.
Park K. Leishmaniasis. In: Park K, editor. Park's Textbook of Preventive and Social Medicine. VI ed. Jabalpur, India: Banarsidas Bhanot; 2007. p. 256-8.  Back to cited text no. 1
    
2.
Singh S, Biswas A, Wig N, Aggarwal P, Sood R, Wali JP. A new focus of visceral leishmaniasis in sub-Himalayan (Kumaon) region of northern India. J Commun Dis 1999;31:73-7.  Back to cited text no. 2
    
3.
Bhat NK, Ahuja V, Dhar M, Ahmad S, Pandita N, Gupta V, et al. Changing epidemiology: A new focus of Kala azar at high-altitude Garhwal region of North India. J Trop Pediatr 2017;63:104-8.  Back to cited text no. 3
    
4.
Pawar S, Ragesh R, Nischal N, Sharma S, Panda PK, Sharma SK. Unique triad of 'Pregnancy, Kala azar and hemophagocytic lymphohistiocytic syndrome from a non-endemic region'. J Assoc Physicians India 2015;63:65-8.  Back to cited text no. 4
    
5.
Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: Advances in patho-physiology, diagnosis, and treatment. J Pediatr 2013;163:1253-9.  Back to cited text no. 5
    
6.
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophago-cytic syndrome. Arthritis Rheumatol 2014;66:2613-20.  Back to cited text no. 6
    
7.
Ahmad S, Chandra H, Bhat NK, Dhar M, Shirazi N, Verma SK. North Indian state of Uttarakhand: A new hot house of visceral leishmaniasis. Trop Doct 2016;46:111-3.  Back to cited text no. 7
    
8.
Chandra H, Chandra S, Kaushik RM, Bhat NK, Shrivastava V. Hemophagocytosis on bone marrow aspirate cytology: Single center experience in North Himalayan region of India. Ann Med Health Sci Res 2014;4:692-6.  Back to cited text no. 8
[PUBMED]  [Full text]  
9.
Mathur SB, Arya AK. Nonmigrant Children with Visceral Leishmaniasis from the Nonendemic Area of Uttarakhand. J Trop Pediatr 2014;60:322-5.  Back to cited text no. 9
    
10.
Kumar A, Rawat V, Thapliyal N, Saxena SR. Kala-azar-A case series from nonendemic area, Uttarakhand. Ann Trop Med Public Health 2013;6:355-7.  Back to cited text no. 10
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Verma SK, Ahmad S, Shirazi N, Kusum A, Kaushik RM, Barthwal SP. Sodium stibogluconate-sensitive visceral leishmaniasis in the non-endemic hilly region of Uttarakhand, India. Trans R Soc Trop Med Hyg 2007;101:730-2.  Back to cited text no. 11
    
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Rao JS, Sharma SK, Bhattacharya D, Saxena NB. Sandfly survey in Nainital and Almora districts of Uttaranchal with particular reference to Phlebotomus argentipes, vector of kala-azar. J Commun Dis 2001;33:7-11.  Back to cited text no. 12
    
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Aggarwal P, Wali JP, Chopra P. Liver in kala-azar. Indian J Gastroenterol 1990;9:135-6.  Back to cited text no. 13
    
14.
Mathur P, Samantaray JC, Samanta P. High prevalence of functional liver derangement in visceral leishmaniasis at an Indian tertiary care center. Clin Gastroenterol Hepatol 2008;6:1170-2.  Back to cited text no. 14
    
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Salgado Filho N, Ferreira TM, Costa JM. Involvement of the renal function in patients with visceral leishmaniasis (kala-azar). Revista da Sociedade Brasileira de Medicina Tropical 2003;36:217-21.  Back to cited text no. 15
    
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Werneck GL, Batista MS, Gomes JR, Costa DL, Costa CH. Prognostic factors for death from visceral leishmaniasis in Teresina, Brazil. Infection 2003;31:174-7.  Back to cited text no. 16
    
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Sigdel B, Bhandary S, Rijal S. Epistaxis in visceral leishmaniasis with hematological correlation. Int J Otolaryngol 2012;2012:809056. doi: 10.1155/2012/809056.  Back to cited text no. 17
    
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Dasgupta S, Saha M, Chakrabarti S, Chakraborty J. Visceral leishmaniasis with pleural effusion in an immunocompetent patient. Lung India: Official organ of Indian Chest Society 2014;31:56.  Back to cited text no. 18
    
19.
Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose liposomal amphotericin B for visceral leishmaniasis in India. N Engl J Med 2010;362:504-12.  Back to cited text no. 19
    
20.
WHO. Visceral leishmaniasis elimination: Intensifying surveillance to overcome last-mile challenges in Nepal. https://www.who.int/neglected_diseases/news/VL-Nepal- intensifying-surveillance-overcome-last-mile-challenges/en/. [Last accessed on 2019 Dec 26].  Back to cited text no. 20
    


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