ABSTRACT.
Substantial gains have been achieved in the control of visceral leishmaniasis (VL) in the four endemic states of India; however, cases are sporadically reported from other nonendemic regions of India such as the sub-Himalayan region, which can be a hurdle to VL elimination. We analyzed VL reports published from the sub-Himalayan regions of India over seven decades (1967–2023) in this systematic review. Medline, Embase, Scopus, and Web of Science were searched for VL cases from sub-Himalayan regions of India. The demographic data, clinical presentation, diagnostic modality, treatment, outcomes of the cases, and overall year-wise and geographical distribution of the cases were analyzed; studies on the sand fly vector were also included. From 535 articles, 33 studies were included in the analysis. Overall, 228 patients were diagnosed with VL in the sub-Himalayan region of India from 1967 to 2023. These cases were reported from Uttarakhand (n = 178), Himachal Pradesh (n = 39), and Jammu and Kashmir (n = 11). Most patients (88.4%) did not have a history of travel outside their native places. Three pediatric cases were reported from Jammu and Kashmir. The DNA of Leishmania donovani was detected in four of the 52 (7.7%) sand flies collected from Himachal Pradesh. The published literature points toward the existence of local transmission of VL in the sub-Himalayan region of India, strongly substantiated by the emergence of pediatric VL in some places. Thus, these difficult-to-reach hilly states of India will require focused surveillance for VL to successfully achieve elimination goals.
INTRODUCTION
Visceral leishmaniasis (VL), also known as kala-azar, is fatal in more than 95% of cases if left untreated. The disease is endemic in 75 countries across Asia, Africa, and the Americas, with India accounting for 18% of the global burden in 2020.1 Owing to a concerted effort with the WHO and other partners for VL control and elimination over three decades, cases in India have decreased by 98.99% (777 cases in 2022) since 1992 (77,102 cases), and India is now facing the last mile challenges of VL elimination.2 The disease now remains a substantial public health problem in only 54 districts across four endemic states—Bihar, Jharkhand, Uttar Pradesh, and West Bengal.2,3 However, despite the VL elimination gains achieved, newer cases are sporadically reported from other states of India, viz., Assam, Gujarat, Himachal Pradesh, Kerala, Madhya Pradesh, Haryana, Sikkim, Tamil Nadu, and Uttarakhand and the union territories of Puducherry and Jammu and Kashmir (J&K).2,4 The control of VL as a public health problem cannot be truly achieved if these cases continue to occur in areas outside the four main endemic states.
The epidemiology of VL is affected by socioeconomic and individual factors such as poverty, malnutrition, poor housing, and immunosuppression.5 Apart from these, population displacement and political factors cause spread of the disease in previously nonendemic areas, as has been reported in Kenya, Ethiopia, and South Sudan.6,7 The disease is also strongly influenced by geo-topographical and climactic factors, particularly changes in temperature, rainfall, and humidity, as a shift in these determinants affect the distribution, survival, and population of the sand fly vectors and reservoir hosts.8 All these factors contribute to the emergence and redistribution of cases and pose a threat to the control programs.
In the Indian subcontinent, the sub-Himalayan region consisting of Himachal Pradesh (31°6′N, 77°10′E), Uttarakhand (30°15′N, 79°15′E), and J&K (33°5′N, 74°47′E) poses a serious challenge for VL control because of its difficult mountainous terrain. Historically, this region was undisputedly known for its endemicity for cutaneous leishmaniasis (CL);9–11 however, reports of VL have only been few, and thus it remains neglected as far as control initiatives are concerned. Visceral leishmaniasis has been sporadically, but consistently, reported from adult populations of this region, and now it appears to have emerged in pediatric populations in areas where it was never reported earlier.12 Thus, to assess the overall situation of VL in this region, in this systematic review we analyzed published cases of VL spanning over seven decades (1960s–2020s) from these sub-Himalayan regions of India.
MATERIALS AND METHODS
Database, information sources, and search strategy.
A systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Supplemental Figure 1). We conducted the search in the electronic databases Medline, Embase, Scopus, and Web of Science using a predefined search strategy up to April 20, 2024 (Supplemental Table 1). We also manually searched the reference lists of the studies and review articles that appeared in the search for additional reports.
Criteria for inclusion and exclusion.
We included case reports; case series; and prospective, retrospective, and cross-sectional studies that reported data on VL cases from the sub-Himalayan region of India. The included studies were those that reported cases of males or females of any age diagnosed with VL using any diagnostic method. Studies on sand fly vector and animal reservoirs that appeared in the search were included. Studies reporting only CL, incomplete clinical data, nonclinical studies, alternate diagnosis, abstracts, reviews, and studies from regions outside India were excluded.
Data extraction.
The authors independently screened the search results to identify relevant studies after removing duplicates. The full-text articles of the studies were retrieved and screened per the inclusion and exclusion criteria. If two or more studies were found with overlapping data, the one with the most complete extractable data was included and the others were excluded. Any differences or discrepancies were resolved after discussion and consensus among the authors. The demographic and clinical data of the cases were entered into a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, WA).
STATISTICAL ANALYSES
The demographic data, clinical presentation, diagnostic modality, treatment, and outcome of the cases were descriptively summarized. A histogram was used to depict the overall year-wise distribution and temporal fluctuation of the reported cases. A map was generated to depict the district-wise geographical distribution of the cases using QGIS v. 3.34.6.
RESULTS
Study selection.
A total of 535 records published from 1978 to 2024 (up to April 20, 2024) were identified from the searched databases and additional sources. These studies reported VL cases spanning over seven decades (1967–2024). After 200 duplicates were removed, the title and abstract of 335 records were screened to determine eligibility. Among them, 286 studies were excluded based on predetermined inclusion and exclusion criteria. Of the remaining 49 studies, 15 were excluded because they focused only on CL, had data/overlap or insufficient data, etc. (Supplemental Figure 1). This left us with 33 studies that reported VL cases, sand fly vectors, or animal reservoirs for final analysis. Of these, 27 studies reported 228 VL cases for analysis of geographical and year-wise distribution of cases (Supplemental Figure 1; Supplemental Table 2), with 181 VL cases having relevant clinical data for descriptive analysis, including one case of post-kala-azar dermal leishmaniasis (PKDL), which was individually discussed and not included in the VL analysis. Five studies on vectors and one on animal reservoirs were included.
Geographical distribution and domicile.
Overall, a total of 228 cases of VL (including one PKDL) were reported in the sub-Himalayan regions of India (i.e., Himachal Pradesh, Uttarakhand, and J&K) from 1967 to 2023. The overall geographical distribution of the cases is depicted in Supplemental Table 3 and Figure 1. Of the 181 VL cases with relevant details available, 160 (88.4%) were reported to be Indigenous cases, whereas the domicile was not mentioned for 21 (11.6%) cases.
Figure 1.
Geographic distribution of VL cases (N = 228) in the sub-Himalayan region of India (Uttarakhand, Himachal Pradesh, and Jammu & Kashmir). The district-wise number of cases is shown; cases without specific location details are shown in boxes adjacent to the respective state/union territory.
A total of 178 cases were reported from the state of Uttarakhand (two divisions—Garhwal and Kumaon). The majority of the cases (n = 88) were concentrated in the Garhwal division. Among these, 13 cases were located in the Dehradun district, three in Rudraprayag, and two in Haridwar; one PKDL case was from the Tehri Garhwal district, whereas the precise locations of the remaining 69 cases were not specified. In the Kumaon division (n = 58), cases were reported from Nainital, Pithoragarh, Champawat, Bageshwar, and Almora districts, with the number of cases ranging from 1 to 34, whereas the precise locations of 15 cases were not specified. In addition, there were 32 cases reported from Uttarakhand without precise location details.
A total of 39 VL cases were reported from the state of Himachal Pradesh. Of these, 26 cases were reported from the districts of Chamba, Hamirpur, Kangra, Kinnaur, Kullu, Shimla, and Solan. Among these districts, Kinnaur had the highest number of cases (n = 9). In addition, there were 13 cases reported from Himachal Pradesh without precise location details.
A total of 11 VL cases were reported from the union territory of J&K (two divisions: Jammu and Kashmir). In the Jammu division, two VL cases were reported from Kathua district and very recently three cases from Poonch, whereas the precise location of two cases was not specified. In the Kashmir division, one case was reported from the Baramulla district, and one case was reported without precise location details. Further, the precise location was not mentioned for two more cases from J&K.
Temporal distribution.
The overall temporal distribution of VL cases over the seven decades is depicted in Supplemental Figure 2, with no discernible pattern. The earliest study reported 13 cases from 1967 and 1977, after which the cases dwindled to only nine during the period from 1980 to 2000, suggesting a possible decline in the incidence of VL or underreporting during that time. Thereafter, an upsurge was observed between 2000 and 2015, with 166 cases reported, comprising 72.8% of the total 228 cases. More recently, after 2015 until April 20, 2024, 39 cases were reported, which represents 17.1% of the total cases, suggesting a decline in cases compared with the preceding period. In 2023, three cases were reported from the Poonch district of J&K, where VL had never been documented in earlier publications.
Age and sex.
Of the total 228 VL cases, relevant data for analysis was available for 181 cases. Table 1 provides a demographic and clinical summary of these cases. Of the 181 cases, the majority were males (77.9%), and the mean age of the patients was 30.8 ± 13.04 years (range: 2–81 years). Interestingly, pediatric cases were also reported from the three regions. In the more endemic state of Uttarakhand, which is contiguous to the highly endemic state of Bihar and the neighboring endemic country of Nepal, pediatric cases were sporadically distributed throughout the years. However, in Himachal Pradesh (total n = 27), only one VL case in a 14-year-old male was reported in 1984, whereas all other cases were reported in adults. In J&K (n = 6), the first pediatric case occurred in 2009 in a 5-year-old male child, followed by three cases in 2023 (two 2-year-old male children and one 2-year-old female child).
Table 1.
Demographic, clinical, diagnostic, treatment, and outcome characteristics of VL cases (N = 181) in the sub-Himalayan regions of India (Uttarakhand, Himachal Pradesh, and Jammu & Kashmir)
| Variables | Number (%) |
|---|---|
| Age (±SD) in Years | 30.8 ±13.04 |
| Sex | |
| Male | 141 (77.9) |
| Female | 40 (22.1) |
| Number of cases in year of publication | |
| 1970–1980 | 1 (0.6) |
| 1980–1990 | 1 (0.6) |
| 1990–2000 | 0 (0) |
| 2000–2010 | 35 (19.3) |
| 2010–2020 | 140 (77.4) |
| 2020–Present | 4 (2.2) |
| Sub-Himalayan State/Union Territory of India | |
| Uttarakhand | 148 (81.8) |
| Himachal Pradesh | 26 (14.4) |
| Jammu & Kashmir | 7 (3.9) |
| Domicile of Case | |
| Indigenous | 160 (88.4) |
| Not Mentioned | 21 (11.6) |
| Clinical Features | |
| Fever | 171 (94.5) |
| Pallor/Anemia | 171 (94.5) |
| Splenomegaly | 91 (50.3) |
| Hepatosplenomegaly | 80 (44.2) |
| Weight Loss | 63 (34.8) |
| Hepatomegaly | 54 (29.8) |
| Lymphadenopathy | 26 (14.4) |
| Loss of Appetite/Anorexia | 21 (11.6) |
| Weakness/Fatigue | 19 (10.5) |
| Malaise | 17 (9.4) |
| Yellow Discoloration of Eyes/Jaundice | 13 (7.2) |
| Bleeding | 12 (6.6) |
| Diarrhea | 8 (4.4) |
| Pain in Abdomen | 4 (2.2) |
| Comorbidities/Associated Conditions* | 9 (4.9) |
| Diagnosis | |
| Microscopy (LD bodies) | 167 (92.3) |
| Anti-rK39 Antibody Detection | 28 (15.5) |
| ELISA | 6 (3.3) |
| PCR | 4 (2.2) |
| Culture | 1 (0.6) |
| Pancytopenia | 103 (56.9) |
| Treatment (N = 125) | |
| Pentavalent Antimonial Drugs | 70 (56) |
| Amphotericin B† | 53 (42.4) |
| Miltefosine Alone | 3 (2.4) |
| Miltefosine with Amphotericin B | 2 (1.6) |
| Outcome of treatment (N = 125) | |
| Improvement/Cure | 114 (91.2) |
| Death | 10 (8) |
| Lost to Follow-Up | 1 (0.8) |
| No Treatment (N = 8) | |
| Death | 4 (50) |
| Lost to Follow-Up | 4 (50) |
LD = Leishman-Donovan; PCR = polymerase chain reaction; TB = tuberculosis.
HIV-positive, TB, typhoid, hepatitis, rheumatoid arthritis.
Three patients switched from pentavalent antimonial drugs to amphotericin B.
Clinical features and diagnosis.
The most common clinical features were fever and pallor/anemia in 94.5%, followed by splenomegaly in 50.3%, hepatosplenomegaly in 44.2%, weight loss in 34.8%, hepatomegaly in 29.8%, lymphadenopathy in 14.4%, and others (Table 1). Pancytopenia was present in 56.9% of cases. Of the 181 cases, 92.3% were diagnosed by microscopy as Leishman-Donovan (LD) bodies. The other diagnostic modalities were antibody detection, polymerase chain reaction (PCR), and culture. The one case of PKDL had a single verrucous lesion, diagnosed by demonstration of LD bodies in the skin biopsy. The patient had a history of VL 4 years ago and was treated with sodium antimony gluconate for the same condition.
Treatment and response.
Information regarding treatment was provided for 133 (73.48%) cases, of which 125 received some drug therapy, whereas eight did not receive any drug for VL (Table 1). Of the 125 cases, the most frequently used drugs were pentavalent antimonial drugs in 70 (56%) cases (three were also given amphotericin B), followed by amphotericin B in 53 (42.4%), miltefosine alone in three (2.4%), and miltefosine with amphotericin B in two (1.6%) cases. Of the eight cases that did not receive any drug for VL, four died and four were lost to follow-up.
Of the 70 cases treated with pentavalent antimonial drugs, 59 (84.29%) showed improvement and were considered cured, and 11 (15.71%) did not respond to the therapy or suffered relapse/recurrence, nine (12.86%) of whom died. Three of the 11 nonresponders were administered amphotericin B, two of whom improved and one who died. There was no temporal decline observed in response to pentavalent antimonial drugs, and the nonresponders were reported only sporadically. Of the 53 cases treated with amphotericin B, 50 (94.34%) showed improvement and were considered cured of the illness, two (3.77%) died, and one was lost to follow-up. The earliest use of amphotericin B was in 2007, and it was the only drug reported to be used in VL patients from 2016 onward. All five cases treated with miltefosine with/without amphotericin B responded to therapy and were considered cured.
Thus, a majority of the treated patients (i.e., 114 [91.2%]) showed improvement on drug therapy. Overall, death was reported in 10/125 (8%) treated patients, in addition to the four deaths in patients who did not receive any drugs for VL.
Vector and animal studies.
Among the included reports, there were two studies conducted on sand flies from Himachal Pradesh, two from Uttarakhand, and one from J&K as well as one study on animal reservoirs in Himachal Pradesh (Supplemental Table 2).
The various sand fly species found in Himachal Pradesh were Phlebotomus (Adlerius) chinensis longiductus, Phlebotomus major, and Phlebotomus (Larroussius) kandelakii burneyi. In the first study done from 2003 to 2007, 62 Phlebotomus sand flies were collected from five villages in each of the Shimla and Kinnaur districts and subjected to cytochrome B and internal transcribed spacer-γ PCR. Of the 62 sand flies, there were 46 P. longiductus species, of which one was found positive for Leishmania tropica DNA by PCR. In the second study done from 2017 to 2019, 52 Phlebotomus sand flies were collected from 16 villages of Rampur (Shimla district), Nirmand (Kullu district), and Nichar (Kinnaur district) and subjected to PCR, of which four (7.7%) P. (Adlerious) longiductus were positive for L. donovani DNA by PCR and restriction fragment-length polymorphism. The L. donovani sequences showed 97% similarity with sequences from CL cases of Himachal Pradesh. In this study, man-hour density of sand flies was also assessed by collection of 291 sand flies, and P. longiductus was found to have the highest density. One study from 2009 reported two (6.5%) out of 31 dogs from the Satluj River valley in Rampur (Shimla district) of Himachal Pradesh were positive for anti–L. donovani antibodies by rK39 immunochromatographic dipstick test. The authors suggested that dogs were potential animal reservoirs. However, they recommended that more research be undertaken to establish the same.
The various species found in sand fly studies from Uttarakhand were Phlebotomus argentipes, Phlebotomus papatasi, Phlebotomus major, and Sergentomyia species from Nainital and Almora districts, and P. argentipes, Sergentomyia babu, and Sergentomyia bailyi from Dehradun. The P. argentipes from Nainital and Almora districts were tested with sera against various mammals, and 17.4% were found to be reactive with human antisera and 82.6% with bovine antisera, depicting the zoophilic nature of sand flies in the region; none of the sand flies were reactive with goat, pig, dog, and bird antisera. In the only study on vectors from J&K, the 18S rRNA sequence of P. argentipes from Jammu was found to have a 100% identity with P. argentipes from other Indian and global sequences.
DISCUSSION
The recent emergence of VL in a pediatric population of J&K prompted us to assess the overall situation of VL in the sub-Himalayan regions of India.12 Our systematic review of the published literature strongly points toward the existence of local transmission of VL in the sub-Himalayan region of India as evidenced by emerging cases in young children with no history of travel, the majority of the cases in adults also being Indigenous, and the identification of L. donovani DNA in the sand fly vectors collected from the region. Fortunately, the intensity of transmission and the burden of the disease are lower than those in the endemic states of India. However, this may be the tip of the iceberg as disease awareness, health-seeking behavior, infrastructure for case detection, and reporting and notification in the hilly regions are not as robust as that in the four endemic states.
We observed no discernible pattern in the occurrence of VL cases from 1967 to 2023. Although on the one hand, the Indian subcontinent has seen a significant decline in the number of new cases since 2005, on the other hand, the sub-Himalayan region witnessed a persistence of cases from 2000 to 2015.13 In view of the target of VL elimination as a public health problem, (i.e., annual incidence below one case per 10,000 population at the subdistrict level, that is, block public health center [PHC]), these regions have a low number of cases and may not be a real threat. However, the criteria of incidence at the PHC level for heavily populated states such as Bihar may not be directly applicable to the less densely populated hilly states. Furthermore, the large reservoir base of CL cases in these regions is capable of continued transmission despite the low incidence. It must be noted that after having seen a dramatic decline in VL in the 1950s and 1960s, India faced a resurgence from just a small area of North Bihar, emphasizing the significance of small pockets of continued transmission.
More recently, an emergence of pediatric VL was observed in J&K, wherein the first pediatric case was reported in 2009, followed by three cases in 2023, all of whom reported no visit to areas outside their native place. The occurrence of VL in this age group is a strong indicator of established Indigenous transmission. Notably, no cases of pediatric VL were reported from Himachal Pradesh, except for one case in 1984. On the other hand, Uttarakhand, which is relatively more endemic, had pediatric cases reported throughout the publications included in the study. It was suggested previously that the cases reported from Himachal Pradesh were likely due to migrating laborers from endemic regions of India to the hydroelectric power projects, construction of townships, and deforestation activities.14 However, we did not find exposure to endemic areas as a risk factor for VL, as most of the cases were natives who never visited any endemic area. Thus, the emergence of pediatric VL in some areas and continued cases in others strongly indicate an ongoing local transmission of VL.
The presence of a substantial vector population is required for establishment of the transmission cycle of VL. Various studies in our analysis reported vector surveillance, and some focused on the presence of the parasite in sand flies. Lata et al.15 were successful in amplifying the DNA of L. donovani from 7.7% of the sand flies collected from Himachal Pradesh. Interestingly, the phylogenetic analyses of L. donovani sequences obtained from sand flies were 97% similar to those obtained from CL cases in the region. In another report from Himachal Pradesh, on sequence analysis of 44 ITS1 and 6-phosphogluconate dehydrogenase sequences, the CL-causing L. donovani was found to have considerable heterogeneity from the VL-causing L. donovani from northeast regions of India. The isolates were more similar to the CL-causing L. donovani from Sri Lanka and Kerela. The authors reported the existence of L. donovani variants causing CL cases in Himachal Pradesh and proposed the possibility of genetic hybrids.16 Recent whole-genome sequencing analysis of a single L. donovani isolate from a case of CL in Himachal Pradesh demonstrated that the atypical phenotype is likely to be an intraspecies hybrid derived from extensive genomic hybridization between two independent L. donovani parents from the “Yeti” ISC1 divergent clade from the neighboring country of Nepal.17 The putative emergence of this novel strain of L. donovani may have serious implications for the control of both VL and CL in India and its neighboring countries. These data, along with the finding that the majority of the cases in our analysis were indigenous, points toward established patent sand fly vectors in this region. As sand flies are more suited to warmer tropical conditions,18 their phenology (i.e., biological activities such as migration, egg laying, and hibernation) is likely affected by temperature changes.8 The Himalayas have undergone warming since 1970, experiencing a warming rate of 0.2°C per decade,19 and the constant rise in temperatures may have led to the expansion of the sand fly distribution, upstream along the Ganges and the tributaries of other several rivers in the region.
Our analysis prompts many questions for future research. The occurrence of VL in children in the Poonch district of J&K needs intensive investigation. Studies are needed on sand fly vectors to understand their impact on VL transmission, the dynamics of the host-vector interface, and the effect of climate on vector distribution. Are the human cases of CL, VL, or PKDL the sole reservoirs of L. donovani in this region, or is there a role of canines or ungulates? Are there any other animal reservoirs for CL, such as rodents? What is the role played by mobile and migratory populations on VL in this region? How genetically similar are the VL-causing L. donovani isolates from this region to those from other endemic states of India and to the isolates from CL patients in this region? If the L. donovani strains causing VL and CL are phylogenetically linked, what causes the parasite to switch its preference from skin to the viscera, or does the host immunity or climate play a role in this phenomenon? What is the role of the hybrid strain of L. donovani in this region on VL? An investigation into these queries will improve our understanding of VL in the sub-Himalayas and aid in its control and elimination.
There are some limitations in our systematic review. We included the published reports of VL from the sub-Himalayan regions of India, which may have caused publication bias, as only a small proportion of the cases were reported in scientific journals. Thus, the numbers in our analysis may not be truly representative of the VL burden in the region. Moreover, only those cases who had no travel history tend to be reported; thus, the role of migratory populations may not be clearly reflected in the publications. Also, most of the published studies from this period did not specify the exact year of the cases, which limited the precision of the temporal analysis. Lastly, we excluded studies from other sub-Himalayan regions outside India, such as those from the neighboring country of Pakistan, Nepal, and Bhutan, which also suffer a substantial burden of VL and face similar challenges of difficult terrain, poor healthcare infrastructure, and limited resources. The situation in these areas is reported in other studies.20,21 The sand flies are likely to traverse the Himalayan range from one region to another and continue to transmit the disease. Envisioning the near future, when the VL elimination program enters the maintenance phase, it may be a prudent step to initiate joint efforts in India, Pakistan, and Nepal to eliminate VL from the sub-Himalayan regions and to prevent resurgence of the disease from unexpected quarters.
CONCLUSION
In conclusion, our analysis corroborates the existence of persistent foci of VL in the sub-Himalayan regions of India. The emergence of VL cases in the pediatric population in J&K strongly indicates that there is an ongoing transmission cycle of VL in the region. Although it is mandatory for all states of India to report VL cases to the National Vector Borne Disease Control Program of India, the mechanisms of surveillance, case diagnosis, and treatment are difficult to establish in mountainous terrains and are not as robust as those in endemic states. It is likely that a much higher number of cases remains undiagnosed, untreated, and unreported. Thus, the hilly states of India also require an elaborate surveillance program for VL control and elimination.17 The goal of VL elimination in India cannot be truly achieved unless the epidemiology of VL outside the endemic states is completely understood.
The VL elimination program is supported by the strong political commitment of the Indian government, along with the uninterrupted aid of the WHO and other international bodies. With the right focus and commitment, it will not be difficult for the government to allocate the necessary resources to these geographically challenging mountainous regions to successfully eliminate this dreadful disease.
Supplemental Materials
ACKNOWLEDGMENT
The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.
Note: Supplemental material appears at www.ajtmh.org.
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