Epidemiology of Post-Kala-azar Dermal Leishmaniasis.

Post-kala-azar dermal leishmaniasis (PKDL) is a cutaneous sequel of visceral leishmaniasis (VL) or kala-azar and has become an entity of epidemiological significance by virtue of its ability to maintain the disease in circulation during inter-epidemic periods. PKDL has been identified as one of the epidemiological marker of "kala-azar elimination programme." Data obtained in 2018 showed PKDL distribution primarily concentrated in 6 countries, which includes India, Sudan, south Sudan, Bangladesh, Ethiopia, and Nepal in decreasing order of case-burden. In India, PKDL cases are mainly found in 54 districts, of which 33 are in Bihar, 11 in West Bengal, 4 in Jharkhand, and 6 in Uttar Pradesh. In West Bengal the districts reporting cases of PKDL cases include Darjeeling, Uttar Dinajpur, Dakshin Dinajpur, Malda, and Murshidabad. The vulnerability on the young age is documented in various studies. The studies also highlights a male predominance of the disease but recent active surveillance suggested that macular form of PKDL shows female-predominance. It is recommended that along with passive case detection, active survey helps in early identification of cases, thus reducing disease transmission in the community. The Accelerated plan for Kala-azar elimination in 2017 introduced by Government of India with the goal to eliminate Kala-azar as a public health problem, targets to reduceing annual incidence <1/10,000. Leishmania donovani is the established causative agent, but others like L. tropica or L. infantum may occasionally lead to the disease, especially with HIV-co-infection. Dermal tropism of the parasite has been attributed to overexpression of parasite surface receptors (like gp 63, gp46). Various host factors are also identified to contribute to the development of the disease, including high pretreatment IL 10 and parasite level, inadequate dose and duration of treatment, malnutrition, immuno-suppression, decreased interferon-gamma receptor 1 gene, etc. PKDL is mostly concentrated in the plains below an altitude of 600 mts which is attributed to the environment conducive for the vector sand fly (Phlebotumus). Risk factors are also linked to the habitat of the sand fly. Keeping these things in mind "Integrated vector control" is adopted under National vector borne disease control programme as one of the strategies to bring down the disease burden. Copyright:

Introduction

About a century ago, in 1922 an article published in Indian Medical Gazette by Dr. U. N. Brahmachari[1] brought into focus a hitherto unknown form of cutaneous leishmaniais. It was identified as a novel type of dermatological manifestation and the probable missing link between visceral and cutaneous leishmaniasis. Later on, others also started reporting similar cases from various parts of India[234] and globe[56] and thus post kala-azar dermal leishmaniasis (PKDL) came to fore and established its imprint in the natural history of leishmaniasis over the following decades.

Leishmaniasis is a group of diseases caused by protozoa Leishmania. More than 20 species of it may be implicated for disease causation. For human to be affected it needs the female phlebotomine sandflies to transmit the disease from affected individuals after an extrinsic incubation period of 6–9 days.[7] The disease manifests mainly in three forms; cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), (also known as kala-azar), and mucocutaneous leishmaniasis (MCL).[8] The most common form is CL, VL being the most severe form and MCL the most disabling form of the disease.[9] PKDL is a cutaneous sequel of VL or kala-azar and appears as macular, papular, or nodular lesions affecting the face, upper arms, trunks, and other parts of the body. This article will deal with PKDL and its related details of VL.

Epidemiological Significance

PKDL is a non-fatal manifestation of leishmaniasis which helps to maintain the disease in circulation during inter-epidemic periods. An interesting study report[10] in 1992 published from School of Tropical Medicine, Calcutta in WHO bulletin, identified the potential threat of PKDL for elimination of leishmaniasis in the region. After being virtually nonexistent in the region for almost 2–3 decades, resurgence was noted around 1980 as an outbreak in a locality of West Bengal. This could not be traced to population movement from endemic areas. However, there was a case with history of kala-azar about 20 years back and he was suffering from PKDL for last 3 years. This subject was recruited for entomological investigation using sandflies. Evidence showed that vectors acquired infectivity potential from the PKDL case and this case probably triggered the outbreak in the locality.[10]

Similar observations were made in Sudan in 1990, when PKDL lesion was identified to harbor the parasite and has the potential to transmit the infection even in the absence of VL in the community.[11] Thus, PKDL was considered to determine the epidemiological behavior of kala-azar in certain geographic foci.[11] It was also observed that absence of kala-azar in few, made the diagnosis delayed (misdiagnosed and treated as lepromatous leprosy) and persistence of disease for up to 10 years in the population makes PKDL an important source of transmission.[12]

Spread

Leishmaniasis has been reported from more than 100 countries across the globe. There are three eco-epidemiological hotspots identified for VL, notably east Africa (Ethiopia, Kenya, Somalia, South Sudan, Sudan, and Uganda) contributing to 45% of global cases, Indian subcontinent (Bangladesh, India, and Nepal) with 28% and Brazil with 20%.[13] However, Brazil, Ethiopia, India, South Sudan, and Sudan are the countries harboring more than 83% of all cases of VL and the figure rises to 90% if Bangladesh, China, Kenya, Nepal, and Somalia are included.[13] In Indian sub-continent, VL was found to be endemic in 52 districts of Bihar, West Bengal, Uttar Pradesh, and Jharkhand, 45 districts in Bangladesh, 12 districts in Nepal.[14]

PKDL is further restricted in its distribution and mostly seen in south eastern Asian countries like India, Bangladesh,[15] Nepal[16] as well as in Sudan and adjoining African nations.[1718] Cases have been reported from Iran,[19] Brazil,[20] China,[21] and Japan[22] albeit with much less frequency. Data obtained in 2018 showed PKDL distribution primarily concentrated in 6 countries, India contributing 75%, Sudan 9%, South Sudan 8%, Bangladesh 7%, Ethiopia 1%, and Nepal less than 1%.[13]

In India, PKDL cases are mainly found in 54 districts, of which 33 are in Bihar, 11 in West Bengal, 4 in Jharkhand, and 6 in Uttar Pradesh [Figure 1]. In West Bengal, the districts reporting PKDL cases include, Darjeeling, Uttar Dinajpur, Dakshin Dinajpur, Malda, and Murshidabad.[23]

Figure 1

Schematic Spot Map of PKDL cases in Indian Subcontinent: 2018

Magnitude

The exact disease burden is not known but the data from different studies in different geographical regions help us to understand the magnitude of the disease. Since the time WHO has identified PKDL as an additional epidemiological marker to assess the kala-azar elimination programme,[13] the focus on PKDL has increased.

VL was known in Indian subcontinent for a long time since 1834. Drastic reduction in cases owes its success to the introduction of DDT through National Malaria Eradication Programme; the VL cases disappeared. In 1960s, with withdrawal of extensive DDT spray, VL cases started reemerging. Outbreaks occurred (100,000 cases in 1977 and 40,000 in 1978), and since then cases are routinely being reported from many states.[24] A recent study conducted in Nepal and India, followed up 9,024 sero-negative individuals for 30 months. It reported VL incidence 4.65/1000 person-year after 1 year follow-up and as 2.80/1,000 person-year after 30 month follow-up. Asymptomatic sero-conversion was recorded as 41.5/1,000 person-year after 1 year and 31.56/1,000 person-year after 30 month follow-up period.[25]

PKDL occurs in an estimated 5–-10% of patients of VL and within 5 years of disease onset.[10] The data regarding the point prevalence varies widely with 4.8/100 population in Africa and 4.8/1000 in Asia.[26] It often remains undetected and untreated. In an early report from Varanasi, India in 1987 noted a prevalence of 48.2/10,000 population,[27] but was later criticized for including PKDL-like lesions and was suggested that the prevalence would drop to 1.8/10,000 if confirmed cases were only included.[28] A survey in Muzaffarpur district in the endemic state of Bihar in 2010 indicated PKDL prevalence of 4.4/10,000 population if confirmed cases were included and go upto 7.8 if probable cases were included too.[28] From the same region of Muzaffarpur, the prevalence was found to have declined to 1.1/10,000 population in 2017.[29] The decline was attributed to greater time lapse between the peak of VL-epidemic in that region, which occurred in 2007–2008.

In India, a total of 52,034 VL cases are reported from 10 states of India from 2013 till June 2020. But Bihar (77.39% of all VL cases) and adjacent Jharkhand (16.79%) contribute to 9 out of 10 reported cases with another 4.55% from West Bengal. During the same period, total 7,535 cases of PKDL have been reported. Only four states contribute to the PKDL problem at present. Maximum cases are reported from Jharkhand (44.3%), followed by Bihar (39.1%), West Bengal (14.8%), and Uttar Pradesh (1.7%). Traditionally for over a century Bihar, Jharkhand, and West Bengal have been known as kala-azar endemic area and probably that explains the predilection of PKDL cases in this region.[2330] The trend of VL and PKDL is represented in Figure 2 and Table 1.[30]

Figure 2

Comparison of trends of reported VL & PKDL cases in India (2013-2020 June)

Table 1

Distribution of VL & PKDL cases from 2013 to 2020 (till June) in four endemic states of India

States	Disease entities	2013	2014	2015	2016	2017	2018	2019	2020 (Till June)
Bihar	PKDL	122	119	247	542	593	731	439	154
	VL	10730	7615	6517	4773	4127	3423	2416	666
JH	PKDL	304	81	153	873	1211	361	281	76
	VL	2515	937	1262	1185	1358	752	539	189
WB	PKDL	73	221	255	240	166	87	51	24
	VL	595	668	576	179	156	95	87	13
UP	PKDL	0	0	0	2	12	66	50	1
	VL	11	11	131	107	115	110	97	26

In the state of West Bengal, the trend is the same with Districts of Malda, Dakshin, and Uttar Dinajpur and Darjeeling being worst hit. The district-wise position of West Bengal from 2013-2016 is depicted in Figure 3a–d.[31]

Figure 3

(a-d) District wise VL and PKDL cases in State of West Bengal from 2013-2016. Note: BIR Birbhum; MSD Murshidabad; UDP Uttar Dinajpur; DDP Dakshin Dinajpur; DRJ Darjeeling; MLD Malda

A study[15] from the neighboring country, Bangladesh in 2009 reported that over last few years, there has been gradual decline in VL cases, however number of PKDL cases were on the rise. A study from Bangladesh found the incidence of PKDL rose from 1 case per 10,000 person-years in 2002–2004 to 21 cases per 10,000 person-years in 2007.[32] In Fulberia, one of the high endemic village in Mymensingh district, point prevalence of PKDL was found to be 3.8/1,000 population in 2007.[33] In the following year a census was performed in the Mymensingh District of Bangladesh and the prevalence of probable PKDL was noted to be 6.2/10,000 population.[34] In another country of Indian subcontinent, Nepal, an extensive survey was undertaken in 2010 in districts having high incidence of VL (2.0–4.0 per 10,000 population year in 2008/2007).[35] The study traced 680 of 742 VL affected patients of the region and found 16 (2.4%) suffered from PKDL; and estimated a risk of PKDL after VL to be 1.4% within 2 years and 3.8% within 8 years of suffering from VL.[35] A similar study conducted in eastern Sudan in 2011, which surveyed 95,609 population and noted that 11,943 (11.5%) had suffered VL and 260 (27.2/10,000 population) developed PKDL within one year of onset of VL.[36]

WHO has categorized countries according to the rate of occurrence of PKDL after suffering from VL into; PKDL rates ≤5% (e.g., Nepal and Kenya), 6–10% (e.g., India and Ethiopia), 11–20% (e.g., Bangladesh), and >20% (e.g., Sudan and South Sudan).[18] The global data on disease burden published very recently by WHO in 2020 documented 7,767 PKDL cases all over the world between 2014 and 18, of which 89% is reported from Indian subcontinent (south-east Asian region) followed by African region (6%) and Eastern Mediterranean region (5%).[13] The data showed almost 2- to 3-fold increase in PKDL from 2014 to 2018.

Age and Sex Distribution

The vulnerability of the young age was brought to attention from a study in Bihar which noted that 8 of 9 cases of PKDL suffered their initial attack of VL when they were less than 13 years of age.[28] In West Bengal, an active surveillance[37] noted the median age of patients to be 23 years (IQR, 16–31.5). Similar survey in Bangladesh[34] found the median age 21.5 years (IQR, 10.7–29.0) and in Nepal[35] it was found to be 28 years (IQR 15–40). In Sudan, the mean age was found to be lower (9.9 ± 5.4 years) and what was interesting was that those with severe disease had significantly (P < 0.001) lower age than those with less severe disease (4.6 ± 3.9 years in grade 3, 6.6 ± 5.3 years in grade 2, 7.8 ± 5.5 years in grade 1).[38]

Regarding the gender bias, it was noted that it is a male predominant disease with studies from Bihar, India,[28] Bangladesh,[34] Nepal,[35] Sudan,[38] all were skewed slightly toward male gender. In an interesting study in West Bengal, India[37] it was noted that the male predominance noted in institution based study (M:F ratio 3.5:1) was lost in active surveillance (M:F ratio 1:1.1), which was explained by the lower healthcare seeking behavior of female because of asymptomatic nature of the disease. It was further noted that with active surveillance, female predominance was noted with macular lesions (M:F ratio 1:1.9) but not with polymorphic lesions (M:F ratio 1.1:1).

Case finding in PKDL: Passive vs. Active Surveillance

Since PKDL cases act as reservoir of infection, early identification (and treatment) of PKDL cases is an integral component of leishmaniasis control programs. Both passive and active methods of case detection are recommended by authorities as PKDL, at least initially, does not cause significant morbidity and hence, all patients may not seek treatment. In passive case detection, patients seek treatment for their illness and treating physician notifies the epidemiological surveillance team. Such a method results in underestimation of the disease burden. Though data for PKDL under-reporting is not established, but for VL actual disease burden has been estimated to be 3.7–8 times higher than the cases recognized by passive case detection.[39] The under-reporting factor was calculated to be 8.13 with only 12.3% cases reported officially.[40] The authors attributed the under-reporting of VL due to the treatment offered for free by the NGOs and those cases were not picked-up in governmental agencies. This particular problem can be taken care of by active case detection. In active case detection, health workers screen the community using case definitions and epidemiological risk factors (endemic area, family history, etc.) and refer suspected cases to health centers where the diagnosis can be confirmed by appropriate investigations. Active case detection helps in early identification of cases, thus reducing disease transmission in the community. Study conducted in Bihar, India noted that active surveillance for VL cases and to treat them is a priority in VL elimination programme but failed to prove the role of PKDL or asymptomatic infection.[41] For patients, it offers the opportunity of early treatment and high chances of clinical benefits. Various strategies for active case detection include house-to-house searches, arranging camps, searching the neighborhood of index case, etc.[39] Also, active case detection helps us in getting a truer epidemiological data.[37] For example, active surveillance tells about the female predominance (M:F ratio 1:1.1) with macular lesion being more common (macular:polymorphic ratio 122:80) against passive surveillance which noted M:F ratio 3.5:1 and macular:polymorphic ratio 23:77.[37] This reflects the lack of health-care seeking behavior among female and those with only hypopigmented macules. Thus active surveillance can bring them under the umbrella of treatment who are reluctant to seek healthcare actively.

Surveillance and Response

Surveillance is the key to success for PKDL identification and VL elimination. Presently both passive and active surveillance using camp approach and snowballing is promoted. The disease is typically underreported, hence active case search plays important role in finding out hidden pockets with active cases.

In addition to history of past VL infection with clinical suspicion, the cases are examined with rk39 rapid test kit, slit skin smear for microscopy and biopsy for histopathology. Species specific PCR may be a useful adjunct for agent identification.

Government of India has come up with an Accelerated Plan for kala-azar Elimination in 2017[23] and management of PKDL is considered to be an integral part of it. The goal has been set to eliminate kala-azar as a public health problem, targeting to reduce annual incidence <1/10,000 at block level. Adopted strategy includes the following:[42]

Early case detection and complete case management

Integrated vector management and vector surveillance

Supervision, monitoring, surveillance, and evaluation

Strengthening capacity of human resource in health

Advocacy, communication, and social mobilization for behavioral impact and intersectoral convergence.

Operational definition for diagnosing PKDL has been laid down for the field level workers.[23] Any patient from an area endemic for kala-azar with multiple hypopigmented macules, papules, or plaques or nodules without any loss of sensitivity and showing positive reaction with rk39 kit is termed as probable PKDL case. Test kit rk39 is an immunochromatographic assay for qualitative detection of antibodies to L. donovani in human serum. The kit is 100% sensitive and 97% specific; gives result in 10 min. If no control line appears and it is considered invalid, a new test strip to be used with fresh blood sample. In HIV-infected individuals, negative test results do not rule out infection. However, the test fails to distinguish between new and relapse cases, hence interpretation of result should be done using appropriate clinical notes.[23]

The cases can be confirmed if parasites can be demonstrated or PCR is positive for slit skin smear/biopsy specimen.

In this part of the country, kala-azar endemic districts are also having substantial leprosy burden and one may lead to diagnostic dilemma for the other. Hence leveraging the ongoing leprosy programme, PKDL detection has been embedded with leprosy case search.

Counseling regarding compliance is essential during treatment. Compliance may be compromised due to long drawn course and adverse drug reactions (ADR). Hence, linkage with pharmacovigilence units has been integrated into the program to monitor ADR.[23] Relapse is more among those with higher pretreatment parasite load or suboptimal treatment of VL in the past.[43] Even those who complete the course, relapse is not uncommon. A study documents about 10-20% relapse in miltefosine-treated PKDL patients within 12 months of follow-up.[44]

Epidemiological Triad

Like every infectious disease, PKDL is also influenced by the agent, host, and environmental factors. The host-factor contributed by the immunology will be highlighted in details in other section of the symposium and will not be discussed in details in this article.

Agent factor

Leishmania donovani was established as the causative agent since its first description by Dr Brahmachari by examining the smear from the skin lesion[1] and later was established by animal studies too.[4] In almost all PKDL cases, L. donovani is the causative agent, but others like L. tropica or L. infantum especially with HIV-coinfection may occasionally lead to the disease too.[45] The isoenzyme characterization from Bangladesh further established that the causative agent match with WHO recommended reference strain of L. donovani (sensu stricto)-MHOM/IN/80/DD8 zymodeme LON41 and were clearly distinguishable from the profiles of L. infantum, L. major, and L. tropica.[46] From Sudan, four zymodemes have been isolated from PKDL patients (belonging to L donovani, L infantum, L archibaldi) but no association could be found between the parasite subspecies and the clinical manifestation.[4547] The dermal tropism of parasite have been explored to explain the persistence of parasite in the skin in spite of cure from VL. In this respect it was found that parasite gene overexpression of surface receptor gp63 and gp46 (promastigote surface antigen A2) is significantly associated with PKDL.[48] In addition, virulence factor A2 of L. donovani which protects against host-defence mechanism has been identified and upregulation of A2 gene has been linked to parasite survival.[49]

Host factors

In south-east Asia, PKDL does not have any animal reservoir and transmission is supposed to be anthroponotic, either cases of VL or PKDL acting as the source.[45] The disease in its natural course passes through vertebrate hosts (amastigote form-LD body) and insects (promastigote-flagellated form). Incubation period for VL to develop after bite of vector is usually 1–4 months but may be extended upto 2 years. PKDL takes longer time to develop, ranging from 1 to 5 years. Extrinsic incubation period, time necessary for sand-fly to achieve infective potential after biting infected human beings, is 6–9 days.[42]

Transmission potential has been reported with blood transfusion or organ transplantation. On very few occasions, vertical transmission has also been recorded. From Germany, a 9-month-old baby was diagnosed with VL. The girl never went to anywhere in the endemic areas, though mother had a travel history to Spain. Mother was never symptomatic. Serological tests conducted for L. donovani was positive for mother, but culture or microscopy was negative. The baby ultimately recovered once treated with liposomal amphotericin-B.[5051]

The disease (VL) may affect any age including infancy. Usually those belonging to the lower socioeconomic strata are most vulnerable. Poverty, malnutrition, especially protein-energy-malnutrition, vitamin A, iron and zinc deficiency increase the risk. This is more common among migrants; working at development projects or agricultural fields, exposed to infected vectors in environment conducive for disease transmission. Disease more commonly affects those who are sleeping outside on the ground.[5253] The infected individuals usually have impaired cell-mediated immunity and recovery from VL may impart lasting immunity. But with recovery of immune system after VL, the chance of IRIS also increases and this immune response manifests itself as PKDL.[54] Re-emergence of VL in VL-free areas occurs periodically and is associated with diminishing herd immunity, the presence of untreated PKDL cases and changing environmental condition. Those residing in areas with clustering of infected individuals and young age, may be considered at higher risk.[535455]

Risk factors for PKDL are not well established. However, various factors have been identified from literature review and summarized below[3856575859606162]:

Before Treatment of VL: Detection of High IL-10 level in the skin and high C-reactive protein level in the blood; parasite strain; higher pre-treatment parasite level.[565758]

During treatment of VL: Treatment with inadequate dosage of drugs or inadequate duration of treatment; incomplete treatment or treatment with substandard drug.[385960]

Post VL treatment: Incomplete clearance of parasite; persistence of parasite as demonstrated by polymerase chain reaction (PCR) in lymph node aspirate after VL treatment leads to higher PKDL rates.[61]

Patient profile: Young age; immunosuppression (malnutrition, HIV coinfection, organ transplants, on immunosuppressive or immunomodulatory therapy); genetic factors [decreased function of the interferon-gamma receptor 1 gene (IFNGR1) and uniform low expression of IFN-γ].[62]

Environmental factor

PKDL is prevalent in areas where VL is also common. It is mostly concentrated in the plains below an altitude of 600 m. Its association with monsoon is known; however recently a shift has been noted in seasonality. Compared to earlier reports, recent study found abundance of sandfly vectors during March–April and again in August–September in the community. Vector control measures need to be aligned with this shift in seasonality. VL or PKDL is a problem typical for rural areas and endogenous cases are almost non-existent in urban community. Encroachment into natural habitat of vectors like during cultivation or development projects escalates the risk of human–vector interaction. Vectors breed in cracks and crevices in soil and adjacent areas. Presence of water bodies, alluvial soil, moist fallow area, weeds, grassland, nearby water body, marshy land, etc. facilitate sandfly survival and breeding. It has been found in animal sheds, chicken coop along with human dwellings. It prefers indoor temperature of 29°–32°C during peak season and 20°–24°C in lean season. Overcrowding, poor ventilation and organic matter inside local environment facilitate transmission. The female sandflies bite at night. About 70% prefer cattle and around 20% are anthrophilic in their biting preference.[5253]

Vectors and their Role in PKDL

Leishmaniasis is propagated through biological transmission; only known vector for VL or PKDL is sandfly. Earlier in 1950s, about 350 species of sandflies were identified[63] but recent studies indicate presence of more than 600 species of the insect in the earth.[64] They can be seen in varied climatic regions like arid areas of Africa, semi-arid terrains of Asia, or rainforest of Latin America. Lutzomyia longipalpis is a common vector for VL in Argentina, Bolivia, Brazil, and other Latin or central American countries, while Phlebotomus argentipes, orientalis, and martini are common in Asia and Africa.[65]

The insect is small, about 2.5 cm in length, prefers moist soil to breed. Sandfly eggs are initially white or light grey in color but often turn dark brown or black within a few hours of oviposition, depending on the species. Environmental factors like air temperature, rainfall, wind speed, relative humidity, soil moisture, temperature, pH, and organic carbon are found to be critical in determining oviposition of sand flies.[66] The eggs are banana shaped and nearly microscopic in size (0.3–0.5 mm in length). Time-to-hatch is highly temperature dependent but averages 6–17 days. After hatching, the larvae burrow down few centimeters below the surface; they feed on decaying organic matters. Larval stage continues for about 10 days, followed by another 7–10 days of pupal stage. Eggs and early stages of larvae are almost impossible to find in their natural habitat, but it is proven that they can withstand hostile environment or water logging for a considerable period of time. Mostly cattle sheds, within few meters of human dwellings, dark, hot humid environment is the classical breeding place of sandflies. The adult ones start feeding and mating within 1–2 days of transformation from pupal stage. They are usually poor fliers, stay within 25 m radius, usually stays indoors. However, recent studies showed their presence over palm trees and banana plantation, outside the dwellings in the outdoors, among vegetation. This observation may have long lasting implication on vector control strategy.[636566]

The several hundred species of sandfly can be grouped into five genera, namely Phlebotomus, Sergentomyia, Lutzomyia, Brumptomyia, and Warileya. Out of those, about 30 species have been recognized as medically important. They harbor or transmit leishmania infection. It is worth mentioning that leishmania parasites can also be of 30 different varieties, of which around 10 are important as medical or veterinary disease agent and P. argentipes is the only known vector of VL or PKDL in India.[67]

Review of decades of research into the biological transmission of the disease, scientists laid down following criteria to attribute the sandfly species for propagation of leishmaniasis in the locality.[67]

The species must feed on humans and the reservoir host

Disease causing leishmania parasite must be repeatedly isolated from wild-caught sandflies

Sandfly must occur in the geographical location where the disease occurs

The sandfly must support the complete development of the parasite

The sandfly must be able to transmit the parasite to a susceptible host while taking a blood meal.

The set criteria are quite rigorous and mostly not retrievable from a single study. Thus, multi-pronged comprehensive review of available research evidence might be a better alternative to update our knowledge base.

The risk factors associated with vector dynamics are mostly dependent on the habitat of the vector and are summarized below:[40]

Indian Subcontinent: Phlebotomus argentipes with high density in cattle shed

Transmission: Anthropnotic

Risk factor for transmission: Sleeping outside or on the ground, livestock are kept close to human dwellings, houses with mud walls and earthen floors, not using bednets

North Sudan and Ethiopia: Phlebotomus orientalis with high density around Acacia and Balanites trees

Transmission: Anthropnotic and Zoonotic

Risk factor for transmission: Presence of cattle, sleeping outside under acacia trees and living in grassy houses

South Sudan, Ethiopia, Kenya: Phlebotomus martini and Phlebotomus celiae with presence around termite mound (Macrotermes species)

Transmission: Anthropnotic

Risk factor for transmission: Presence of house near termite mound

Preventing Transmission

Along with early detection and case management of PKDL, integrated vector control is obligatory part in the program.[23] Integrated vector control was adopted under national vector borne disease control program as one of the strategies to bring down the disease burden. Indoor residual spraying is mainstay of vector control. DDT (50%) may be used at 1 g/m2 if no other alternative is available. The duration of effective action with permethrin is around 4 months and that with DDT is >6 months. However, recent studies from Bihar indicate widespread and ever increasing trend of DDT resistance among sandflies coupled with poor quality of IRS with DDT resulting in reduced effective action.[68] Though frequent DDT resistance has been documented in case of malaria vectors, it is sporadic and less critical in case of sandflies. Though resistance was noted as early as 1979 among P. papatasi but not among P.argentipes.[69] But of late, use of DDT has been banned in Nepal and Bangladesh. Synthetic pyrethroids like deltamethrin, alpha-cypermethrin are replacing DDT now-a-days. Review of available reports from 1978 to 2014 indicated increasing resistance against DDT; few reports decreased susceptibility against malathion or even deltamethrin.[68] Global convention in 2006 suggested replacement of DDT for IRS with other synthetic pyrethroids. Presently synthetic pyrethroids like alpha-cypermethrin (ACyp) 5% WP is applied to the walls of households/animal shelters at 0.025 g/m2.[68]

Another recent study from India showed that out of various interventions, long lasting insecticide treated bednets coupled with chlorpyrifos spray outside in the potential breeding places yielded best result for 22 months compared to other measures including indoor residual spraying.[70]

On the other hand, a report published in 2012 from a study carried out in Sudan showed that species P. papatasi was sensitive to DDT and permethrine but found resistant to malathione and propoxure in some of the study sites. The authors felt it might be related to the antimalarial measures taken for last five decades that has resulted in this resistance pattern.[71]

Kala-azar and PKDL Elimination Response of the Government and Other Stake Holders

The Kala-azar elimination programme evolved in India with series of changes in the planning and implementation. [Table 2][14232472737475767778] In India, Kala-azar control measures started in 1977–80 but were discontinued due to low case load. It again started to gain shape in 1990–91 after a rapid resurgence of cases but only after Government of India's National health policy of 2002 with the goal to eliminate kala-azar by 2010 (which was later revised to 2015), the kala-azar elimination programme gained pace.[77] In India, kala-azar elimination came under the ambit of “National to Vector Borne Disease Control Programme” in 2004–05. In 2005, a memorandum of understanding (MoU) was signed between the Governments of Bangladesh, India, and Nepal and aimed at reduction of the burden of VL from about 30 cases per 10,000 to less than 1 per 10,000 in each of the three countries by 2015.[79] In 2014, this MoU was extended to Bhutan and Thailand and the deadline was extended to 2017.[80] In the same year 2014, WHO formulated the “Regional Strategic Framework” for elimination of kala-azar from the South-East Asia Region (2011-2015)[81] and only this time PKDL was identified as the reservoir and elimination strategy included PKDL as well. In response to WHO's effort in eliminating PKDL, the pharmaceutical companies, donors, endemic countries, and non-government organizations came forward to sustain, expand, and extend drug access programme to ensure the necessary supply of drugs and other interventions to help control of kala-azar by 2020 (London declaration on Neglected Tropical Diseases).[82] In India, the National kala-azar elimination programme formulated the “accelerated plan for elimination of Kala-azar” in 2017 made special effort to trace PKDL in the community and formulated its treatment guidelines [Table 2].

Table 2

Evolution of Kala-Azar elimination programme in India

Period	Programme	Strategy	Outcome
<1947	No specific programme as such	Areas with high burden identified. Treatment through hospital-based case management. Clinical and laboratory findings were noted in detail.	Some pockets of UP, Bihar, Jharkhand and West Bengal were suffering from considerable case load and mortality. Research and documentation during the earlier days cleared mist; Recognized as a separate disease entity only in early part of twentieth century
1953-1958	National Malaria Control Programme	Insecticidal residual spray (IRS) with DDT; monitoring and surveillance of cases; and treatment of patients.	Huge success, Malaria cases came down drastically.
			VL control resulted as a secondary outcome
			VL cases were almost Nil from earlier reported 60,000[14] cases across the country
1958-1964	National Malaria Eradication Programme	Efforts were intensified for an overambitious target to eradicate malaria	Success stories continued, but gradually complacency seeped in.
			Malaria and VL cases were very few.
			DDT resistant malaria vectors were found; DDT spray gradually became less popular.
			Malaria resurgence noted.[72,73]
			However chronic cases of VL/PKDL were neglected and treatment of VL was haphazard and not standardised.
1970s	--	--	Huge number of 1,00,000 VL cases reported from India[73]
1977-80	Kala azar control measures	Earlier measures & stress on case management. In selected areas/states	Programme discontinued with apparently lower case load of about 13,000. However, PKDL were neglected once more. Though SAG resistance was noted, it was continued in the same dose Resurgence once more >2,50,000 cases
1990-91	Kala azar control measures	Earlier measures & stress on case management. In selected areas/states	Programme discontinued after 3 years, SAG resistance among 50% cases while PKDL was again neglected in the programme.[74]
2004-05	National Vector Borne Disease Control Programmae (NVBDCP)[24]	Kala azar elimination came under the ambit of comprehensive NVBDCP under the umbrella of NRHM.  Vector control through Residual insecticide spray  Early diagnosis & treatment through primary health care  Health education and community participation  Training of health personnel	Cases started to come down, from 77000 cases in 1992 it was 33,000 cases in 2008. Amphotericin B and miltefosine were included in the programme. Separate budget head fixed for kala-azar programme. Earlier allocation was through NMEP.[74,75]
2014	National Kala-azar Elimination Programme (NVBDCP)[24]	Target: To reduce the annual incidence of Kala-azar to less than one per 10,000 populations at block PHC level by the end of 2015. The Elimination strategy:  I. Early diagnosis & complete case management  II. Integrated Vector Management and Vector Surveillance  III. Supervision, monitoring, surveillance and evaluation  IV. Strengthening capacity of human resource in health  V. Advocacy, communication and social mobilization for behavioral impact and inter-sectoral convergence  VI. Programme management	With support from WHO and other agencies, NVBDCP designed a comprehensive plan. In close liaison with neighbouring countries like Bangladesh, Nepal etc. planned for regional elimination through intelligence sharing.
2017	National Kala-azar Elimination Programme (NVBDCP)	Accelerated Plan for Elimination of Kala-azar 2017[23]  To intensify activities towards kala-azar elimination for remaining period of 2017.[76]  The deadline was later reset to 2020.[24]  For purpose of acceleration towards elimination and sustenance after elimination, endemic areas stratified into 4 categories  Special effort to be made to trace PKDL in the community  Guidelines of treatment for kala-azar and PKDL	This is the ongoing programme. By end of 2016, 85% of blocks achieved the elimination target. This plan is meant to eliminate the disease from all the blocks within stipulated time frame and sustain it.[767778]

Conclusion

Though PKDL is not life threatening; beyond its importance in the macro-epidemiology of epidemic triggering potential, it disturbs the individual in its microcosm in very different way. It has led to many a case of marital disharmony, stigma and social backlash. Leishmaniasis and PKDL in general is closely associated with poor socioeconomic situation. Every subject harbors a story under their lesions; lack of awareness, diagnostic delay and psychological stress out of disfigurement, ostracize the PKDL victims. The women are as usual the worst hit in our sexist society with additional burden of affected fecundity. Case studies indicate persisting stigma among the vulnerable community; the need for comprehensive communication can never be undermined along with appropriate clinical case management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.