|Year : 2020 | Volume
| Issue : 2 | Page : 161-169
Changing clinico-epidemiology of post-kala-azar dermal leishmaniasis (PKDL) in India: Results of a survey in four endemic states
Suman Saurabh1, Pritam Roy2, Dhruv K Pandey3, Dipanjan Ray4, Shourabh Tarak5, Rajesh Pandey6, Dileep Kumar7, Sarosh Jamil8, Anand Paulraj9, Amarendra Kumar10, Siddhartha Dutta11
1 WHO, Muzaffarpur, currently AIIMS, Jodhpur, India
2 WHO, Kolkata, India
3 WHO, New Delhi, India
4 WHO, Maldah, India
5 WHO, Darjeeling, India
6 WHO, Patna, India
7 WHO, Purnea, India
8 WHO, Raipur, India
9 WHO, Dumka, India
10 WHO, Ranchi, India
11 WHO, Gorakhpur, India
|Date of Submission||23-Jul-2018|
|Date of Acceptance||29-Jan-2019|
|Date of Web Publication||14-Jul-2021|
Dr Suman Saurabh
Assistant Professor, Department of Community Medicine and Family Medicine, 2nd floor, Academic building, All India Institute of Medical Sciences (AIIMS), Jodhpur 342005
Source of Support: None, Conflict of Interest: None
Background & objectives: Detection and treatment of post-kala-azar dermal leishmaniasis (PKDL) cases is considered important for kala-azar elimination. The objective of our study was to find out the proportion of different forms of lesions, interruption of treatment and rate of treatment completion, cure rates of PKDL, risk factors for developing severe forms of PKDL and utilization of services offered by the kala-azar elimination program.
Methods: A cross-sectional survey of PKDL patients registered for treatment at all levels of care during 2015 and 2016 was done.
Results: 576 PKDL patients who had started treatment in 2015 and 2016 were studied. Three-fourths of all patients were found to be clinically cured after a year of follow-up. Around 90% lesions were of macular type. Interruption of treatment was observed in one-fourth of PKDL patients. Median duration between kala-azar treatment and development of PKDL was 4.5 years. Around 79% patients had past history of kala-azar treatment. Discontinuation of treatment during earlier kala-azar episode was significantly associated with the development of papular and nodular forms of lesion. 43% of patients had received the incentive of INR 2000 after completion of treatment. Around three-fourths women in the reproductive age group were found not to use any contraceptive method during PKDL treatment.
Interpretation & conclusion: PKDL treatment interruption should be reduced through ensuring drug supply and timely retrieval of patients. Directly observed treatment should be implemented and combination regimen should be explored to improve final cure rate. Delivery of financial incentive to PKDL patients and counselling and contraception to women of reproductive age group should be improved.
Keywords: India; Miltefosine; post-kala-azar dermal leishmaniasis; treatment interruption; Visceral Leishmaniasis
|How to cite this article:|
Saurabh S, Roy P, Pandey DK, Ray D, Tarak S, Pandey R, Kumar D, Jamil S, Paulraj A, Kumar A, Dutta S. Changing clinico-epidemiology of post-kala-azar dermal leishmaniasis (PKDL) in India: Results of a survey in four endemic states. J Vector Borne Dis 2020;57:161-9
|How to cite this URL:|
Saurabh S, Roy P, Pandey DK, Ray D, Tarak S, Pandey R, Kumar D, Jamil S, Paulraj A, Kumar A, Dutta S. Changing clinico-epidemiology of post-kala-azar dermal leishmaniasis (PKDL) in India: Results of a survey in four endemic states. J Vector Borne Dis [serial online] 2020 [cited 2021 Aug 5];57:161-9. Available from: https://www.jvbd.org/text.asp?2020/57/2/161/310875
| Introduction|| |
Post-kala-azar Dermal Leishmaniasis (PKDL) is an immunologically mediated skin lesion, which is a sequela of visceral leishmaniasis (kala-azar), appearing mostly after apparent successful treatment of kala-azar. It is characterized by macular, maculopapular, and nodular lesions starting from face and spreading to chest, arms and legs depending on the severity. These patients are usually otherwise asymptomatic and do not seek treatment which delays diagnosis of PKDL.
Patients with PKDL are considered a reservoir of Leishmania donovani during the inter-epidemic period. Therefore, in order to sustain elimination of kala-azar, active surveillance of PKDL is needed. There has been a continuous decline in annual kala-azar cases from 2007 to 2020. On the other hand, number of PKDL cases being reported were found to be rising from 2012-2017 with subsequent decline [Figure 1]. This could be attributed mainly to improvement in awareness regarding PKDL among frontline health workers and physicians at the level of primary healthcare. Routine reporting of PKDL cases is required by the kala-azar elimination program under National Vector Borne Diseases Programme, India (NVBDCP). The asymptomatic nature of PKDL contributes to its persistence in the community due to delay in seeking diagnosis. A 12-week oral course of miltefosine is the recommended first-line treatment for PKDL in the programme. This prolonged treatment and related adverse events result in patients discontinuing treatment. Strong motivation to complete treatment and regular follow-up visits to report and manage the adverse events is required to achieve treatment completion. Thus, difficulty in diagnosis, delay of diagnosis and incomplete treatment of PKDL cases are the challenges faced by the programme.
Literature search done by us revealed that PKDL had been studied mostly in tertiary care settings in India. There is a paucity of studies focusing on PKDL in the community in India, which would have represented patients treated not only at tertiary level but also in primary and secondary health care settings. The main aim of this study was to collect current evidence regarding clinical epidemiology of PKDL. Our objective was to assess the proportion of papular and nodular forms of lesion, interruption of treatment and rate of treatment completion, cure rates of PKDL, risk factors for developing severe forms of PKDL and provision of services offered by the kala-azar elimination programme.
| Material & Methods|| |
A cross-sectional field survey was planned in the four kala-azar endemic states of India (Bihar, Jharkhand, West Bengal and Uttar Pradesh) during January 2017. PKDL patients are routinely being diagnosed and treated as per operational guidelines for kala-azar in India,. Probable PKDL is defined as “a patient from an area where visceral leishmaniasis is endemic with or without a previous history of visceral leishmaniasis who has a symmetrical macular, papular or nodular rash often starting on the face with further spread to other parts of the body without loss of sensation”. Up to January 2017, a confirmed case was being operationally defined as “a probable PKDL case with parasite infection confirmed by PCR or a slit-skin smear or biopsy”. Subsequently, decision was taken in the National PKDL Workshop held on 12 January 2017 to consider rk39 positivity as sufficient for confirmation of PKDL at the primary care level. At the time of the study the cases were a mix of both probable and confirmed PKDL cases depending on the diagnostic facility available at the point of care. Final clinical cure in PKDL was defined as complete disappearance of lesions at 12 months followup after treatment as per programme guidelines.
Sampling design and sampling strategy
Around 2286 PKDL patients were reported in the states of West Bengal, Bihar, Jharkhand and Uttar Pradesh during the years 2015 and 2016, which was considered the sampling frame. Sample size was calculated based on the estimated prevalence reported by earlier studies regarding two of the primary study objectives, 52% patients having lesions of papular and nodular type and 85% patients being finally cured by miltefosine. A two-tailed Z score of 1.96 corresponding to alpha value (probability of type 1 error) of 0.05 and absolute precision of 5% (d) was applied in the following formula along with prevalence obtained from previous studies (p).
After taking an additional margin of 20% patients, a sample size of 460 and 235 treated PKDL patients was obtained respectively for these objectives. The larger sample size of 460 treated PKDL patients was aimed for this study. Out of the 54 kala-azar endemic districts across Bihar, Jharkhand, Uttar Pradesh and West Bengal, 16 districts were selected purposively taking into account administrative convenience and possible yield of cases. We aimed to cover all the PKDL patients in the sampled districts.
A semi-structured questionnaire-cum-form was developed, and field tested in the four endemic states. Line lists of PKDL patients were obtained from the District Vector Borne Disease Control Officer. Patients were explained the purpose of the study and their anonymity was maintained. Persons collecting the data were experienced in using data collection formats for monitoring the Pulse Polio immunization programme and routine immunization campaigns. Training of the persons collecting data and field-level monitoring of data collection was mainly done by medical officers with the neglected tropical diseases department of World Health Organisation (WHO) India.
Informed consent was taken from individual adult participants and from legal guardian of those aged less than 18 years. The study was carried out in accordance with the Helsinki Declaration and as per the Indian Council of Medical Research (ICMR) Guidelines for Biomedical Research involving human participants.
Data entry and analysis
Data entry was done in Microsoft Excel and the entry was cross-checked. Data were analyzed with SPSS v20. Odds ratios with 95% confidence interval were derived separately with univariable analysis for the plausible risk factors for developing papular and nodular forms of lesions in PKDL. Next, those risk factors with p-value < 0.1 and age and gender were analyzed multivariably with logistic regression in order to address any confounding in the univariable analysis. A p-value less than 0.05 was considered significant.
Conflict of interest: None
| Results|| |
A total of 576 confirmed PKDL cases were studied against a targeted sample size of 460 cases. This was since all the eligible PKDL cases in the selected districts were contacted for inclusion in the study and no sub-sampling was done within the districts. Out of these, 496 had completed treatment at the time of study and were eligible for assessment of initial cure and payment of incentives [Table 1]. Also, only those 136 patients who had completed their treatment in 2015 were eligible for assessment of final cure. Three-fourths of these patients were found to have been finally cured [Table 2].
|Table 1: Description of PKDL cases studied (denominator is N=576 unless otherwise specified).|
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|Table 2: Treatment outcome, treatment interruption and services offered to PKDL patients (denominator N=576 patients for all percentages unless otherwise specified).|
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Among the studied patients, majority were males (54.9%). Mean age was 26.1 yr with a standard deviation of 14.4 yr. The median period between onset of symptoms and detection of PKDL was 3 months (interquartile range 1–8 months) with values ranging from 1 month to 15 yr. 91.5% patients reported macular lesions [Table 1]. Nearly three-fourths of cases were referred by ASHA (Accredited Social Health Activist) worker or were found by active case search in the field [Table 1].
Around one-fourth of all PKDL patients had interrupted their treatment. Median duration of interruption was 6 weeks (interquartile range 4–12 weeks) with most interruptions being longer than 4 weeks [Table 2]. Nearly half of the patients had experienced at least one adverse event during their treatment with vomiting being the most common event reported [Table 2].
History of kala-azar
Nearly 79% of the interviewed patients had a history of treatment of kala-azar. Median duration between kala-azar treatment and onset of PKDL was 4.5 yr (interquartile range 2–10 years). More than 60% of patients had developed PKDL by the time 5 yr had elapsed after their kala-azar treatment [Table 1]. Miltefosine had been the most common treatment of kala-azar for the studied patients (40%). Around 11% patients of patients who had history of kala-azar treatment had discontinued their kala-azar treatment in the middle (49 out of 454 patients). Interruption of kala-azar treatment was found to be associated with future development of nodular and papular forms of PKDL, individually and after adjusting for other potential confounders [Table 3] and [Table 4].
|Table 3: Risk factors for papular or nodular forms of PKDL as compared to macular forms (univariate analysis).|
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|Table 4: Results of multivariable logistic regression analysis for risk of development of papular or nodular lesions as compared to macular lesions while adjusting for age and gender.|
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Awareness and access to services
Around 70% of the patients were aware about the disease and treatment duration. Three-fourths of the PKDL patients had all rooms and animal shelters of their homes sprayed in 2016. Incentive was provided to only 42.9% of the PKDL patients who had completed their treatment. There was wide regional variation at 64.5, 30.3 and 9.6%, none of eligible patients were paid incentives respectively in West Bengal, Jharkhand, Bihar and Uttar Pradesh.
Information on pregnancy testing and contraception advice was not initially included in the survey tool and therefore could not be collected during the interview in the field. Out of the 174 women in the reproductive age range of 15–49 yr, 65 were telephonically interviewed regarding pregnancy test and contraception advice. Two women had adopted permanent method of contraception. Out of the remaining 63 women, more than three-fourths had neither been advised pregnancy test nor had the couple used any method of contraception as a protection against potential teratogenicity of miltefosine treatment [Figure 2].
|Figure 2: Pregnancy test and contraception advice to female PKDL patients in reproductive age group (N=63).|
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| Discussion|| |
The present study emerged to be a large community survey of post-kala-azar dermal leishmaniasis (PKDL) patients wherein all levels of care and all the four endemic states of India were represented. Majority of PKDL patients were male which had also been reported earlier,,,. Male predominance of PKDL was explained to be due to high levels of testosterone. However, a primarily greater incidence of kala-azar among males might be subsequently responsible for a greater proportion of PKDL patients being males. An age distribution of most PKDL patients being younger than 30 yr has also been observed by other studies in India,,.
Onset to diagnosis of PKDL
The median time found between appearance of lesions and diagnosis was 3 months, whereas it was 12 months to 30 months in studies done earlier,. This was a positive finding and could be explained by majority of cases being detected earlier through referral done by ASHA workers and through active case search. Early detection of PKDL cases is important for both the patient and the community as it lowers the chances of developing more severe and infective forms of the lesions and is also considered to reduce the chance of kala-azar transmission.
Distribution and type of lesions
In our study, PKDL lesions were distributed mainly over face, leg and arms which are the sites mainly exposed to sandfly bites. It matches the classical description of the PKDL lesions starting around the mouth and then spreading to other parts of the body depending on severity. Similar findings were observed in study done at a referral centre in Patna, Bihar, India.
Majority of the lesions found in our study were macular. The study done at Patna, Bihar found nearly 52% of lesions to be papular and nodular. In another study done in Bihar, 42% PKDL cases had only hypopigmented macular lesions, 25% cases had papulo-erythematous lesion and 33% cases had mixed lesions. A preponderance of macular lesions could be explained mainly due to greater representation of less severe PKDL cases diagnosed and treated at primary health centre and community health centre level as compared to the hospital-based studies done earlier. Since we didn’t directly observe the initial presentation of lesions, some severe lesions would have been recalled by patients as macular once they experienced improvement upon starting treatment. In the East African setting this finding is reversed with majority of lesions in Sudan found to be of mixed type with pre-ponderance of nodules - 15.9% macular, 36.3% papulo-nodular and 47.8% with macules and papulo-nodules.
Many studies have suggested role of PKDL in maintaining kala-azar transmission in community,, coinciding with an increase of post-kala-azar dermal leishmaniasis (PKDL). Macular lesions are much less infective to sandfly vectors as compared to papular and nodular lesions. Their abundance in the present study appears to support the emerging evidence in India that PKDL might not be as important in maintaining transmission in the community as compared to the kala-azar cases. Also, a recent longitudinal study in India found that transmission to members of households of PKDL patients was no different from the households of the rK39-sero-negative controls. Furthermore, PKDL has not been implicated in kala-azar outbreaks in previously non-endemic areas for around two decades. This has important implications in guiding the programme, especially regarding combining early diagnosis and treatment of both PKDL and kala-azar cases through sensitization of frontline health workers and quack informers, and integrating active case search of PKDL and kala-azar together.
History of kala-azar
In the present study, nearly four-fifths of patients had a history of kala-azar. Similar observations ranging between 73–90% were found in other studies,,,. The median duration between onset of PKDL and kala-azar in our study was 4.5 yr matching that of 2–7.5 yr reported by others in India,,. In the Indian sub-continent this time interval is much longer than the usual interval of six months among patients in East Africa,. Much variation in this time interval has been observed, ranging from 6 months to 32 yr or even more. Nearly 38% of PKDL patients in Bangladesh had manifestations within one year as compared to 34% being reported within two years in our study. Therefore, progression from kala-azar to PKDL was slower in our study as compared to that in Bangladesh.
In our study, most patients received miltefosine for their kala-azar episode while in the earlier study enrolling patients during 1999–2007, it was observed that PKDL had been treated for kala-azar with a full course of sodium stibogluconate (SSG) in nearly 73% of cases. This could be explained by the present study describing a recent cohort of kala-azar patients developing PKDL, especially after inclusion of miltefosine for kala-azar treatment in national programme in 2005. We found no particular kala-azar treatment regimen as a risk factor for developing severe forms of PKDL. In view of longer kala-azar treatments having been prone to treatment discontinuation, they could also be associated with development of PKDL and its more severe forms. Therefore, introduction of single dose Liposomal Amphotericin B as first line choice for kala-azar treatment has the potential to reduce the risk of PKDL by eliminating chance of treatment discontinuation altogether.
Treatment of PKDL
One-fourth of patients interrupting their PKDL treatment could be considered a cause of concern for the programme. Median duration of interruption of treatment was high at 6 weeks. We missed to explore the reason of interruption. Local reason analysis could reveal hurdles in drug supply or patients not taking the drug strips from the health facility on a timely basis. Further, lack of compliance in some patients on daily basis could also have affected final cure rate apart from reported interruptions.
Miltefosine has been reported to have cured 32 out of 33 patients in an exploratory study conducted in a hospital in Muzaffarpur, Bihar. Our study reported a final cure rate of 75% which more closely reflected effectiveness in programme setting, taking into account treatment discontinuation and non-compliance as well. Also, a recent hospital-based follow-up study reported decline in efficacy of monotherapy by oral miltefosine and reported an overall final cure rate of 85%. Cure rate in miltefosine used in dose of 100 mg per day was only 68.8% in this study. This raises concern regarding reduction in treatment efficacy over time either due to low compliance or increase of resistance,,. Erstwhile programme guidelines for kala-azar treatment with miltefosine had recommended directly observed therapy. This needs to be implemented for PKDL treatment also. As a first step, a move to directly observe or supervise at least one of the two daily doses of miltefosine treatment in PKDL patients could be done through incentivizing the frontline health workers. Studies should be done to assess day-to-day compliance of patients to miltefosine when the drug is available with patients, apart from the situation when treatment was discontinued due to unavailability of drug at the health centre or patient not visiting the health centre to take the drug. This could pave the way for introduction of reminder systems to improve compliance similar to other diseases.
With emerging concerns regarding treatment effectiveness and since the treatment duration is already long at 12 weeks, a combination regimen could also be explored to achieve better cure rates. This would protect the frontline drug from development of resistance due to monotherapy. However, a consequent increase in adverse events could also result in treatment discontinuation. Therefore, any change in treatment regimen must consider the various mutually interacting factors influencing the final cure rate [Figure 3].
|Figure 3: Pathways through which PKDL treatment regimen could influence patient’s final clinical cure.|
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Reported adverse event during current treatment showed predominance of gastrointestinal side effects which was similar to that of other studies,. The finding that nearly half the patients had one or more adverse events calls for strengthening Adverse Events reporting among PKDL patients. An initiative in this regard has been taken by Pharmacovigilance Programme of India to introduce adverse events reporting of kala-azar and PKDL patients in the endemic districts.
Payment of incentives and counselling of patients in reproductive age group
Government of India had introduced a wage loss compensation of INR 2000 to PKDL patients upon treatment completion which has further been revised to INR 4000 from financial year 2018-19 onwards. When properly advertised, this also incentivizes patients to report to the health centres and get treated early. Payment of this incentive was found inadequate and needs to be improved through periodic monitoring. Infrequent advice for contraception being given to women of reproductive age points to the need to train health providers regarding assessing pregnancy in women of reproductive age group before starting treatment and advising them accordingly.
Guidelines recommend contraception for the entire duration of PKDL treatment and for 4–6 months after treatment completion. This is because the terminal half-life of miltefosine is 31 days, and around 4–5 half-lives must elapse to ensure nearly complete elimination of the drug from the body. This is also supported by pharma-cokinetic modelling study that recommended 4 months contraceptive cover after completing the 28 days course of miltefosine for kala-azar. Furthermore, due to PKDL not being a clinically urgent condition, it is a advised to postpone PKDL treatment in women in whom pregnancy testing and contraception cannot be guaranteed and it is advisable to wait for starting treatment until the time it could be guaranteed.
Those cases treated by dermatologists in private sector could not be studied. Secondly, recall bias could have crept in, especially for the patients treated in 2015 and the first half of 2016. Thirdly, certain information like incentives and mode of diagnosis were taken from patient interview and could not be crosschecked from other sources. Our study results could have limited generalizability due to purposive sampling having been used to select the districts. This was mainly due to paucity of time as the survey had to be completed and data had to be compiled for the National Workshop on PKDL which was held on 12 January 2017.
| Conclusion|| |
Most PKDL cases being detected through frontline workers and active case search was an encouraging finding. Consequently in order to facilitate diagnosis and treatment of PKDL in primary settings, programme has decided to consider probable PKDL as sufficient criteria for starting treatment from January 2017. This is in accordance with WHO recommendations which advise confirmatory tests only at referral level. Sensitization of formal and informal care providers needs to be done in an integrated manner to achieve early diagnosis and treatment of both kala-azar and PKDL cases. Since majority of cases were of macular type and were likely to stay at home, integration with active case search campaigns such as Leprosy Case Detection Campaign could be done. Services for PKDL patients such as counselling about duration of disease and treatment, contraception advice to women and timely distribution of incentives need to be improved. There is need to minimize treatment interruption and to improve compliance through directly observed treatment. In view of concern of reduced treatment efficacy with single drug and long duration of treatment, combination regimen should be explored, while also considering adverse events and ease of administration.
| Acknowledgements|| |
We would like to acknowledge the conceptualization of the study and technical inputs of Dr Saurabh Jain who is currently Scientist, Global Leishmaniasis Programme, WHO Headquarters, Geneva. We deeply acknowledge the support of Surveillance Medical Officers of WHO India, external monitors, Kala-azar Technical Supervisors and ASHA workers in the areas where the data collection was done. We are thankful to the District Programme Officers, District VBD consultants and State Programme Officers of NVBDCP for kind support during the entire study. We would also like to convey our gratitude to the people affected by PKDL for their patience and kind cooperation during the entire study.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]