Visceral leishmaniasis (VL) is a parasitic disease characterized by immune suppression. Successful treatment is usually followed by immune reconstitution and a dermatosis called post-Kala-azar dermal leishmaniasis (PKDL). Recently, PKDL was described as one of the immune reconstitution syndromes (IRISs) in HIV/VL patients on HAART. This study aimed to present PKDL as a typical example of paradoxical IRIS in non-HIV/AIDS individuals. Published and new data on the pathogenesis and healing of PKDL was reviewed and presented. The data suggested that PKDL is a typical example of paradoxical IRIS, being a new disease entity that follows VL successful treatment and immune recovery. PKDL lesions are immune inflammatory in nature with granuloma, adequate response to immunochemotherapy, and an ensuing hypersensitivity reaction, the leishmanin skin test (LST). The data also suggested that the cytokine patterns of PKDL pathogenesis and healing are probably as follows: an active disease state dominated by IL-10 followed by spontaneous/treatment-induced IL-12 priming, IL-2 stimulation, and INF-
More than fifty percent of successfully treated Sudanese VL patients develop an inflammatory skin rash, called postkala-azar dermal leishmaniasis (PKDL). A number of hypotheses have been put forward to explain the aetiology of PKDL: undertreatment, UVB light exposure, and ethnicity [
Immune reconstitution inflammatory syndrome (IRIS) is a well-documented phenomenon that follows immune reconstitution in HIV patients who have recently started HAART. It is a stereotyped immune inflammatory state that is characterized by transient worsening or appearance of new symptoms/signs following successful treatment. IRIS has been described in patients with parasitic, bacterial, viral and autoimmune diseases [
Recently, PKDL was reported as an IRIS phenomenon from Africa and Europe in HIV/AIDS/VL co-infected patients [
This study aimed to present PKDL as a form of paradoxical IRIS in non-HIV/AIDS patients with plethora of cytokines production, granuloma formation, and delayed-type skin hypersensitivity reaction (LST) without activation of existing opportunistic infection.
Archived supernatant samples from in vitro stimulated PBMCs of thirty PKDL patients were selected from the samples bank of the Institute of Endemic Diseases, University of Khartoum. PKDL patients were enrolled in an immunochemotherapy study and were randomized to two study arms: patients in group I received four intradermal doses of 100
The study protocol was reviewed and passed by the Ethics and Scientific Committees of the Institute of Endemic Diseases, University of Khartoum and the Ethics Committee of the Federal Ministry of Health, Khartoum. Samples were from patients who consented previously for the storage and use of their samples for further future testing. Patients were enrolled in the study based on specific inclusion and exclusion criteria as described previously [
PKDL patients were subjected to physical examination, pregnancy testing, DAT/HIV serological test, skin biopsy, haematological and chemical tests, LST, ECG, and cytokines at screening (D2), during treatment (D0, D7, D14, and D21) and follow up (D30, D40, D60, and D90) periods.
PBMCs were harvested using the density gradient centrifugation and were counted using Trypan blue exclusion technique with a haemocytometer. PBMCs cultures were stimulated with soluble
Total number of patients enrolled in this group was fifteen.
IL-2, IL-12, INF-
ID | Day 2 | Day 60 | Treatment outcome | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
IL-2 | IL-12 | INF- |
IL-10 | LST | IL-2 | IL-12 | INF- |
IL-10 | LST | ||
110* |
|
00 |
|
16 | 00 | 135 | 4.8 |
|
22 |
|
Not healed |
107* | 55 | 2.9 |
|
21 | 03 | 80 | 07 |
|
08 |
|
Healed |
104* |
|
4.8 |
|
38 | 03 |
|
18 |
|
47 |
|
Healed |
116* | 00 | 00 |
|
33 | 08 | 34 | 03 |
|
81 |
|
Healed |
105* |
|
00 |
|
00 | 00 | 30 | 18 | 27 | 48 |
|
Healed |
121* | 00 | 08 | 00 | 00 | 00 | 20 | 04 |
|
22 |
|
Healed |
123* | 00 | 00 | 101 | 04 | 00 | 00 | 06 |
|
09 |
|
Healed |
118* | 00 | 02 |
|
12 | 08 | 00 | 4.8 | 85 | 36 |
|
Healed |
129* | 00 | 00 |
|
19 | 06 | 15 | 16.5 |
|
40 |
|
Healed |
102* | 00 | 1.8 | 74 | 00 | 00 | 42 | 4.8 |
|
35 |
|
Healed |
112 |
|
06 |
|
345 | 03 | 45 | 00 | 151 | 08 |
|
Healed |
109 | 00 | 3.6 |
|
09 | 00 | 25 | 05 |
|
17 |
|
Healed |
108 | 155 | 00 |
|
19 | 00 | 185 | 00 |
|
00 |
|
Healed |
106 | 45 | 4.8 |
|
00 | 00 |
|
10.5 |
|
29 | 00 | Healed |
103 | 00 | 3.6 |
|
00 | 00 | 52 | 10 |
|
12 |
|
Healed |
101 | 25 | 18 |
|
33 | 00 | 100 | 02 |
|
32 | 00 | Not healed |
130 | 00 | 1.2 |
|
102 | 04 | 00 | 00 | 14 | 20 | — | Not healed |
115 | 00 | 00 |
|
113 |
|
23 | 18 |
|
62 |
|
Healed |
127 | 00 | 6.0 | 00 | 46 | 00 | 00 | 12.9 |
|
65 |
|
Healed |
It is evident that all patients in the Alum/ALM vaccine + BCG group passed the anti-inflammatory stage when screened (low to absent IL-10), some were in the pro-inflammatory (IL-2/IL-12/IFN-
IL-10 levels were uniformly low in response to soluble
Total number of patients enrolled in this arm was fifteen.
IL-10 levels in response to soluble
Some of the patients in the SSG/vaccine diluent were in a state of immune paresis (high leishmania antigen load) and were unable to mount an IL-12 priming and IL-2/IFN-
Data from this study showed the clear dichotomy of immune response in PKDL patients as was previously reported [
Case reports from Africa and Europe introduced PKDL as an immune reconstitution phenomenon in HIV/VL co-infected patients at the start of HAART [
The authors declared that they have no conflict of interests.
The authors would like to express their thanks and gratitude to the staff of the Tropical Diseases Hospital, Omdurman, for their considerable help. The team received financial support from the Institute of Endemic Diseases, University of Khartoum.