Clinical and immunological aspects of post-kala-azar dermal leishmaniasis in Bangladesh

Abstract

We conducted active surveillance for kala-azar and post-kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala-azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitor of matrix metalloproteinase-1 (TIMP1) ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent.

Figure 1.

Epidemic curves for incident kala-azar (KA) and PKDL from January of 2002 to December of 2010. Smoothed incidence curves were obtained by fitting a cubic smoothing spline to the Nelson–Aalen cumulative hazard estimates and taking the first derivative. Annual KA incidence peaked in 2005 at 90/10,000 person-years. Annual PKDL incidence peaked in 2007 at 28/10,000 person-years.

Figure 2.

(A) The Kaplan–Meier survival curve with 95% confidence intervals for PKDL onset among KA cases. Incident PKDL occurred in 153 of 1,002 KA patients. Based on this analysis, 3% of KA patients develop PKDL within 1 year, 10% of KA patients develop PKDL within 2 years, and 17% of KA patients develop PKDL within 5 years. (B) Kaplan–Meier survival curves for PKDL onset among KA cases stratified by age at the time of KA onset. Incident PKDL occurred in 102 of 595 KA patients younger than 15 years compared with 51 of 407 KA patients 15 years or older (P = 0.023 by log-rank test).

Figure 3.

Photographs of patients with PKDL. (A) Perioral hypopigmented plaques. (B) Perioral hypopigmented macules. (C) Papular lesions on the legs of a child. (D–E) Nodular lesions on the face and arms.

Figure 4.

(A) Kaplan–Meier survival curve for resolution of PKDL treated with SSG. Estimated resolution rates: 42% within 1 year of onset (6 months after treatment completion), 72% within 2 years, and 92% within 5 years. (B) Kaplan–Meier survival curve for resolution of untreated PKDL. Of 98 untreated PKDL patients, 48 patients had lesion resolution during the follow-up period. Estimated resolution rates: 8% within 1 year of onset, 34% within 2 years, and 67% within 5 years.

Figure 5.

Scatter plots showing levels of cytokines among patients with untreated KA, treated cured KA, and untreated active PKDL and healthy North American controls.

Figure 6.

Scatter plots showing levels of TIMPs and MMPs among patients with untreated KA, treated cured KA, and untreated active PKDL and healthy North American controls.

Figure 7.

Scatter plots showing levels of cytokines by PKDL lesion type.