Case Report: An Atypical Case of Post-Kala-Azar Dermal Leishmaniasis with Ulcers and Verrucous Lesions: Clinical and Therapeutic Implications.

About 75% cases of post-kala-azar dermal leishmaniasis (PKDL) occur in India. Although the classic description of PKDL is the progression from initial hypopigmented macular lesions to papules to plaques and nodular lesions, atypical morphologies are also seen and are easily missed or misdiagnosed. We report a case of a 27-year-old man who presented to us with multiple acral ulcers and verrucous lesions for 5 years. A diagnosis of PKDL was made based on slit skin smear, histopathology, and quantitative polymerase chain reaction. The patient was given combination therapy with four doses of liposomal amphotericin B and miltefosine 50 mg twice daily for 45 days. In this report, we discuss unusual morphologies of PKDL, the pathway to the diagnosis, and the therapeutic options available along with their efficacy.

Experimental structure based drug design (SBDD) applications for anti-leishmanial drugs: A paradigm shift?

Leishmaniasis is a group of neglected tropical diseases caused by at least 20 species of Leishmania protozoa, which are spread by the bite of infected sandflies. There are three main forms of the disease: cutaneous leishmaniasis (CL, the most common), visceral leishmaniasis (VL, also known as kala-azar, the most serious), and mucocutaneous leishmaniasis. One billion people live in areas endemic to leishmaniasis, with an annual estimation of 30,000 new cases of VL and more than 1 million of CL. New treatments for leishmaniasis are an urgent need, as the existing ones are inefficient, toxic, and/or expensive. We have revised the experimental structure-based drug design (SBDD) efforts applied to the discovery of new drugs against leishmaniasis. We have grouped the explored targets according to the metabolic pathways they belong to, and the key achieved advances are highlighted and evaluated. In most cases, SBDD studies follow high-throughput screening campaigns and are secondary to pharmacokinetic optimization, due to the majoritarian belief that there are few validated targets for SBDD in leishmaniasis. However, some SBDD strategies have significantly contributed to new drug candidates against leishmaniasis and a bigger number holds promise for future development.

A case report on para-kala-azar dermal leishmaniasis: an unresolved mystery.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis that occurs 2-3 years after an apparently successful treatment of visceral leishmaniasis (VL). In rare cases, PKDL occurs concurrently with VL and is characterized by fever, splenomegaly, hepatomegaly or lymphadenopathy, and poor nutritional status and is known as Para-kala-azar dermal leishmaniasis (Para-KDL). Co-association of active VL in PKDL patients is documented in Africa, but very few case reports are found in South Asia. We present a case of Para-kala-azar Dermal Leishmaniasis (Para-KDL) in a 50-year-old male patient with a history of one primary Visceral Leishmaniasis (VL) and 2 times relapse of Visceral Leishmaniasis (VL). The patient presented with fever, skin lesions, and hepatosplenomegaly. Laboratory tests revealed LD bodies in the slit skin smear and splenic biopsy. The patient was treated with two cycles of Amphotericin B with Miltefosine in between cycles for 12 weeks to obtain full recovery. CONCLUSION: This case report serves as a reminder that Para-kala-azar dermal leishmaniasis can develop as a consequence of prior visceral leishmaniasis episodes, even after apparently effective therapy. Since para-kala-azar is a source of infectious spread, endemics cannot be avoided unless it is effectively recognized and treated.

The leishmaniases in Kenya: A scoping review.

BACKGROUND: The leishmaniases are a group of four vector-borne neglected tropical diseases caused by 20 species of protozoan parasites of the genus Leishmania and transmitted through a bite of infected female phlebotomine sandflies. Endemic in over 100 countries, the four types of leishmaniasis-visceral leishmaniasis (VL) (known as kala-azar), cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and post-kala-azar dermal leishmaniasis (PKDL)-put 1.6 billion people at risk. In Kenya, the extent of leishmaniasis research has not yet been systematically described. This knowledge is instrumental in identifying existing research gaps and designing appropriate interventions for diagnosis, treatment, and elimination. METHODOLOGY/PRINCIPAL FINDINGS: This study used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology to determine the state of leishmaniases research in Kenya and identify research gaps. We searched seven online databases to identify articles published until January 2022 covering VL, CL, MCL, and/or PKDL in Kenya. A total of 7,486 articles were found, of which 479 underwent full-text screening, and 269 met our eligibility criteria. Most articles covered VL only (n = 141, 52%), were published between 1980 and 1994 (n = 108, 39%), and focused on the theme of "vectors" (n = 92, 34%). The most prevalent study types were "epidemiological research" (n = 88, 33%) tied with "clinical research" (n = 88, 33%), then "basic science research" (n = 49, 18%) and "secondary research" (n = 44, 16%). CONCLUSION/SIGNIFICANCE: While some studies still provide useful guidance today, most leishmaniasis research in Kenya needs to be updated and focused on prevention, co-infections, health systems/policy, and general topics, as these themes combined comprised less than 4% of published articles. Our findings also indicate minimal research on MCL (n = 1, <1%) and PKDL (n = 2, 1%). We urge researchers to renew and expand their focus on these neglected diseases in Kenya.

Clinical Manifestation of Cutaneous Leishmaniasis Following a Mechanical Trauma.

Unusual skin ulcers frequently represent a diagnostic challenge. When the most common disease entities such as arterial, venous or diabetic ulcers have been excluded, the question of further differential diagnoses and procedures arises. Other possible causes include chronic inflammatory diseases, neoplasia, self-inflicted wounds, primary infectious diseases and physical/chemical damage to the skin. To narrow down the differential diagnoses, a detailed history of the patient is essential, which also needs to include events further back in time.

Immune recovery-related patterns of post kala-azar dermal and ocular leishmaniasis in people living with HIV.

OBJECTIVE: Post kala-azar dermal leishmaniasis (PKDL) is a rare complication of visceral leishmaniasis. We aimed at reporting PKDL cases in people living with HIV (PLHIV) and compare their characteristics based on whether PKDL occurred in the context of immune recovery under antiretroviral therapy (ART) or not. DESIGN: National survey and literature review. METHODS: We called for observations in France in October 2020 and performed a literature review from PubMed (Medline) and Web of Science up to December 2020. Two groups of patients were defined based on whether PKDL occurred in the context of immune recovery under ART (group 1) or not (group 2), and compared. RESULTS: Three PLHIV with PKDL identified in France in the last decade were described and added to 33 cases from the literature. Compared with group 2 (16/36, 44.4%), patients from group 1 (20/36, 55.6%) originated more frequently from Europe (12/20, 60% vs. 2/16, 12.5%; P  = 0.0038), had higher median blood CD4 + cell counts (221/µl vs. 61/µl; P  = 0.0005) and increase under ART (122/µl, interquartile range 73-243 vs. 33/µl, interquartile range 0-53; P  = 0.0044), had less frequently concomitant visceral leishmaniasis (3/20, 15% vs. 8/12, 66.7%; P  = 0.006), and a trend to more frequent ocular involvement (7/20, 35% vs. 1/16, 6.25%; P  = 0.0531). CONCLUSION: In PLHIV, PKDL occurs after a cured episode of visceral leishmaniasis as part of an immune restoration disease under ART, or concomitant to a visceral leishmaniasis relapse in a context of AIDS. For the latter, the denomination 'disseminated cutaneous lesions associated with visceral leishmaniasis' seems more accurate than PKDL.

Are the clinical features of leprosy and American tegumentary leishmaniasis worse in patients with both diseases?

This cross-sectional population-based study compared clinical features of leprosy and American tegumentary leishmaniasis (ATL) in patients diagnosed with both diseases (n=414) and in those diagnosed with only leprosy (n=27,790) or only ATL (n=24,357) in Mato Grosso State, which is a hyperendemic area for both diseases in Midwest Brazil. All new cases of leprosy and ATL reported in the area from 2008 to 2017 were included. Patients diagnosed with both diseases were identified by a probabilistic linkage procedure applied to leprosy and ATL databases of the national reporting system. The distribution of the frequency of clinical features between groups was compared by the chi-square test, followed by a multivariate logistic regression. Patients diagnosed with both leprosy and ATL presented higher odds of having nerve damage (OR: 1.34; 95% CI: 1.09-1.66) and leprosy reactions (OR: 1.35; 95% CI: 1.04-1.76) compared to patients diagnosed only with leprosy. Mucocutaneous leishmaniasis (OR: 2.29; 95% CI: 1.74-3.00) was more frequent among patients with both diagnoses when compared to patients who only had ATL. In conclusion, patients diagnosed with both leprosy and ATL present more severe clinical features of such diseases. Our data can be useful for designing health policies aimed at timely and integrated management of leprosy and ATL in co-endemic areas.

Amputation of a type II diabetic patient with cutaneous leishmaniasis due to Leishmania major.

BACKGROUND: Leishmaniases are neglected tropical diseases of public health concern in Algeria. The immunocompromised patients with HIV, autoimmune diseases, or chronic alcohol abuse are at a higher risk of leishmaniasis. Herein, we present the case of an immunocompetent diabetic patient infected by Leishmania major, leading to life-threatening consequences. CASE PRESENTATION: An Algerian diabetic patient developed a cutaneous lesion with large polymorphous inflamed granuloma and pyoderma gangrenosum in the left foot, following L. major infection. A delayed follow-up led to a treatment failure, resulting in the amputation. CONCLUSIONS: This report highlights the absence of timely treatment of Leishmania infection as a life-threatening point among high-risk diabetic patients. Clinicians should be aware of this parasitosis leading to severe complications in diabetic patients.

The impact of diabetes on cutaneous leishmaniasis: a case-control field assessment.

This study aimed to assess the associated-risk determinants for cutaneous leishmaniasis (CL) in patients with diabetes mellitus (DM) compared to patients without DM. This case-control study was performed between 2017 and 2019 in southeastern Iran. Overall, 206 participants were selected from patients with DM without CL (11.2%), patients with CL without DM (6.2%), and DM patients concomitance with CL (27.6%) as case groups and healthy individuals as a control group 64 (76%). These cases were compared for parasitological, immunological, biochemical, and hematological parameters. The findings demonstrated that parasitological factors regarding the number, duration, and size of the lesion in CL patients showed a significant difference among patients with and without DM (p < 0.05). Data analysis showed that six major risk factors, including female (odds ratio (OR) = 3.47, confidence interval (CI) = 1.84-6.53, p < 0.001), total protein in CL group (OR = 4.9, CI = 2.3-10.44, p < 0.001), alanine aminotransferase (ALT) concentration in CL group (OR = 0.87, CI = 0.81-0.93, p < 0.001) and DM co-infected with CL group (OR = 0.8, CI = 0.72-0.88, p < 0.001) than healthy group, aspartate aminotransferase (AST) concentration in DM group (OR = 0.86, CI = 0.76-0.98, p = 0.02), transforming growth factor beta)TGF-ß( level in the CL group (OR = 1.03, CI = 1.003-1.05, p = 0.02), and presence of diabetes disease (OR = 2.07, CI = 1.16-3.7, p < 0.05), were significantly linked with the induction of CL lesion. The findings demonstrated a significant relationship between DM and CL in distinct risk determinants. Also, the study revealed that DM enhanced the severity of active CL.

Influence of Intestinal Helminth Burden on Clinical Manifestations, Therapeutic Response, and Leishmania braziliensis Load in Patients with New World Cutaneous Leishmaniasis.

Leishmania braziliensis is the most important cause of cutaneous leishmaniasis (CL) in the Americas. A Th1-type immune response is required to control Leishmania infection, but an exaggerated inflammatory response leads to the development of ulcers seen in CL. Infection with intestinal helminths has the potential to inhibit the Th1 response in a manner that depends both on the species of helminth present as well as the burden of helminthiasis. We conducted a prospective cohort study of CL patients from an endemic area between January and December 2017 with either negative or high intestinal helminth burden to characterize relationships between helminth burden, L. braziliensis quantification within CL lesions, clinical aspects of CL, and therapeutic response. Of 234 participants with leishmaniasis who underwent stool examination at the time of diagnosis, 45% had detectable helminth infection. The overall cure rate after 90 days was 66%, with a median time to resolution of disease of 40 days (interquartile range: 30-65 days). There was no significant association between the type of helminth infection or the magnitude of intestinal helminth burden at the time of diagnosis and L. braziliensis genomic DNA (gDNA) detected in biopsies from CL lesions. Likewise, there was no association between helminth burden and response to treatment after 90 days. Considering quantification of parasite DNA in CL lesions, participants who were cured at 90 days had a median of 0.017 ng/mg gDNA, and participants who failed therapy had a median of 0.091 ng/mg gDNA (P = 0.03). The results indicate that cutaneous Leishmania load may influence therapeutic response in CL.

An 18-year-old man with tropical verrucous syndrome: Leishmaniasis or sporotrichosis? / [Hombre de 18 años con síndrome verrugoso tropical: ¿leishmaniasis o esporotricosis?]

The tropical verrucous syndrome includes infectious, chronic, and granulomatous skin conditions appearing with plaques, nodules, or ulcers with a warty surface which gives name to the syndrome. It includes forms of chromoblastomycosis, sporotrichosis, paracoccidioidomycosis, lobomycosis, leishmaniasis, and tuberculosis verrucosa cutis with ample distribution in tropical and subtropical areas. The diagnoses may be difficult and confused among them, especially between sporotrichosis and leishmaniasis. Clinical, epidemiologic, intradermal reactions, direct smears, skin biopsies, cultures, immunofluorescence, and PCR are used to differentiate them, although several of these methods are not commonly used. We present an 18-year-old man with extensive verrucous plaques in one knee interpreted by clinic, epidemiology, and biopsy as verrucous cutaneous leishmaniasis. He was treated with Glucantime® for 20 days without improvement. A new biopsy was made that was also interpreted as cutaneous leishmaniasis. The revision of both biopsies showed inflammation with abscessed granulomas and asteroid sporotrichotic bodies at the center of the granulomas that led to the diagnosis of sporotrichosis later confirmed by the fungus culture. The patient responded to the treatment with itraconazole. As clinical and epidemiological findings of leishmaniasis and sporotrichosis can be similar, skin biopsy and other paraclinical studies are necessary to establish a proper diagnosis. The asteroid sporotrichotic body is pathognomonic of this mycosis. We review here the essential concepts of leishmaniasis and sporotrichosis and the criteria to differentiate them.

El síndrome verrugoso tropical comprende condiciones cutáneas infecciosas, crónicas y granulomatosas que cursan con placas, nódulos o úlceras verrugosas, de ahí su nombre. Este síndrome incluye la cromoblastomicosis, la esporotricosis, la paracoccidioidomicosis, la lobomicosis, la leishmaniasis y la tuberculosis cutánea verrugosa, todas ellas enfermedades de amplia distribución en áreas tropicales y subtropicales. Sus diagnósticos pueden ser difíciles y confundirse entre sí, lo cual es más frecuente entre la esporotricosis y la leishmaniasis. Para distinguirlas se recurre a criterios clínicos y epidemiológicos, y a métodos diagnósticos como intradermorreacción, examen directo, biopsia, cultivo, inmunofluorescencia y PCR, algunos de los cuales no son de uso común. El diagnóstico preciso conduce al tratamiento adecuado. Se presenta el caso de un hombre de 18 años con extensas placas verrugosas en una rodilla, inicialmente interpretadas como leishmaniasis verrugosa por la clínica, la epidemiología y la biopsia. Se le trató con Glucantime® durante 20 días, pero no presentó mejoría, por lo que se tomó una nueva biopsia que también se interpretó como leishmaniasis cutánea. La revisión de ambas biopsias evidenció inflamación con granulomas abscedados y presencia de cuerpos asteroides esporotricósicos, que condujeron al diagnóstico de esporotricosis, el cual se confirmó luego con el cultivo del hongo. Las lesiones remitieron con la administración de itraconazol. La clínica y la epidemiología de la leishmaniasis y las de la esporotricosis pueden ser semejantes, por lo que la biopsia y los estudios de laboratorio son esenciales para establecer el diagnóstico. El cuerpo asteroide esporotricósico es patognomónico de esta entidad.

Sandfly Fever Sicilian Virus-Leishmania major co-infection modulates innate inflammatory response favoring myeloid cell infections and skin hyperinflammation.

BACKGROUND: The leishmaniases are a group of sandfly-transmitted diseases caused by species of the protozoan parasite, Leishmania. With an annual incidence of 1 million cases, 1 billion people living in Leishmania-endemic regions, and nearly 30,000 deaths each year, leishmaniasis is a major global public health concern. While phlebotomine sandflies are well-known as vectors of Leishmania, they are also the vectors of various phleboviruses, including Sandfly Fever Sicilian Virus (SFSV). Cutaneous leishmaniasis (CL), caused by Leishmania major (L. major), among other species, results in development of skin lesions on the infected host. Importantly, there exists much variation in the clinical manifestation between individuals. We propose that phleboviruses, vectored by and found in the same sandfly guts as Leishmania, may be a factor in determining CL severity. It was reported by our group that Leishmania exosomes are released into the gut of the sandfly vector and co-inoculated during blood meals, where they exacerbate CL skin lesions. We hypothesized that, when taking a blood meal, the sandfly vector infects the host with Leishmania parasites and exosomes as well as phleboviruses, and that this viral co-infection results in a modulation of leishmaniasis. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, we observed modulation by SFSV in MAP kinase signaling as well as in the IRF3 pathway that resulted in a pro-inflammatory phenotype. Additionally, we found that SFSV and L. major co-infection resulted in an exacerbation of leishmaniasis in vivo, and by using endosomal (Toll-like receptor) TLR3, and MAVS knock-out mice, deduced that SFSV's hyperinflammatory effect was TLR3- and MAVS-dependent. Critically, we observed that L. major and SFSV co-infected C57BL/6 mice demonstrated significantly higher parasite burden than mice solely infected with L. major. Furthermore, viral presence increased leukocyte influx in vivo. This influx was accompanied by elevated total extracellular vesicle numbers. Interestingly, L. major displayed higher infectiveness with coincident phleboviral infection compared to L. major infection alone. CONCLUSION/SIGNIFICANCE: Overall our work represents novel findings that contribute towards understanding the causal mechanisms governing cutaneous leishmaniasis pathology. Better comprehension of the potential role of viral co-infection could lead to treatment regimens with enhanced effectiveness.

Individuals co-exposed to sand fly saliva and filarial parasites exhibit altered monocyte function.

BACKGROUND: In Mali, cutaneous leishmaniasis (CL) and filariasis are co-endemic. Previous studies in animal models of infection have shown that sand fly saliva enhance infectivity of Leishmania parasites in naïve hosts while saliva-specific adaptive immune responses may protect against cutaneous and visceral leishmaniasis. In contrast, the human immune response to Phlebotomus duboscqi (Pd) saliva, the principal sand fly vector in Mali, was found to be dichotomously polarized with some individuals having a Th1-dominated response and others having a Th2-biased response. We hypothesized that co-infection with filarial parasites may be an underlying factor that modulates the immune response to Pd saliva in endemic regions. METHODOLOGY/PRINCIPAL FINDINGS: To understand which cell types may be responsible for polarizing human responses to sand fly saliva, we investigated the effect of salivary glands (SG) of Pd on human monocytes. To this end, elutriated monocytes were cultured in vitro, alone, or with SG, microfilariae antigen (MF ag) of Brugia malayi, or LPS, a positive control. The mRNA expression of genes involved in inflammatory or regulatory responses was then measured as were cytokines and chemokines associated with these responses. Monocytes of individuals who were not exposed to sand fly bites (mainly North American controls) significantly upregulated the production of IL-6 and CCL4; cytokines that enhance leishmania parasite establishment, in response to SG from Pd or other vector species. This selective inflammatory response was lost in individuals that were exposed to sand fly bites which was not changed by co-infection with filarial parasites. Furthermore, infection with filarial parasites resulted in upregulation of CCL22, a type-2 associated chemokine, both at the mRNA levels and by its observed effect on the frequency of recruited monocytes. CONCLUSIONS/SIGNIFICANCE: Together, our data suggest that SG or recombinant salivary proteins from Pd alter human monocyte function by upregulating selective inflammatory cytokines.

Investigations on the effects of anti-Leishmania major serum on the progression of Leishmania infantum infection in vivo and in vitro - implications of heterologous exposure to Leishmania spp.

Leishmaniasis is a vector-borne parasitic disease caused by protozoa of the genus Leishmania. Twenty different species are known to cause disease in humans with varying degrees of pathology. These diseases are transmitted throughout the geographic range of phlebotomine sandflies, found between the latitudes 50°N and 40°S. This study explores antibody dependent enhancement (ADE) as the cause of disease exacerbation in heterologous exposure of L. major primed mice to L. infantum challenge. BALB/c mice received serum from L. major infected or naive mice. All mice were challenged with L. infantum and tissue parasite burdens were recorded. Animals that received anti-L. major serum exhibited significantly higher parasite burdens. Surprisingly, these parasite burdens were higher than those of mice infected with L. major and challenged with L. infantum. In vitro phagocytosis assays were carried out to measure parasite uptake in the presence of naive vs. anti-L. major serum. J774A.1 murine monocytes were cultured with either L. major or L. infantum in the presence of anti-L. major serum, naive serum, or no serum. Significantly higher rates of L. major uptake by J774A.1 cells occurred in the presence of anti-L. major serum, but no measurable increase of L. infantum phagocytosis was seen. Our results suggest that increased disease severity observed in vivo in mice previously exposed to L. major and challenged with L infantum is not a result of extrinsic ADE. We speculate that intrinsic ADE, due to biased memory T cell responses caused by Fcγ signaling, could account for disease exacerbation seen in the animal model.

Treatment of tegumentary leishmaniasis in two hemodialysis patients with end-stage renal disease using two series of pentamidine.

In this study, we present two cases of cutaneous leishmaniasis in patients with end-stage renal disease, who were treated solely with intramuscular pentamidine. In such cases, treatment implies a fine line between therapeutic efficacy and toxicity. This is suggestive of a knowledge gap; however, findings indicate that this is still the fastest and safest alternative to the treatment with antimonials. Also, it can help avoid the side effects that occur upon using antimonials.