Leishmaniasis is a chronic intracellular parasitic infection that travelers, immigrants, deployed military personnel, and refugees from endemic global areas acquire from the bite of infected sand ...flies and carry with them, including to non-endemic countries where leishmaniasis may be an unfamiliar illness to medical providers. This commentary discusses the first clinical practice guidelines produced by the Infectious Diseases Society of America and American Society of Tropical Medicine and Hygiene for the diagnosis and management of leishmaniasis, targeted for clinicians in North America.
This review summarizes recent important and interesting articles investigating the challenging treatment of the parasitic infection, leishmaniasis. In addition, it compares and contrasts ...leishmaniasis clinical practice treatment guidelines.
Studies show that, in contrast to experience in India, visceral leishmaniasis in East Africa requires higher doses of liposomal amphotericin for effective treatment results and that pentavalent antimonial drugs remain efficacious. A retrospective study of visceral leishmaniasis in organ transplant patients suggests that there may be a role for secondary prophylaxis after treatment akin to HIV coinfection recommendations. The pros and cons of oral therapy with miltefosine, which cuts across leishmaniasis syndromes in its spectrum, are discussed. Cutaneous leishmaniasis clinical practice guidelines vary, although the recent European guidelines favor species-directed therapy.
Leishmaniasis remains a neglected tropical disease, with a need for additional clinical trials with better design and reported endpoints to lead evidence-based treatment recommendations--especially in cutaneous leishmaniasis and leishmaniasis in the immunocompromised host.
Leishmaniasis, a chronic and persistent intracellular protozoal infection caused by many different species within the genus
, is an unfamiliar disease to most North American providers. Clinical ...presentations may include asymptomatic and symptomatic visceral leishmaniasis (so-called Kala-azar), as well as cutaneous or mucosal disease. Although cutaneous leishmaniasis (caused by
in the United States) is endemic in some southwest states, other causes for concern include reactivation of imported visceral leishmaniasis remotely in time from the initial infection, and the possible long-term complications of chronic inflammation from asymptomatic infection. Climate change, the identification of competent vectors and reservoirs, a highly mobile populace, significant population groups with proven exposure history, HIV, and widespread use of immunosuppressive medications and organ transplant all create the potential for increased frequency of leishmaniasis in the U.S. Together, these factors could contribute to leishmaniasis emerging as a health threat in the U.S., including the possibility of sustained autochthonous spread of newly introduced visceral disease. We summarize recent data examining the epidemiology and major risk factors for acquisition of cutaneous and visceral leishmaniasis, with a special focus on implications for the United States, as well as discuss key emerging issues affecting the management of visceral leishmaniasis.
Background Sand fly saliva exposure plays an important role in immunity against leishmaniasis where it has mostly been associated with protection. Phlebotomus (Ph.) alexandri transmits Leishmania ...(L.) infantum, the causative agent of visceral leishmaniasis (VL), in Iraq. Our group recently demonstrated that 20% of Operation Iraqi Freedom (OIF) deployers had asymptomatic VL (AVL) indicative of prior infection by the parasite L. infantum. Little is known about Ph. alexandri saliva, and the human immune response to it has never been investigated. Here, we characterize the humoral and cellular immune response to vector saliva in OIF deployers naturally exposed to bites of Ph. alexandri and characterize their immunological profiles in association to AVL. Methodology/Principal findings The humoral response to Ph. alexandri salivary gland homogenate (SGH) showed that 64% of 200 OIF deployers developed an antibody response. To assess the cellular immune response to saliva, we selected a subcohort of subjects based on their post-travel (median 4 months; range 1-22 months) antibody response (SGH Antibody Ab positive or negative) as well as their AVL status; ten never-traveled controls were also included. Banked peripheral blood mononuclear cells (PBMC), collected ~10 years after end of deployment, were stimulated with SGH for 96 hours. The levels of IFN- gamma, IL-6, IL-10, IL-13 and IL-17 were determined by ELISA. Our findings indicate that OIF deployers mounted a cellular response to SGH where the anti-SGH+ asymptomatic subjects developed the highest cytokine levels. Further, stimulation with SGH produced a mixture of pro-inflammatory and anti-inflammatory cytokines. Contrary to our hypothesis, we observed no correlation between the cellular immune response to Ph. alexandri SGH and prevention from asymptomatic infection with L. infantum. Conclusions/Significance As we found, although all infected deployers demonstrated persistent disease control years after deployment, this did not correlate with anti-saliva systemic cellular response. More exposure to this vector may facilitate transmission of the L. infantum parasite. Since exposure to saliva of Ph. alexandri may alter the human immune response to bites of this vector, this parameter should be taken into consideration when considering the VL risk.
The effectiveness of systemic antimonial (sodium stibogluconate, Pentostam, SSG) treatment versus local heat therapy (Thermomed) for cutaneous leishmaniasis was studied previously and showed similar ...healing rates. We hypothesized that different curative immune responses might develop with systemic and local treatment modalities.
We studied the peripheral blood immune cells in a cohort of 54 cutaneous Leishmania major subjects treated with SSG or TM. Multiparameter flow cytometry, lymphoproliferative assays and cytokine production were analyzed in order to investigate the differences in the immune responses of subjects before, on and after treatment.
Healing cutaneous leishmaniasis lead to a significant decline in circulating T cells and NKT-like cells, accompanied by an expansion in NK cells, regardless of treatment modality. Functional changes involved decreased antigen specific CD4+ T cell proliferation (hyporesponsiveness) seen with CD8+ T cell depletion. Moreover, the healing (or healed) state was characterized by fewer circulating regulatory T cells, reduced IFN-γ production and an overall contraction in polyfunctional CD4+ T cells.
Healing from cutaneous Leishmaniasis is a dynamic process that alters circulating lymphocyte populations and subsets of T, NK and NKT-like cells. Immunology of healing, through local or systemic treatments, culminated in similar changes in frequency, quality, and antigen specific responsiveness with immunomodulation possibly via a CD8+ T cell dependent mechanism. Understanding the evolving immunologic changes during healing of human leishmaniasis informs protective immune mechanisms.
Hundreds of thousands of American service members have been deployed to Afghanistan and Iraq since 2001. With emphasis on the common infections and the chronic infections that may present or persist ...on their return to the United States, we review the data on deployment-associated infections. These infections include gastroenteritis; respiratory infection; war wound infection with antibiotic-resistant, gram-negative bacteria; Q fever; brucellosis; and parasitic infections, such as malaria and leishmaniasis.
Bacille Calmette-Guérin (BCG) vaccination is known to cause false-positive tuberculin skin test (TST) results from cross-reactions with mycobacterial antigens. However, the duration of BCG ...vaccination influence on the TST is poorly characterized. The objective of this study was to assess the long-term effect of BCG vaccination on TST reactivity.
Data on TST reactivity were prospectively collected during 1935 to 1947 as part of a clinical trial among Native Americans/Alaskan Natives and were retrospectively collected thereafter between 1948 and 1998. TST induration of ≥ 10 mm was defined as a positive reaction. Kaplan-Meier analysis and multivariate Cox regression were used to compare the time to TST conversion and reversion between the BCG and placebo groups.
BCG vaccination after infancy was associated with an increased risk of TST reactivity in the first 15 years after vaccination (adjusted hazard ratio HR, 2.33). This association remained during the interval 16 to 55 years after vaccination, although the effect was attenuated (adjusted HR, 1.26). Age at vaccination modestly impacted the effect of BCG on TST results in the first 15 years. Positive TST results among the BCG-vaccinated group were more likely to revert to negative results during the first 15 years but not in the latter period.
This study provides evidence that BCG vaccination after infancy may influence TST results beyond the 10-year period conventionally accepted by the Centers for Disease Control and Prevention (CDC), extending up to 55 years after vaccination. This suggests that BCG vaccination should be taken into account when interpreting TST results regardless of the time elapsed since vaccination.
The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. We report long-term results from three clinical ...trials to evaluate gammaretroviral vector-engineered T cells for HIV. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). CAR T cells were detected in 98% of samples tested for at least 11 years after infusion at frequencies that exceeded average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells; integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells had stable levels of engraftment, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient-years of follow-up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.
Abstract
Background
Visceral leishmaniasis (VL), due to Leishmania infantum, is a persistent intracellular parasitic infection transmitted by the bite of infected sand flies. Symptomatic VL has been ...reported in U.S. soldiers with Iraq deployment. Untreated symptomatic VL can be fatal; asymptomatic VL (AVL) may establish a lifelong risk of reactivation. We report prevalence and AVL risk factors in Operation Iraqi Freedom (OIF) deployers during 2002–11.
Methods
Healthy soldiers exposed to VL endemic areas in Iraq and 50 controls who never traveled to endemic regions were recruited through military healthcare facilities (2015–17). Responses to a risk factor survey and blood samples were obtained. Leishmania research diagnostics utilized included enzyme-linked immunosorbent assay (ELISA), rk39 test strips, quantitative polymerase chain reaction (PCR), and interferon gamma release (IGRA) assays. Statistical analyses included Fisher exact test, Pearson χ2 test, Mann-Whitney U test, and logistic regression.
Results
200 deployed subjects were enrolled, mostly males (84.0%), of white ethnicity (79.0%), and median age 41 (range 24–61) years. 64% were seropositive for Phlebotomus alexandri saliva antibodies. Prevalence of AVL (any positive test result) was 39/200 (19.5%, 95% confidence interval 14.4%–25.8%). Two (1.0%) PCR, 10 (5%) ELISA, and 28 (14%) IGRA samples were positive. Travel to Ninewa governorate increased risk for AVL (P = .01).
Conclusion
AVL was identified in 19.5% of OIF deployers; travel to northwest Iraq correlated with infection. Further studies are needed to inform risk for reactivation VL in US veterans and to target additional blood safety and surveillance measures.
Approximately 20% of US soldiers deployed to Iraq were found to be infected with Leishmania by blood assays performed at least a decade after deployment. This disease burden and risk for reactivation in US military personnel is underrecognized.
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