Cutaneous leishmaniasis as a manifestation of IRIS may appearance, following the introduction of HAART and consequent restoration of immunity, as a new disease or as the progression of latent disease . In the present report, the patient’s lesions developed five months after the initiation of antiretroviral therapy, concurrent with the recovery of the number of CD4+ T-cells.
To the best of our knowledge, only two other cases of patients infected with HIV and the clinical form of mucocutaneous leishmaniasis as a manifestation of IRIS have been described to date . In both of these cases, disseminated skin lesions (on the arms, lower limbs and feet) and lesions in the nasal, oropharyngeal, as well as genital mucosa were reported. Although genital lesions have been reported in one-third of HIV/Leishmania co-infected patients [12,13], the patient described herein did not show genital involvement or widespread skin lesions. His lesions were restricted to the facial area, especially in the nasal and oropharyngeal mucosa, with intense inflammation resulting in destruction of the nasal septum.
Our results suggest that the mucosal damage resulting from mucocutaneous leishmaniasis as a manifestation of IRIS in this patient was correlated with an unspecific inflammatory milieu. During the course of IRIS, CD4+ and CD8+ T-lymphocytes produced very low levels of IFN-γ and TNF-α in response to Leishmania antigens, yet high levels of IFN-γ by both CD4+ and CD8+ T-cells were observed in the absence of antigen stimulation. Conversely, after the lesions healed, a specific immune response to Leishmania antigens was reestablished and a profound reduction in the spontaneous production of cytokines was observed. The decreased T-cell proliferation and low antigen-induced cytokine responses observed in this patient during the course of IRIS could be more suggestive of immunosuppression to Leishmania antigens than a hyper-responsive state. However, the fact that the lesions appeared at the same time the patient’s immune system demonstrated recovery (the CD4+ T lymphocyte count was higher than 500 cells/mm3 and HIV viral load was undetectable) is supportive of an IRIS diagnosis. Moreover, the initial clinical presentation of mucosal leishmaniasis, which appeared five months after HAART initiation, progressed to an intense inflammatory response with partial destruction of the nasal septum in less than four months.
During IRIS, the patient had a positive skin test for Leishmania, while his antigen-specific T-cell proliferation was undetectable. This discrepancy could be explained by the dynamic of immune restoration following HAART. The restoration of antigen-specific CD4+ T-cell responses in vitro is mostly correlated with CD4+ memory T-cell reconstitution; whereas the improvement of delayed type hypersensitivity is associated with the suppression of viraemia . However, it was not possible to quantify antigen-specific central and effector memory CD4+ T-lymphocytes for this patient, during IRIS or after healing of lesions. In addition, an impairment of in vitro proliferative response to Leishmania antigens could be linked to the activation and exhaustion of immune system found during IRIS . Yet, intrinsic differences among tests for measuring cellular immune function could explain these divergent results.
In the present case, the participation of a specific response to Leishmania antigens with respect to the development of skin and mucosal lesions cannot be excluded, since a Leishmania-specific response was not evaluated in situ. A specific recruitment of CD4+ and CD8+ T-cells to the ulcerative lesion is described in patients with both cutaneous and mucosal leishmaniasis [16,17]. Specifically, in the mucosal lesions it is observed high number of IFN-γ-producing cells . Indeed, a decreased type-1 immune response to Leishmania antigens in peripheral blood is associated with intense recruitment of Leishmania-specific T-cells to the lesions, which is classically found in HIV-uninfected patients with disseminated leishmaniasis, yet cytokine production in tegumentary lesions was observed to be similar to that found in patients with mucocutaneous and cutaneous leishmaniasis . Following healing, though CD4+ and CD8+ T-cells persist in treated lesions, the number of circulating antigen-specific CD4+ and CD8+ T-cells increases in peripheral blood [19,20]. Thus, in this patient the absence of proliferative response to Leishmania antigens during IRIS might be due to sequestration of T-cells inside lesions. After healing, these cells were redistributed to peripheral blood.
The elevated cytokine production observed in non-stimulated cells may be a consequence of activated memory CD4+ T-cells specific for pathogens other than Leishmania. These cells recirculate from lymphoid organs into the peripheral blood stream during the first two months of HAART [1,21]. Moreover, the chronic activation of the immune system by HIV itself may also contribute to the inflammatory state observed during the course of IRIS .
High levels of IL-6 and TNF-α have been previously described in patients with other infectious diseases in association with IRIS [23-25]. Additionally, elevated pro-inflammatory cytokine production is considered to be a predictor of IRIS development in HIV-infected patients at the onset of HAART . Considering the plasma levels of TNF-α in two HIV-uninfected patients with active mucocutaneous leishmaniasis evaluated at our laboratory (22 pg/mL and 13 pg/mL) , the levels observed in this patient during IRIS were similar. Following treatment with Amphotericin B and corticosteroids, an increase in plasmatic IFN-γ, as well as in the IFN-γ/IL-10 ratio, was observed in the present case, while TNF-α remained stable. Although treatment with corticosteroids usually decreases the production of inflammatory cytokines , a decrease in the spontaneous production of IFN-γ and TNF-α was observed in this patient only in vitro, but not in his plasma. This finding may be due to the fact that post-treatment cytokine quantification was performed in the plasma by a single measurement just one day following the conclusion of treatment. It is possible that subsequent measurements would have found decreases in TNF-α in the plasma.
Furthermore, the nonspecific activation of the immune system could be a consequence of an impaired regulatory T-cell response or a decrease in the proportion of these cells, since IL-10 produced by Leishmania-specific CD4+ T-lymphocytes was not detected during the course of IRIS . The proportion of regulatory T-cells (1.8%) in our patient prior to treatment was found to be low (data not shown). An imbalance between the effector and regulatory responses may also play a role in the pathogenesis of IRIS [29,30].
IRIS is characterized by an intense inflammatory reaction, leading to tissue destruction concurrent with an increase in the number of CD4+ T-cells following HAART. No convincing evidence has been presented in regard to whether CD4+ T-cells specific to opportunistic pathogens are deregulated during IRIS, much less if these cells are involved in the pathogenesis of IRIS. Moreover, the literature contains no reports that directly link CD4+ T-cells specific to Leishmania antigens with clinical manifestations of leishmaniasis in association with IRIS. However, several reports have shown a recovery of CD4+ T-cells specific to Mycobacterium tuberculosis, Mycobacterium avium complex and Cryptococcal neoformans in patients who developed IRIS in association with these infections [18,29,31]. Interestingly, another study found no clear association between the recovery of M. tuberculosis-specific CD4+ T-cells and tuberculosis in association with IRIS .
It has been suggested that the absence of T-cells, such as occurs in the course of AIDS, may lead to the growth of intracellular pathogens inside macrophages that never become fully activated, and thus exert no effector function. When antigen-specific CD4+ T-cells are restored following HAART, these cells may intensely stimulate macrophages and possibly other innate immune cells that produce large amounts of proinflammatory cytokines, resulting in inflammation and tissue destruction .