Leprosy as immune reconstitution inflammatory syndrome in patients living with HIV: Description of French Guiana's cases over 20 years and systematic review of the literature.

BACKGROUND: HIV infection is highly prevalent in French Guiana, a territory where leprosy is also endemic. Since the introduction of Highly Active Antiretroviral Treatment (HAART) in the management of HIV, leprosy has been reported as part of the immune reconstitution inflammatory syndrome (IRIS). METHODOLOGY/PRINCIPAL FINDINGS: We aimed to present a general description of these forms of leprosy as IRIS, highlighting clinical and therapeutic specificities. A retrospective study was conducted in French Guiana, including patients living with HIV (PLHIV) with advanced infection (CD4 < 200/mm3) and developing leprosy or a leprosy reaction within six months of HAART initiation, from 2000 to 2020. Clinical, histological and biological data were collected for all these patients. Six patients were reported in French Guiana. A systematic review of the literature was conducted, and its results were added to an overall analysis. Overall, seventy-three PLHIV were included. They were mainly men (74%), aged 22-54 years (median 36 years), mainly from Brazil (46.5%) and India (32.8%). Most leprosy cases (56.2%) were borderline tuberculoid (BT). Leprosy reactions were frequent (74%), mainly type 1 reaction (T1R) (68.5%), sometimes intense with ulceration of skin lesions (22%). Neuritis was observed in 30.1% of patients. The outcome was always favorable under multidrug therapy (MDT), continuation of HAART and additional corticosteroid therapy in case of neuritis or ulceration. There was no relapse. CONCLUSION: Leprosy as IRIS in PLHIV mainly presents as a BT leprosy in a T1R state, sometimes with ulcerated skin lesions. Response to MDT is usually good. Systemic corticosteroids are necessary and efficient in case of neuritis.

Severe type 1 upgrading leprosy reaction in a renal transplant recipient: a paradoxical manifestation associated with deficiency of antigen-specific regulatory T-cells?

BACKGROUND: Due to its chronic subclinical course and large spectrum of manifestations, leprosy often represents a diagnostic challenge. Even with proper anti-mycobacteria treatment, leprosy follow up remains challenging: almost half of leprosy patients may develop reaction episodes. Leprosy is an infrequent complication of solid organ transplant recipients. This case report illustrates the challenges in diagnosing and managing leprosy and its reactional states in a transplant recipient. CASE PRESENTATION: A 53-year-old man presented 34 months after a successful renal transplantation a borderline-tuberculoid leprosy with signs of mild type 1 upgrading reaction (T1R). Cutaneous manifestations were atypical, and diagnosis was only made when granulomatous neuritis was found in a cutaneous biopsy. He was successfully treated with the WHO recommended multidrug therapy (MDT: rifampicin, dapsone and clofazimine). However he developed a severe T1R immediately after completion of the MDT but no signs of allograft rejection. T1R results from flare-ups of the host T-helper-1 cell-mediated immune response against Mycobacterium leprae antigens in patients with immunologically unstable, borderline forms of leprosy and has been considered an inflammatory syndrome in many aspects similar to the immune reconstitution inflammatory syndromes (IRS). The T1R was successfully treated by increasing the prednisone dose without modifying the other immunosuppressive drugs used for preventing allograft rejection. Immunological study revealed that the patient had a profound depletion of both in situ and circulating regulatory T-cells and lack of expansion of the Tregs upon M. leprae stimulation compared to T1R leprosy patients without iatrogenic immunosuppression. CONCLUSIONS: Our case report highlights that leprosy, especially in the transplant setting, requires a high degree of clinical suspicion and the contribution of histopathology. It also suggests that the development of upgrading inflammatory syndromes such as T1R can occur despite the sustained immunosuppressors regimen for preventing graft rejection. Our hypothesis is that the well-known deleterious effects of these immunosuppressors on pathogen-induced regulatory T-cells contributed to the immunedysregulation and development T1R.

Erythema Nodosum Leprosum-Like Lesions Are a Histopathologic Pattern in Whipple's Disease and a Sign of the Immune Reconstitution Inflammatory Syndrome: A Case Series and Review of the Literature.

Inflammatory and subcutaneous nodules can arise in treated and untreated cases of Whipple disease (WD). The inflammatory immune reconstitution syndrome describes paradoxical clinical inflammatory worsening of a preexisting condition because of a return of immune function. Clinicopathologic examination of 4 patients with WD who presented with erythema nodosum leprosum (ENL)-like lesions and the findings of a systematic review of this phenomenon revealed that ENL-like lesions occurred in predominantly middle-aged male patients who suffered from WD, mostly on the legs. Patients showed a nonvasculitic, mostly septal panniculits with neutrophils, macrophages, and lymphocytes. Numerous bacteria-laden periodic acid-Schiff + macrophages and free bacilli were detected in the dermis, as well as subcutaneous septae and adipose lobules. These lesions occurred in both untreated and treated patients as part of inflammatory immune reconstitution syndrome. In conclusion, ENL-like lesions represent a characteristic histopathologic pattern associated with WD, which can occur in different contexts whenever there is a change in the immunological status of the patient. This change can be triggered by antimicrobial treatment, immunomodulatory and immunosuppressant therapy, or occur spontaneously, rarely.

Nerve abscess in Hansen's disease as part of immune reconstitution inflammatory syndrome: a case report.

Immune reconstitution inflammatory syndrome is an inflammatory reaction in HIV-infected patients after initiation of antiretroviral therapy resulting from restored immunity to specific infectious or non-infectious antigens. A 36-year-old male patient on highly active antiretroviral therapy of six months duration, presented with reddish, tender lesions over medial aspect of arm and a single, anaesthetic patch. Tender fluctuant swellings were seen on the medial aspect of left forearm. A few of them had ruptured spontaneously discharging pus. A skin biopsy from the anaesthetic patch showed caseating epitheloid granulomas. A diagnosis of Hansen's disease borderline tuberculoid in type 1 reversal reaction, with formation of nerve abscess due to Immune Reconstitution Inflammatory Syndrome was made. The patient was started on multibacillary multidrug therapy as per WHO guidelines and highly active antiretroviral therapy was continued.

Lepromatous leprosy and human immunodeficiency virus co-infection associated with phenomenon of Lucio versus immune reconstitution inflammatory syndrome / Lepra lepromatosa y coinfección con el virus de la inmunodeficiencia humana asociada a fenómeno de Lucio versus síndrome inflamatorio de reconstitución inmune

Diffuse lepromatous leprosy (DLL) is a severe clinical outcome of lepromatous leprosy (LL). The aetiologic cause is believed to be different from Mycobacterium leprae. A new species, Mycobacterium lepromatosis, was identified from a group of Mexican patients with DLL, and severe leprosy reactional state type 3 (Lucio's phenomenon). However, a total sequencing of its genome is necessary to prove the existence of this new species. This is a report on a non-typical Colombian case of leprosy - HIV coinfection, associated with an immune reconstitution inflammatory syndrome clinically compatible with a leprosy reaction type 3 or Lucio's phenomenon.

La lepra difusa (LLD) es una variedad de la lepra lepromatosa (LL), frecuente enMéxico. El agente etiológico se cree que es diferente a Mycobacterium leprae y se considerauna especie nueva denominada Mycobacterium lepromatosis, hecho que no se ha comprobado.El reporte de este caso se realiza para dar a conocer el cuadro clínico atípico que presentóuna paciente colombiana con coinfección VIH---LL variedad difusa (LLD), asociado a síndromede reconstitución inmunológica, compatible clínicamente con una leprorreacción tipo 3 o fenó-meno de Lucio.

Clinical manifestations of leprosy after BCG vaccination: an observational study in Bangladesh.

BACKGROUND: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy, developed symptoms 2-10 months after vaccination. This study describes contacts of leprosy patients in Bangladesh who developed leprosy within 12 weeks after receiving a single BCG dose. METHODS: A cluster RCT in Bangladesh aims to study the effectiveness of the BCG vaccine versus BCG in combination with single dose rifampicin (SDR) given 2 to 3 months after BCG, in the prevention of leprosy among contacts of newly diagnosed leprosy patients. During the first 1,5 years of this ongoing trial we identified contacts who developed leprosy within the first 12 weeks after receiving BCG vaccination, the timeframe before SDR is given. RESULTS: We identified 21 contacts who developed leprosy within 12 weeks after BCG vaccination among 5196 vaccinated contacts (0.40%). All 21 cases presented with paucibacillary (PB) leprosy, including children and adults. About half of these cases had previously received BCG vaccination as indicated by the presence of a BCG scar; 43% presented with signs of nerve function impairment and/or Type 1 (reversal) reaction, and 56% of the index patients had multibacillary (MB) leprosy. CONCLUSION: An unexpectedly high proportion of healthy contacts of leprosy patients presented with PB leprosy within 12 weeks after receiving BCG vaccination, possibly as a result of boosted cell-mediated immunity by homologues of Mycobacterium leprae antigens in BCG. Various immunological mechanisms could underlie this phenomenon, including an immune reconstitution inflammatory syndrome (IRIS). Further studies are required to determine whether BCG vaccination merely altered the incubation period or actually changed the course of the infection from self-limiting, subclinical infection to manifest disease.

Immune reconstitution inflammatory syndrome associated with bacterial infections.

INTRODUCTION: Immune reconstitution inflammatory syndrome (IRIS) is defined by various clinical manifestations following the initiation of antiretroviral treatment (ART) in HIV patients primarily infected with Mycobacteria. IRIS has clinical similarities with lepromatous reactions in patients with leprosy following antibiotic initiation. AREAS COVERED: Tuberculosis and more rarely lepromatous leprae and Whipple's disease are the main diseases caused by actinobacteria associated with IRIS, regardless of HIV status. The pathogenesis of this syndrome remains complex and partially understood. The treatment for IRIS is non-evidence-based, except for corticosteroids in tuberculosis-IRIS. Thalidomide and other immunomodulatory drugs have been successfully used in case series. EXPERT OPINION: IRIS is mainly observed during infections (viral, fungal or bacterial) which involve inefficient macrophages for the clearance of bacteria, namely Actinobacteria such as Mycobacterium leprae, M. tuberculosis and Tropheryma whipplei. The restoration of macrophage competence after ART or antibiotic initiation results from a complex mechanism, probably involving a sudden and violent immune reaction with a cytokine storm, such as TNF-α and IFN-γ. This overreaction might be controlled using corticosteroids and thalidomide.

Síndrome inflamatória da recuperação imune em hanseníase: relato de caso clínico / Immune reconstitution inflammatory syndrome in leprosy: report of a clinical case

Relatamos a ocorrência da Síndrome Inflamatória da RecuperaçãoImune (IRIS), após reversão de agranulocitose, induzida por poliquimioterapia,em paciente do sexo feminino acometida por hanseníasedimorfa-virchowiana. Propomos que em todos os pacientes submetidosà poliquimioterapia para hanseníase sejam efetuados periodicamenteexames laboratoriais que possam identificar precocementedistúrbios hematológicos graves

We report the occurrence of Immune Reconstitution InflammatorySyndrome (IRIS) after reversal of agranulocytosis provoked by drugor drugs used in the treatment of leprosy. After suspension of thedrugs under suspicion and the recovery of the hematologic disturbanceand as consequence the restoration of the immune conditionwe started an alternate treatment for Hansen’s disease. Takingthis case as an example, we propose that all patients with leprosyand under treatment with drugs such as dapsone and/ or rifampicinshould have a periodical hemogram to identify premature hematologicanomalies.

Ulcerating type 1 lepra reaction mimicking lazarine leprosy: an unusual presentation of immune reconstitution inflammatory syndrome in an HIV-infected patient.

Leprosy maybe "unmasked" in the context of immune reconstitution inflammatory syndrome and treating dermatologists, particularly in highly endemic areas for Hansen's disease, need to be cognizant to this possibility. It may also reflect emergence of a previously clinically silent infection in the course of immunologic restoration.

Skewing of the CD4(+) T-cell pool toward monofunctional antigen-specific responses in patients with immune reconstitution inflammatory syndrome in The Gambia.

BACKGROUND: A common complication of starting antiretroviral therapy (ART) for human immunodeficiency virus (HIV) is the development of immune reconstitution inflammatory syndrome (IRIS) in approximately 25% of patients. Despite similarities with paradoxical reactions to tuberculosis and reversal reactions in leprosy, the exact mechanisms, and therefore potential determinants, of IRIS are still unknown. METHODS: In this longitudinal cohort study, we analyzed 20 patients who developed IRIS following initiation of ART and 16 patients who did not, matched for ART time point. Peripheral blood mononuclear cells were stimulated overnight with a positive control antigen and 2 tuberculosis-specific antigens (purified protein derivative [PPD] and ESAT-6/CFP10), followed by polychromatic flow cytometry for analysis of cytokine production from CD4(+) and CD8(+) T cells. RESULTS: Responses to PPD were significantly higher in IRIS patients compared to controls during the IRIS time point, but CD4(+) and CD8(+) T-cell responses to the positive control stimulation were significantly lower in IRIS patients at all time points. Furthermore, whereas control patients had rejuvenated polyfunctional T-cell responses by 3 months after ART, IRIS patients were strikingly monofunctional (generally interferon γ alone), even up to 6 months of ART in response to all stimulations. CONCLUSIONS: Our findings suggest that the peripheral T-cell responses to the underlying pathogen are exaggerated in IRIS patients but that the overall quality of the peripheral T-cell pool is significantly reduced compared to non-IRIS patients. Furthermore, these effects are apparent at least up to 3 months after cessation of IRIS.

Immune reconstitution reactions in human immunodeficiency virus-negative patients: report of a case and review of the literature.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is a phenomenon initially described in patients with human immunodeficiency virus. Upon initiation of combination antiretroviral therapy, recovery of cellular immunity triggers inflammation to a preexisting infection or antigen that causes paradoxical worsening of clinical disease. A similar phenomenon can occur in human immunodeficiency virus-negative patients, including pregnant women, neutropenic hosts, solid-organ or stem cell transplant recipients, and patients receiving tumor necrosis factor inhibitors. OBSERVATIONS: We report a case of leprosy unmasking and downgrading reaction after stem cell transplantation that highlights some of the challenges inherent to the diagnosis of IRIS, especially in patients without human immunodeficiency virus infection, as well as review the spectrum of previously reported cases of IRIS reactions in this population. CONCLUSIONS: The mechanism of immune reconstitution reactions is complex and variable, depending on the underlying antigen and the mechanism of immunosuppression or shift in immune status. Use of the term IRIS can aid our recognition of an important phenomenon that occurs in the setting of immunosuppression or shifts in immunity but should not deter us from thinking critically about the distinct processes that underlie this heterogeneous group of conditions.

Enfermedad de Hansen y VIH: un caso de síndrome inflamatorio de reconstitución inmune (IRIS) / No disponible

El síndrome inflamatorio de reconstitución inmune (IRIS) es la expresión aguda sintomática de una infección latente, durante la recuperación del sistema inmune como respuesta a la terapia antirretroviral altamente agresiva (HAART). Muchas infecciones oportunistas pueden desencadenar un IRIS. Existe un número limitado de casos donde se observa la co-infección VIH y M. leprae. Se presenta un caso único de IRIS en un paciente co-infectado con el VIH y M. leprae que presenta una exacerbación de su enfermedad de Hansen dentro de los 6 meses de haber iniciado terapia HAART (AU)

Immune reconstitution inflammatory syndrome (IRIS) is an acute symptomatic expression of a latent infection during the recovery of the immune system usually as a response to highly aggressive antiretroviral therapy (HAART). Opportunistic infections can trigger IRIS. There have been a limited number of case reports reporting the presentation of the co-infection of HIV and M. leprae. We report a unique case of IRIS in a patient coinfected with HIV and M. leprae that presents an exacerbation of Hansen's disease within 6 months after starting HAART therapy (AU)

Tuberculoid leprosy and cytomegalovirus retinitis as immune restoration disease in a patient with AIDS.

Here we report a unique case of tuberculoid leprosy and cytomegalovirus retinitis in a 27-year-old female patient with AIDS, suggestive of highly active antiretroviral therapy (HAART)-induced immune restoration disease. After initiation of HAART, the patient presented with decreased visual acuity, hypoesthetic patch with local nerve thickening, and an increase in her CD4+ T cell count. On further investigations cytomegalovirus retinitis and tuberculoid leprosy were confirmed. To our knowledge no case with such a co-existence has previously been reported.

Treated Whipple disease with erythema nodosum leprosum-like lesions: cutaneous PAS-positive macrophages slowly decrease with time and are associated with lymphangiectases: a case report.

Pathologically, Whipple disease (WD) is characterized by the accumulation of myriad macrophages parasitized by Tropheryma whipplei (TW) bacilli denoted by periodic acid-Schiff (PAS) positivity. These PAS+ macrophages are typically found in the duodenum associated with lymphangiectasia. Recently, we reported the presence of PAS+ macrophages and free TW in erythema nodosum leprosum (ENL)-like lesions and normal skin in a patient with WD who suffered from the immune reconstitution inflammatory syndrome (IRIS). We extend that report by describing the clinical and pathologic findings over 5 years of follow-up. First, the IRIS gradually diminished and abated over 18-month time. Second, at no point did WD recur, and all duodenal and skin biopsies tested by polymerase chain reaction were negative for TW DNA. Third, PAS+ macrophages were identified in 26 of 27 skin biopsies (96%) and decreased along with free TW over time. Fourth, ENL-like lesions had significantly greater numbers of PAS+ macrophages than normal skin. Moreover, normal abdominal skin (region of ENL-like lesions) had greater PAS+ counts than arm skin (not a site of IRIS). Last, lymphangiectases, a histologic sign of lymphostasis, was found in all skin biopsies. Overall, these findings implicate bacillary burden as a factor in the immune tolerance to live TW in active WD and the initiation of ENL-like nodules against dead/nonreplicative TW in treated WD. In addition, poor lymphatic drainage is likely responsible for the gradual clearance of TW from the skin and the impaired delayed-type hypersensitivity reaction (absence of activated macrophages) against TW found in WD, presumptively due to reduced/absent immune cell trafficking necessary for lymphocyte-macrophage interactions and induction of adaptive immunity.

Evaluation of cellular phenotypes implicated in immunopathogenesis and monitoring immune reconstitution inflammatory syndrome in HIV/leprosy cases.

BACKGROUND: It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR). However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. METHODS/PRINCIPAL FINDINGS: Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%), dropping significantly (p<0,05) during post-IRIS/RR moments (median: 29,7%). Furthermore, an increase of cellular activation seems to occur prior to IRIS/RR. CONCLUSION/SIGNIFICANCE: These data suggest CD38 expression in CD8+ T cells interesting tool identifying HIV/leprosy individuals at risk for IRIS/RR. So, a comparative investigation to leprosy patients at RR should be conducted.

Immune reconstitution inflammatory syndrome in leprosy.

Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical deterioration in the clinical status of a patient infected with human immunodeficiency virus (HIV) on highly active antiretroviral treatment (HAART). The immune suppression caused by the virus can initially suppress the clinical manifestations of leprosy which can then be unmasked after treatment with HAART or an inflammatory reaction can occur in the initial months of therapy, resulting from dysregulated recovery of immunity to specific antigens. Both these conditions are identified as IRIS in leprosy. Though this syndrome is a widely recognized entity presently, there is still a lack of universally acceptable diagnostic criteria for the condition. The first case published case of leprosy- associated immune reconstitution disease was reported in 2003 and about 47 confirmed cases of IRIS in leprosy have been reported since then, mostly from Brazil and India. Anti-inflammatory drugs and steroids are the drugs of choice in inflammatory episodes with continuation of antiretroviral therapy. With increasing affordability of antiretroviral therapy, clinicians will put more and more number of human immunodeficiency virus infected patients on therapy and hence an increase in the incidence of IRIS is expected. Therefore, it is important to understand all facets of this syndrome which is becoming more prevalent with each passing day.

Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy.

BACKGROUND: Tuberculosis-HIV (TB-HIV) coinfection remains an important cause of mortality in antiretroviral therapy (ART) programs. In a cohort of TB-HIV-coinfected patients starting ART, we examined the incidence and predictors of early mortality. METHODS: Consecutive TB-HIV-coinfected patients eligible for ART were enrolled in a cohort study at the Mulago National Tuberculosis and Leprosy Program clinic in Kampala, Uganda. Predictors of mortality were assessed using Cox proportional hazards analysis. RESULTS: Three hundred and two patients [median CD4 count 53 cells/µL (interquartile range, 20-134)] were enrolled. Fifty-three patients died, 36 (68%) of these died within the first 6 months of TB diagnosis. Male sex [hazard (HR): 2.19; 95% confidence interval (CI): 1.19 to 4.03; P = 0.011], anergy to tuberculin skin test [HR: 2.59 (1.10 to 6.12); P = 0.030], a positive serum cryptococcal antigen result at enrollment (HR: 4.27; 95% CI: 1.50 to 12.13; P = 0.006) and no ART use (HR: 4.63; 95% CI: 2. 37 to 9.03; P < 0.001) were independent predictors of mortality by multivariate analysis. Six (10%) patients with TB immune reconstitution inflammatory syndrome died, and in most, an alternative contributing cause of death was identified. CONCLUSIONS: Mortality among these TB-HIV-coinfected patients was high particularly when presenting with advanced HIV disease and not starting ART, reinforcing the need for timely and joint treatment for both infections. Screening for a concomitant cryptococcal infection and antifungal treatment for patients with cryptococcal antigenemia may further improve clinical outcome.

Leprosy and HIV coinfection: a critical approach.

An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought.

Immune reconstitution inflammatory syndrome and tropical dermatoses.

The human immunodeficiency virus (HIV) pandemic has disproportionately affected tropical regions of the world, where dermatoses, such as leprosy and leishmaniasis, rarely encountered in temperate climates, are endemic. Although the introduction of highly active antiretroviral therapy (HAART) has been lifesaving, a few patients undergoing HAART experience clinical deterioration caused by immune reconstitution inflammatory syndrome (IRIS). This article explores the range of tropical dermatoses that are reported to date with associated IRIS events.