RESUMEN

Antiretroviral therapy (ART) has represented a major advancement in the care of people living with HIV (PLWHH), resulting in significant reductions in morbidity and mortality through immune reconstitution and attenuation of homeostatic disruption. Importantly, restoration of immune function in PLWH with opportunistic infections occasionally leads to an intense and uncontrolled cytokine storm following ART initiation known as immune reconstitution inflammatory syndrome (IRIS). IRIS occurrence is associated with the severe and rapid clinical deterioration that results in significant morbidity and mortality. Here, we detail the determinants underlying IRIS development in PLWH, compiling the available knowledge in the field to highlight details of the inflammatory responses in IRIS associated with the most commonly reported opportunistic pathogens. This review also highlights gaps in the understanding of IRIS pathogenesis and summarizes therapeutic strategies that have been used for IRIS.

RESUMEN

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage human immunodeficiency virus (HIV) infection who have commenced antiretroviral treatments (ART). Virtually any opportunistic pathogen can provoke this type of immune restoration disorder. In this review, we focus on recent developments in the identification of risk factors for Cryptococcal IRIS and on advancements in our understanding of C-IRIS immunopathogenesis. We overview new findings in blood and cerebrospinal fluid which can potentially be useful in the prediction and diagnosis of cryptococcal meningitis IRIS (CM-IRIS). We assess current therapeutic regimens and novel treatment approaches to combat CM-IRIS. We discuss the utility of biomarkers for clinical monitoring and adjusting treatment modalities in acquired immunodeficiency syndrome (AIDS) patients co-infected with Cryptococcus who have initiated ART.

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Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, who often have some inflammatory condition and, therefore, end up using glucocorticoids, such as dexamethasone and methylprednisolone. Although the effects of this class of molecules during cryptococcosis have been investigated, their consequences for the biology of C. neoformans is less explored. Here, we studied the effects of dexamethasone and methylprednisolone on the metabolism and on the induction of virulence factors in C. neoformans. Our results showed that both glucocorticoids increased fungal cell proliferation and surface electronegativity but reduced capsule and secreted polysaccharide sizes, as well as capsule compaction, by decreasing the density of polysaccharide fibers. We also tested whether glucocorticoids could affect the fungal virulence in Galleria mellonella and mice. Although the survival rate of Galleria larvae increased, those from mice showed a tendency to decrease, with infected animals dying earlier after glucocorticoid treatments. The pathogenesis of spread of cryptococcosis and the interleukin secretion pattern were also assessed for lungs and brains of infected mice. While increases in the spread of the fungus to lungs were observed after treatment with glucocorticoids, a significant difference in brain was observed only for methylprednisolone, although a trend toward increasing was also observed for dexamethasone. Moreover, increases in both pulmonary and cerebral IL-10 production, reduction of IL-6 production but no changes in IL-4, IL-17, and INF-γ were also observed after glucocorticoid treatments. Finally, histopathological analysis confirmed the increase in number of fungal cells in lung and brain tissues of mice previously subjected to dexamethasone or methylprednisolone treatments. Together, our results provide compelling evidence for the effects of dexamethasone and methylprednisolone on the biology of C. neoformans and may have important implications for future clinical treatments, calling attention to the risks of using these glucocorticoids against cryptococcosis or in immunocompromised individuals.

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BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management. METHODS: Plasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model. RESULTS: We identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort. CONCLUSIONS: Systemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART. CLINICAL TRIALS REGISTRATION: NCT00286767.

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Motor neuron disease (MND) have an incidence of 2 in 100 000 persons, resulting in the death of 1 in every 500 people affected. The most common disease in MND spectrum is amyotrophic lateral sclerosis (ALS). We describe the case of an ALS-like syndrome in a HIV patient. This case report presents a 38 years old male from Peru with HIV who after 2 months of combined antiretroviral treatment (cART) initiation was admitted to the hospital for spastic paraplegia. On his first admission, rapid plasma reagent (RPR) was positive and he was treated for neurosyphilis and discharged. Nevertheless, one month after, he was admitted for the second time because paraplegia persisted. Laboratory tests, electromyography and imaging were performed, and ALS was diagnosed. Normally, HIV treated patient with ALS tend to have a better prognosis, however this was not the case. In this case report, we discuss possible association between ALS and immune reconstitution inflammatory syndrome in HIV patients.

RESUMEN

In human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) patients with very low CD4 cell counts, there is a temporal relationship between administration of antiretroviral therapy (ART) and an increased inflammatory response state known as the immune reconstitution inflammatory syndrome (IRIS). The predominant clinical presentation of IRIS is an infectious disease that can be life-threatening. IRIS-related infectious events are distributed similarly between adult males and females, albeit a few studies have shown a skewing toward the male sex in pediatric IRIS. Here, we assessed sex-specific differences in the causes and extent of IRIS infectious events in HIV-infected pediatric patients on ART. We carried out a prospective clinical analysis (from 2000 to 2018) of IRIS-related infectious events after ART in a cohort of 82 Brazilian children and adolescents infected with HIV-1 through mother-to-child transmission as well as a comprehensive cross-referencing with public records on IRIS-related infectious causes in pediatric HIV/AIDS. Twelve events fulfilling the criteria of IRIS occurred exclusively in 11 females in our cohort. The median age at IRIS events was 3.6 years. The infectious causes included Mycobacterium bovis, varicella-zoster virus, molluscum contagiosum virus, human papillomavirus, cytomegalovirus, and Mycobacterium tuberculosis. In one female, there was regional bacillus Calmette-Guérin dissemination and cytomegalovirus esophagitis. There was complete health recovery after 10 IRIS events without the use of corticosteroids or ART interruption. One case of IRIS-associated miliary tuberculosis was fatal. The biological female sex was a significant risk factor for IRIS events (odds ratio: 23.67; 95% confidence interval 95%: 1.341-417.7; P = 0.0016 and P < 0.01 by the multivariable analysis). We observed an effect of the advanced HIV/AIDS variable in IRIS females as compared with non-IRIS females (mean CD4+ T cell percentage 13.36 vs. 18.63%; P = 0.0489 and P < 0.05 by the multivariable analysis), underpinning the exclusively skewed distribution toward the female sex of this cohort. Moreover, the IRIS females in our cohort had higher mean CD4+ T cell percentages before (13.36%) and after IRIS (26.56%) than those of the IRIS females (before IRIS, 4.978%; after IRIS, 13.81%) in previous studies conducted worldwide. The exclusively skewed distribution of pediatric IRIS toward the female sex in the cohort was not linked to preferential X-chromosome inactivation rates. We concluded that the exclusively skewed distribution of pediatric IRIS toward females is associated with more advanced AIDS.

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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.

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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.

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