Cytomegalovirus infection as an underestimated trigger for checkpoint inhibitor-related pneumonitis in lung cancer: a retrospective study.

OBJECTIVES: Checkpoint inhibitor-related pneumonitis (CIP) is a rare but potentially fatal complication of immune checkpoint inhibitors (ICIs). At present, the mechanism of CIP is not completely clear. Cytomegalovirus (CMV) infection is widespread in the population. Chemotherapy and radiotherapy can lead to the reactivation of CMV. We aimed to investigate the association between CMV infection and CIP. MATERIALS AND METHODS: We retrospectively identified all lung cancer patients treated with ICIs at our institute from January 2016 to May 2020. The association between the development of CIP and CMV infection status was analyzed. RESULTS: Among 251 cases analyzed, 29 (11.6%) patients with CIP were identified, of whom 12 (4.78%) cases had grade 3-4 CIP. All 12 patients with grade 3-4 pneumonitis were CMV-IgG-positive, indicating a previous CMV infection. Except for one CMV-DNA-positive patient, the other patients were CMV-DNA-negative. All but one patient was CMV pp65 antigen-positive, indicating an early reactivation of the virus. The histological features of CMV pneumonia were not found in all available lung tissues, including lung transplantation pathology in one patient and lung biopsies in three patients. Except for one patient who received delayed antiviral therapy, the symptoms improved after glucocorticoid combined with antiviral therapy. CONCLUSIONS: The use of ICIs can restore the immune function and cause an immune response to CMV antigen while the infection is still latent. Our study suggests that CIP may be an immune reconstitution syndrome associated with CMV infection. CMV infection may represent a potentially important trigger for CIP. Patients with severe CIP should be vigilant against CMV infection. The early use of glucocorticoid combined with antiviral therapy is pivotal to good prognosis.

Histoplasmosis diseminada asociada a síndrome de reconstitución inmune en un paciente con virus de la inmunodeficiencia humana / Disseminated histoplasmosis associated to immune reconstitution syndrome in a patient with human immunodeficiency virus

Introducción: La histoplasmosis es una micosis profunda o sistémica causada por un hongo dimórfico que se puede diseminar principalmente en pacientes con inmunosupresión, como los que tienen diagnóstico de virus de la inmunodeficiencia humana. El síndrome de reconstitución inmune consiste en un empeoramiento paradójico de una condición conocida o de nueva aparición después del inicio de la terapia antirretroviral. Objetivo: Describir un caso de histoplasmosis diseminada asociada a síndrome de reconstitución inmune en un paciente con infección por virus de la inmunodeficiencia humana. Caso clínico: Paciente masculino de 32 años con diagnóstico de infección por virus de la inmunodeficiencia humana, con cuadro clínico de tres semanas de evolución. Este cuadro inició posterior al comienzo de la terapia antirretroviral, que consistió en pápulo-nódulos umbilicados diseminados, con compromiso pulmonar; además, tenía histopatología y cultivo positivos para Histoplasma capsulatum sl. y prueba de antigenuria para histoplasma también positiva. Se consideró un diagnóstico de histoplasmosis diseminada con presentación cutánea, fue la expresión de un síndrome de reconstitución inmune por desenmascaramiento. Se inició manejo con anfotericina B liposomal y se mantuvo la terapia antirretroviral; posteriormente se continuó el tratamiento con itraconazol durante 12 meses con mejoría de las lesiones. Conclusiones: El diagnóstico clínico, histopatológico y microbiológico fue oportuno; el paciente presentó una adecuada respuesta al tratamiento. Esta es una micosis curable e incluso prevenible, si se diagnostica a tiempo, se inicia tratamiento precoz y se mantiene la terapia retroviral(AU)

Introduction: Histoplasmosis is a deep or systemic mycosis caused by a dimorphic fungus which may disseminate mainly in immunocompromised patients, such as those diagnosed with human immunodeficiency virus. Immune reconstitution syndrome is a paradoxical worsening of a known condition or a condition appearing after the start of antiretroviral therapy. Objective: Describe a case of disseminated histoplasmosis associated to immune reconstitution syndrome in a patient with human immunodeficiency virus infection. Case report: A case is presented of a male 32-year-old patient diagnosed with human immunodeficiency virus with a clinical status of three weeks' evolution. The current status developed after the start of antiretroviral therapy. It consisted in disseminated umbilicated papular nodules with pulmonary involvement, as well as positive Histoplasma capsulatum sl. histopathology and culture, and a positive histoplasma antigen test. A diagnosis of disseminated histoplasmosis with a cutaneous presentation was considered. It was the expression of immune reconstitution syndrome by unmasking. Treatment was started with liposomal amphotericin B, maintaining the antiretroviral therapy. Management was then continued with itraconazole for 12 months with improvement of the lesions. Conclusions: Timely clinical, histopathological and microbiological diagnosis was performed. The patient displayed an adequate response to treatment. This mycosis is curable and even preventable when a diagnosis is made in time, treatment is started early and the retroviral therapy is maintained(AU)

Perforación intestinal por citomegalovirus durante un Síndrome de Reconstitución Inmune / Intestinal Perforation for Cytomegalovirus in Immune Reconstitution Syndrome

RESUMEN El síndrome de reconstitución inmune se produce debido a un aumento de la inmunocompetencia en pacientes previamente inmunocomprometidos. La situación es frecuente tras iniciar un tratamiento antirretroviral de alta eficacia, en pacientes con infección por el virus de inmunodeficiencia humana. En determinados casos, puede conllevar un empeoramiento paradójico de una infección previa. El citomegalovirus, es un germen oportunista que, en el seno de un síndrome de reconstitución inmune, puede dar lugar a perforación intestinal multifocal y peritonitis secundaria de difícil tratamiento. Es más frecuente en pacientes con recuento de linfocitos cooperadores inferior a 50 células/mm3 al iniciar el tratamiento antirretroviral. El objetivo es comunicar dicha situación a través, de un caso clínico para facilitar su sospecha lo más pronto posible, y realizar un tratamiento adecuado. Presentamos el caso de un paciente con virus de inmunideficiencia humana de reciente diagnóstico, en tratamiento con terapia antirretroviral de alta eficacia, que acude a urgencias con abdomen agudo secundario a perforación por citomegalovirus. La infección conlleva importante morbimortalidad, siendo imprescindible un diagnóstico temprano e iniciar precozmente el tratamiento antiviral intravenoso, asociado generalmente a tratamiento quirúrgico(AU)

ABSTRACT Immune reconstitution syndrome occurs due to increased immunocompetence in previously immunocompetent patients. The condition is frequent in patients with human immunodeficiency virus infection who have started a highly active antiretroviral therapy. In certain cases, the syndrome can lead to a paradoxical worsening of a previous infection. Cytomegalovirus is an opportunistic germ that, during an immune reconstitution syndrome, can lead to multifocal intestinal perforation and secondary peritonitis, in cases that are difficult to treat. The syndrome is more frequent in patients with CD4 lymphocyte count below 50/mm3 at the time of starting antiretroviral treatment. The objective is to communicate this situation through a clinical case presentation in order to facilitate suspicion as soon as possible, and to carry out appropriate treatment. We present the case of a patient with a recently diagnosed human immunodeficiency virus, under treatment with highly active antiretroviral therapy, who attended the emergency department with an acute abdomen secondary to perforation due to cytomegalovirus. Infection carries significant morbidity and mortality, and early diagnosis is essential and intravenous antiviral treatment should be started early, generally associated with surgical treatment(AU)

Assessing endocrine and immune parameters in human immunodeficiency virus-infected patients before and after the immune reconstitution inflammatory syndrome

ABSTRACT Objective The present study compares immune and endocrine parameters between HIV-infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 ± 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results Concentrations of IL-6 (7.9 ± 1.9 pg/mL) and IL-18 (951.5 ± 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 ± 1.0 pg/mL and 461.0 ± 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 ± 124.2 vs. 782.5 ± 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 ± 123.8 vs. 1203.7 ± 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response in these patients, which may reflect the severity of the disease.

Síndrome de reconstitución inmune en un paciente de sida con una tuberculosis diseminada / Immune reconstitution syndrome in an AIDS patient with disseminated tuberculosis

La tuberculosis es un factor de riesgo en los pacientes con sida, ya que una vez iniciado el tratamiento antirretroviral pueden de desarrollar un síndrome de reconstitución inmune, lo que favorecería el deterioro del su estado clínico. Se presenta el caso de un paciente masculino, de 24 años de edad, diagnosticado de sida hace 4 años, y tratamiento irregular con antirretrovirales. Acudió al Hospital Universitario Clínico Quirúrgico "Comandante Faustino Pérez Hernández" con fiebre elevada, acompañado de cuadro general, manifestaciones respiratorias y dolor inguinal derecho. En el examen físico se constató un cuadro adénico generalizado, fue hospitalizado para estudio y tratamiento. Se diagnosticó un síndrome de reconstitución inmune en un paciente de sida con una tuberculosis diseminada, el cual fallece a pesar de la terapéutica impuesta. Este síndrome se caracteriza por una restauración gradual de la inmunidad patógeno-específica, donde el sistema inmune es capaz de reconocer patógenos presentes pero clínicamente ocultos. Se asocia a otros factores de riesgo y puede ser letal; de ahí que el reconocimiento oportuno de los pacientes con alto riesgo de contraerlo, así como un adecuado manejo sobre cuándo iniciar la terapia antirretroviral en cada caso específico, es quizá la única forma de prevenir su desarrollo (AU).

Tuberculosis is a risk factor in patients with AIDS, because once the retroviral treatment begins they can develop an immune reconstitution syndrome that would favor the deterioration of their clinical status. The case of a male patient, aged 24 years is presented. He was diagnosed with AIDS four years ago, and was irregularly treated with antiretroviral. The patient assisted the Clinic-surgical University Hospital "Comandante Faustino Pérez Hernández" with high fever accompanied by general characteristics, respiratory manifestations and right inguinal pain. At the physical examination, generalized adenic characteristics were found. A syndrome of immune reconstitution was diagnosed in an AIDS patient with disseminated tuberculosis; the patient died in spite of the imposed therapy. This syndrome is characterized by the gradual restoration of the pathogen-specific immunity, where the immune system is able of recognizing the pathogens that are present but clinically hidden. It is associated to other risk facts and may be lethal; therefore the timely recognition of the patients at high risk of suffering it, and also an adequate management about when to begin the anti-retroviral therapy in each specific case, is the unique way of preventing its development (AU).

Síndrome de reconstitución inmune en un paciente de sida con una tuberculosis diseminada / Immune reconstitution syndrome in an AIDS patient with disseminated tuberculosis

La tuberculosis es un factor de riesgo en los pacientes con sida, ya que una vez iniciado el tratamiento antirretroviral pueden de desarrollar un síndrome de reconstitución inmune, lo que favorecería el deterioro del su estado clínico. Se presenta el caso de un paciente masculino, de 24 años de edad, diagnosticado de sida hace 4 años, y tratamiento irregular con antirretrovirales. Acudió al Hospital Universitario Clínico Quirúrgico "Comandante Faustino Pérez Hernández" con fiebre elevada, acompañado de cuadro general, manifestaciones respiratorias y dolor inguinal derecho. En el examen físico se constató un cuadro adénico generalizado, fue hospitalizado para estudio y tratamiento. Se diagnosticó un síndrome de reconstitución inmune en un paciente de sida con una tuberculosis diseminada, el cual fallece a pesar de la terapéutica impuesta. Este síndrome se caracteriza por una restauración gradual de la inmunidad patógeno-específica, donde el sistema inmune es capaz de reconocer patógenos presentes pero clínicamente ocultos. Se asocia a otros factores de riesgo y puede ser letal; de ahí que el reconocimiento oportuno de los pacientes con alto riesgo de contraerlo, así como un adecuado manejo sobre cuándo iniciar la terapia antirretroviral en cada caso específico, es quizá la única forma de prevenir su desarrollo (AU).

Tuberculosis is a risk factor in patients with AIDS, because once the retroviral treatment begins they can develop an immune reconstitution syndrome that would favor the deterioration of their clinical status. The case of a male patient, aged 24 years is presented. He was diagnosed with AIDS four years ago, and was irregularly treated with antiretroviral. The patient assisted the Clinic-surgical University Hospital "Comandante Faustino Pérez Hernández" with high fever accompanied by general characteristics, respiratory manifestations and right inguinal pain. At the physical examination, generalized adenic characteristics were found. A syndrome of immune reconstitution was diagnosed in an AIDS patient with disseminated tuberculosis; the patient died in spite of the imposed therapy. This syndrome is characterized by the gradual restoration of the pathogen-specific immunity, where the immune system is able of recognizing the pathogens that are present but clinically hidden. It is associated to other risk facts and may be lethal; therefore the timely recognition of the patients at high risk of suffering it, and also an adequate management about when to begin the anti-retroviral therapy in each specific case, is the unique way of preventing its development (AU).

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.

Síndrome de reconstitución inmune / Immune reconstitution syndrome

ResumenEl síndrome inflamatorio de reconstitución inmune se presenta en pacientes con infección por VIH o infección avanzada por el virus, días, semanas o meses después del inicio de la terapia antirretroviral. Se caracteriza por una restauración gradual de la inmunidad patógeno-específica donde el sistema inmune es capaz de reconocer atógenos presentes pero clínicamente ocultos. Característicamente se presenta después de iniciar la TARV cuando el sistema inmunitario comienza a recuperarse. Puede ser leve o potencialmente mortal.

AbstractThe immune reconstitution inflammatory syndrome occurs in patients with advanced HIV infection or HIV infection, days, weeks or months after initiation of antiretroviral therapy. It is characterized by a gradual restoration of pathogen specific immunity where the immune system is able to recognize pathogens presents but clinically occult.Characteristically it occurs after starting antiretroviral therapy when the immune system starts to recover. It can be mild or life threatening.

[Immune reconstitution syndrome in an HIV-infected patient and Pneumocystis jirovecii pneumonia]. / Síndrome de reconstitución inmune en HIV y neumonía por Pneumocystis jirovecii.

Immune reconstitution syndrome is a set of acute inflammatory phenomena that occur as a result of restored immunity generating a paradoxical worsening of a prior infection or an inflammatory process. This syndrome occurs in human immunodeficiency virus infected patients after starting antiretroviral treatment. The most frequent associated infections are those produced by mycobacteria, herpes, cryptococcosis, hepatitis B, cytomegalovirus, Pneumocystis jirovecii and worsening of progressive multifocal leukoencephalopathy secondary to JC virus. We present the case of a patient with human immunodeficiency virus who developed the immune reconstitution syndrome secondary to Pneumocystis jirovecii.

Síndrome de reconstitución inmune en HIV y neumonía por Pneumocystis jirovecii / Immune reconstitution syndrome in an HIV-infected patient and Pneumocystis jirovecii pneumonia

El síndrome de reconstitución inmune es un conjunto de fenómenos inflamatorios agudos, que se producen como consecuencia de la recuperación de la inmunidad, generando un empeoramiento paradójico de una infección o de un proceso inflamatorio previo. En los pacientes infectados con el virus de inmunodeficiencia humana este síndrome se produce luego de iniciado el tratamiento antirretroviral. Las infecciones más frecuentes asociadas a esta entidad son las producidas por micobacterias, herpes, criptococosis, hepatitis B, citomegalovirus, Pneumocystis jirovecii y el empeoramiento de la leucoencenfalopatía multifocal progresiva por el virus JC. Presentamos un paciente con virus de inmunodeficiencia humana que desarrolló el síndrome de reconstitución inmune por Pneumocystis jirovecii.(AU)

Immune reconstitution syndrome is a set of acute inflammatory phenomena that occur as a result of restored immunity generating a paradoxical worsening of a prior infection or an inflammatory process. This syndrome occurs in human immunodeficiency virus infected patients after starting antiretroviral treatment. The most frequent associated infections are those produced by mycobacteria, herpes, cryptococcosis, hepatitis B, cytomegalovirus, Pneumocystis jirovecii and worsening of progressive multifocal leukoencephalopathy secondary to JC virus. We present the case of a patient with human immunodeficiency virus who developed the immune reconstitution syndrome secondary to Pneumocystis jirovecii.(AU)

Síndrome de reconstitución inmune en HIV y neumonía por Pneumocystis jirovecii / Immune reconstitution syndrome in an HIV-infected patient and Pneumocystis jirovecii pneumonia

El síndrome de reconstitución inmune es un conjunto de fenómenos inflamatorios agudos, que se producen como consecuencia de la recuperación de la inmunidad, generando un empeoramiento paradójico de una infección o de un proceso inflamatorio previo. En los pacientes infectados con el virus de inmunodeficiencia humana este síndrome se produce luego de iniciado el tratamiento antirretroviral. Las infecciones más frecuentes asociadas a esta entidad son las producidas por micobacterias, herpes, criptococosis, hepatitis B, citomegalovirus, Pneumocystis jirovecii y el empeoramiento de la leucoencenfalopatía multifocal progresiva por el virus JC. Presentamos un paciente con virus de inmunodeficiencia humana que desarrolló el síndrome de reconstitución inmune por Pneumocystis jirovecii.

Immune reconstitution syndrome is a set of acute inflammatory phenomena that occur as a result of restored immunity generating a paradoxical worsening of a prior infection or an inflammatory process. This syndrome occurs in human immunodeficiency virus infected patients after starting antiretroviral treatment. The most frequent associated infections are those produced by mycobacteria, herpes, cryptococcosis, hepatitis B, cytomegalovirus, Pneumocystis jirovecii and worsening of progressive multifocal leukoencephalopathy secondary to JC virus. We present the case of a patient with human immunodeficiency virus who developed the immune reconstitution syndrome secondary to Pneumocystis jirovecii.

Immune reconstitution inflammatory syndrome in treatment-experienced HIV-infected patients

We described two cases of treatment-experienced HIV-infected patients who presented with cytomegalovirus uveitis and Cryptococcus neoformans adenitis as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during salvage treatment. Little is known about IRIS in highly experienced patients, and this report suggests that IRIS should be considered in this setting if there is a favorable response to salvage therapy

Criptococcosis diseminada y síndrome de reconstitución inmune: presentación de un caso

La criptococosis es una enfermedad oportunista definitoria de sida con bajo incidencia en población pediátrica y de elevada mórbida-mortalidad. Presentamos el caso de un adolescente con diagnóstico reciente de sida con criptococosis diseminada como parte de un síndrome de reconstitución a la séptima semana de inicio de terapia antirretroviral, quien recibió manejo de forma exitosa con anfotericina B en monoterapia y sin complicaciones a un año de seguimiento.

Cryptococcosis is an AIDS-defining opportunistic disease with low incidence in the pediatric population associated with high morbidity and mortality. We report the case of a teenager newly diagnosed with AIDS with disseminated cryptococcosis as part of an immune reconstitution syndrome in the seventh week of initiation of antiretroviral therapy, who received mono therapy with amphotericin B without complications to a year follow up

Immune reconstitution syndrome in patients treated for HIV and tuberculosis in Rio de Janeiro

We made a retrospective longitudinal study from January 2000 to January 2003 to examine cases of immune reconstitution syndrome (IRS) and its incidence rate in tuberculosis (TB)-human immunodeficiency virus (HIV) co-infected patients. The incidence rate (IR) was calculated using a Poisson regression. The confidence interval (CI) that was stipulated was 95 percent. IRS occurred in 10/84 HIV and TB-positive patients; nine of them were on highly active anti-retroviral therapy (HAART) during a mean of 61.7 (±59) days following the introduction of antiretrovirals. Lymph-node enlargement was the sole clinical manifestation. CD4 counts were <100 cells/mm³in 50 percent of the patients, at the time of TB diagnosis. All but two patients were treated with prednisone, and recovered from TB within a mean of 91 days (±30 days). One relapse of TB was observed, but there were no IRS-related deaths. The incidence rate was higher (IR=11.18; CI, 1.41-88.76) in patients that had superficial lymph node enlargement at the moment of TB diagnosis (not associated with TB), extrapulmonary TB (IR=1.97; CI, 0.44-8.79), were antiretroviral naive (IR=1.85; CI, 0.48-7.16), and CD4 counts <100 cells/mm³ (IR=1.50; CI, 0.40-5.59), although with a wide CI. IRS was frequent in our sample, occurred more frequently in HIV-naive patients with lymph-node enlargement and extrapulmonary TB. No cases of new pulmonary lesions or worsening of pulmonary infiltrates were observed.