Protocol for the systematic review of the Pneumocystis jirovecii-associated pneumonia in non-HIV immunocompromised patients.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a well-known and frequent opportunistic infection in HIV patients. However, there has been an increase in the number of reports of PJP in other immunosuppressed patients with autoimmune inflammatory disorders or because of chemotherapy and high doses of steroids, especially when used in combination as part of immunosuppressive therapy. OBJECTIVE: Despite the increasing importance of PJP in non-HIV patients, there is a lack of comprehensive and updated information on the epidemiology, pathogenesis, diagnosis, microbiology, treatments, and prophylaxis of this infection in this population. Therefore, the objective of this systematic review is to synthesize information on these aspects, from a perspective of evidence-based medicine. METHODS: The protocol is prepared following the preferred reporting items for systematic reviews and meta-analyses (PRISMA-P) guidelines. We will perform a systematic review of literature published between January 2010 and July 2023, using the databases PubMed, Google Scholar, ScienceDirect, and Web of Science. In addition, manual searches will be carried out through related articles, and references to included articles. The main findings and clinical outcomes were extracted from all the eligible studies with a standardized instrument. Two authors will independently screen titles and abstracts, review full texts, and collect data. Disagreements will be resolved by discussion, and a third reviewer will decide if there is no consensus. We will synthesize the results using a narrative or a meta-analytic approach, depending on the heterogeneity of the studies. EXPECTED RESULTS: It is expected that this systematic review will provide a comprehensive and up-to-date overview of the state-of-the-art of PJP in non-HIV patients. Furthermore, the study will highlight possible gaps in knowledge that should be addressed through new research. CONCLUSIONS: Here, we present the protocol for a systematic review which will consider all existing evidence from peer-reviewed publication sources relevant to the primary and secondary outcomes related to diagnosing and managing PJP in non-HIV patients.

Progression of Type 2 Helper T Cell-Type Inflammation and Airway Remodeling in a Rodent Model of Naturally Acquired Subclinical Primary Pneumocystis Infection.

Subclinical primary Pneumocystis infection is the most common pulmonary infection in early infancy, making it important to determine whether it damages the lung. Pneumocystis peaks at 2 to 5 months of age, when respiratory morbidity coincidently increases. We have documented that Pneumocystis increases mucus production in infant lungs, and animal models reveal lung lesions that warrant characterization. Herein, immunocompetent rats infected at birth with Pneumocystis by cohabitation, to resemble community-acquired infection, underwent lung assessments at 45, 60, and 75 days of age. Lungs fixed by vascular perfusion to prevent collapse during necropsy were used for morphometry evaluations of mucus production, airway epithelial thickening, perivascular and peribronchiolar inflammation, and structural airway remodeling. Changes in these histologic features indicate lung disease. Selected immune markers were assessed in parallel using fresh-frozen lung tissue from sibling rats of the same cages. Sequential activation of NF-κB and an increased Gata3/T-bet mRNA level ratio, consistent with a type 2 helper T-cell-type inflammatory response, and subacute fibrosis were recognized. Therefore, documenting subclinical Pneumocystis infection induces lung disease in the immunocompetent host. Taken together with the peak age of primary Pneumocystis infection, results warrant investigating the clinical impact of this often subclinical infection on the severity of respiratory diseases in early infancy. This model can also be used to assess the effects of airway insults, including coinfections by recognized respiratory pathogens.

[Pneumocystis jiroveci infection in patients with and without HIV: A comparison]. / Comparación de infecciones por Pneumocystis jiroveci en pacientes con y sin diagnóstico de infección por VIH.

BACKGROUND: Respiratory infection caused by Pneumocystis jiroveci is a common opportunistic infection in patients with human immunodeficiency virus (HIV) with CD4 counts < 200 cells/mm(3). However, it has also been reported in patients with other causes of immunosuppression. OBJECTIVES: To compare the characteristics, severity and mortality of respiratory infection by P. jiroveci in patients with and without HIV infection. METHODS: Retrospective cohort follow-up of adult patients admitted to our hospital with infection by P. jiroveci since 2006 to 2013. RESULTS: We included 82 patients with respiratory infection by P. jiroveci of which 55% (45) were not infected with HIV. In this group, 68.8% (31) had diagnosis of cancer and 20% (9) received solid-organ transplant. 57.9% (26) were hospitalized in an intensive care unit. 42.2% (19) suffered multiple organ failure (MOF), 46.7% (21) required mechanical ventilation (MV) and 40.9% (18) inotropic drugs. Mortality was 33.3% (15). Statistically significant differences were observed between groups in age (p < 0.001), requirement of MV (p < 0.001) inotropic drugs (p 0.001) and MOF (p < 0.001). Mortality was higher in the HIV-positive group, reaching statistical significance (p 0.007). CONCLUSION: Pneumocystis pneumonia mortality was higher in patients without HIV, who suffered more complications and progression to respiratory failure with MOF.

Características de la neumonía por Pneumocystis jiroveci en adultos con SIDA con y sin terapia antiretroviral / Pneumocystis jiroveci pneumonia characteristics in adults with AIDS with or without antiretroviral therapy

La terapia antiretroviral (TARV) de alta actividad cambió la epidemiología de la neumonía por Pneumocystis jiroveci (NPj) en pacientes con SIDA. La incidencia global ha descendido y ahora prevalece en pacientes sin TARV o con fracaso de ésta. Además, la restauración inmune por TARV genera una forma de NPj incluida en los síndromes inflamatorios por restauración inmune (SIRI). A fines del 2004, 75,5% de pacientes con infección por VIH en control en el Hospital de Enfermedades Infecciosas Dr. Lucio Córdova tenían TARV. Esta serie describe las características clínicas de la NPj, comparando el grupo con TARV (n: 6) y sin TARV (n: 12). De aquellos con TARV, 83,3% (5/6) estaban con fracaso inmunológico y 16,7% (1/6) en éxito virológico. El recuento de CD4 fue bajo en ambos grupos (mediana 20 céls/mm3 sin TARV y 51 céls/mm3 con TARV). No hubo diferencia en la mayoría de las características de la NPj, tampoco casos de SIRI. El grupo con TARV tuvo menos severidad y complicaciones, y menos indicación de corticoterapia (p 0,023).

[Pneumocystis jiroveci pneumonia characteristics in adults with AIDS with or without antiretroviral therapy]. / Características de la neumonía por Pneumocystis jiroveci en adultos con SIDA con y sin terapia antiretroviral.

Highly active antiretroviral therapy (HAART) has changed the epidemiology of Pneumocystis jiroveci pneumonia (PCP) in AIDS patients. Global incidence of PCP has decreased and now it is prevalent in AIDS patients who do not receive HAART or are unsuccessfully treated with persistent immune depression. Moreover, the immunologic response to HAART has caused a PCP form which is included in the immune restoration inflammatory syndrome (IRIS). As of late 2004, 75.5% of patients cared for at Dr. Lucio Córdova Infectious Diseases Hospital were receiving HAART. This study compares PCP clinical characteristics in patients under the effect of HAART (n: 6) with those without antiretroviral therapy (n: 12). Among those with HAART, 83.3% (5/6) were without immunologic responses and 16.7% with virologic response. The median CD4 counts were low in both groups: 20 cells/mm(3) without HAART and 51 cells/mm(3) with HAART. There were no differences in most of PCP characteristics, and no IRIS cases were observed. HAART-receiving group had less severe disease and lower frequency of both, complications and steroidal therapy prescription (P 0.023).

Immunohistochemical study of the cellular immune response in human Pneumocystis carinii pneumonia

OBJETIVO: Trabalhos experimentais demonstram que as defesas do hospedeiro frente ao Pneumocystis carinii incluem interações complexas entre as células imunes, principalmente linfócitos TCD4+ e macrófagos alveolares. Sendo esse um agente importante associado às imunodeficiências, nosso objetivo foi caracterizar a resposta inflamatória em pulmão de necrópsias de pacientes com AIDS. MÉTODOS: Foram selecionadas 25 necrópsias com diagnóstico de pneumonia por Pneumocystis carinii para pesquisa imuno-histoquímica de linfócitos TCD4+, TCD8+, macrófagos CD68+, células NK CD57+ e células com expressão de TNF-alfa. As células imunomarcadas foram quantificadas e analisadas estatisticamente. RESULTADOS: Todos os espécimes evidenciaram elevado parasitismo na luz dos alvéolos. Observou-se espessamento septal com infiltrado inflamatório constituído predominantemente por linfócitos e macrófagos. Houve diminuição no número de linfócitos TCD4+ e aumento de linfócitos TCD8+, macrófagos e células NK. No septo alveolar freqüentemente observaram-se células expressando TNF-alfa. CONCLUSÕES: A imunossupressão relacionada à AIDS induz a diminuição de linfócitos TCD4+ e favorece a permanência de elevado parasitismo. Os componentes celulares que caracterizam o infiltrado inflamatório contribuem para os danos irreversíveis no pulmão desses pacientes.

Defective antigen-induced lymphocyte proliferation in the X-linked hyper-IgM syndrome.

We examined T-cell proliferation in five patients with X-linked hyper-IgM syndrome (XHIM), using a panel of antigens and lectins. All patients had impaired antigen-induced proliferation, whereas their lectin responses were normal. Thus, in addition to severely depressed antibody responses, patients with XHIM have a defect in antigen-specific T-cell proliferation, which may explain their susceptibility to pathogens such as Pneumocystis carinii.

Pneumocystis carinii pneumonia versus wasting syndrome among AIDS cases in Puerto Rico: a survival analysis.

OBJECTIVE: To compare mortality of wasting syndrome (WS) versus Pneumocystis carinii pneumonia (PCP) in AIDS patients reported in Puerto Rico after controlling for gender, age, and CD4 levels. METHODS: AIDS patients for which a diagnosis of WS (n = 1,180) or PCP (n = 765), who were reported to the AIDS Surveillance System of Puerto Rico between 1989 and 1992, were used to analyze the mortality risk among these diagnoses using a Cox's proportional hazard regression model. RESULTS: Cox model showed that WS patients had a 14% to 33% reduction in mortality risk compared with PCP patients after adjusting for gender and age (95% confidence level). Mortality risks for males were 18% (95% CI: 1%, 39%) higher than females risk after adjusting for AIDS defining condition and age. It was shown that a decrease in 100 CD4 cells increased the mortality by 37% (95% CI: 16%, 62%) after adjusting for AIDS defining conditions, gender, and age.

Pneumocystis carinii pneumonia versus wasting syndrome among AIDS cases in Puerto Rico: a survival analysis

OBJECTIVE: To compare mortality of wasting syndrome (WS) versus Pneumocystis carinii pneumonia (PCP) in AIDS patients reported in Puerto Rico after controlling for gender, age, and CD4 levels. METHODS: AIDS patients for which a diagnosis of WS (n = 1,180) or PCP (n = 765), who were reported to the AIDS Surveillance System of Puerto Rico between 1989 and 1992, were used to analyze the mortality risk among these diagnoses using a Cox's proportional hazard regression model. RESULTS: Cox model showed that WS patients had a 14 per cent to 33 per cent reduction in mortality risk compared with PCP patients after adjusting for gender and age (95 per cent confidence level). Mortality risks for males were 18 per cent (95 per cent CI: 1 per cent, 39 per cent) higher than females risk after adjusting for AIDS defining condition and age. It was shown that a decrease in 100 CD4 cells increased the mortality by 37 per cent (95 per cent CI: 16 per cent, 62 per cent) after adjusting for AIDS defining conditions, gender, and age.

Encephalopathy in children with perinatally acquired human immunodeficiency virus infection. Pediatric Spectrum of Disease Clinical Consortium.

OBJECTIVE: To define the incidence, characteristics, and survival of children with perinatally acquired human immunodeficiency virus (HIV) infection and encephalopathy. DESIGN: Cross-sectional and longitudinal data collected from 1811 HIV-infected children in a multicenter active surveillance study. SETTING: Health departments and medical centers in six areas of the United States. RESULTS: HIV encephalopathy was diagnosed in 178 (23%) of 766 children with perinatally acquired immunodeficiency syndrome (AIDS). The median age at diagnosis of encephalopathy was 19 months. Among infected children, the estimated risk of having HIV encephalopathy by age 12 months was 4.0% (95% confidence interval, 2.6% to 6.0%). Children with HIV encephalopathy had more hospitalizations (median, 4) than children with other AIDS-defining conditions (median, 2; p = 0.002) and lower CD4+ T-lymphocyte counts in the first year of life (median, 444 cells/mm3). Estimated median survival after diagnosis was 22 months, similar to the 20 months for children with Pneumocystis carinii pneumonia. CONCLUSION: HIV encephalopathy in children with perinatally acquired AIDS is a common condition and is associated with severe morbidity evidenced by frequent hospitalizations, severe immunodeficiency, and short survival.

Pneumocystis carinii pneumonia in a term newborn infant with a transiently depressed T lymphocyte count, primarily of cells carrying the CD4 antigen.

A term infant without infection by human immunodeficiency virus had pneumocystis pneumonia at 17 days of life. Initial counts of T lymphocytes carrying the CD4 antigen were approximately 50% of the lower limits of normal; later the counts of T lymphocytes carrying the CD3 and CD8 antigens decreased as well. By 7 weeks after resolution of the pneumonia, CD3+, CD4+ and CD8+ cell counts had returned to normal. These observations suggest that a primary transient deficiency of T cell production or maturation, especially involving CD4+ cells, may occur in otherwise normal newborn infants.

Dysfunction of natural killer cells in human immunodeficiency virus-infected children with or without Pneumocystis carinii pneumonia.

The development of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus (HIV)-infected children with normal T-cell numbers is contrary to previous experience with HIV-infected adults, in whom low CD4+ T-cell numbers predict susceptibility to PCP. To determine whether PCP in HIV-infected children reflects a qualitative T-cell or other immune defect, we studied four HIV-infected children who also had PCP and 10 others without PCP for T-cell and natural killer (NK) cell function. Most of the HIV-infected children had normal T-cell numbers for age, and all had CD4+ T-cell numbers greater than those predictive of PCP in HIV-infected adults. All HIV-infected children had normal T-cell function in vitro. The HIV-infected children as a whole had deficient NK cell cytolysis. We obtained a significant interactive effect of age by health status for NK cell function between patients and age-matched control subjects. All HIV-infected children with defective NK cell function failed to enhance their NK cell cytolysis when their mononuclear cells were stimulated with recombinant interferon alfa (r-IFN-alpha). This NK cell defect in HIV-infected children may facilitate the development of secondary infection.

Predicting risk of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected children.

Effective prophylaxis exists against Pneumocystis carinii pneumonia, a major cause of illness and death among human immunodeficiency virus-infected children and adults. While adults with CD4 counts less than 0.2 x 10(9)/L are at highest risk for Pneumocystis carinii, clinical or laboratory markers of high risk in children infected with the human immunodeficiency virus have not yet been established. A chart review of 13 infants with perinatally acquired human immunodeficiency virus infection and children with Pneumocystis carinii pneumonia revealed that infants younger than 12 months developed Pneumocystis carinii pneumonia despite CD4 counts that were normal by adult standards. In contrast to the markedly increased serum IgG levels seen in most children infected with the human immunodeficiency virus, five children with Pneumocystis carinii pneumonia had IgG levels less than 3.0 g/L. Twelve patients had pre-existing symptoms consistent with human immunodeficiency virus infection before the episode of Pneumocystis carinii pneumonia. In addition to clinical symptoms, low IgG levels and CD4 counts adjusted for age may serve to identify those children who are most at risk for Pneumocystis carinii pneumonia and therefore candidates for prophylaxis. Prophylaxis should be offered to all infants under age 12 months with proven, or clinical symptoms compatible with, human immunodeficiency virus infection. For children older than 12 months, CD4 counts less than 0.3 x 10(9)/L appear to be predictive of risk for Pneumocystis carinii pneumonia, and these children should also receive prophylaxis.

Opportunistic infections and Kaposi's sarcoma among Haitians: evidence of a new acquired immunodeficiency state.

Twenty Haitian patients, hospitalized from 1 April 1980 to 20 June 1982, had Pneumocystis carinii pneumonia, central nervous system toxoplasmosis, esophageal candidiasis, cryptococcosis, disseminated cytomegalovirus, progressive herpes simplex virus, chronic enteric coccidiosis, or invasive Kaposi's sarcoma. Ten patients died. Opportunistic infections were frequently multiple and were recurrent in three patients. In seven patients disseminated tuberculosis preceded the other infections by 2 to 15 months. There was no evidence of an underlying immunosuppressive disease, and no history of homosexuality or intravenous drug abuse. At least three patients probably acquired the syndrome in Haiti. Lymphadenopathy was common. Seventeen patients tested had anergy, and 18 had lymphopenia. Monoclonal antibody analysis of peripheral-blood T-cell subsets done on 11 patients showed a marked decrease in T-helper cells and an inversion of the normal ratio of T-helper cells to T-suppressor cells. This syndrome among heterosexual Haitians is strikingly similar to the syndrome of immunodeficiency described recently among American homosexuals.