Anti-Synthetase Syndrome: A Case Report on the Elevated Risk of Pneumocystosis.

Pneumocystis carinii pneumonia (PCP), now referred to as Pneumocystis jirovecii pneumonia (PJP), occurs in immunocompromised patients. It is particularly associated with cellular immunodeficiency due to certain diseases or treatments. The risk of PCP is likely correlated with the severity of cellular immunity damage. However, excluding AIDS, the precise degree of immunosuppression required to develop PCP is not yet clearly understood. We report the case of a 58-year-old patient who presented with progressively worsening dyspnea. The clinical examination revealed a SaO2 of 88% on room air and the appearance of mechanic's hands. A thoracic CT scan showed interstitial lung disease (ILD). The immunological work-up was positive for antinuclear antibodies (ANA) and anti-JO-1 antibodies. Bronchoscopy with bronchoalveolar lavage (BAL) was performed, and the test for PJP came back positive.

Perception of pneumocystis jirovecii pneumonia (PJP) prophylaxis in glioma patients receiving concurrent temozolomide and radiation- a patient and physician survey.

PURPOSE: Pneumocystis jirovecii pneumonia (PJP) prophylaxis is required by provincial and national drug monographs during glioma treatment using temozolomide (TMZ) concurrently with radiation (TMZ-RT). However, real-world data suggest the potential benefits of PJP prophylaxis may not outweigh its potential harms in this population. METHODS: We conducted a single-center patient survey and a national physician survey to explore the role of PJP prophylaxis amongst glioma patients undergoing TMZ-RT. RESULTS: 23% (31/133) of physicians and 60% (44/73) of patients completed a survey. The median patient age was 42 (range 20-77); 85% (34/40) had completed adjuvant TMZ. Although only 2.4% (1/41) of patients received PJP prophylaxis, only one person (without PJP prophylaxis) was hospitalized for pneumonia. When presented with hypothetical PJP risks, 13.2% (5/38) of patients were concerned about PJP infection, while 26% (10/38) were concerned about potential side effects from prophylactic antibiotics. Most physicians (77%, 17/22) perceived the evidence for PJP prophylaxis as weak; 58% (11/19) did not routinely prescribe prophylaxis, and 73% (16/22) felt that PJP prophylaxis should be limited to patients with additional risk factors. Over 95% of physicians estimated that the incidence of PJP was < 1% in their last 5 years of practice regardless of PJP prophylaxis. For 73% (16/22) of physicians, to prescribe PJP prophylaxis, the risk of PJP infection needed to be 3-8%. CONCLUSION: The current recommendation to routinely prescribe PJP prophylaxis in patients receiving TMZ-RT in the absence of other risk factors warrants reconsideration.

Pneumocystis jirovecii Pneumonia in HIV-Negative, Non-transplant Patients: Epidemiology, Clinical Manifestations, Diagnosis, Treatment, and Prevention.

Purpose of Review: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that is increasingly seen in HIV-negative patients with immune compromise due to other etiologies. We lack comprehensive clinical recommendations for this population. Recent Findings: In non-HIV cases, PJP has a mortality rate of up to 50%, which is unacceptable despite the presence of safe and effective prophylaxis and therapy. Steroid use is one of the most common risk factors for disease development. New data suggests that lower doses of the preferred treatment regimen, TMP-SMX, may be equally effective for treatment while limiting side effects. While commonly used, the benefit of corticosteroids for the treatment of PJP has recently been called into question, with a recent multicenter cohort demonstrating no benefit among solid organ transplant recipients. Summary: A high suspicion of PJP in individuals with pneumonia during immunosuppressant use is crucial. Therapeutic options are evolving to decrease potential side effects while maintaining efficacy in this highly morbid disease.

Prognostic Factors of In-hospital Mortality in Patients without Human Immunodeficiency Virus Infection with Pneumocystis Pneumonia: A Retrospective Cohort Study.

Objective This study explored the prognostic factors of in-hospital mortality in patients with Pneumocystis pneumonia (PCP) without human immunodeficiency virus (HIV) infection, using a Japanese nationwide inpatient database. Methods We extracted the data of patients with PCP without HIV infection between July 2010 and March 2022 from the Diagnosis Procedure Combination database. We performed multivariable logistic regression analyses to identify the prognostic factors of in-hospital mortality in with PCP without HIV infection. Results We identified 1,704 patients with PCP without HIV infection and 404 (23.7%) in-hospital deaths. Higher in-hospital mortality was associated with advanced age, male sex (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-2.00), a low Barthel index score, non-hematological malignancy (OR, 1.81; 95% CI, 1.22-2.70), receipt of mechanical ventilation (OR, 2.49; 95% CI, 1.47-4.21), and administration of antibiotics (OR, 1.52; 95% CI, 1.12-2.06) and antifungal drugs (OR, 1.83; 95% CI, 1.26-2.67). Lower in-hospital mortality was associated with connective tissue disease and vasculitis (OR, 0.55; 95% CI, 0.37-0.81), hematological malignancy (OR, 0.59; 95% CI, 0.38-0.93), and early trimethoprim-sulfamethoxazole treatment (OR, 0.63; 95% CI, 0.44-0.90). Conclusions These findings will help physicians identify patients who may benefit from early aggressive therapeutic interventions.

Infection prophylaxis among patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis: a scoping review.

Severe infections associated with the use of strong immunosuppressive medication are a leading cause of morbidity and mortality in patients with ANCA vasculitis (AV). While guidelines conditionally recommend trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia in AV patients, robust evidence on prophylaxis strategies is lacking. This scoping review aimed to assess the existing evidence on infection prophylaxis in AV patients, identify knowledge gaps, and guide future study design. A comprehensive search of six databases and relevant references identified original studies in English from January 1, 2000, to July 31, 2020. Inclusion criteria encompassed studies evaluating the impact of any antimicrobial prophylaxis strategy on infection-related outcomes in AV patients receiving immunosuppressive treatment. Studies were screened by four researchers using a blinded approach. Data was extracted by two reviewers, with differences resolved via consensus in consultation with a third reviewer. Nineteen studies met inclusion criteria, including two randomized trials and 17 cohort studies, with TMP-SMX being the most commonly assessed prophylactic strategy. The studies varied in sample sizes, outcomes measured, prophylactic strategies employed, and proportion of patients who received the regimen. Most cohort studies included no or limited control of potential confounding factors. This scoping review suggests significant variation in AV patients' receipt of TMP-SMX and alternative infection prophylaxis approaches. Observational studies using large secondary healthcare databases with rigorous designs are needed to provide high-quality evidence of the real-world effectiveness of antimicrobial prophylactic regimens, to improve clinical decision-making and quality of care for AV patients receiving immunosuppressive treatment.

Interpretation of results of PCR and B-D-glucan for the diagnosis of Pneumocystis Jirovecii Pneumonia in immunocompromised adults with acute respiratory failure.

BACKGROUND: The accuracy of a diagnostic test depends on its intrinsic characteristics and the disease incidence. This study aims to depict post-test probability of Pneumocystis pneumonia (PJP), according to results of PCR and Beta-D-Glucan (BDG) tests in patients with acute respiratory failure (ARF). MATERIALS AND METHODS: Diagnostic performance of PCR and BDG was extracted from literature. Incidence of Pneumocystis pneumonia was assessed in a dataset of 2243 non-HIV immunocompromised patients with ARF. Incidence of Pneumocystis pneumonia was simulated assuming a normal distribution in 5000 random incidence samples. Post-test probability was assessed using Bayes theorem. RESULTS: Incidence of PJP in non-HIV ARF patients was 4.1% (95%CI 3.3-5). Supervised classification identified 4 subgroups of interest with incidence ranging from 2.0% (No ground glass opacities; 95%CI 1.4-2.8) to 20.2% (hematopoietic cell transplantation, ground glass opacities and no PJP prophylaxis; 95%CI 14.1-27.7). In the overall population, positive post-test probability was 32.9% (95%CI 31.1-34.8) and 22.8% (95%CI 21.5-24.3) for PCR and BDG, respectively. Negative post-test probability of being infected was 0.10% (95%CI 0.09-0.11) and 0.23% (95%CI 0.21-0.25) for PCR and BDG, respectively. In the highest risk subgroup, positive predictive value was 74.5% (95%CI 72.0-76.7) and 63.8% (95%CI 60.8-65.8) for PCR and BDG, respectively. CONCLUSION: Although both tests yield a high intrinsic performance, the low incidence of PJP in this cohort resulted in a low positive post-test probability. We propose a method to illustrate pre and post-test probability relationship that may improve clinician perception of diagnostic test performance according to disease incidence in predefined clinical settings.

Pneumocystis Pneumonia Presenting With Peripheral Predominant Consolidation and Traction Bronchiectasis.

Pneumocystis jirovecii pneumonia (PCP) typically presents as a predominant ground-glass opacity (GGO) in the upper lobes. We report a case of a patient with PCP that mimicked organizing pneumonia or nonspecific interstitial pneumonia, showing peripheral predominant consolidation with traction bronchiectasis and peribronchovascular thickening in the lower lobes on high-resolution computed tomography (HRCT). Pneumocystis jirovecii was detected in bronchoalveolar lavage (BAL), and no other pathogens were isolated. After confirmation of a high plasma human immunodeficiency virus (HIV)-RNA titer and a low CD4+ cell count, the patient was diagnosed with PCP associated with HIV infection. The peripheral predominant consolidation was successfully resolved after treatment with trimethoprim-sulfamethoxazole. To the best of our knowledge, no previous case of PCP presenting with peripheral predominant consolidation, traction bronchiectasis, or peribronchovascular thickening has been reported. Physicians should consider PCP as a differential diagnosis even in cases suspected as organizing pneumonia or nonspecific interstitial pneumonia on HRCT.

Opportunistic Infections, Mortality Risk, and Prevention Strategies in Patients With Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.

Clinical characteristics and prognosis of patients with severe pneumonia with Pneumocystis jirovecii colonization: A multicenter, retrospective study.

BACKGROUND: For decades, the incidence and clinical characteristics of Pneumocystis jirovecii (P. jirovecii) colonization in patients with severe pneumonia was remained unclear. RESEARCH QUESTION: What are the clinical features and outcomes associated with P. jirovecii colonization in individuals diagnosed with severe pneumonia? STUDY DESIGN AND METHODS: In this multicenter, retrospective, matched study, severe pneumonia patients who underwent bronchoalveolar lavage clinical metagenomics from 2019 to 2023 in the ICUs of 17 medical centers were enrolled. Patients were diagnosed based on clinical metagenomics, pulmonary CT scans, and clinical presentations. Clinical data were collected retrospectively, and according to propensity score matching and Cox multivariate regression analysis, the prognosis of patients with P. jirovecii colonization was compared to that of P. jirovecii-negative patients. RESULTS: 40% of P. jirovecii positive patients are considered to have P. jirovecii colonization. P. jirovecii colonization group had a higher proportion of patients with immunosuppression and a lower lymphocyte count compared to P. jirovecii-negative group. More frequent detection of cytomegalovirus, Epstein-Barr virus, human herpesvirus-6B, human herpesvirus-7, and torque teno virus in the lungs was associated with P. jirovecii colonization than with P. jirovecii negativity. By constructing two cohorts through propensity score matching, we incorporated codetected microorganisms and clinical features into a Cox proportional hazards model and revealed that P. jirovecii colonization was an independent risk factor for mortality in severe pneumonia patients. According to sensitivity analyses, which included or excluded codetected microorganisms, as well as patients not receiving TMP-SMX treatment, similar conclusions were reached. INTERPRETATION: Immunosuppression and a reduced lymphocyte count were identified as risk factors for P. jirovecii colonization in non-PCP patients. More frequent detection of various viruses was observed in P. jirovecii colonization patients, and P. jirovecii colonization was associated with an increased 28-day mortality in patients with severe pneumonia.

Clinical course and prognostic factors of Pneumocystis pneumonia with respiratory failure in non-HIV patients.

Background: Compared with Human Immunodeficiency Virus (HIV) patients, non-HIV patients with Pneumocystis pneumonia (PCP) have more rapid onset, more rapid progression, and higher mortality. Objectives: To investigate the predictive value of variables obtained upon hospital admission for in-hospital death and 90-day outcomes in non-HIV-PCP patients with respiratory failure (RF). Methods: This was a single center retrospective study in a tertiary care institution over 15 years. It included all adults inpatients (≥18 years old) with laboratory confirmed non-HIV-PCP with RF who were discharged or died from Peking University First Hospital between April 1st, 2007 and November 1st, 2022. Epidemiological, clinical, laboratory, imaging and outcome data were collected from patient records. Results: In this study, a total of 146 non-HIV-PCP patients with RF were included. There were 57 patients (39%) died during hospitalization, 44 patients (53%) died in Intensive care unit (ICU). A total of 137 patients completed 90 days of follow-up, of which 58 (42.3%) died. The multivariable regression analysis revealed that a CD8+ T cell count <115/µl (P=0.009), bronchoalveolar lavage fluid (BALF)-neutrophil percentage ≥50% (P=0.047), the time from corticosteroids withdrawal to symptom onset ≤5 days (P=0.012), and the time from visit to initiation of sulfonamides ≥2 days (P=0.011) were independent risk factors for in-hospital death. Furthermore, a CD8+ T cell count < 115/µl (P=0.001) and the time from visit to initiation of sulfonamides therapy ≥2 days (P=0.033) was independently associated with 90-day all-cause death. Conclusions: A low CD8+ T cell count in peripheral blood, a high percentage of BALF-neutrophils, a short time from corticosteroids withdrawal to symptom onset, and a long time from visit to initiation of sulfonamides are associated with poor prognosis in non-HIV-PCP patients with RF.

Breakthrough Pneumocystis jirovecii Pneumonia in an Allogeneic Hematopoietic Stem Cell Transplant Recipient.

Pneumocystis carinii pneumonia (PCP), which is currently referred to as Pneumocystis jirovecii pneumonia, is an opportunistic fungal infection that commonly affects immunocompromised patients, and it is potentially fatal. Individuals at risk include those whose host immunity has been altered by underlying disease states, such as HIV and cancer patients, as well as transplant recipients and those taking immunosuppressive medications. Here, we present a case of a breakthrough PCP infection of an adult allogeneic hematopoietic stem cell transplant patient who was infected despite prophylaxis with inhaled pentamidine. The patient's transplant course was complicated by acute graft-versus-host disease (GVHD), which was treated with tacrolimus, prednisone, beclomethasone, and budesonide. Treatments for GVHD, which include immunosuppressive therapies, are a risk factor for PCP. Thus, the patient was on prophylactic treatment with inhaled pentamidine. The case presents challenges that immunocompromised patients face, particularly those undergoing allogeneic hematopoietic stem cell transplantation. While the patient received prophylactic treatment, there was still a breakthrough PCP infection. We highlight the risks this infection can cause and the need to promptly address these infections to prevent complications and optimize prophylactic regimens.

Fungal infections in immunocompromised critically ill patients.

Diverse pathogenic fungi can produce severe infections in immunocompromised patients, thereby justifying intensive care unit (ICU) admissions. In some cases, the infections can develop in immunocompromised patients who were previously admitted to the ICU. Aspergillus spp., Pneumocystis jirovecii, Candida spp., and Mucorales are the fungi that are most frequently involved in these infections. Diagnosis continues to be challenging because symptoms and signs are unspecific. Herein, we provide an in-depth review about the diagnosis, with emphasis on recent advances, and treatment of these invasive fungal infections in the ICU setting.

Immune checkpoint inhibitor increased mortality in lung cancer patients with Pneumocystis jirovecii pneumonia: a comparative retrospective cohort study.

Introduction: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening infection in immunocompromised individuals. Immune checkpoint inhibitor (ICI) has brought significant survival benefit in lung cancer patients. Although the few studies showed there was high mortality in PJP patients with ICI use, these studies had no comparative control groups. Methods: A retrospective study was conducted to compare the mortality in PJP patients with lung cancer between those treated with ICI and a concurrent control group treated without ICI. Results: A total number of 20 non-human immunodeficiency virus (HIV) patients with confirmed PJP and co-existing lung cancer were included in the current study, and classified into ICI group (n=9) and non-ICI group (n=11).There was a clear trend to a shorter onset of PJP in ICI group than non-ICI group (118.9 ± 60.9 vs 253.0 ± 185.1 days), although without statistical significance (p=0.053). Bronchoscopic alveolar lavage fluid were collected from all patients and used to identify Pneumocystis jirovecii. In both groups, metagenomics next-generation sequencing (mNGS) were the most used diagnostic techniques. Within 28 days after the onset of PJP, mortality was significantly higher in the ICI group than non-ICI group (33.3% vs 0, p=0.042). Conclusion: Lung cancer patients with ICI use had a higher mortality rate after PJP infection than patients without ICI use. Prospective studies with larger sample size and a multi-center design are warranted to further verify the present results.

Pneumocystis jirovecii pneumonia in non-HIV patients: need for a more extended prophylaxis.

Background: Pneumocystis jirovecii pneumonia (PCP) has a significant mortality rate for non-HIV immunocompromised patients. Prevention is primarily based on combined trimethoprim and sulfamethoxazole (TMP-SMX) but guidelines on pneumocystosis prophylaxis are scattered and not consensual. Objectives: This study aims to describe PCP in non-HIV patients and to review case by case the prior indication of prophylaxis according to specific guidelines.We included patients with confirmed diagnosis of PCP admitted to one university hospital from 2007 to 2020. Prior indication for pneumocystis prophylaxis was assessed according to the specific guidelines for the underlying pathology or treatment. Results: Of 150 patients with a medical diagnosis of PCP, 78 were included. Four groups of underlying pathologies were identified: hematological pathologies (42%), autoimmune diseases (27%), organ transplantation (17%), and other pathologies at risk of PCP (14%). A small subgroup of 14 patients (18%) had received a prior prescription of pneumocystis prophylaxis but none at the time of the episode. Transfer to intensive care was necessary for 33 (42%) patients, and the mortality rate at 3 months was 20%. According to international disease society guidelines, 52 patients (59%) should have been on prophylaxis at the time of the pneumocystis episode. Lowest compliance with guidelines was observed in the hematological disease group for 24 patients (72%) without prescription of indicated prophylaxis. Conclusion: Infectious disease specialists should draw up specific prophylactic guidelines against pneumocystis to promote a better prevention of the disease and include additional criteria in their recommendations according to individual characteristics to prevent fatal cases.

Variance in Pneumocystis jirovecii prophylaxis practice for pediatric patients undergoing hematopoietic cell transplantation.

Pneumocystis jirovecii pneumonia (PJP) in hematopoietic cell transplant (HCT) recipients can be prevented by efficient prophylaxis. We surveyed HCT centers in North America to assess their PJP prophylaxis practices. Most institutions used intravenous (IV) pentamidine (29.6%) or inhaled pentamidine (14.8%); 37% institutions changed from trimethoprim/sulfamethoxazole (TMP-SMX) to another medication after conditioning; and 44% administered no PJP prophylaxis during the pre-engraftment period. Most institutions avoided using TMP-SMX during the pre-engraftment period, mainly because of concerns about myelotoxicity, despite this being the preferred PJP prophylaxis agent. There is a need to evaluate the effects of TMP-SMX on engraftment.

Metabolic modulation: Pneumocystis phosphoglucomutase is a target influencing host recognition.

Herein, this manuscript explores the significance of the phosphoglucomutase (PGM) enzyme in Pneumocystis spp., focusing on its role in fungal surface mannoprotein formation. Through expression of the Pneumocystis murina Pmpgm2 in a Saccharomyces cerevisiae pgm2Δ strain, we demonstrate restoration of binding to the mannose receptor (MR) and macrophages to wildtype yeast levels in this complemented strain. Gas Chromatography-Mass Spectroscopy (GC-MS) confirmed reduced mannose content in the pgm2Δ yeast strain compared to the wild-type and complemented Pmpgm2 cDNA-expressing strains. This study underscores fungal PGM function in dolichol glucosyl phosphate biosynthesis, crucial for proper cell wall mannoprotein formation. Furthermore, highlighting the conservation of targetable cysteine residues across fungal pathogens, PGM inhibition maybe a potential therapeutic strategy against a broad spectrum of fungal infections.

Metagenomic Next-Generation Sequencing for Accurate Diagnosis of Pneumocystis jirovecii Pneumonia: A Comparative Study with Traditional Methods.

Background: Metagenomic next-generation sequencing (mNGS) is a high-throughput sequencing technique that identifies a wide array of pathogens directly from clinical specimens. This study evaluates the diagnostic value of mNGS in Pneumocystis jirovecii pneumonia (PJP) and compares its efficacy with traditional detection methods, including Grocott's Methenamine Silver (GMS) staining, serum (1-3)-ß-D-Glucan (BDG) testing, and Lactate Dehydrogenase (LDH) testing. Methods: Seventy-eight patients hospitalized between January 2022 and March 2023 with suspected pulmonary infections were included. Patients were eligible for mNGS if they exhibited symptoms such as fever, cough, dyspnea, or progressive hypoxemia, and met specific clinical criteria for PJP. Specimens obtained included bronchoalveolar lavage fluid, sputum, and peripheral blood. Positive rates and pathogen distributions detected by mNGS and traditional methods were compared. Results: In the PJP group, 25%, 37.5%, and 9.38% of patients had solid organ tumors, corticosteroid use, and skin diseases, respectively, significantly higher than in the non-PJP group. The sensitivity and specificity of mNGS were both 100%, significantly higher than those of serum BDG (sensitivity 50%, specificity 81.8%) and LDH (sensitivity 9.3%, specificity 91.3%). Significant differences in microbial composition between the PJP and Non-PJP groups were observed. mNGS detected multiple mixed pathogens in 96.88% of PJP cases, with 68.75% exhibiting mixed bacterial and viral infections. Notably, 71% of patients improved following antibacterial treatment based on mNGS results. Conclusion: mNGS technology shows superior sensitivity and specificity in diagnosing PJP and guides precise treatment for complex pulmonary infections.

Pneumocystis murina promotes inflammasome formation and NETosis during Pneumocystis pneumonia.

Pneumocystis jirovecii pneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30%-60% mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages in Pneumocystis infections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed neutrophil extracellular trap (NET) presence in the lungs of the P. murina-infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated with P. murina. Isolated NETs compromised P. murina viability in vitro, highlighting the potential role of neutrophils in controlling fungal growth and promoting inflammation during P. murina pneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes during Pneumocystis infection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.IMPORTANCEPneumocystis jirovecii pneumonia (PjP) affects individuals with weakened immunity, such as HIV/AIDS, cancer, and organ transplant patients. Severe PjP triggers lung inflammation, impairing function and potentially causing acute respiratory distress syndrome. Non-HIV individuals face a 30%-60% mortality rate, underscoring the need for deeper insight into PjP's inflammatory responses. Past research focused on macrophages in managing Pneumocystis infection and its inflammation, while the role of neutrophils was generally overlooked. In contrast, our findings in P. murina-infected mouse lungs showed neutrophil involvement during inflammation and increased expression of NLRP3 inflammasome and NETosis pathways. Detection of neutrophil extracellular traps further indicated their involvement in the inflammatory process. Although beneficial in combating infection, unregulated neutrophil activation poses a potential threat to lung tissues. Understanding the behavior of neutrophils in Pneumocystis infections is crucial for controlling detrimental reactions and formulating treatments to reduce lung damage, ultimately improving the survival rates of individuals with PjP.

Cutaneous Pneumocystis Jirovecii Infection in an Allogeneic Stem Cell Transplant Recipient.

Pneumocystis jirovecii is an opportunistic fungus that infects the lungs but can involve other organs, including the skin and lymph nodes. Risk factors include human immunodeficiency virus (HIV), solid organ/haematological malignancies and a CD4 cell count of fewer than 200 cells/µl. Pneumocystis jirovecii pneumonia (PJP) infection is reported less frequently these days with the advent of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX). We report a case of extrapulmonary PJP infection in a patient while receiving pentamidine prophylaxis in a T-cell prolymphocytic leukaemia, who underwent an allogeneic stem cell transplant. There are plenty of reported cases of PJP on pentamidine prophylaxis; however, none had cutaneous PJP infection. Cutaneous P. jirovecii infection (CPJ) is an extrapulmonary infection that is rarely reported. Our patient's skin biopsy was inconclusive, but the skin nodules improved once he was initiated on TMP-SMX. Many transplant patients cannot tolerate TMP-SMX for various reasons and are placed on second-line prophylaxis for PJP, which does not prevent extrapulmonary PJP infections. Our case highlights the challenges of diagnosing such a rare infection in immunocompromised patients. Extrapulmonary PJP should be suspected in patients with a history of pulmonary PJP and persistent elevated Fungitell® levels in low CD4 counts. LEARNING POINTS: Extrapulmonary Pneumocystis jirovecii pneumonia (PJP) infection can happen while receiving pentamidine prophylaxis.It is extremely rare to see a cutaneous infection, and no case has been reported in the last two decades.Trimethoprim-sulfamethoxazole (TMP-SMX) remains the first-line treatment for pulmonary and extrapulmonary PJP.