antibodies

2026-03-13 | Pneumocystis jirovecii pneumonia in patients with CNS tumors receiving dexamethasone: clinical outcomes and prophylaxis gaps.

PURPOSE: Pneumocystis jirovecii pneumonia (PCP) now predominantly affects non-HIV immunocompromised patients, with corticosteroid exposure a major risk factor. Patients receiving high-dose dexamethasone for central nervous system (CNS) tumor–related indications represent a vulnerable but understudied subgroup. We sought to characterize outcomes in this population and compare disease severity and mortality with other immunocompromised patients with PCP. METHODS: We performed a retrospective multicenter cohort study of adults with proven or probable Pneumocystis jirovecii pneumonia (PCP) according to EORTC diagnostic criteria between January 1, 2017, and December 31, 2025. Patients receiving chronic dexamethasone for CNS tumor–related indications (vasogenic edema, mass effect, or spinal cord compression) were identified and compared with the remainder of the PCP cohort. Logistic regression was used to evaluate differences in 30-day and 90-day mortality between the CNS tumor subgroup and other patients with PCP. Severe disease was assessed as a secondary outcome and defined as the requirement for high-flow nasal cannula, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Within the CNS tumor subgroup, logistic regression was used to evaluate associations between 30-day mortality and age, dexamethasone dose, and tumor etiology (primary vs. metastatic). RESULTS: Among 865 patients with PCP, 46 (5.3%) were receiving dexamethasone for CNS tumor–related indications. Median steroid exposure prior to diagnosis was 33 days (IQR 25–49), and only 4.4% were receiving PCP prophylaxis. All-cause 30-day mortality was 41.3% and 90-day mortality was 52.2%. Compared with other immunocompromised patients with PCP, CNS tumor patients had higher odds of severe disease (OR 2.24, 95% CI 1.20–4.18; p = 0.011), 30-day mortality (OR 2.45, 95% CI 1.33–4.50; p = 0.004), and 90-day mortality (OR 2.69, 95% CI 1.48–4.90; p = 0.001). Within the CNS tumor subgroup, age, dexamethasone dose, and tumor etiology were not significantly associated with 30-day mortality or severe disease. CONCLUSIONS: PCP developing during dexamethasone therapy for CNS tumors is associated with greater severity and mortality. Prophylaxis should be strongly considered when initiating prolonged corticosteroids in this high-risk population.

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2025-10-06 | Modulation of host lung immunity in Pneumocystis pneumonia: a review of current concepts and future prospects for novel adjunctive immune-based therapies.

Pneumocystis jirovecii pneumonia remains a significant cause of mortality and morbidity in immunocompromised populations worldwide. Mortality rates range from 5% to 30% in HIV-positive individuals and 4% to 76% in those without HIV. Recognizing its public health impact, the World Health Organization (WHO) included Pneumocystis jirovecii in its 2022 "Fungal Priority Pathogens" list. In this review, we will summarize published findings over the last 14 years on the immunopathogenic mechanisms underlying Pneumocystis pneumonia-related lung injury and examine the potential for targeting these pathways in adjunctive immune modulation therapy. Notably, recent studies have identified promising immune-based interventions, including PD-1/PD-L1 blockade and IL-7 therapy, which may enhance pathogen clearance while controlling damaging inflammation. Additionally, small molecule inhibitors such as BRD5529 and ALW-II-41-27 have shown potential in reducing lung injury by modulating proinflammatory signaling pathways in Pneumocystis pneumonia.

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2025-08-01 | Abrupt Breathlessness: Pneumocystis jirovecii Pneumonia Associated with Inebilizumab in Neuromyelitis Optica Spectrum Disorder: A Case Report and Literature Review

Opportunistic infections pose significant challenges in patients undergoing immunosuppressive treatment for autoimmune disorders. Neuromyelitis optica spectrum disorder (NMOSD) is a rare disabling autoimmune condition requiring both acute attack management and long-term relapse prevention. B-cell depleting therapies, such as inebilizumab have demonstrated efficacy in reducing relapse rates and disability progression in NMOSD. Here, we present the first known NMOSD case who developed Pneumocystis jirovecii pneumonia following maintenance therapy with inebilizumab, showing a probable association (Naranjo score=6). We explored the underlying mechanisms linking B-cell depletion to Pneumocystis jirovecii, including antibody-dependent and immunomodulatory pathways. Furthermore, we provided an overview of Pneumocystis jirovecii pneumonia in autoimmune central nervous system disorders and summarized its clinical features, previous medication use, and prognostic factors. We advocate for risk-adapted prophylaxis to reduce morbidity and mortality associated with opportunistic infections in NMOSD.

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2025-04-25 | Homozygous STAT-1 Loss of Function Presenting with Recurrent Respiratory Infections and Pneumocystis jirovecii Pneumonia

Background Autosomal recessive complete STAT-1 deficiency is a rare primary immunodeficiency characterized by predisposition to life-threatening viral and mycobacterial infections due to loss of STAT-1–dependent responses to type I/II interferons. We present a case of complete STAT-1 deficiency presenting with severe respiratory infections. Case A 5-week-old, ex–full-term female infant was admitted for RSV bronchiolitis with superimposed MRSA pneumonia and bacteremia requiring intubation. At 2 months, she required noninvasive ventilatory support for rhinovirus infection and treatment for aspiration pneumonia. At 4 months, she was treated for COVID-19 pneumonia. Her history prompted workup for immunodeficiency; she had normal T and B cells, immunoglobulins, and adequate titers to killed vaccines. Genetic testing revealed homozygous deletion in STAT1 (exons 7-9). Functional studies demonstrated absence of STAT-1 phosphorylation to interferon-gamma, supportive of complete STAT-1 deficiency. She was started on prophylactic IVIG and acyclovir and regularly screened for EBV, CMV, and HHV-6. At 5 months, she presented with fever, respiratory distress, and recurrent emesis with leukocytosis and elevated inflammatory markers without a clear source. Ultimately, Pneumocystis jirovecii pneumonia was diagnosed by PCR from bronchoalveolar lavage; she improved with trimethoprim-sulfamethoxazole. During infectious workup, Karius testing returned positive for Mycobacterium abscessus. Given high risk for mycobacterial infection, empiric treatment with azithromycin, amikacin, and linezolid was initiated. At 10 months, she underwent an alpha-beta T cell–depleted haploidentical peripheral blood SCT from her father. Planned conditioning regimen was rituximab, targeted dosing rATG, targeted busulfan, targeted fludarabine, and thiotepa. She had an anaphylactic reaction to Rituximab on Day -1; no further doses of rituximab were given. Graft-versus-host prophylaxis was tocilizumab and abatacept. Engraftment occurred on Day +13. Immediate post-transplant course was initially complicated by persistent host T cells, concerning for a high risk of immunological rejection, but she has since continued to have improvement of donor CD3 chimerism. She is currently Day +50 without signs of GVHD or viral reactivation and continues abatacept monthly. Discussion Complete STAT1 deficiency is a severe immunodeficiency that is historically fatal in early life without curative HSCT. Our case supports the need for early transplant before the acquisition of and complications due to severe infections.

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2024-10-25 | Atypical presentation of PJP: hypercalcemia and kidney injury in an allogeneic stem cell transplant recipient.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that primarily affects immunocompromised individuals. Typical symptoms of PJP include the subacute onset of dyspnea, nonproductive cough, and low-grade fever. In hematology patients, particularly those who are allogeneic stem cell transplant recipients, the disease often presents with a more aggressive clinical course. While hypercalcemia has been documented as a manifestation of PJP in some solid organ transplant recipients, it has not been reported in hematology or stem cell transplant patients. Here, we present a case of PJP in a 56-year-old male allogeneic stem cell transplant recipient, who developed hypercalcemia and renal failure during the late post-transplant period. The patient had a history of allogeneic stem cell transplantation due to acute myeloid leukemia. He presented with symptoms of fatigue and weakness. Laboratory tests revealed hypercalcemia (13.8 mg/dL) and elevated serum creatinine levels (2.3 mg/dL). The patient was hospitalized, and despite initial treatment with hydration and furosemide, the hypercalcemia persisted, leading to the administration of denosumab. During follow-up, hypoxia was detected, and a chest CT scan revealed mosaic attenuation and ground-glass opacities. Bronchoscopy was performed, and PCR testing confirmed the presence of Pneumocystis jirovecii. Other causes of hypercalcemia were ruled out, with PTH measured at 13.8 pg/mL (normal range 15-65 pg/mL), albumin at 3.71 g/dL, 1.25-dihydroxy vitamin D3 at 96 ng/dL (normal range 26-95 ng/dL), and 25-hydroxy vitamin D at 32.5 ng/mL (normal range 20-40 ng/mL). A PET-CT scan demonstrated no pathological FDG uptake, with the exception of findings suggestive of a pulmonary infection. Following treatment with trimethoprim-sulfamethoxazole and denosumab, the patient's hypercalcemia and infection resolved. Although rare, PJP can present with hypercalcemia and kidney injury in allogeneic stem cell transplant recipients. Early diagnosis and treatment can improve both PJP and hypercalcemia.

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vaccines

2026-07-15 | Evaluating the impact of immunization with the "pan-fungal" vaccine, NXT-2, on the gut mycobiome and microbiome in non-human primates (NHPs).

Fungal infections remain a significant public health concern with high mortality, morbidity, and increasing associated health costs. This burden is projected to rise due to expansion of at-risk populations, limited therapeutics, increasing drug resistance, and the emergence of new fungal pathogens. Even with these challenges, there are currently no approved vaccines. We previously developed a "pan-fungal" vaccine candidate, NXT-2, that confers protection against multiple invasive fungal infections such as pulmonary aspergillosis, pneumocystosis, and invasive candidiasis, as well as non-invasive vulvovaginal candidiasis. NXT-2 is a 90 amino acid consensus peptide designed from a conserved region of the fungal antigen (KEX1). We assessed the effect of NXT-2 immunization on gut microbial diversity, composition, and functional capacity in non-human primates. To do this, we monitored changes in the gut mycobiome and microbiome pre- and post-vaccination using ITS2 and metagenomic sequencing, respectively, in Japanese and rhesus macaque cohorts. NXT-2 elicited a robust antibody response without disrupting the gut microbial communities in both macaque species. The mycobiome exhibited stability with no significant changes in alpha and beta diversity, taxonomic composition, or functional guild distributions. The relative abundance of gut resident Candida and Aspergillus species remained stable and was not significantly altered following vaccination. The microbiome showed stability with preserved alpha and beta diversities, taxonomic composition, and functional capacity. Results from this study show the first cross-kingdom analysis demonstrating that antifungal vaccination can achieve protective immunity without perturbing gut microbial communities. This establishes a framework for microbiome-informed vaccine assessment beyond conventional immunogenicity and adverse effect monitoring.IMPORTANCEFungal infections cause millions of deaths annually, yet no vaccines are approved despite growing drug resistance and limited treatment options. NXT-2 is a pan-fungal vaccine that protects against multiple fungal infections such as pneumocystosis, candidiasis, and aspergillosis. Here, we demonstrate in NHPs that NXT-2 elicits robust protective antibody responses without altering gut bacterial or fungal communities. This is the first study to assess antifungal vaccination across both microbial kingdoms and establish that protective antifungal immunity can be achieved while preserving resident microbiota. This work provides a framework for incorporating microbiome assessment into vaccine development beyond conventional immunogenicity and adverse event monitoring.

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2026-02-02 | Protective efficacy of a 'pan-fungal' vaccination strategy against experimental Pneumocystis infection in drug-immunosuppressed macaques.

Pneumocystis jirovecii causes life-threatening fungal pneumonia (PJP) and other serious pulmonary sequelae in HIV infected individuals and other immunocompromised populations. In recent years, while the frequency of PJP has declined in HIV infected individuals treated with anti-retroviral therapies, the incidence has increased among non-HIV populations due to the expanding use of corticosteroids and other immunomodulatory agents to treat immune-mediated inflammatory diseases and hematologic and solid malignancies. Despite the success of trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, patients who are unable to tolerate treatment, take drugs where TMP-SMX is contraindicated, or experience breaks in daily compliance remain at risk. Immunocompromised populations would benefit from vaccine strategies that reduce morbidity and mortality due to acute PJP. Herein, we used a newly established non-human primate (NHP) model of Pneumocystis infection in the context of drug-induced immunosuppression to test the immunogenicity and protective efficacy of a vaccine strategy administered prior to and throughout drug-induced immunosuppression using the 'pan-fungal' vaccine candidate NXT-2a. Longitudinal blood and bronchoalveolar lavage sampling was performed to monitor anti-NXT-2a antibody titers, lymphocyte populations, and infection status. Immunization with NXT-2a prior to immunosuppression induced robust humoral immune responses in healthy outbred macaques. Subsequent therapeutic boosting throughout drug-induced immunosuppression prevented protective antibody titer decline. Our collective vaccination strategy provided significant protection against Pneumocystis infection throughout the duration of the study. These studies demonstrate the efficacy and feasibility of an NXT-2a based vaccination strategy in a NHP model with a planned immunosuppressive regimen. This strategy may be further applied toward other opportunistic fungal pathogens, such as Candida spp. and Aspergillus spp. in similarly immunosuppressed populations.

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2026-01-02 | Development of a vaccine construct against Pneumocystis jirovecii pneumonia using computational tools.

Pneumocystis jirovecii poses a significant threat to immunocompromised individuals, necessitating the development of an effective vaccine. This study employs an immunoinformatics approach to design a promising vaccine candidate against P. jirovecii. Utilizing various computational tools, the study identified potential antigenic epitopes capable of eliciting immune responses within the P. jirovecii major surface glycoprotein C. The chosen epitopes were evaluated using computational tools for their allergenicity, interferon-γ and interleukin activation ability, and toxicity, ensuring the selection of immunogenic and safe candidates. These analyses led to the selection of 10 epitopes, which were then linked with adjuvants to model a potential vaccine candidate. Molecular docking and molecular dynamics simulations were performed in a solvent environment to investigate the binding interactions between the vaccine candidate and toll-like receptors, along with calculations of thermodynamic properties. Finally, in silico immune simulations were performed to analyze the immunogenic potential of the vaccine candidate. Future prospects include in vitro and in vivo validation of the vaccine candidate and the exploration of novel adjuvants to enhance its immunogenicity. This study contributes to the ongoing efforts to develop a preventive solution against P. jirovecii infections, addressing a critical gap in the protection of immunocompromised individuals.

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2024-07-31 | Designing an mRNA Vaccine against P. jirovecii Involved in Fatal Pneumonia Infections via Comparative Proteomics and Reverse Vaccinology Approaches.

Pneumocystis jirovecii is the most emerging life-threating health problem that causes acute and fatal pneumonia infection. It is rare and more contagious for patients with leukemia and immune-deficiency disorders. Until now there is no treatment available for this infection therefore, it is needed to develop any treatment against this pathogen. In this work, we used comparative proteomics, robust immune-informatics, and reverse vaccinology to create an mRNA vaccine against Pneumocystis jirovecii by targeting outer and transmembrane proteins. Using a comparative subtractive proteomic analysis of two Pneumocystis jirovecii proteomes, a distinct non-redundant Pneumocystis jirovecii (strain SE8) proteome was chosen. Seven Pneumocystis jirovecii transmembrane proteins were chosen from this proteome based on hydrophilicity, essentiality, virulence, antigenicity, pathway interaction, protein-protein network analysis, and allergenicity. The reverse vaccinology approach was used to predict the immunogenic and antigenic epitopes of major histocompatibility complex (MHC) I, II and B-cells from the selected proteins on the basis of their antigenicity, toxicity and allergenicity. These immunogenic epitopes were linked together to construct the mRNA-based vaccine. To enhance the immunogenicity, suitable adjuvant, linkers (GPGPG, KK, and CYY), and PRDRE sequences were used. Through predictive modeling and confirmation via the Ramachandran plot, we assessed secondary and 3D structures. The adjuvant RpfE was incorporated to enhance the vaccine construct's immunogenicity (GRAVY index: -0.271, instability index: 39.53, antigenicity: 1.0428). The physiochemical profiling of vaccine construct was predicted it an antigenic, efficient, and potential vaccine. Notably, strong interactions were observed between the vaccine construct and TLR-3/TLR-4 (-1301.7 kcal/mol-1 and -1374.7 kcal/mol-1). The results predicted that mRNA-based vaccines trigger a cellular and humoral immune response, making the vaccine potential candidate against Pneumocystis jirovecii and it is more suitable for in-vitro analysis and validation to prove its effectiveness.

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2022-12-26 | A therapeutic vaccine strategy to prevent Pneumocystis pneumonia in an immunocompromised host in a non-human primate model of HIV and Pneumocystis co-infection.

Pneumocystis is a ubiquitous fungal pathogen that causes pneumonia (PCP) and pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. With the success of anti-retroviral therapy for HIV-infected individuals the frequency of PCP in that population has decreased, however, PCP remains a significant cause of morbidity and mortality in individuals with hematologic and solid malignancies, and in individuals treated with immunosuppressive therapies for autoimmune diseases, and following bone marrow and solid organ transplantation. Despite the clinical need, there is no approved vaccine to prevent PCP in vulnerable populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pneumocystis. Toward this goal, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) and identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pneumocystis immunity in immune-competent macaques that is durable and prevents PCP following simian immunodeficiency virus (SIV)-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide B cell help under conditions of reduced CD4+ T cell help. In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with the iNKT cell-activating adjuvant α-galactosylceramide (α-GC) and KEX1 (α-GC+KEX1) can effectively boost anti-Pneumocystis humoral immunity following virus-induced immunosuppression. Immunization of antigen-experienced NHPs with α-GC+KEX1 during the early chronic phase of SIV-infection significantly boosted anti-Pneumocystis humoral immunity by increasing memory B cells and antibody titers, and enhanced titer durability during SIV-induced immunosuppression. This therapeutic vaccination strategy boosted anti-Pneumocystis immune responses during SIV-infection and contributed to protection against Pneumocystis co-infection in KEX1-vaccinated macaques. These studies present a novel strategy for stimulating durable anti-Pneumocystis humoral immunity in the context of complex, chronic SIV-induced immunosuppression and may be further applied to immunization of other immunosuppressed populations, and toward other common recall antigens.

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small molecules

2026-09-16 | Unanticipated global emergence and evolution of Pneumocystis jirovecii mutations and resistance driven by a human-targeted drug.

Nearly all known cases of antimicrobial resistance have been linked to agents that directly target microbes. This paradigm overlooks other drivers of microbial evolution and resistance. Here, we report compelling evidence of resistance-associated mutations in Pneumocystis jirovecii, a high-priority fungal pathogen designated by WHO as having unknown resistance. These mutations emerged under selective pressure from mycophenolic acid (MPA), a widely used immunosuppressant not used for Pneumocystis pneumonia (PCP) treatment. A potent inhibitor of inosine monophosphate dehydrogenase (IMPDH), MPA has been linked to altered P. jirovecii susceptibility in solid organ transplant (SOT) recipients. Genetic analysis of 163 P. jirovecii samples from PCP outbreaks in SOT recipients and nontransplant controls across six countries identified six impdh mutations, four of which were previously unreported. These mutations showed strong associations with prior MPA exposure, geographic segregation, and temporal shifts. They arose independently in 11 distinct strains worldwide between 2005 and 2019, with evidence of switching within and between strains, suggesting ongoing adaptive evolution. Structural modeling predicted that these mutations reduced IMPDH stability and MPA binding; accordingly, all mutations conferred MPA resistance in enzyme inhibition assays. Our findings uncover the unanticipated global emergence of multiple resistance-associated mutations in P. jirovecii driven by a human-targeted immunosuppressant, likely conferring a survival advantage in SOT recipients and facilitating transmission and outbreaks. These results challenge the current status quo on P. jirovecii's unknown resistance, calling for reevaluating immunosuppressive strategies and infection control measures and highlighting the broader potential for other pathogens to evolve under selective pressures imposed by human-targeted therapies.

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2026-09-15 | Survival in Immunocompromised Adults with Pneumocystis jirovecii Pneumonia: A Multicenter ID-IRI Study.

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection in immunocompromised patients. The aim of this study was to identify risk factors associated with in-hospital 30-day all-cause mortality among PJP in patients with HIV and hematologic malignancies where PJP is the most prevalent. We conducted a multicenter, international, retrospective cohort study of consecutive hospitalized patients aged > 17 years with PJP between January 1, 2010, and March 1, 2024. Only patients with laboratory-confirmed PJP were included. Overall, 156 patients were included to study. Of the 156 patients, 115 (73.7%) were male, and the median age was 43 years (IQR 35-52). Of the patients, 130 (83.3%) were people living with HIV, including 126 newly diagnosed cases, while 26 (16.7%) had hematologic malignancies. Overall, PJP prophylaxis was used in only 4.5% of patients. According to the immunofluorescence assay or conventional staining methods used as the reference standard, the positivity rate of P. jirovecii PCR in BAL samples was 96.4%. Intensive care unit admission was required for 60 patients (38.5%), of whom 51 (85.0%) required mechanical ventilation. The overall in-hospital 30-day all-cause mortality rate was 14.1%. In the multivariable logistic regression analysis, higher respiratory rate (OR 1.092; 95% CI 1.002-1.190), higher SOFA score (OR 1.757; 95% CI 1.311-2.356), increased neutrophil count (OR 1.332; 95% CI 1.141-1.555), pleural effusion on chest X-ray (OR 7.268; 95% CI 1.382-38.212), and a prior history of PJP (OR 19.537; 95% CI 1.462-261.2) were independently associated with increased in-hospital 30-day all-cause mortality. Our findings indicate that greater clinical severity and respiratory compromise are associated with increased mortality risk, underscoring the value of early recognition of high-risk patients to guide timely management.

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2026-09-10 | Clinical characteristics and prognostic factors in non-HIV patients with Pneumocystis jirovecii pneumonia and BALF cytomegalovirus co-detection: a retrospective cohort study.

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic infection in immunocompromised patients. BALF cytomegalovirus (CMV) co-detection is frequently observed in PJP patients, but its clinical characteristics and prognostic impact in non-HIV populations remain unclear. In this single-center retrospective cohort study, we enrolled 62 non-HIV patients with confirmed PJP between 2019 and 2023. BALF CMV co-detection was defined as detectable CMV DNA in bronchoalveolar lavage fluid via metagenomic next-generation sequencing (mNGS), combined with compatible respiratory symptoms and chest computed tomography abnormalities. The Benjamini-Hochberg false discovery rate (FDR) correction was applied for multiple comparisons. Overall, 31 patients (50.0%) had BALF CMV co-detection. The 28-day all-cause mortality was significantly higher in the CMV co-detection group than in the PJP-only group (54.84% vs. 19.35%, p = 0.008), and dyspnea was more prevalent (p = 0.024). After FDR correction for 39 laboratory parameters, only fibrinogen remained significantly lower in the co-detection group (q = 0.039), while (1,3)-β-D-glucan (BDG) and D-dimer showed independent associations with CMV co-detection in multivariable analyses. mNGS revealed more concurrent viral and fungal pathogens in the co-detection group, and multiple co-pathogens were more frequent in non-survivors within this subgroup. Interleukin-6 (IL-6), procalcitonin (PCT) and D-dimer were identified as independent prognostic factors for 28-day mortality in the CMV co-detection subgroup. In this single-center retrospective cohort, BALF CMV co-detection is associated with substantially elevated unadjusted 28-day mortality in non-HIV patients with PJP. These findings are hypothesis-generating; IL-6, PCT and D-dimer show potential as exploratory prognostic markers. Comprehensive mNGS-based pathogen screening combined with biomarker monitoring may facilitate risk stratification in this high-risk population, pending validation in larger prospective cohorts.

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2026-08-28 | The role of corticosteroids in management of non-HIV immunocompromised patients hospitalized for Pneumocystis jirovecii pneumonia.

Caused by pneumocystis jirovecii, pneumocystosis is a severe opportunistic infection primarily affecting immunocompromised patients who are not infected with HIV. Mortality in this heterogeneous population is high, with estimates ranging from 25% to 50%. While the benefits of corticosteroids for HIV-infected patients are well-established, in other immunosuppression contexts their role remains uncertain, with contradictory results reported in the literature. This single-center retrospective study included 101 non-HIV immunocompromised patients hospitalized at Caen University Hospital between 2013 and 2024 for proven or probable pneumocystosis. Thirty-nine patients received adjunctive corticosteroid therapy. Thirty-day mortality was 26% in the corticosteroid group versus 18% in the non-corticosteroid group, with no significant difference after adjustment. Similarly, no benefit was observed at 90 days or at one year. Nor did corticosteroid therapy reduce the duration of oxygen therapy, affect the incidence of secondary infections or, more generally, emerge as protective. Conversely, the factors associated with higher survival rates were admission to conventional care units and younger age. In contrast with HIV settings, this study does not show corticosteroid therapy to be beneficial for non-HIV patients with pneumocystosis,. However, recent data from the PIC trial suggest potentially improved benefit 90-day survival in the most severe forms; further targeted studies consequently appear justified, particularly with regard to immunodeficiency subtypes.

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2026-08-06 | Adjunctive corticosteroids in non-HIV immunocompromised patients with Pneumocystis jirovecii pneumonia: a systematic review and meta-analysis.

Pneumocystis jirovecii pneumonia (PJP) in non-HIV immunocompromised adults carries 30%-60% mortality. Adjunctive corticosteroids are standard in HIV-PJP but remain contested in non-HIV PJP. To determine whether adjunctive corticosteroids reduce mortality and invasive mechanical ventilation (IMV) in non-HIV PJP, and whether effect estimates differ between randomized and observational study designs. Systematic review and meta-analysis. Six databases and two trial registers were searched from inception to February 7, 2026. Randomized and observational studies comparing adjunctive corticosteroids versus no corticosteroids or placebo in non-HIV adults with PJP were eligible. Random-effects meta-analyses (restricted maximum likelihood) of two co-primary outcomes included subgroup, sensitivity, E-value, and Grading of Recommendations Assessment analyses. Twenty-eight studies were included (one randomized controlled trial (RCT), 27 observational; ∼ 5300 patients): 22 contributed corticosteroid-versus-no-corticosteroid comparisons and six contributed dose-comparison data only. Evidence was discordant by design (interaction p = 0 . 006 ): the RCT showed lower IMV (hazard ratio (HR) 0.36, 95% CI 0.14-0.90) and lower 90-day mortality (HR 0.59, 0.37-0.93); regression-adjusted observational studies suggested harm (odds ratio (OR) 1.56, 1.10-2.22); propensity-based estimates were null-compatible. Pre-specified mortality pools were non-significant short-term (OR 1.22, 0.88-1.70) and intermediate-term (OR 1.39, 0.85-2.29). Secondary infections ( k = 4 ): OR 1.04 (0.63-1.72); RCT 0.59 (0.32-1.06). E-values for RCT effects (3.44 IMV; 2.24 mortality) exceeded the 1.81 E-value of the adjusted observational mortality pool. Certainty was very low for pooled mortality and moderate for RCT outcomes. Reliable inference rests on the single RCT rather than the pooled observational estimate, which is discordant by design and most consistent with confounding by indication. In the RCT, corticosteroids did not significantly reduce 28-day mortality but lowered IMV and 90-day mortality and sped respiratory recovery, without clear excess secondary infections (low certainty). Corticosteroids may be considered for severe respiratory failure using the PIC (ClinicalTrials.gov NCT02944045) protocol; adequately powered confirmatory trials are needed. Trial registration: PROSPERO CRD420261304396.

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proteins

2026-03-01 | Identification of compound heterozygous LRBA variants associated with Pneumocystis jirovecii pneumonia and toxoplasmosis

Background: Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM #614700. The LRBA protein is crucial for immune regulation, receptor recycling, and autophagy. LRBA deficiency is linked to various clinical manifestations, including autoimmunity, lymphoproliferation, and humoral immune deficiency. Aim: To describe the clinical course and diagnosis of a patient identified with LRBA deficiency. Methods: A thorough review of the patient’s medical chart was performed. Results: We report the case of a 42-year-old female born prematurely and diagnosed with Bartter syndrome, with features of immune dysregulation presenting during childhood, manifesting as recurrent bacterial and viral sinopulmonary infections, lymphadenopathy, pancytopenia, and atopy. Her clinical status deteriorated in adulthood with multi-organ involvement, including granulomatous lymphocytic interstitial lung disease, progressive hepatosplenomegaly with resultant portal hypertension; acute on chronic kidney disease with nephrocalcinosis; and severe immune dysfunction characterized by low T and B cells, recurrent bacterial, fungal and viral infections and susceptibility to opportunistic infections including Candida, Pneumocystis jirovecii and Toxoplasma gondii. Research-based analysis of the patient’s clinical exome identified two variants in the LRBA gene, a rare missense c.6697G>A (p. Ala2233Thr) change and a novel intronic splice site c.4005-210G>C (p.?) change strengthening the acceptor splice site of a pseudo-exon, classified as variants of unknown significance. In addition to her genetic findings pertaining to Bartter syndrome (SLC12A1: c.596G>A [p. Arg199His], and c.1543 G>T [p. Ala515Ser]), a heterozygous variant of uncertain significance in NOD2, c.866A>G (p. Asn289Ser), was identified. A positive pathogenic heterozygous mutation in DOCK8 was also found, although follow-up functional testing for DOCK8 expression did not confirm a DOCK8 deficiency, with adequate expression of DOCK8 protein in T and NK cells. Based on the LRBA genetic variants identified by exome sequencing, add-on therapy with abatacept, a recombinant cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein, was initiated as a targeted therapy for LRBA deficiency. Conclusion: This case expands our knowledge of the clinical manifestations of LRBA deficiency and the potential associations across the spectrum of immune dysregulation. Early incorporation of genetic sequencing into the diagnostic evaluation, may play a beneficial role in early diagnosis and treatment, particularly in individuals at risk for life-threatening immunodeficiencies and rare disorders. Statement of novelty: We report the diagnostic journey of a patient with compound heterozygous variants in the LRBA gene, along with findings of a NOD2 variant and her known diagnosis of Bartter syndrome. Identifying the variants in LRBA enabled the use of targeted therapies, which have demonstrated clinical and multi-organ benefits in affected individuals.

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2016-05-24 | Treatment with Interleukin-7 Restores Host Defense against Pneumocystis in CD4+ T-Lymphocyte-Depleted Mice.

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4(+) T lymphocytes are critical for host defense against this infection, but in the absence of CD4(+) T lymphocytes, CD8(+) T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8(+) T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8(+) T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-γ)-positive CD8(+) central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8(+) T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8(+) T lymphocytes.

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2015-08-31 | Eosinophils Contribute to Early Clearance of Pneumocystis murina Infection.

Pneumocystis pneumonia remains a common opportunistic infection in the diverse immunosuppressed population. One clear risk factor for susceptibility to Pneumocystis is a declining CD4(+) T cell count in the setting of HIV/AIDS or primary immunodeficiency. Non-HIV-infected individuals taking immunosuppressive drug regimens targeting T cell activation are also susceptible. Given the crucial role of CD4(+) T cells in host defense against Pneumocystis, we used RNA sequencing of whole lung early in infection in wild-type and CD4-depleted animals as an unbiased approach to examine mechanisms of fungal clearance. In wild-type mice, a strong eosinophil signature was observed at day 14 post Pneumocystis challenge, and eosinophils were increased in the bronchoalveolar lavage fluid of wild-type mice. Furthermore, eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice were more susceptible to Pneumocystis infection when compared with BALB/c controls, and bone marrow-derived eosinophils had in vitro Pneumocystis killing activity. To drive eosinophilia in vivo, Rag1(-/-) mice were treated with a plasmid expressing IL-5 (pIL5) or an empty plasmid control via hydrodynamic injection. The pIL5-treated mice had increased serum IL-5 and eosinophilia in the lung, as well as reduced Pneumocystis burden, compared with mice treated with control plasmid. In addition, pIL5 treatment could induce eosinophilia and reduce Pneumocystis burden in CD4-depleted C57BL/6 and BALB/c mice, but not eosinophilopoiesis-deficient Gata1(tm6Sho)/J mice. Taken together, these results demonstrate that an early role of CD4(+) T cells is to recruit eosinophils to the lung and that eosinophils are a novel candidate for future therapeutic development in the treatment of Pneumocystis pneumonia in the immunosuppressed population.

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2011-04-28 | IL-33 and M2a alveolar macrophages promote lung defense against the atypical fungal pathogen Pneumocystis murina.

We have recently reported that mice deficient in the myeloid Src-family tyrosine kinases Hck, Fgr, and Lyn (Src triple knockout [TKO]) had augmented innate lung clearance of Pneumocystis murina that correlated with a higher ability of alveolar macrophages (AMs) from these mice to kill P. murina. In this article, we show that despite possessing enhanced killing, AMs from naive Src TKO mice did not demonstrate enhanced inflammatory responses to P. murina. We subsequently discovered that both AMs and lungs from P. murina-infected Src TKO mice expressed significantly greater levels of the M2a markers RELM-α and Arg1, and the M2a-associated chemokines CCL17 and CCL22 than did wild-type mice. IL-4 and IL-13, the primary cytokines that promote M2a polarization, were not differentially produced in the lungs between wild-type and Src TKO mice. P. murina infection in Src TKO mice resulted in enhanced lung production of the novel IL-1 family cytokine IL-33. Immunohistochemical analysis of IL-33 in lung tissue revealed localization predominantly in the nucleus of alveolar epithelial cells. We further demonstrate that experimental polarization of naive AMs to M2a resulted in more efficient killing of P. murina compared with untreated AMs, which was further enhanced by the addition of IL-33. Administration of IL-33 to C57BL/6 mice increased lung RELM-α and CCL17 levels, and enhanced clearance of P. murina, despite having no effect on the cellular composition of the lungs. Collectively, these results indicate that M2a AMs are potent effector cells against P. murina. Furthermore, enhancing M2a polarization may be an adjunctive therapy for the treatment of Pneumocystis.

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2009-08-18 | Effects of decreased calmodulin protein on the survival mechanisms of alveolar macrophages during Pneumocystis pneumonia.

Pneumocystis infection causes increased intracellular levels of reactive oxygen species (ROS) and the subsequent apoptosis of alveolar macrophages (Amø). Assessments of key prosurvival molecules in Amø and bronchoalveolar lavage fluids from infected rats and mice showed low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and reduced activation of phosphoinositide-3 kinase (PI-3K). Ubiquitous calcium-sensing protein calmodulin protein and mRNA levels were also reduced in Amø during Pneumocystis pneumonia (Pcp). Calmodulin has been implicated in control of GM-CSF production and PI-3K activation in other immune cell types. Experiments to determine the control of GM-CSF and PI-3K by calmodulin in Amø showed that GM-CSF expression and PI-3K activation could not be induced when calmodulin was inhibited. Calmodulin inhibition also led to increased levels of ROS and apoptosis in cells exposed to bronchoalveolar lavage fluids from infected animals. Supplementation of Amø with exogenous calmodulin increased survival signaling via GM-CSF and PI-3K and reduced ROS and apoptosis. These data support the hypotheses that calmodulin levels at least partially control survival signaling in Amø and that restoration of GM-CSF or PI-3K signaling will improve host response to the organism.

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2024-02-08 | Extracellular vesicles from Pneumocystis carinii-infected rats impair fungal viability but are dispensable for macrophage functions.

Pneumocystis spp. are host obligate fungal pathogens that can cause severe pneumonia in mammals and rely heavily on their host for essential nutrients. The lack of a sustainable in vitro culture system poses challenges in understanding their metabolism, and the acquisition of essential nutrients from host lungs remains unexplored. Transmission electron micrographs show that extracellular vesicles (EVs) are found near Pneumocystis spp. within the lung. We hypothesized that EVs transport essential nutrients to the fungi during infection. To investigate this, EVs from P. carinii- and P. murina-infected rodents were biochemically and functionally characterized. These EVs contained host proteins involved in cellular, metabolic, and immune processes as well as proteins with homologs found in other fungal EV proteomes, indicating that Pneumocystis may release EVs. Notably, EV uptake by P. carinii indicated their potential involvement in nutrient acquisition and a possibility for using engineered EVs for efficient therapeutic delivery. However, EVs added to P. carinii in vitro did not show increased growth or viability, implying that additional nutrients or factors are necessary to support their metabolic requirements. Exposure of macrophages to EVs increased proinflammatory cytokine levels but did not affect macrophages' ability to kill or phagocytose P. carinii. These findings provide vital insights into P. carinii and host EV interactions, yet the mechanisms underlying P. carinii's survival in the lung remain uncertain. These studies are the first to isolate, characterize, and functionally assess EVs from Pneumocystis-infected rodents, promising to enhance our understanding of host-pathogen dynamics and therapeutic potential.IMPORTANCEPneumocystis spp. are fungal pathogens that can cause severe pneumonia in mammals, relying heavily on the host for essential nutrients. The absence of an in vitro culture system poses challenges in understanding their metabolism, and the acquisition of vital nutrients from host lungs remains unexplored. Extracellular vesicles (EVs) are found near Pneumocystis spp., and it is hypothesized that these vesicles transport nutrients to the pathogenic fungi. Pneumocystis proteins within the EVs showed homology to other fungal EV proteomes, suggesting that Pneumocystis spp. release EVs. While EVs did not significantly enhance P. carinii growth in vitro, P. carinii displayed active uptake of these vesicles. Moreover, EVs induced proinflammatory cytokine production in macrophages without compromising their ability to combat P. carinii. These findings provide valuable insights into EV dynamics during host-pathogen interactions in Pneumocystis pneumonia. However, the precise underlying mechanisms remain uncertain. This research also raises the potential for engineered EVs in therapeutic applications.

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2022-01-24 | First case of low-dose umbilical cord blood therapy for pediatric acute respiratory distress syndrome induced by Pneumocystis carinii pneumonia.

This study aimed to present the case of a boy with acute distress syndrome (ARDS) treated with low-dose umbilical cord blood (UCB) therapy and explore the underlying possible mechanism. A 7-year-old boy with severe Pneumocystis carinii pneumonia and severe ARDS was treated with allogeneic UCB as salvage therapy. The patient did not improve after being treated with lung protective ventilation, pulmonary surfactant replacement, and extracorporeal membrane oxygenation (ECMO) for 30 days. However, his disease reversed 5 days after allogeneic UCB infusion, and he weaned from ECMO after 7 days of infusion. Bioinformatics confirmed that his Toll-like receptor (TLR) was abnormal before UCB infusion. However, after the infusion, his immune system was activated and repaired, and the TLR4/MyD88/NF-κB signaling pathway was recovered. Allogenic UCB could treat ARDS by repairing the TLR4/MyD88/NF-κB signaling pathway, thereby achieving stability of the immune system.

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2021-06-04 | Toward a humanized mouse model of Pneumocystis pneumonia.

Pneumocystis is an important opportunistic fungus that causes pneumonia in children and immunocompromised individuals. Recent genomic data show that divergence of major surface glycoproteins may confer speciation and host range selectivity. On the other hand, immune clearance between mice and humans is well correlated. Thus, we hypothesized that humanize mice may provide information about human immune responses involved in controlling Pneumocystis infection. CD34-engrafted huNOG-EXL mice controlled fungal burdens to a greater extent than nonengrafted mice. Moreover, engrafted mice generated fungal-specific IgM. Fungal control was associated with a transcriptional signature that was enriched for genes associated with nonopsonic recognition of trophs (CD209) and asci (CLEC7A). These same genes were downregulated in CD4-deficient mice as well as twins with bare lymphocyte syndrome with Pneumocystis pneumonia.

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2020-04-27 | Circulating and Pulmonary T-cell Populations Driving the Immune Response in Non-HIV Immunocompromised Patients with Pneumocystis jirovecii Pneumonia.

Background: Previous studies in human subjects have mostly been confined to peripheral blood lymphocytes for Pneumocystis infection. We here aimed to compare circulating and pulmonary T-cell populations derived from human immunodeficiency virus (HIV)-uninfected immunocompromised patients with Pneumocystis jirovecii pneumonia (PCP) in order to direct new therapies. Methods: Peripheral blood and bronchoalveolar lavage samples were collected from patients with and without PCP. Populations of Th1/Tc1, Th2/Tc2, Th9/Tc9, and Th17/Tc17 CD4+ and CD8+ T cells were quantified using multiparameter flow cytometry. Results: No significant differences were found between PCP and non-PCP groups in circulating T cells. However, significantly higher proportions of pulmonary Th1 and Tc9 were observed in the PCP than in the non-PCP group. Interestingly, our data indicated that pulmonary Th1 was negatively correlated with disease severity, whereas pulmonary Tc9 displayed a positive correlation in PCP patients. Conclusions: Our findings suggest that pulmonary expansion of Th1 and Tc9 subsets may play protective and detrimental roles in PCP patients, respectively. Thus, these specific T-cell subsets in the lungs may serve as targeted immunotherapies for patients with PCP.

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2019-04-18 | CD4+ T Cell Regulation of Antibodies Cross-Reactive with Fungal Cell Wall-Associated Carbohydrates after Pneumocystis murina Infection.

Pneumocystis pneumonia is a life-threatening opportunistic fungal infection observed in individuals with severe immunodeficiencies, such as AIDS. Molecules with the ability to bind β-glucan and signal at Fcγ receptors enhance defense against Pneumocystis f. sp. murina, though it is unclear whether antibodies reactive with fungal cell wall carbohydrates are induced during Pneumocystis infection. We observed that systemic and lung mucosal immunoglobulins cross-reactive with β-glucan and chitosan/chitin are generated after Pneumocystis infection, with increased quantities within the lung mucosal fluid after challenge. While IgG responses against Pneumocystis protein antigens are markedly CD4+ T cell dependent, CD4+ T cell depletion did not impact quantities of IgG cross-reactive with β-glucan or chitosan/chitin in the serum or mucosa after challenge. Notably, lung mucosal quantities of IgA cross-reactive with β-glucan or chitosan/chitin are decreased in the setting of CD4+ T cell deficiency, occurring in the setting of concurrent reduced quantities of active transforming growth factor β, while mucosal IgM is significantly increased in the setting of CD4+ T cell deficiency. Interleukin-21 receptor deficiency does not lead to reduction in mucosal IgA reactive with fungal carbohydrate antigens after Pneumocystis challenge. These studies demonstrate differential CD4+ T cell-dependent regulation of mucosal antibody responses against β-glucan and chitosan/chitin after Pneumocystis challenge, suggesting that different B cell subsets may be responsible for the generation of these antibody responses, and suggest a potential immune response against fungi that may be operative in the setting of CD4+ T cell-related immunodeficiency.

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