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The coronavirus disease 2019 (COVID-19) pandemic emerged in Wuhan, China, in late 2109, and has rapidly spread around the world. Until May 25, 2020, there were 133,521 confirmed COVID-19 cases and 7359 deaths in Iran. The role of opportunistic fungal infections in the morbidity and mortality of COVID-19 patients remains less defined. Based on our multicenter experiences, we categorized the risks of opportunistic fungal infections in COVID-19 patients in Iran. The COVID-19 patients at high risk included those with acute respiratory distress syndrome, in intensive care units, receiving broad-spectrum antibiotics, immunosuppressants or corticosteroid, and supported by invasive or noninvasive ventilation. The patients were most likely to develop pulmonary aspergillosis, oral candidiasis, or pneumocystis pneumonia. Most diagnoses were probable as the accurate diagnosis of opportunistic fungal infections remains challenging in resource-poor settings. We summarize the clinical signs and laboratory tests needed to confirm candidiasis, aspergillosis, or pneumocystosis in our COVID-19 patients.

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. 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. 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. 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. 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.

The substantial decline in the Pneumocystis jirovecii pneumonia (PCP) incidence in HIV-infected patients after the introduction of antiretroviral therapy (ART) in resource-rich settings and the growing number of non-HIV-infected immunocompromised patients at risk leads to considerable epidemiologic changes with clinical, diagnostic, and treatment consequences for physicians. HIV-infected patients usually develop a subacute course of disease, while non-HIV-infected immunocompromised patients are characterized by a rapid disease progression with higher risk of respiratory failure and higher mortality. The main symptoms usually include exertional dyspnea, dry cough, and subfebrile temperature or fever. Lactate dehydrogenase may be elevated. Typical findings on computed tomography scans of the chest are bilateral ground-glass opacities with or without cystic lesions, which are usually associated with the presence of AIDS. Empiric treatment should be initiated as soon as PCP is suspected. Bronchoalveolar lavage has a higher diagnostic yield compared to induced sputum. Immunofluorescence is superior to conventional staining. A combination of different diagnostic tests such as microscopy, polymerase chain reaction, and (1,3)-β-D-glucan is recommended. Trimeth­oprim/sulfamethoxazole for 21 days is the treatment of choice in adults and children. Alternative treatment regimens include dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine. Patients with moderate to severe disease should receive adjunctive corticosteroids. In newly diagnosed HIV-infected patients with PCP, ART should be initiated as soon as possible. In non-HIV-infected immunocompromised patients, improvement of the immune status should be discussed (e.g., temporary reduction of immunosuppressive agents). PCP prophylaxis is effective and depends on the immune status of the patient and the underlying immunocompromising disease.

ObjectivesTo investigate the efficacy and safety of trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) in patients with rheumatic diseases receiving high-dose steroids.MethodsThe study included 1522 treatment episodes with prolonged (≥4 weeks) high-dose (≥30 mg/day prednisone) steroids in 1092 patients over a 12-year period. Of these, 262 treatment episodes involved TMP-SMX (prophylaxis group) while other episodes involved no prophylaxis (control group). Differences in 1-year PCP incidence and its mortality between the two groups were estimated using Cox regression. To minimise baseline imbalance, propensity score matching was performed and efficacy outcome was mainly assessed in the postmatched population (n=235 in both groups).ResultsDuring a total of 1474.4 person-years, 30 PCP cases occurred with a mortality rate of 36.7%. One non-fatal case occurred in the prophylaxis group. TMP-SMX significantly reduced the 1-year PCP incidence (adjusted HR=0.07(95% CI 0.01 to 0.53)) and related mortality (adjusted HR=0.08 (95% CI 0.0006 to 0.71)) in the postmatched population. The result of the same analysis performed in the whole population was consistent with that of the primary analysis. Incidence rate of adverse drug reactions (ADR) related to TMP-SMX was 21.2 (14.8–29.3)/100 person-years. Only two serious ADRs (including one Stevens-Johnson syndrome case) occurred. The number needed to treat for preventing one PCP (52 (33–124)) was lower than the number needed to harm for serious ADR (131 (55–∞)).ConclusionTMP-SMX prophylaxis significantly reduces the PCP incidence with a favourable safety profile in patients with rheumatic disease receiving prolonged, high-dose steroids.

Key Points Pneumocystis pneumonia (PCP) remains the most prevalent opportunistic infection in patients with AIDS and is a significant cause of severe pneumonia in immunocompromised patients with cancer, organ transplant recipients or those receiving immunosuppressant medications. Pneumocystis is an intractable fungal pathogen classified phylogenetically with the Ascomycetes. Pneumocystis has pathways involved in cell-cycle control, signal transduction and metabolism that are analogous to the pathways in these yeast. Pneumocystis has a unique life cycle alternating between small trophic forms and cysts, which contain 2, 4 or 8 intracystic bodies. The airborne route of transmission is currently the favoured model for the spread of infection. Pneumocystis interacts with the lung epithelium and immune cells of the lower respiratory tract, resulting in inflammation, which is hazardous to the host. This is a complex interaction involving surface antigens of the organism and host surfactant proteins, adhesion molecules, macrophages, neutrophils, lymphocytes, and cytokine and chemokine responses. Drug targets for the treatment of PCP include metabolic pathways for dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR), DNA and protein synthesis inhibition, sterol metabolism, cytochrome b complex and cell-wall construction through inhibition of the GSC1 glucan synthetase. Mutations in DHPS, DHFR, and cytochrome b have raised the concern of emerging resistance to the medications currently in use. The efforts of the Pneumocystis research community have contributed substantially to the current understanding of the complex biology of Pneumocystis and the intricate association with the host. Continued research is essential to continue investigating the biology of this organism in the hope of developing novel treatment strategies for PCP. Pneumonia caused by the fungus Pneumocystis is the most prevalent opportunistic infection in patients with AIDS. Here, Charles Thomas and Andrew Limper review the latest knowledge on the biology and pathogenesis of this opportunistic fungal pathogen. The fungal infection Pneumocystis pneumonia is the most prevalent opportunistic infection in patients with AIDS. Although the analysis of this opportunistic fungal pathogen has been hindered by the inability to isolate it in pure culture, the use of molecular techniques and genomic analysis have brought insights into its complex cell biology. Analysis of the intricate relationship between Pneumocystis and the host lung during infection has revealed that the attachment of Pneumocystis to the alveolar epithelium promotes the transition of the organism from the trophic to the cyst form. It also revealed that Pneumocystis infection elicits the production of inflammatory mediators, culminating in lung injury and impaired gas exchange. Here we discuss these and other recent findings relating to the biology and pathogenesis of this intractable fungus.

Background Pneumocystis jirovecii pneumonia (PJP) is a fatal opportunistic infectious disease. We conducted this study to describe the clinical characteristics and explore the prognostic factors of patients with concurrent malignancies and PJP (malignancy-PJP). Methods We retrospectively enrolled consecutive patients with malignancies diagnosed with PJP in our center from January 2014 to December 2022. The participants were classified into a hematological malignancy group and a non-hematological malignancy group. Cox regression models were used to analyze prognostic factors. Results Fifty-six malignancy-PJP patients were enrolled in our study with an average age of 63 (52, 68) years, 60.7% of whom were males. There were 33 (58.9%) hematological malignancy patients and 23 (41.1%) non-hematological malignancy patients. Overall, 29 (51.8%) patients died. Compared with the non-hematological malignancy group, more patients received mechanical ventilation ( p  = 0.03) in the hematological malignancy group. Moreover, shorter periods from the onset of underlying malignancies ( p  < 0.01) and from the first dosage of chemotherapy ( p  = 0.04) to PJP infection were significantly more common in patients with hematological malignancies. However, patients with non-hematological malignancies presented more pleural thickening ( p  = 0.03) on chest computed tomography (CT). Multivariate analysis revealed that non-solid malignancies (HR = 2.77, p  = 0.03, 95% CI: 1.12–6.89), cytomegalovirus (CMV) viremia (HR = 3.33, p  < 0.01, 95% CI: 1.51–7.33), bacterial hospital-acquired pneumonia (HAP) (HR = 2.21, p  = 0.04, 95% CI: 1.03–4.77), and pneumomediastinum (HR = 2.50, p  < 0.05, 95% CI: 1.01–6.14) were independent risk factors for survival in malignancy-PJP patients. Conclusions Compared with patients with non-hematological malignancies, patients with hematological malignancies were more likely to require mechanical ventilation and to be infected with PJP within a shorter time from the onset of underlying malignancies and from the first chemotherapy treatment. Non-solid malignancies, CMV viremia, bacterial HAP, and pneumomediastinum were independent risk factors for survival in patients with malignancy-PJP.

Background Children with Langerhans cell histiocytosis (LCH) are particularly susceptible to infections such as Pneumocystis jirovecii pneumonia (PJP) due to the immunosuppressive effects of chemotherapy, which can progress to acute respiratory distress syndrome (ARDS) and respiratory failure. The use of Extracorporeal Membrane Oxygenation (ECMO) to manage hypoxemia secondary to PJP in LCH presents unique challenges, including the prevention of catheter-related bloodstream infections associated with arterial and venous access. This study explores a case wherein ECMO was crucial in treating severe PJP-induced respiratory failure in a pediatric patient with LCH. Case presentation A 3-year-old female with a history of LCH, undergoing long-term chemotherapy and corticosteroid treatment, was admitted with fever, dyspnea, and lethargy. Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid confirmed Pneumocystis jirovecii (PJ). Despite aggressive management with invasive high-frequency ventilation, inhaled nitric oxide, and prone positioning, the patient’s oxygenation remained critically low, with severe hypercapnia and resultant severe respiratory acidosis, necessitating vasopressor support for hemodynamic stability and venoarterial (VA) ECMO intervention. Early initiation of VA ECMO facilitated ultraprotective lung ventilation and circulatory support, effectively preventing hemodynamic collapse. The patient was successfully decannulated after 13 days of ECMO support. Conclusion While PJP is a rare and extremely serious opportunistic infection, the VA ECMO support in this pediatric case effectively managed severe PJP without ECMO-related complications. This highlights ECMO as a potentially viable, relatively effective, and safe adjunctive therapy in the management of severe PJP infections in children.

Background Idiopathic inflammatory myopathies (IIM) are associated with a significantly higher risk of opportunistic infections including Pneumocystis jirovecii pneumonia (PJP), a potentially fatal opportunistic infection. However, no prior studies have evaluated PJP infection in subtypes of IIM. Objectives To investigate the prevalence and mortality rate of PJP infection in subgroups of IIM patients stratified according to myopathy-specific antibodies. Methods In the first part of the study, 463 consecutive patients with IIM were prospectively followed for a period of at least 1 year to analyze the incidence of PJP. In the second part of the study, we enrolled 30 consecutive PJP patients with any rheumatic disease in order to identify the mortality rate and risk factors by Cox regression analysis. The Kaplan-Meier method with log-rank testing was used to assess differences in survival. Results The prevalence of PJP in IIM patients was found to be 3.0/100 person-years, while in MDA5 + DM patients it was 7.5/100 person-years and in MDA5 − IIM patients 0.7/100 person-years ( P < 0.05). PJP typically occurred in the first 2 months in the case of MDA5 + DM patients who had a significant decrease in their CD4 + T cell counts and lymphocyte counts ( P < 0.05). In PJP patients, 3-month mortality was higher for MDA5 + DM patients than in those with other rheumatic diseases (83.3% vs 38.9%, P < 0.05). Alarmingly, MDA5 + DM patients seemed not to benefit from prompt anti-PJP treatment, unlike patients with other rheumatic diseases whose survival improved when anti-PJP treatment was started within 6 days ( P < 0.05). Conclusion PJP has an alarming high incidence and mortality in MDA5 + DM patients. Timely treatment for PJP seems not to improve the prognosis of patients with this particular subtype. Hence, there remains a crucial unmet need to develop PJP prophylaxis for MDA5 + DM patients.

BackgroundPneumocystis jirovecii (P. jirovecii) is increasingly identified on lower respiratory tract specimens of COVID-19 patients. Our narrative review aims to determine whether the diagnosis of pneumocystis jirovecii pneumonia (PJP) in COVID-19 patients represents coinfection or colonization based on the evidence available in the literature. We also discuss the decision to treat COVID-19 patients with coinfection by PJP. MethodsA literature search was performed through the Pubmed and Web of Science databases from inception to March 10, 2021.ResultsWe identified 12 COVID-19 patients suspected to have PJP coinfection. All patients were critically ill and required mechanical ventilation. Many were immunosuppressed from HIV or long-term corticosteroids and other immunosuppressive agents. In both the HIV and non-HIV groups, severe lymphocytopenia was encountered with absolute lymphocyte and CD4+T cell count less than 900 and 200 cells/mm, respectively. The time to PJP diagnosis from the initial presentation was 7.8 (range 2–21) days. Serum lactate dehydrogenase and beta-D-glucan were elevated in those coinfected with PJP. All patients were treated with anti-PJP therapy, predominantly sulfamethoxazole-trimethoprim with corticosteroids. The overall mortality rate was 41.6%, and comparable for both HIV and non-HIV groups. ConclusionAs the current evidence is restricted to case reports, the true incidence, risk factors, and prognosis of COVID-19 patients with PJP coinfections cannot be accurately determined. Comorbidities of poorly controlled HIV with lymphocytopenia and multiple immunosuppressive therapies are likely predisposing factors for PJP coinfection.

The fungus Pneumocystis causes severe pneumonia in patients with weakened immune systems. It possesses a genetic system to vary the antigens at the surface of its cells that are presented to the immune system of the patient. We report for the first time that this system may have been implicated in the infections of renal transplant recipients involved in a suspected outbreak. Our observations suggest that the antigens presented might be selected to avoid the elimination of the fungus by the immune response specific to each patient. The resistance of the fungus to the immunosuppressant mycophenolate administered to these patients to prevent organ rejection probably also played a role in the infections during the suspected outbreak.