Significance of positive semi-quantitative PCR tests on bronchoalveolar lavage for Pneumocystis jirovecii pneumonia in HIV-negative immunocompromised ICU patients with acute respiratory failure

Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality. To assess the effectiveness of PCP prophylaxis among non-HIV immunocompromised patients; and to define the type of immunocompromised patient for whom evidence suggests a benefit for PCP prophylaxis. Electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE and EMBASE (to March 2014), LILACS (to March 2014), relevant conference proceedings; and references of identified trials. Randomised controlled trials (RCTs) or quasi-RCTs comparing prophylaxis with an antibiotic effective against PCP versus placebo, no intervention, or antibiotic(s) with no activity against PCP; and trials comparing different antibiotics effective against PCP among immunocompromised non-HIV patients. We only included trials in which Pneumocystis infections were available as an outcome. Two review authors independently assessed risk of bias in each trial and extracted data from the included trials. We contacted authors of the included trials to obtain missing data. The primary outcome was documented PCP infections. Risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the random-effects model. Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP-related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all-cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients). Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non-HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.

BackgroundPneumocystis jirovecii pneumonia (PJP) is one of the most common opportunistic infections in immunocompromised patients. However, the accurate prediction of the development of PJP in non-HIV immunocompromised patients is still unclear.MethodsNon-HIV immunocompromised patients confirmed diagnosis of PJP by the clinical symptoms, chest computed tomography and etiological results of metagenomic next-generation sequencing (mNGS) were enrolled as observation group. Another group of matched non-HIV immunocompromised patients with non-PJP pneumonia were enrolled to control group. The risk factors for the development of PJP and the co-pathogens in the bronchoalveolar lavage fluid (BALF) detected by mNGS were analyzed. ResultsA total of 67 (33 PJP, 34 non-PJP) participants were enrolled from Fujian Provincial Hospital. The ages, males and underlying illnesses were not significantly different between the two groups. Compared to non-PJP patients, PJP patients were more tends to have the symptoms of fever and dyspnea. The LYM and ALB were significantly lower in PJP patients than in non-PJP patients. Conversely, LDH and serum BDG in PJP patients were significantly higher than in non-PJP controls. For immunological indicators, the levels of immunoglobulin A, G, M and complement C3, C4, the numbers of T, B, and NK cells, had no statistical difference between these two groups. Logistic multivariate analysis showed that concomitant use of corticosteroids and immunosuppressant (OR 14.146, P = 0.004) and the lymphocyte counts < 0.7 × 109/L (OR 6.882, P = 0.011) were risk factors for the development of PJP in non-HIV immunocompromised patients. 81.82% (27/33) and 64.71% (22/34) mixed infections were identified by mNGS in the PJP group and non-PJP group separately. CMV, EBV and Candida were the leading co-pathogens in PJP patients. The percentages of CMV and EBV identified by mNGS in PJP group were significantly higher than those in the control group(p < 0.005). ConclusionsClinicians should pay close attention to the development of PJP in non-HIV immunocompromised patients who possess the risk factors of concomitant use of corticosteroids and immunosuppressant and the lymphocyte counts < 0.7 × 109/L. Prophylaxis for PJP cannot rely solely on CD4+ T counts in non-HIV immunocompromised patients. Whether CMV infection increases the risk of PJP remains to be further investigated.

Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality. To assess the effectiveness of PCP prophylaxis among non-HIV immunocompromised patients. To define the type of immunocompromised patients for whom evidence suggests a benefit for PCP prophylaxis. Electronic searches of The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 1, 2007), PubMed (March 2007), LILACS (March 2007), relevant conference proceedings; references of identified trials; the first author of each included trial was contacted. RCTs or quasi- RCTs comparing prophylaxis with an antibiotic effective against Pneumocystis versus placebo, no intervention, an antibiotic/s with no activity against Pneumocystis or another antibiotic effective against Pneumocystis for immune-compromised non-HIV patients. Only trials pre-defining Pneumocystis infections as an outcome were included. Two authors independently appraised the quality of each trial and extracted data from included trials. Relative risks (RR), with 95% confidence intervals (CI) were estimated and pooled using the random effects model. Eleven trials including 1155 patients (520 children), performed between the years 1974 and 1997, were included. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was a 91% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR 0.09 (95% CI 0.02 to 0.32), eight trials, 821 patients. No significant difference was encountered in all cause mortality, RR 0.81 (95% CI 0.27 to 2.37), five trials, 509 patients, while PCP-related mortality was significantly reduced, RR 0.17 (95% CI 0.03 to 0.94), seven trials, 701 patients. Occurrence of leukopenia, neutropenia and their duration were not reported consistently. No significant difference in any adverse event was seen comparing trimethoprim/sulfamethoxazole to no treatment/ placebo (four trials, 470 patients). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients). Given an event rate of 7.5% as in included trials' control group, prophylaxis for PCP using TMP/SMX is highly effective among non-HIV patients, with a number needed to treat of 15 patients (95% CI 13 to 20). Prophylaxis should be considered for the types of patients with hematological malignancies, bone marrow transplantation and solid organ transplantation included in these trials.

Objectives: Pneumocystis jirovecii pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection.Material and Methods: A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and Pneumocystis jirovecii (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5–30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34–35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated.Results: From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages of the patients with PCP were HIV-negative. Only 11 (7%) of the 153 patients had received prophylaxis, despite that in 133 (87%) cases prophylaxis was indicated according to guidelines.Conclusion: In regions where HIV testing and treatment is available without restrictions, PCP is mainly diagnosed in non-HIV immunocompromised patients. More than four out of five patients with PCP had not received prophylaxis. Strategies to improve awareness of antimicrobial prophylaxis guidelines in immunocompromised patients are urgently needed.

Polymerase Chain Reaction-Based Detection of Pneumocystis jirovecii in Bronchoalveolar Lavage Fluid for the Diagnosis of Pneumocystis Pneumonia

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening fungal infection in HIV-infected and non-HIV immunocompromised patients. Diagnosis usually relies on the observation of the fungal forms (acsi or trophic) in lower respiratory specimens (bronchoalveolar lavage or induced sputum). Fungal load is lower in non-HIV immunocompromised patients, making microscopical diagnosis strenuous. Biomarkers such as P. jirovecii DNA detection by PCR and β-D-glucan (BDG) detection were developed in the 1990s to circumvent microscopic examination lacking sensitivity when fungal load is low. These biomarkers have high negative predictive value, resulting in exclusion of PCP when negative. Positive BDG results would urge for the detection of other fungal infection, especially in non-HIV immunocompromised patients. For diagnostic use, quantitative PCR (qPCR) is the gold standard, and positive PCR results must be interpreted quantitatively. No consensus has been reached on defined thresholds. Combined strategies using qPCR in respiratory samples and BDG detection or qPCR in serum appear promising.

Objective: To examine the clinical features of patients with acute respiratory failure (ARF) caused by pneumocystis pneumonia (PCP) admitted into two medical intensive care units (ICU) in non- human immunodeficiency virus (HIV) infected immunocompromised patients. Methods: A retrospective review was conducted among 92 non-HIV patients with ARF caused by PCP in medical ICU of Peking Union Medical College Hospital and China-Japan Friendship Hospital between Jan 2010 and Dec 2015. Patient characteristics, clinical presentation, laboratory and radiological findings, complications, as well as therapy and mortality were included in the analysis. Results: All patients were immunocompromised before PCP, among which 69.6% (64/92) patients were suffered from autoimmune disease. The diagnosis of PCP was made by the identification of P. jiroveci organisms with Giemsa or polymerase chain reaction in specimens of bronchoalveolar lavage, sputum or tracheal aspiration. The Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ was high (19±5) and the partial pressure of oxygen/ fraction of inspiration oxygen(PaO2/FiO2) ratio was low[(139.6±65.4) mmHg]on ICU admission, with all patients diagnosed as acute respiratory failure during ICU stay. Radiologic findings showed bilateral diffused ground glass opacity (94.6%, 87/92). All patients received Compound Sulfamethoxazole (SMZ/TMP) and only 3.3% (3/92) patients were not given conjunctive corticosteroid. 57.6% (53/92) and 21.7% (20/92) patients were coinfected by cytomegalovirus (CMV) and aspergillos. Invasive ventilatory support was required in 90% (81/90) patients. 22% (18/82) patients used non-invasive positive pressure ventilation (NPPV) on ICU admission but most of them (83.3%, 15/18) failed and switched to invasive positive pressure ventilation (IPPV). Median ICU and hospital length of stay were 11 and 17 days, respectively. The overall hospital mortality rate was 76.1% (70/92). Conclusions: Among patients with ARF secondary to non-HIV related PCP, autoimmune system diseases are the most common primary diagnosis. The clinical manifestations were severe and coinfections are common, with poor prognosis.

Comparison of 2 real-time PCR assays for diagnosis of Pneumocystis jirovecii pneumonia in human immunodeficiency virus (HIV) and non-HIV immunocompromised patients

BackgroundThe increasing incidence of life-threatening Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients is a global concern. Yet, no reports have examined the prognostic significance of pre-existing interstitial lung disease (ILD) in non-HIV PCP.MethodsWe retrospectively reviewed the medical records of non-HIV PCP patients with (ILD group) or without (non-ILD group) pre-existing ILD. The clinical features and outcomes of the ILD group were compared with those of the non-ILD group. Cox regression models were constructed to identify prognostic factors.Results74 patients were enrolled in this study. The 90-day mortality was significantly higher in the ILD group than in the non-ILD group (62.5% versus 19.0%, p<0.001). In the ILD group, patients with a higher percentage of bronchoalveolar lavage fluid neutrophils had worse outcomes compared to those having a lower percentage (p=0.026). Multivariate analyses revealed that pre-existing ILD (p=0.002) and low levels of serum albumin (p=0.009) were independent risk factors for 90-day mortality. Serum levels of β-d-glucan were significantly reduced after treatment of PCP in both groups, whereas levels of Krebs von den Lungen-6 (KL-6) significantly increased in the ILD group. In the ILD group, the 90-day mortality of patients with increasing KL-6 levels after treatment was significantly higher than those with decreasing levels (78.9% versus 0%, p=0.019).ConclusionIn non-HIV PCP patients, pre-existing ILD is associated with a poorer prognosis. Prophylaxis for PCP is needed in patients with pre-existing ILD under immunosuppression.

Pneumocystis carinii pneumonia: a review of current issues in diagnosis and management.

Pneumocystis pneumonia (PCP) is a frequent opportunistic infection associated with a high mortality rate. PCP is of increasing importance in non-HIV immunocompromised patients, who present with severe respiratory distress with low fungal loads. Molecular detection of Pneumocystis in broncho-alveolar lavage (BAL) has become an important diagnostic tool, but quantitative PCR (qPCR) needs standardization. Despite a high negative predictive value, the positive predictive value of qPCR is moderate, as it also detects colonized patients. Attempts are made to set a cut-off value of qPCR to discriminate between PCP and colonization, or to use noninvasive samples or combined strategies to increase specificity. It is easy to set a qPCR cut-off for HIV-infected patients. In non-HIV IC patients, a gain in specificity could be obtained by combining strategies, that is, qPCR on BAL and a noninvasive sample, or qPCR and serum beta-1,3-D-glucan dosage.

Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Pneumocystis jiroveciipneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has been a decline inPneumocystis jiroveciipneumonia incidence in HIV since the introduction of antiretroviral medications. However, its incidence is increasing in non-HIV immunocompromised patients including those with solid organ transplantation, hematopoietic stem cell transplantation, solid organ tumors, autoimmune deficiencies, and primary immunodeficiency disorders. We aim to review and summarize the etiology, epidemiology, clinical presentation, diagnosis, and management ofPneumocystis jiroveciipneumonia in HIV, and non-HIV patients. HIV patients usually have mild-to-severe symptoms, while non-HIV patients present with a rapidly progressing disease. Induced sputum or bronchoalveolar lavage fluid can be used to make a definitive diagnosis ofPneumocystis jiroveciipneumonia. Trimethoprim-sulfamethoxazole is considered to be the first-line drug for treatment and has proven to be highly effective forPneumocystis jiroveciipneumonia prophylaxis in both HIV and non-HIV patients. Pentamidine, atovaquone, clindamycin, and primaquine are used as second-line agents. While several diagnostic tests, treatments, and prophylactic regimes are available at our disposal, there is need for more research to prevent and manage this disease more effectively.

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.

BackgroundLong-term outcomes in non-HIV immunocompromised patients with disseminated Mycobacterium avium complex (dMAC) infections are unknown and the need for post-treatment secondary prophylaxis against MAC is uncertain in this setting. The objective of this study was to determine the need of continuing secondary anti-MAC prophylaxis in non-HIV patients after completing treatment of the primary dMAC episode.MethodsWe conducted a ten-year multi-center analysis of non-HIV immunosuppressed patients with dMAC infections in Hong Kong.ResultsWe observed sixteen patients with dMAC during the study period of which five (31 %) were non-HIV immunosuppressed patients. In the non-HIV immunosuppressed group, three patients completed a treatment course without secondary prophylaxis, one patient received azithromycin-based secondary prophylaxis and one patient was still receiving therapy for the first dMAC episode. All the three patients who completed treatment without being given secondary prophylaxis developed recurrent dMAC infection requiring retreatment.ConclusionsIn view of the high rate of dMAC infection recurrence in non-HIV immunocompromised patients following treatment completion, our data support long-term anti-MAC suppression therapy after treatment of the first dMAC infection episode in immunocompromised non-HIV patients, as is recommended for patients with advanced HIV. Tests of cell mediated immune function need to be evaluated to guide prophylaxis discontinuation in non-HIV patients.