Introduction

Pneumocystis jirovecii pneumonia (PCP) is an opportunistic pulmonary fungal infection caused by Pneumocystis jirovecii, and it is a major cause of acute respiratory distress syndrome (ARDS) in immunocompromised patients.1 Recent epidemiological data show that the incidence of PCP is increasing in immunocompromised patients without human immunodeficiency virus (HIV), such as those who have undergone organ or bone marrow transplantation or those using corticosteroids or cytotoxic drugs.2 Compared to HIV-infected PCP patients, non-HIV immunocompromised PCP patients rapidly progress to respiratory failure, with more than 50% requiring intensive care unit (ICU),3 and mortality rates ranging from 50% to 60%.3,4 An overactive inflammatory response is considered to contribute to lung lesions in non-HIV immunocompromised PCP patients. The accumulation of inflammatory factors and robust neutrophil recruitment in the lung interstitial and alveolar cavities, combined with unmodifiable risks from previous diseases, are the main cause of mortality in patients.5

It has been hypothesized that corticosteroids may attenuate the inflammatory response induced by anti-pneumocystis treatment. The two largest trials conducted among hypoxemic HIV-positive patients showed that corticosteroid therapy significantly reduced the need for mechanical ventilation and mortality during PCP episodes.6–8 Unfortunately, there is no corresponding evidence for the efficacy of adjunctive corticosteroids in HIV-negative patients with PCP, and results from available retrospective studies are conflicting.9–11 Furthermore, the majority of the published data did not focus on patients with respiratory failure nor provided detailed corticosteroid regimens.

Based on this limited and conflicting evidence from available studies, this study aimed to assess the effectiveness of standard-dose steroid therapy in non-HIV PCP patients with ARDS compared with low-dose steroids.

Methods Study Design and Patients

The study was a retrospective cohort analysis conducted in the respiratory intensive care unit (RICU) of Beijing Chao-Yang Hospital. And this study used anonymized historical data, making informed consent unnecessary (informed consent was waived), and had received approval from the Ethics Committee of Beijing Chao-Yang Hospital (No.2022-ke-65) in compliance with ethical and privacy standards.

We selected all non-HIV PCP patients with ARDS admitted to RICU from 1 October 2015 to 31 July 2022. Eligible patients met the following inclusion criteria: (1) negative HIV serology test confirming non-HIV status; (2) diagnosis of ARDS; and (3) diagnosis of Pneumocystis pneumonia (PCP) based on established clinical and microbiological criteria. Patients younger than 18 years, those with incomplete clinical data, or those with concurrent COVID-19 infection were excluded from this study.

The diagnosis of ARDS was based on the Berlin definition criteria.12 The diagnostic criteria for PCP include: (1) an underlying immunosuppressive condition, such as malignancy, bone marrow or solid organ transplantation, autoimmune disease, or the use of corticosteroids or immunosuppressive therapy; (2) consistent clinical symptoms, including fever, cough, and dyspnea; (3) chest CT findings of bilateral diffuse ground-glass opacities; (4) positive identification of Pneumocystis jirovecii in respiratory specimens confirmed by nucleic acid testing through metagenomic next-generation sequencing or polymerase chain reaction (PCR); and (5) elevated serum 1.3-β-glucan levels (BDG).13 Patients with Pneumocystis jirovecii colonization, defined as a positive nucleic acid test result in respiratory specimens without typical PCP symptoms, characteristic imaging findings, or elevated BDG levels, were excluded.14

Definitions

Patients in this study were categorized based on corticosteroid dosage into the standard-dose and low-dose groups. The standard-dose group received intravenous methylprednisolone at 40 mg twice daily for the initial 5 days, followed by 40 mg once daily for the subsequent 5 days, and then tapered to 20 mg daily over the remaining 11 days. In contrast, the low-dose methylprednisolone regimen involved a daily administration of less than 40 mg of methylprednisolone. The entire corticosteroid treatment course spanned 21 days,3 with adjustments made as clinically indicated to accommodate individual patient needs. Extracorporeal membrane oxygenation (ECMO) was considered if PFR<50 mmHg over 30 minutes or if patients developed barotrauma, including pneumothorax, pneumomediastinum, or pneumoderma.

Data Collection

The data were obtained from electronic medical records (EMR), including daily prescription information for corticosteroids and trimethoprim-sulfamethoxazole (TMP-SMX), verified by two individuals. Baseline characteristics and medical history data collected included age, sex, smoke status, body mass index, comorbidities, immunocompromised status, corticosteroid and immunosuppressant treatment regimens (within 30 days). Serum BDG levels, respiratory Pneumocystis PCR results, and additional respiratory pathogens detected from the same sample (BAL fluid or aspiration) used for PCP diagnosis were collected to identify potential respiratory coinfections. Clinical data collected at the time of admission included symptoms, oxygen requirements, severity evaluation [sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Murray Score], laboratory results, blood gas analysis, and lymphocyte subsets (CD3+ T cell, CD4+ T cell, CD8+ T cell).

Outcome

The primary outcomes were 28-day mortality and 60-day mortality. Secondary outcomes investigated were length of ICU stay, ICU mortality, the incidence and duration of invasive mechanical ventilation (IMV), the need for ECMO, and complications.

Statistical Analysis

Continuous variables, presented as mean (±standard deviation) or median (interquartile range), were compared between groups using unpaired Student’s t-tests or Mann–Whitney U-tests. Categorical variables, presented as frequencies and percentages, were compared using chi-squared tests or Fisher’s exact tests. Univariate and multivariate Cox regression models were used to examine the association between participant demographics, laboratory tests, steroid therapy, and mortality. The Kaplan-Meier method and Log rank test were used to compare survival differences between groups. Analyses were performed on the complete cases without imputation of missing data. ECMO and IMV were analyzed separately due to their distinct mechanisms and clinical implications. Stratified analyses were conducted in subgroups defined by age, sex, smoke, IMV, albumin, lactic dehydrogenase (LDH), PFR, and bacterial infection. Sensitivity analyses were performed as follows: first, to account for the potential impact of chronic pulmonary disease on primary outcomes, we restricted analyses to patients without chronic pulmonary disease at baseline; second, given that a longer interval between the onset of respiratory symptoms and ICU admission is associated with worse prognosis,15 we excluded patients with an interval exceeding 14 days. All analyses were performed using SPSS software version 25.0 and GraphPad Prism version 7.0. Two-tailed p-values < 0.05 were considered statistically significant.

Results Baseline Characteristics of the Study Cohort

Between 1 October 2015 and 31 July 2022, 141 non-HIV PCP patients with ARDS were screened. Of these, 105 patients were included in the analysis: 57 in the low-dose steroid therapy group and 48 in the standard-dose steroid group (Figure 1).

Figure 1 Study flow.

Abbreviations: HIV, human immunodeficiency virus; PCP, Pneumocystis jirovecii pneumonia; ARDS acute respiratory distress syndrome; RICU respiratory intensive care unit; PCR polymerase chain reaction.

Of the 105 patients, the mean age was 52.9±13.9 years, and 67 (63.8%) were male. The main causes of immunocompromised status were solid organ transplantation, connective tissue disease, and hematologic malignancy. Among the connective tissue diseases, rheumatoid arthritis was the most common (9 cases, 8.6%), followed by dermatomyositis/polymyositis (6 cases, 5.7%), Sjögren’s syndrome (6 cases, 5.7%), and systemic lupus erythematosus (4 cases, 3.8%). A total of 69 cases (65.7%) cases were treated with immunosuppressants prior to admission, and 83 cases (79.0%) cases were treated with corticosteroids. The baseline demographic of the two groups were similar, as expected for age (55.5±14.2 years in the low-dose steroid group vs 50.5±12.6 years in the standard-dose steroid group, p=0.04) (Table 1).

Table 1 Comparison of Baseline Characteristics Between Standard-steroid and Low-dose Steroid Groups

Clinical Characteristics on Admission

Fever (95 cases, 90.5%), cough (86 cases, 91.4%), and sputum (62 cases, 59.0%) were common clinical manifestations in our cohort (Table 2). In terms of respiratory support, 21 patients (20.0%) required IMV upon admission. Additionally, 38 patients (36.2%) used non-IMV to maintain oxygenation, and 14 patients (13.3%) used nasal high-flow oxygen therapy. The median SOFA score on admission was 4(3–6), the acute APACHE II score was 14(11–16), and the Murray score was 2.75(2.25–3). No difference was found in the duration between admission and initiation of treatment (p=0.93) or in the proportion of patients starting treatment after 96 hours (p=0.76) between the two groups. However, Delayed TMP-SMX treatment (≥96 hours after admission) was associated with significantly higher ICU mortality compared to early treatment (<96 hours after admission) (64.3% vs 34.1%, p=0.03). (Table S1) The median PFR and CD4+T cell count were 143(108–200) vs 144(104–174) mmHg and 97(62–158) vs 94(46–230) cells/ul, respectively.

Table 2 Differences in Clinical Characteristics on Admission

Comparison of Outcomes Between Standard-dose and Low-dose Steroid Groups

As shown in Table 3, there was no significant difference in 28-day mortality (50.8% vs 35.4%, p=0.11) and time from onset of symptoms to ICU [7(5–10) days vs 9(6–12) days, p=0.23]. However, there was a significant difference in the 60-day mortality across groups, with rates of 63.2% (36/57) in the low-dose steroid group and 43.8% (21/48) in the standard-dose steroid group (p=0.04). There was no significant difference in ICU mortality, length of ICU stay, IMV, and other secondary outcomes between the two groups. The overall incidence of complications was similar in both groups (Table 3).

Table 3 Clinical Outcomes and Complications in Patients Receiving Low-dose versus Standard-dose Steroid Therapy

After adjustment for potential confounders (age, BMI, Murray score, APACHEII score, SOFA score, oxygen requirement, immunocompromised status albumin, LDH, PFR, and CD4+T cell), the 28-day mortality (adjusted hazard ratio [aHR]: 0.339, 95% confidence interval [CI]:0.147–0.78), p=0.011) and 60-day mortality (aHR: 0.328, 95% CI:0.152–0.760), p=0.005) was significantly lower in the standard-dose group than in the low-dose group (Table 4). The Kaplan-Meier curves for 60-day mortality observed in different groups of this cohort are illustrated in Figure 2 (p=0.04).

Table 4 Multivariate Cox Regression Analysis of Steroid Therapy on 28-Day Mortality and 60-Day Mortality

Figure 2 Kaplan-Meier overall survival curves and number at risk table for patients receiving low-dose and standard-dose steroid treatments.

Subgroup Analysis

The standard-dose steroid therapy was associated with lower 60-day mortality in patients aged <65 years (aHR: 0.290, 95% CI:0.125–0.697), in no-smokers (aHR:0.410, 95% CI: 0.174–0.962), in patients requiring IMV (aHR: 0.232, 95% CI: 0.075–0.716), in those with albumin<30 g/L (aHR: 0360, 95% CI: 0.153–0.848), and in patients with PFR<150mmHg (aHR: 0.316, 95% CI: 0.122–0.814), while no interaction was observed (Table 5).

Table 5 Subgroup Analysis of the Association Between Steroid Treatment and 60-Day Mortality

Sensitivity Analysis

Sensitivity analyses showed essentially similar results after excluding patients with chronic pulmonary disease (28-day mortality: aHR 0.396, 95% CI: 0.172–0.911, p=0.029; 60-day mortality: aHR 0.370, 95% CI: 0.171–0.803, p=0.014) (Table S2) or excluding patients with an interval of more than 14 days at inclusion (28-day mortality: aHR:0.258, 95% CI: 0.093–0.711, p=0.009; 60-day mortality: aHR: 291, 95% CI: 0.117–0.728, p=0.008) (Table S3).

Discussion

The main finding of our study is that the standard-dose steroid therapy significantly reduced 60-day mortality without major complications in non-HIV PCP patients with ARDS, particularly among patients < 65 years, non-smokers, those requiring IMV, those with albumin<30 g/L, and those with a PFR <150 mmHg.

Corticosteroids have been suggested for the treatment of community-acquired Pneumonia, as they reduce the time to clinical cure, the length of hospital and ICU stays, the development of respiratory failure or shock not present at the onset of pneumonia, and the rate of pneumonia complications.16 However, in immunosuppressed patients, Pneumocystis jirovecii releases exogenous pro-inflammatory substances that trigger intense pulmonary and systemic inflammation, leading to severe respiratory impairment. Given the potent anti-inflammatory and immunomodulatory effects of corticosteroids, these agents may help mitigate the imbalance between immune and inflammatory responses.17

Few large, retrospective studies have evaluated glucocorticoids in non-HIV PCP patients with severe respiratory conditions admitted to the ICU. While the adjunctive use of steroids in HIV patients with PCP has shown significant efficacy, evidence supporting their use in non-HIV patients remains limited.18 Since Pareja et al19 demonstrated that steroids were associated with shorter ICU stays and reduced IMV duration in non-HIV patients, an increasing number of studies have focused on the role of adjunctive steroids in clinical outcomes. Unfortunately, the current evidence so far is not convincing. In a 2013 study of 139 patients, the 72 patients who received adjunctive high-dose steroids (≥1mg/kg/day) had an increased risk of death.11 Wieruszewski et al9 found no differences in 30-day mortality, length of stay, or need for IMV between early (within 48 hours) steroid recipients and non-recipients. A real-world study using the national database reported a lower risk of mortality rate in non-HIV PCP patients with severe respiratory status (PaO2 ≤60 mmHg) treated with adjunctive corticosteroid group. Furthermore, a meta-analysis of 16 studies suggested that corticosteroid combination therapy may be associated with higher mortality in non-HIV PCP patients (OR: 1.37; 95% CI: 1.07–1.75; p= 0.01). However, subgroup analyses indicated lower mortality in patients with hypoxia (OR: 0.69; 95% CI: 0.47–1.01; p = 0.05) and respiratory failure (OR: 0.63; 95% CI 0.41–0.95; p = 0.03).20

There were no differences between the two groups in baseline demographics (sex, BMI) or disease severity scores (SOFA score, APACHE II score, Murray score), except for age in our study, which may reduce the bias of the findings. Furthermore, multivariable Cox logistic models, adjusted for baseline demographics, immunocompromised status, disease severity, and risk factors for poor outcome, confirm previous research showing that standard-dose steroids reduce 28-day and 60-day mortality in these patients. Contrary to the findings by Pareja and inoue, who reported that adjunctive corticosteroids shortened the duration of IMV in non-HIV PCP,10,19 our study found no statistically significant differences in the length of ICU stay, the need for IMV, or the duration of IMV between the standard-dose corticosteroid group and the control group. This discrepancy may be related to the greater severity of respiratory failure in the participants included in our study. Furthermore, we did not include patients with COVID-19 infection, as ICU admission policies during the pandemic prioritized COVID-19-related cases, which limited the inclusion of non-COVID-19 respiratory diseases. The overlapping symptoms and signs of PCP and COVID-19 made distinguishing between the two conditions particularly challenging in patients outside high-risk groups, who were often managed under the assumption of COVID-19 infection.21

Glucocorticoid therapy is not recommended for non-HIV patients with mild respiratory failure. The results of the above meta-analysis showed that adjunctive corticosteroid treatment had no significant effect on outcomes in non-HIV PCP patients with hypoxemia. Similarly, Inoue et al also found that adjunctive corticosteroids had no significant differences in mortality in the moderate non-HIV PCP. Consistent with the above studies, subgroup analysis in our study showed that standard-dose steroids were associated with lower 60-day mortality in patients requiring IMV, those with albumin< 30 g/L, and those with PFR<150mmHg. Our findings suggest that patients with a strong inflammatory response and severe respiratory failure may derive greater benefit from standard-dose glucocorticoid therapy.

Delayed treatment of Pneumocystis jirovecii has been consistently associated with worse outcomes, particularly in non-HIV immunocompromised patients. Li et al22 demonstrated that delayed diagnosis and treatment of PCP led to significantly higher mortality rates in non-HIV-infected individuals. Kamel et al highlighted the critical impact of timely prophylaxis and early initiation of therapy on improving survival in intensive care patients with PCP, emphasizing the detrimental effects of treatment delay.23 Consistent with these findings, our study observed that delayed initiation of TMP-SMX (≥96 hours after admission) was associated with higher ICU mortality. This underscores the importance of early clinical recognition and treatment of PCP, particularly in non-HIV patients, who often experience rapid disease progression and worse prognoses. When considering the use of corticosteroids in these patients, it is crucial to account for short-term side effects such as hyperglycemia, delirium, and secondary infections. Hyperglycemia, the most significant adverse effect of glucocorticoids, has been demonstrated in several studies, and reactive hyperglycemia was also observed in our study. Long-term side effects, such as myopathy and osteoporosis, should also be considered, although these are less likely to occur with a standard 21-day course.24 Notably, the standard-dose steroid therapy was not associated with an increased incidence of nosocomial infections or gastrointestinal hemorrhage.

We recognize several limitations in our study. First, clinicians tend to prescribe steroids during acute exacerbations of comorbidities or severe disease episodes. To minimize this bias, we included only patients who received steroids within 24 hours of admission. Second, the broad spectrum of immunosuppressive disorders highlights the challenge of grouping a highly heterogeneous population of non-HIV PCP patients. Third, the sample size of our study is relatively small. Finally, the extended time span of this single-center study may introduce time-related bias. However, to ensure accuracy, two experienced respiratory physicians thoroughly reviewed each case in detail.

Conclusions

The standard-dose methylprednisolone therapy was associated with a significant reduction in 28-day and 60-day mortality without increasing the risk of major complications in Pneumocystis pneumonia with ARDS in non-HIV immunocompromised patients. These findings underscore the potential benefits of optimized corticosteroid dosing, which should be further validated in prospective cohorts or randomized controlled studies to confirm its efficacy and safety.

Abbreviation

PCP, Pneumocystis jirovecii pneumonia; ARDS, acute respiratory distress syndrome; HIV, human immunodeficiency virus; ICU, intensive care unit; PFR, PaO2/FiO2 ratio; PCR, polymerase chain reaction; IMV, invasive mechanical ventilation; LRT, lower respiratory tract; TMP-SMX, trimethoprim-sulfamethoxazole; ECMO, extracorporeal membrane oxygenation; LDH, lactic dehydrogenase; SOFA, sequential organ failure assessment; APACHE II, Acute Physiology and Chronic Health Evaluation II; OR, odd ratio.

Data Sharing Statement

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Consent to Participate

The study was approved by the Ethics Committee of Beijing Chao-Yang Hospital (No.2022-ke-65), and complies with the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of the cohort study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

No funding was received.

Disclosure

The authors declare that they have no conflicts of interest.

This paper has been uploaded to ResearchSquare as a preprint: https://www.research-square.com/article/rs-4423359/v1.

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