Abstract
Background
Evidence supporting the efficacy of adjunctive corticosteroid therapy in human immunodeficiency virus (HIV)-negative patients with Pneumocystis jirovecii pneumonia (PJP) who present with respiratory failure is increasing. However, the optimal dosing regimen remains uncertain. Our study aimed to evaluate the effectiveness of high-dose versus low-dose adjunctive corticosteroid therapy in this population.
Methods
This retrospective cohort study included HIV-negative patients diagnosed with PJP who received adjunctive corticosteroid therapy in Zhongnan Hospital of Wuhan University from June 2018 to March 2023. Patients were categorized into high-dose group (≥1 mg/kg/day of prednisone equivalent) and low-dose group (<1 mg/kg/day). The risk was estimated by the time-dependent Cox regression analyses with inverse probability of treatment weighting (IPTW). Subgroup analysis focused on patients with respiratory failure.
Results
Ultimately, 120 HIV-negative PJP patients were included (high-dose, n=72; low-dose, n=48). The overall 30- and 90-day mortality rates were 30.8% and 41.7%, respectively. No significant differences were observed in 30-day mortality (P=0.80 before analysis; P=0.62 after analysis) and 90-day mortality (P=0.86 before analysis; P=0.97 after analysis) between the two groups before and after IPTW analysis. Results in the respiratory failure subgroup were consistent with the overall findings.
Conclusions
In conclusion, low-dose adjunctive corticosteroid therapy may be adequate for treating HIV-negative PJP.
Keywords: Human immunodeficiency virus negative (HIV-negative), Pneumocystis jirovecii pneumonia (PJP), adjunctive corticosteroid, immunocompromised, mortality
Highlight box.
Key findings
• In this retrospective cohort of 120 human immunodeficiency virus (HIV)-negative patients with Pneumocystis jirovecii pneumonia (PJP), no significant differences in 30- or 90-day mortality were observed between high-dose (≥1 mg/kg/day prednisone equivalent) and low-dose (<1 mg/kg/day) adjunctive corticosteroid therapy, both in the overall cohort and in the respiratory failure subgroup, after inverse probability of treatment weighting adjustment. Secondary outcomes, including respiratory component of the Sequential Organ Failure Assessment improvement, intubation rate, intensive care unit admission, co-infection incidence, and hospital stay, also showed no significant differences.
What is known and what is new?
• Adjunctive corticosteroids are recommended for moderate-to-severe PJP in HIV-positive patients; their use may lower mortality in HIV-negative PJP with respiratory failure, but optimal dosing is unclear, with conflicting prior study results and poor baseline adjustment.
• This study adds robust, propensity score-adjusted evidence that high-dose corticosteroids do not confer superior survival or clinical benefits over low-dose regimens in HIV-negative PJP patients, even among those with respiratory failure.
What is the implication, and what should change now?
• Low-dose adjunctive corticosteroids should be preferred for HIV-negative PJP given the lack of additional benefit. Clinicians need not pursue high-dose regimens; future guidelines should update dosing recommendations for this population, prioritizing low-dose therapy.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is a non-purulent interstitial pneumonia caused by the opportunistic fungus Pneumocystis jirovecii (PJ). Historically, it has been a major cause of morbidity and mortality among patients infected with human immunodeficiency virus (HIV) (1,2). However, in recent decades, the incidence of PJP has substantially increased in HIV-negative populations, primarily due to the extensive application of chemoradiotherapy for malignancies, the rising numbers of solid tumor and hematopoietic stem cell transplantations, and the widespread administration of immunosuppressive therapies (3-5). Notably, HIV-negative patients often present with atypical early clinical manifestations compared with their HIV-positive counterparts, frequently leading to delayed diagnosis and treatment. This delay may ultimately culminate in mortality due to acute respiratory failure (6,7). Despite antibiotic therapy with trimethoprim-sulfamethoxazole (TMP-SMX), PJP remains a life-threatening complication in immunosuppressed HIV-negative patients, with sustained mortality rates ranging from 34% to 58% (3). Given the high morbidity and mortality in this population, development of adjunctive therapies is urgently needed.
Adjunctive corticosteroid therapy has been shown to reduce mortality and the need for mechanical ventilation in hypoxemic HIV-positive patients with PJP (8,9). Current consensus guidelines recommend early initiation of adjunctive corticosteroid therapy for adults with moderate-to-severe HIV-associated PJP, with an initial prednisone-equivalent dose of 80 mg/day (10). For HIV-negative PJP, a recent systematic review of 16 observational studies suggested that adjunctive corticosteroid therapy may lower mortality in patients with respiratory failure (11). However, the optimal corticosteroid dosing strategy in this population remains uncertain. A small retrospective study in 1998 reported that compared with low-dose regimens, high-dose corticosteroid therapy (≥60 mg/day prednisone equivalent) accelerated recovery but did not improve survival (12). Whereas, another retrospective study of 139 intensive care unit (ICU)-admitted HIV-negative PJP patients found that high-dose corticosteroids (≥1 mg/kg/day prednisone equivalent) were associated with increased mortality (13). These conflicting findings highlight the need for further investigation on the efficacy of different dosing strategies in this population. On the other hand, most prior studies did not adjust for patient baseline characteristics when comparing dosing regimens, making it difficult to distinguish whether observed outcome differences stemmed from the treatment regimens themselves or underlying baseline disparities.
To address these limitations and clarify the efficacy differences among adjunctive corticosteroid dosing regimens in HIV-negative PJP patients, we conducted a single-center retrospective study to evaluate the effectiveness of high-dose adjunctive corticosteroid therapy compared with low-dose regimens in this population, after adjusting for baseline characteristics. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1984/rc).
Methods
Study population and grouping criteria
This study was a single-center, retrospective, observational cohort study. We collected and analyzed the clinical data of HIV-negative patients with PJP who received adjunctive corticosteroid therapy at Zhongnan Hospital of Wuhan University between June 1, 2018, and March 31, 2023. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (approval No. 2025202K). Given the retrospective design, the requirement for informed consent was waived and all data were anonymized before analysis.
Inclusion criteria were: (I) adult patients with an initial diagnosis of PJP at our hospital; (II) negative HIV antibody test; and (III) administration of adjunctive corticosteroid therapy.
Exclusion criteria were: (I) confirmed PJ colonization rather than active infection; (II) total length of hospital stay less than 3 days; and (III) loss to follow-up within 90 days of treatment initiation.
According to established diagnostic guidelines and previous studies (7,14), the diagnosis of PJP was based on the following comprehensive criteria: (I) presence of at least one of the following clinical manifestations: cough, sputum production, fever, or progressive dyspnea; (II) chest computed tomography (CT) findings compatible with PJP, including but not limited to diffuse interstitial infiltrates, multiple ground-glass opacities, patchy consolidations, segmental infiltrates, or nodular lesions; and (III) microbiological evidence of PJ infection, defined as a positive polymerase chain reaction (PCR) result for PJ in induced sputum or bronchoalveolar lavage (BAL) fluid, or detection of PJ sequences via metagenomic next-generation sequencing (mNGS).
Patients were classified into two groups according to their adjunctive corticosteroid dosage: low-dose group (<1 mg/kg/day prednisone equivalent) and high-dose group (≥1 mg/kg/day prednisone equivalent), based on a 2013 study of adjunctive corticosteroid therapy in severe HIV-negative PJP patients (13). Methylprednisolone pulse therapy was defined as intravenous administration of 500–1,000 mg of methylprednisolone per day (15). Subgroup analysis targeted patients with respiratory failure. Due to missing arterial blood gas data in several patients, respiratory failure was defined as the need for invasive or non-invasive positive pressure ventilation for more than 24 hours to maintain adequate oxygenation and ventilation (16).
Data collection
Data were obtained from electronic medical records, including demographics (age, sex, weight), underlying comorbidities [interstitial lung disease (ILD), solid tumors, hematologic malignancy, connective tissue diseases (CTD), organ transplantation], use of immunosuppressants (prednisone, other immunosuppressants, or biologic agents; long-term use defined as ≥30 days), history of chemotherapy or radiotherapy, TMP-SMX prophylaxis, time from symptom onset to treatment initiation, clinical manifestations, chest CT findings, corticosteroid therapy (initiation time, dose and duration), respiratory support (none, conventional oxygen therapy including nasal cannula and high-flow oxygen, or mechanical ventilation) and initial treatment regimens [TMP-SMX, intravenous immunoglobulin (IVIG), caspofungin]. Additional information included arterial blood gas analysis, daily oxygen concentration and saturation, date of intubation, ICU admission, occurrence of co-infections, total length of hospital stay, and survival status at 30 and 90 days.
The first day of corticosteroid administration was designated as “day 1”. Respiratory function was assessed using the respiratory component of the Sequential Organ Failure Assessment (SOFA-resp) score, calculated from the PaO2/FiO2 (P/F) ratio (17). When arterial blood gas results were unavailable, the SpO2/FiO2 (S/F) ratio was used to estimate the P/F ratio via nonlinear imputation (18). SOFA-resp change was calculated as baseline score (day 1) minus the score on day 5; if discharged earlier, the last available score was used. A positive value indicated clinical improvement (17). Co-infection was defined as the microbiologically confirmation of bacterial, viral, or fungal pulmonary infection concurrent with PJP (18).
Outcomes
The primary outcomes were 30- and 90-day mortality after the initiation of treatment. The secondary outcomes included SOFA-resp improvement, tracheal intubation on day 5, ICU admission rate, incidence of co-infections, and total length of hospital stay.
Statistical analysis
Continuous variables were expressed as median [interquartile range (IQR)] and compared using the Student’s t-test. Categorical variables were presented as counts (percentages) and compared using the Chi-squared test. To address potential confounding, propensity scores (PSs) were calculated to estimate the probability of receiving high-dose corticosteroid therapy. Multicollinearity among covariates was evaluated (variance inflation factor, VIF <5). Logistic regression was performed with high-dose corticosteroid therapy as the dependent variable and age, sex, day-1 SOFA score, underlying comorbidities, long-term immunosuppression, baseline respiratory support, and prophylaxis as covariates. Inverse probability of treatment weighting (IPTW) based on stabilized PS was used to balance baseline characteristics between groups. Covariate balance was assessed by standardized mean difference (SMD), with an absolute SMD <0.1 indicating acceptable balance. Kaplan-Meier survival curves were generated for 30- and 90-day mortality, and compared with the log-rank test. Cox proportional hazards models were used for time-to-event outcomes (30- and 90-day mortality). Binary logistic regression was applied to assess binary outcomes (SOFA-resp improvement, tracheal intubation on day 5, ICU admission, and incidence of co-infections). Linear regression was used for the continuous outcome (total length of hospital stay). Subgroup analysis was performed for patients with respiratory failure. All statistical analyses were performed using R software (version 4.4.2) with two-sided P value <0.05 considered statistically significant.
Results
A flowchart of patient selection is presented in Figure 1. A total of 490 patients diagnosed with PJP were screened, of whom 370 were excluded according to predefined eligibility criteria. Ultimately, 120 HIV-negative patients with PJP who received ad-junctive corticosteroid therapy were included in the final analysis. Patients were stratified into low-dose and high-dose groups based on corticosteroid dosage. Seventy-two patients received high-dose adjunctive corticosteroid therapy, and 48 received low-dose therapy. In the subgroup analysis, 69 patients with respiratory failure were identified from the overall cohort, including 44 in high-dose group and 25 in the low-dose group.
Figure 1.
Flowchart of patient screening and grouping. HIV, human immunodeficiency virus; PJ, Pneumocystis jirovecii; PJP, Pneumocystis jirovecii pneumonia.
Baseline characteristics and clinical outcomes in HIV-negative PJP patients
The baseline characteristics of 120 patients (72 high-dose, 48 low-dose) are summarized in Table 1. Compared with the low-dose group, patients in the high-dose group were younger (54 vs. 61 years; P=0.008) and had a lower proportion of males (58.3% vs. 77.1%; P=0.03). The most common comorbidities in the overall cohort were organ transplantation (n=38, 31.7%), CTD (n=29, 24.2%), and solid tumors (n=27, 22.5%). Hematologic malignancies were less frequent in the high-dose group (5.6% vs. 18.8%; P=0.02), whereas organ transplantation was more common (43.1% vs. 14.6%; P=0.001).
Table 1. Baseline characteristics of HIV-negative PJP patients.
| Baseline characteristics | Total population (n=120) | Low-dose group (n=48) | High-dose group (n=72) | P value |
|---|---|---|---|---|
| Males | 79 (65.8) | 37 (77.1) | 42 (58.3) | 0.03* |
| Age (years) | 56.88 (15.76) | 61.44 (15.99) | 53.83 (14.95) | 0.008** |
| Underlying comorbidities | ||||
| ILD | 22 (18.3) | 10 (20.8) | 12 (16.7) | 0.56 |
| Solid tumor | 27 (22.5) | 12 (25.0) | 15 (20.8) | 0.59 |
| Hematologic malignancy | 13 (10.8) | 9 (18.8) | 4 (5.6) | 0.02* |
| CTD | 29 (24.2) | 13 (27.1) | 16 (22.2) | 0.54 |
| Organ transplantation | 38 (31.7) | 7 (14.6) | 31 (43.1) | 0.001** |
| Use of immunosuppressants | ||||
| Long-term Immunosuppression | 74 (61.7) | 25 (52.1) | 49 (68.1) | 0.08 |
| Prednisone | 71 (59.2) | 23 (47.9) | 48 (66.7) | 0.04* |
| Immunosuppressant | 57 (47.5) | 17 (35.4) | 40 (55.6) | 0.048* |
| Biologic agents | 15 (12.5) | 8 (16.7) | 7 (9.7) | 0.40 |
| History of chemotherapy or radiotherapy | 0.02* | |||
| None | 87 (72.5) | 29 (60.4) | 58 (80.6) | |
| Radiotherapy | 2 (1.7) | 0 (0.0) | 2 (2.8) | |
| Chemotherapy | 8 (6.7) | 6 (12.5) | 2 (2.8) | |
| Chemoradiotherapy | 23 (19.2) | 13 (27.1) | 10 (13.9) | |
| Prophylactic therapy | 24 (20.0) | 6 (12.5) | 18 (25.0) | 0.09 |
| Time from symptom onset to treatment initiation (days) | 11.92 (9.96) | 13.94 (12.04) | 10.57 (8.10) | 0.17 |
| Clinical manifestation | ||||
| Fever | 94 (78.3) | 37 (77.1) | 57 (79.2) | 0.79 |
| Cough | 75 (62.5) | 27 (56.3) | 48 (66.7) | 0.25 |
| Dyspnea | 89 (74.2) | 35 (72.9) | 54 (75.0) | 0.80 |
| Baseline status | ||||
| SOFA | 4.77 (2.82) | 4.75 (2.69) | 4.78 (2.92) | 0.95 |
| Day 1 OI (mmHg) | 214.33 (100.90) | 211.40 (102.89) | 216.28 (100.24) | 0.73 |
| Day 1 SOFA-resp | 2.34 (1.14) | 2.40 (1.11) | 2.31 (1.17) | 0.67 |
| Shock | 12 (10.0) | 5 (10.4) | 7 (9.7) | >0.99 |
| Baseline respiratory support | 0.85 | |||
| No oxygen therapy | 12 (10.0) | 4 (8.3) | 8 (11.1) | |
| Conventional oxygen therapy | 78 (65.0) | 31 (64.6) | 47 (65.3) | |
| Mechanical ventilation | 30 (25.0) | 13 (27.1) | 17 (23.6) | |
| Initial treatment regimen | ||||
| TMP-SMX | 116 (96.7) | 45 (93.8) | 71 (98.6) | 0.30 |
| Immunoglobulin | 52 (43.3) | 21 (43.8) | 31 (43.1) | 0.94 |
| Caspofungin | 65 (54.2) | 23 (47.9) | 42 (58.3) | 0.26 |
Data are presented as n (%) or mean (standard deviation). Statistically significant variables are marked as *, P<0.05; **, P<0.01. CTD, connective tissue diseases; HIV, human immunodeficiency virus; ILD, interstitial lung disease; OI, oxygenation index; PJP, Pneumocystis jirovecii pneumonia; SOFA, Sequential Organ Failure Assessment; TMP-SMX, trimethoprim-sulfamethoxazole.
Systemic prednisone was administered to 71 patients (59.2%) and other immunosuppressants to 57 patients (47.5%). Prednisone use (66.7% vs. 47.9%; P=0.04) and immunosuppressant use (55.6% vs. 35.4%; P=0.048) were more frequent in the high-dose group, whereas anti-tumor chemoradiotherapy was less frequent (19.4% vs. 39.6%; P=0.02). There were no significant differences between the two groups in the average time from onset to treatment, the incidence of clinical manifestations (fever, cough, dyspnea), the proportion of prophylactic treatment, baseline status [total SOFA score, day 1 oxygenation index (OI), day 1 SOFA-resp score], baseline respiratory support, or initial treatment regimen (all P>0.05).
In addition, we summarized the adjunctive corticosteroid usage in both groups as shown in Table 2. In the low-dose group, none of the 48 patients (0.0%) received methylprednisolone pulse therapy, while in the high-dose group, 25.0% received pulse therapy. The median duration of corticosteroid use was 11 days (IQR, 7–15 days) in the low-dose group and 14 days (IQR, 9–22.75 days) in the high-dose group. Regarding the daily corticosteroid dose, the median dose was 0.83 mg/kg/d (IQR, 0.68–0.87 mg/kg/d) in the low-dose group and 1.32 mg/kg/d (IQR, 1.12–2.07 mg/kg/d) in the high-dose group.
Table 2. Usage of adjunctive corticosteroid therapy.
| Treatment characteristics | Low-dose group (n=48) | High-dose group (n=72) |
|---|---|---|
| Pulse therapy | 0 (0.0) | 18 (25.0) |
| Duration of corticosteroid use (days) | 11 [7, 15] | 14 [9, 22.75] |
| Daily corticosteroid dose (mg/kg/d) | 0.83 [0.68, 0.87] | 1.32 [1.12, 2.07] |
Data are presented as n (%) or median [interquartile range].
Clinical outcomes are summarized in Table 3. There were no significant differences between the high-dose group and the low-dose group in in-hospital, 30-day, or 90-day mortality (all P>0.05). Similarly, no differences were observed in the improvement of SOFA-resp score on day 5, tracheal intubation rate on day 5, ICU admission rate, or the incidence of co-infections (all P>0.05). However, the incidence of cytomegalovirus (CMV) infection was significantly higher in the high-dose group (25.0% vs. 6.2%; P=0.02). The high-dose group also had a longer total hospital stay (median 26 vs. 20 days; P=0.02).
Table 3. Comparison of clinical outcomes in HIV-negative PJP patients.
| Outcome variable | Overall population | Low-dose group (n=48) | High-dose group (n=72) | P value |
|---|---|---|---|---|
| In-hospital mortality | 26 (21.7) | 12 (25.0) | 14 (19.4) | 0.62 |
| 30-day mortality | 37 (30.8) | 17 (35.4) | 20 (27.8) | 0.49 |
| 90-day mortality | 50 (41.7) | 22 (45.8) | 28 (38.9) | 0.57 |
| The SOFA-resp improvement on day 5 | 40 (33.3) | 16 (33.3) | 24 (33.3) | >0.99 |
| Tracheal intubation rate on day 5 | 9 (7.5) | 3 (6.2) | 6 (8.3) | 0.94 |
| ICU admission rate | 36 (30.0) | 16 (33.3) | 20 (27.8) | 0.66 |
| Co-infections | 56 (46.7) | 19 (39.6) | 37 (51.4) | 0.28 |
| Viral infections | 38 (31.7) | 11 (22.9) | 27 (37.5) | 0.14 |
| EBV | 20 (16.7) | 4 (8.3) | 16 (22.2) | 0.08 |
| CMV | 21 (17.5) | 3 (6.2) | 18 (25.0) | 0.02* |
| Bacterial infections | 10 (8.3) | 3 (6.2) | 7 (9.7) | 0.74 |
| Fungal infections | 17 (14.2) | 6 (12.5) | 11 (15.3) | 0.87 |
| Total length of hospital stay (days) | 23 (14.0, 35.0) | 20 (11.3, 27.8) | 26 (16, 49.5) | 0.02* |
Data are presented as n (%) or median (interquartile range). Statistically significant variables are marked as *, P<0.05. CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; ICU, intensive care unit; PJP, Pneumocystis jirovecii pneumonia; SOFA, Sequential Organ Failure Assessment.
Comparison of baseline characteristics in HIV-negative PJP patients before and after IPTW analysis
Baseline characteristics for the overall cohort are shown in Table 4. In the unadjusted cohort, several variables were imbalanced between the high-dose and low-dose corticosteroid groups (SMD >0.1), including sex, age, prophylaxis, baseline respiratory support, ILD, hematologic malignancy, CTD, organ transplantation, and long-term immunosuppression. Following IPTW adjustment, covariates incorporated into the PS model—such as age, sex, day 1 SOFA-resp score, prophylaxis, underlying comorbidities and long-term immunosuppression—achieved adequate balance between the two groups (SMD <0.1). Baseline respiratory support approached acceptable balance (SMD =0.121). Additionally, several variables not included in the PS model—such as day 1 OI, prednisone dose, use of immunosuppressants, and biologic agents—were also well balanced (SMD <0.1).
Table 4. Comparison of baseline characteristics in HIV-negative PJP patients before and after IPTW analysis.
| Baseline characteristics | Unadjusted cohort | IPTW cohort | |||||
|---|---|---|---|---|---|---|---|
| Low-dose group (n=48) | High-dose group (n=72) | SMD | Low-dose group (n=122.5) | High-dose group (n=117.4) | SMD | ||
| Males | 37 (77.1) | 42 (58.3) | 0.409 | 77.7 (63.4) | 75.3 (64.1) | 0.016 | |
| Age (years) | 61.44 (15.99) | 53.83 (14.95) | 0.491 | 56.21 (17.17) | 56.36 (14.56) | 0.010 | |
| Underlying comorbidities | |||||||
| ILD | 10 (20.8) | 12 (16.7) | 0.107 | 23.0 (18.8) | 22.9 (19.5) | 0.018 | |
| Solid tumor | 12 (25.0) | 15 (20.8) | 0.099 | 28.9 (23.6) | 27.7 (23.6) | 0.001 | |
| Hematologic malignancy | 9 (18.8) | 4 (5.6) | 0.412 | 12.3 (10.0) | 10.7 (9.1) | 0.03 | |
| CTD | 13 (27.1) | 16 (22.2) | 0.113 | 31.1 (25.4) | 29.1 (24.7) | 0.015 | |
| Organ transplantation | 7 (14.6) | 31 (43.1) | 0.662 | 38.7 (31.6) | 38.0 (32.4) | 0.018 | |
| Use of immunosuppressants | |||||||
| Long-term Immunosuppression | 25 (52.1) | 49 (68.1) | 0.331 | 75.9 (61.9) | 72.2 (61.5) | 0.009 | |
| Prednisone | 23 (47.9) | 48 (66.7) | 0.386 | 72.4 (59.1) | 70.6 (60.1) | 0.022 | |
| Immunosuppressants | 17 (35.4) | 40 (55.6) | 0.413 | 59.7 (48.7) | 57.4 (48.9) | 0.003 | |
| Biologic agents | 8 (16.7) | 7 (9.7) | 0.206 | 16.6 (13.6) | 13.1 (11.1) | 0.074 | |
| History of chemotherapy or radiotherapy | 0.592 | 0.338 | |||||
| None | 29 (60.4) | 58 (80.6) | 84.1 (68.6) | 88.8 (75.6) | |||
| Radiotherapy | 0 (0.0) | 2 (2.8) | 0.0 (0.0) | 3.4 (2.9) | |||
| Chemotherapy | 6 (12.5) | 2 (2.8) | 9.7 (7.9) | 4.3 (3.7) | |||
| Chemoradiotherapy | 13 (27.1) | 10 (13.9) | 28.7 (23.4) | 21.0 (17.9) | |||
| Prophylactic treatments | 6 (12.5) | 18 (25.0) | 0.324 | 28.1 (22.9) | 24.0 (20.5) | 0.059 | |
| Baseline respiratory status | |||||||
| Day 1 SOFA-resp | 2.40 (1.11) | 2.31 (1.17) | 0.079 | 2.48 (1.06) | 2.39 (1.15) | 0.081 | |
| Day 1 OI (mmHg) | 211.40 (102.89) | 216.28 (100.24) | 0.048 | 198.15 (96.88) | 207.27 (99.08) | 0.093 | |
| Baseline respiratory support | 0.113 | 0.121 | |||||
| No oxygen therapy | 4 (8.3) | 8 (11.1) | 9.0 (7.4) | 11.1 (9.5) | |||
| Oxygen inhalation | 31 (64.6) | 47 (65.3) | 76.8 (62.6) | 76.7 (65.3) | |||
| Mechanical ventilation | 13 (27.1) | 17 (23.6) | 36.7 (30.0) | 29.6 (25.2) | |||
| Initial treatment regimen | |||||||
| TMP-SMX | 45 (93.8) | 71 (98.6) | 0.256 | 116.1 (94.7) | 115.4 (98.3) | 0.193 | |
| Immunoglobulin | 21 (43.8) | 31 (43.1) | 0.014 | 63.4 (51.8) | 47.6 (40.5) | 0.227 | |
| Caspofungin | 23 (47.9) | 42 (58.3) | 0.210 | 50.2 (41.0) | 65.3 (55.6) | 0.296 | |
Data are presented as n (%) or mean (standard deviation). CTD, connective tissue diseases; HIV, human immunodeficiency virus; ILD, interstitial lung disease; IPTW, inverse probability of treatment weighting; OI, oxygenation index; PJP, Pneumocystis jirovecii pneumonia; SMD, standardized mean difference; SOFA, Sequential Organ Failure Assessment; TMP-SMX, trimethoprim-sulfamethoxazole.
Comparison of clinical outcomes in HIV-negative PJP patients before and after IPTW analysis
Primary outcomes
In the unadjusted cohort, there were no statistically significant differences in 30-day mortality [hazard ratio (HR) =0.91; 95% confidence interval (CI): 0.43–1.90; P=0.80] or 90-day mortality (HR =1.06; 95% CI: 0.56–2.00; P=0.86) between the high-dose and low-dose corticosteroid groups. After IPTW adjustment, the analysis similarly revealed no significant association between corticosteroid dose and 30-day mortality (HR =0.80; 95% CI: 0.33–1.93; P=0.62) or 90-day mortality (HR =1.01; 95% CI: 0.47–2.17; P=0.97) (Table 5).
Table 5. Comparison of clinical outcomes in HIV-negative PJP patients before and after IPTW analysis.
| Outcome variable | Unadjusted cohort | IPTW cohort | |||||
|---|---|---|---|---|---|---|---|
| Effect size | 95% CI | P value | Effect size | 95% CI | P value | ||
| 30-day mortality† | 0.91 | 0.43, 1.90 | 0.80 | 0.80 | 0.33, 1.93 | 0.62 | |
| 90-day mortality† | 1.06 | 0.56, 2.00 | 0.86 | 1.01 | 0.47, 2.17 | 0.97 | |
| The SOFA-resp improvement on day 5‡ | 0.93 | 0.33, 2.63 | 0.90 | 0.88 | 0.32, 2.41 | 0.80 | |
| Tracheal intubation rate on day 5‡ | 5.13 | 0.70, 57.37 | 0.13 | 6.59 | 0.66, 66.17 | 0.11 | |
| Occurrence of co-infections‡ | 1.33 | 0.55, 3.23 | 0.53 | 1.22 | 0.48, 3.07 | 0.67 | |
| ICU admission rate‡ | 0.78 | 0.27, 2.20 | 0.63 | 0.67 | 0.24, 1.91 | 0.45 | |
| Total length of hospital stay§ | 4.26 | −5.45, 13.97 | 0.39 | 6.78 | −1.36, 14.92 | 0.10 | |
†, the effect size is a hazard ratio; ‡, the effect size is an odds ratio; §, the effect size is a mean difference. CI, confidence interval; HIV, human immunodeficiency virus; ICU, intensive care unit; IPTW, inverse probability treatment weighting; PJP, Pneumocystis jirovecii pneumonia; SOFA, Sequential Organ Failure Assessment.
Secondary outcomes
Neither the unadjusted nor IPTW-adjusted analyses demonstrated statistically significant differences between the high-dose and low-dose groups for the SOFA-resp improvement on day 5 [odds ratio (OR) =0.88; 95% CI: 0.32–2.41; P=0.80] or tracheal intubation on day 5 (OR =6.59; 95% CI: 0.66–66.17; P=0.11). Similarly, there were no significant differences in the incidence of co-infections (OR =1.22; 95% CI: 0.48–3.07; P=0.67) or ICU admission (OR =0.67; 95% CI: 0.24–1.91; P=0.45). The total length of hospital stay also did not differ significantly between groups (mean difference =6.78 days; 95% CI: −1.36 to 14.92; P=0.10) (Table 5).
In addition, Kaplan-Meier survival curves comparing the high- and low-dose groups before (Figure 2A) and after (Figure 2B) IPTW adjustment demonstrated no statistically significant differences in survival rates, as assessed by log-rank tests (P ≥0.05).
Figure 2.
Kaplan-Meier survival curves for HIV-negative PJP patients. (A) Kaplan-Meier survival curves for HIV-negative PJP patients before IPTW analysis; (B) Kaplan-Meier survival curves for HIV-negative PJP patients after IPTW analysis. HIV, human immunodeficiency virus; IPTW, inverse probability of treatment weighting; PJP, Pneumocystis jirovecii pneumonia.
Comparison of baseline characteristics in the respiratory failure subgroup before and after IPTW analysis
Baseline characteristics of the respiratory failure subgroup before and after IPTW adjustment are presented in Table 6. In the unadjusted cohort, significant imbalances between the high-dose and low-dose adjunctive corticosteroid groups (SMD ≥0.1) were observed for sex, baseline respiratory support, hematologic malignancy, CTD, organ transplantation, and long-term immunosuppression. In addition, several covariates not included in the PS model (including initial treatment regimen, use of biologic agents, and chemoradiotherapy) also showed intergroup differences (SMD ≥0.1). After IPTW adjustment, all covariates included in the PS equation achieved balance (SMD <0.1), except for baseline respiratory support, which approached but did not meet the threshold for adequate balance (SMD =0.20).
Table 6. Comparison of baseline characteristics in the respiratory failure subgroup before and after IPTW analysis.
| Baseline characteristics | Unadjusted cohort | IPTW cohort | |||||
|---|---|---|---|---|---|---|---|
| Low-dose group (n=25) | High-dose group (n=44) | SMD | Low-dose group (n=67.1) | High-dose group (n=68.1) | SMD | ||
| Males | 19 (76.0) | 24 (54.5) | 0.463 | 42.8 (63.8) | 41.7 (61.2) | 0.052 | |
| Age (years) | 58.24 (16.67) | 58.14 (14.55) | 0.007 | 57.91 (16.23) | 57.97 (15.11) | 0.004 | |
| Underlying comorbidities | |||||||
| ILD | 5 (20.0) | 9 (20.5) | 0.011 | 15.7 (23.5) | 14.1 (20.6) | 0.068 | |
| Solid tumor | 5 (20.0) | 10 (22.7) | 0.067 | 16.4 (24.4) | 14.6 (21.5) | 0.070 | |
| Hematologic malignancy | 3 (12.0) | 2 (4.5) | 0.273 | 4.9 (7.3) | 4.1 (6.0) | 0.053 | |
| CTD | 9 (36.0) | 13 (29.5) | 0.138 | 24.6 (36.6) | 21.8 (32.1) | 0.096 | |
| Organ transplantation | 5 (20.0) | 12 (27.3) | 0.172 | 15.8 (23.6) | 17.6 (25.8) | 0.053 | |
| Use of immunosuppressants | |||||||
| Long-term Immunosuppression | 17 (68.0) | 26 (59.1) | 0.186 | 41.7 (62.1) | 42.2 (61.9) | 0.004 | |
| Prednisone | 15 (60.0) | 26 (59.1) | 0.019 | 38.5 (57.3) | 41.9 (61.6) | 0.087 | |
| Immunosuppressants | 11 (44.0) | 19 (43.2) | 0.017 | 28.9 (43.0) | 31.2 (45.8) | 0.056 | |
| Biologic agents | 3 (12.0) | 7 (15.9) | 0.113 | 10.0 (14.9) | 10.3 (15.1) | 0.007 | |
| History of chemotherapy or radiotherapy | 0.538 | 0.428 | |||||
| None | 17 (68.0) | 35 (79.5) | 45.8 (68.3) | 54.8 (80.5) | |||
| Radiotherapy | 0 (0.0) | 1 (2.3) | 0.0 (0.0) | 1.1 (1.6) | |||
| Chemotherapy | 4 (16.0) | 1 (2.3) | 7.5 (11.2) | 1.8 (2.6) | |||
| Chemoradiotherapy | 4 (16.0) | 7 (15.9) | 13.8 (20.5) | 10.4 (15.3) | |||
| Prophylactic treatments | 4 (16.0) | 6 (13.6) | 0.067 | 11.5 (17.2) | 10.6 (15.6) | 0.042 | |
| Baseline respiratory status | |||||||
| Day 1 SOFA-resp | 2.80 (1.04) | 2.86 (0.82) | 0.068 | 2.96 (1.00) | 2.87 (0.83) | 0.093 | |
| Day 1 OI (mmHg) | 169.56 (91.11) | 172.52 (74.60) | 0.036 | 152.95 (82.66) | 172.26 (75.66) | 0.244 | |
| Baseline respiratory support | 0.223 | 0.200 | |||||
| No oxygen therapy | 0 (0.0) | 1 (2.3) | 0.0 (0.0) | 1.0 (1.5) | |||
| Oxygen Inhalation | 15 (60.0) | 27 (61.4) | 37.8 (56.4) | 41.1 (60.4) | |||
| Mechanical ventilation | 10 (40.0) | 16 (36.4) | 29.2 (43.6) | 25.9 (38.1) | |||
| Initial treatment regimen | |||||||
| TMP-SMX | 24 (96.0) | 44 (100.0) | 0.289 | 63.7 (95.0) | 68.1 (100.0) | 0.324 | |
| Immunoglobulin | 16 (64.0) | 26 (59.1) | 0.101 | 42.4 (63.2) | 38.2 (56.1) | 0.146 | |
| Caspofungin | 10 (40.0) | 23 (52.3) | 0.248 | 25.4 (37.9) | 33.3 (48.9) | 0.222 | |
Data are presented as n (%) or mean (standard deviation). CTD, connective tissue diseases; ILD, interstitial lung disease; IPTW, inverse probability of treatment weighting; OI, oxygenation index; SMD, standardized mean difference; SOFA, Sequential Organ Failure Assessment; TMP-SMX, trimethoprim-sulfamethoxazole.
Comparison of clinical outcomes in the respiratory failure subgroup before and after IPTW analysis
A subgroup analysis was performed in patients with respiratory failure to evaluate the effect of corticosteroid dosage. In both unadjusted and IPTW-adjusted analyses, there were no statistically significant differences in 30-day mortality (HR =0.59; 95% CI: 0.21–1.62; P=0.30) or 90-day mortality (HR =0.68; 95% CI: 0.28–1.63; P=0.38) between the high- and low-dose corticosteroid groups. Similarly, no significant differences were observed between groups for secondary outcomes, including SOFA-resp improvement on day 5, tracheal intubation on day 5, incidence of co-infections, ICU admission rate, and total length of hospital stay (Table 7).
Table 7. Comparison of clinical outcomes in the respiratory failure subgroup before and after IPTW analysis.
| Outcome variable | Unadjusted cohort | IPTW cohort | |||||
|---|---|---|---|---|---|---|---|
| Effect size | 95% CI | P value | Effect size | 95% CI | P value | ||
| 30-day mortality† | 0.68 | 0.29, 1.61 | 0.38 | 0.59 | 0.21, 1.62 | 0.30 | |
| 90-day mortality† | 0.76 | 0.35, 1.65 | 0.49 | 0.68 | 0.28, 1.63 | 0.38 | |
| The SOFA-resp improvement on day 5‡ | 0.86 | 0.22, 3.36 | 0.83 | 0.81 | 0.22, 2.95 | 0.75 | |
| Tracheal intubation rate on day 5‡ | 6.06 | 0.65, 159.23 | 0.17 | 12.29 | 0.44, 346.31 | 0.14 | |
| Occurrence of co-infections‡ | 1.25 | 0.38, 4.04 | 0.70 | 1.19 | 0.37, 3.78 | 0.77 | |
| ICU admission rate‡ | 1.06 | 0.33, 3.48 | 0.92 | 0.85 | 0.26, 2.85 | 0.79 | |
| Total length of hospital stay§ | 7.84 | −6.81, 22.49 | 0.30 | 10.33 | −0.83, 21.50 | 0.07 | |
†, the effect size is a hazard ratio; ‡, the effect size is an odds ratio; §, the effect size is a mean difference. CI, confidence interval; ICU, intensive care unit; IPTW, inverse probability treatment weighting; SOFA, Sequential Organ Failure Assessment.
Further, Kaplan-Meier curves for the respiratory failure subgroup were plotted to compare survival between the high- and low-dose groups before (Figure 3A) and after (Figure 3B) IPTW adjustment. Log-rank tests indicated no statistically significant differences in survival rates between the two groups, irrespective of confounding adjustment (P≥0.05).
Figure 3.
Kaplan-Meier survival curves for the respiratory failure subgroup. (A) Kaplan-Meier survival curves for the respiratory failure subgroup before IPTW analysis; (B) Kaplan-Meier survival curves for the respiratory failure subgroup after IPTW analysis. IPTW, inverse probability of treatment weighting.
Discussion
As a life-threatening opportunistic infection, PJP is a major cause of morbidity and mortality in immunocompromised individuals, with or without AIDS (19). The American Thoracic Society (ATS) fungal infection guidelines recommend adjunctive corticosteroid therapy for PJP regardless of the underlying immunosuppressive condition (20). Previous studies have confirmed that adjunctive corticosteroids combined with TMP-SMX significantly reduce mortality in HIV-positive patients with PJP (8). Emerging evidence indicates that corticosteroids may also improve survival in HIV-negative PJP patients with respiratory failure (11,21,22). However, the optimal corticosteroid dosing regimen for HIV-negative PJP patients remains undefined. Existing studies investigating dosing regimens in this population have reported conflicting results and most lacked adequate adjustment for baseline characteristics (15). Therefore, this study aimed to further compare the efficacy differences between high-dose and low-dose adjunctive corticosteroid therapy in HIV-negative patients with PJP after adjusting for baseline characteristics.
The overall 30- and 90-day mortality rates in this single-center cohort were 30.8% and 41.7%, respectively, which are consistent with findings reported in 2025 and exceed those reported in HIV-positive patients (23,24). This disparity is often attributed to severe pulmonary inflammation, although the precise mechanisms remain unclear (24,25). It is noteworthy that two studies by Ohmura et al. focusing on patients with systemic rheumatic diseases (SRD) complicated by PJP reported 30-day survival rates exceeding 90% (26,27). We believe the disparity in outcomes can be attributed to two main factors. First, there are fundamental differences in the composition of underlying diseases among the study populations. Our cohort primarily consisted of organ transplant recipients (31.7%), patients with CTD (24.2%), and those with solid tumors (22.5%). Substantial evidence indicates that the nature of the underlying disease significantly influences the clinical outcomes of PJP (28). Statistics show that organ transplant recipients with PJP face mortality rates as high as 50%, while earlier research by Lee et al. emphasized that patients with solid tumors face a significantly higher risk of mortality compared to those with rheumatoid arthritis or other CTD (29-31). Consequently, compared to study populations composed mainly of patients with SRD, our cohort exhibits a higher-risk profile in terms of underlying conditions. Second, the overall disease severity was greater in our study population. Approximately 60% of our patients developed respiratory failure, with only about 10% not requiring oxygen therapy. In contrast, the studies by Ohmura et al. included a lower proportion of patients requiring oxygen therapy or mechanical ventilation, reflecting a generally less severe patient cohort.
In addition to the type of underlying disease, prior immunosuppressive therapy is also a critical factor determining the prognosis of PJP. Ohmura et al. indicated that the average daily prednisolone dose within the 90 days before PJP onset exhibits a weak association with patient mortality (26). In the present study, although a higher proportion of patients in the high-dose group had received long-term prednisone or other immunosuppressive treatments prior to disease onset, these variables were effectively balanced between the groups through IPTW adjustment. Furthermore, in this study, the co-infection incidence was 46.7%, with viral infections (31.7%) being the most common co-infections. The infection rate of CMV in the high-dose group was significantly increased (25.0% vs. 6.2%; P=0.02). Previous reports have expressed concern that adjunctive corticosteroid therapy may increase viral reactivation risk in immunocompromised HIV-negative patients (32). However, our analysis showed that, after baseline adjustment, high-dose corticosteroid use was not associated with an increased risk of co-infection. This finding is consistent with Lemiale et al. (13).
It is noteworthy that in actual clinical practice, physicians often administer higher doses of corticosteroids to severe HIV-negative patients with PJP, influenced by the high-dose tapering regimen commonly used for moderate to severe HIV-associated PJP (10). Our data further corroborate this tendency: the high-dose group accounted for 60% of the total cases, with approximately 25% of them receiving pulse therapy; among the subgroup with respiratory failure, the high-dose group also showed a higher proportion. Such a treatment preference may have led to an imbalance in baseline disease severity between the groups. However, after appropriate statistical adjustment for baseline severity characteristics, no significant differences in 30- or 90-day mortality were observed between high-dose and low-dose groups in the overall cohort. This aligns with Ding et al., whose meta-analysis of seven studies reported no significant association between corticosteroid dose and mortality in HIV-negative PJP (11). Given that patients with respiratory failure are more frequently administered empiric high-dose corticosteroid therapy in clinical practice, we specifically analyzed this subgroup to evaluate whether such an empiric high-dose strategy could provide significant additional benefit for severe patients. The results demonstrated that even within this high-risk subpopulation, there was no significant difference in mortality between the high-dose and low-dose treatment groups. This finding is consistent with the results reported by Pareja et al., whose study also showed comparable mortality rates among patients treated with different corticosteroid doses (12). Collectively, these results suggest that high-dose corticosteroid therapy confers no additional survival benefit over low-dose regimens for HIV-negative PJP patients, even in severe cases with respiratory failure.
Consistent with our findings, a retrospective study by Inoue et al. demonstrated that a prednisone-equivalent dose of 0.40–0.71 mg/kg/day was associated with lower 60-day mortality in patients with respiratory failure, while higher doses offered no further benefit (22). However, their study only focused on 60-day mortality rates without in-depth exploration of other clinical outcomes such as SOFA-resp improvement, tracheal intubation on day 5, ICU admission rate, incidence of co-infections, and total length of hospital stay. These indicators are critical for clinicians to evaluate the risk-benefit profile of different corticosteroid dosing regimens in HIV-negative PJP patients (17,33). Therefore, in addition to mortality, the above five endpoints were also included in our study.
Initially, the high-dose group had a significantly longer total length of hospital stay (median 26 vs. 20 days; P=0.02), but this difference disappeared after baseline adjustment, indicating confounding effects rather than a true treatment difference. Similarly, high-dose corticosteroids did not improve SOFA-resp score, reduce the rates of tracheal intubation on day 5, or lower ICU admission rates. These findings contrast with an earlier study from 1998, which suggested that high-dose corticosteroids delayed mechanical ventilation and ICU admission in HIV-negative immunocompromised adults (12). That discrepancy may be attribute to the small sample size in that earlier study and their inadequate adjustment for baseline patient characteristics, making it challenging to determine whether their outcomes reflect true treatment effects or are caused by baseline differences (15,17).
There are several strengths in this study. IPTW was applied to minimize baseline confounding, including age, comorbidities, and immune status, improving intergroup comparability. We also focused on HIV-negative PJP patients with respiratory failure, who represented 57.5% of the total population and at particularly high risk (34). Beyond mortality, we evaluated multiple clinical endpoints—SOFA-resp improvement, tracheal intubation on day 5, ICU admission rate, incidence of co-infections, and total length of hospital stay—providing a multidimensional assessment of treatment efficacy.
Nonetheless, limitations must be considered. First, as a retrospective study, residual confounding cannot be excluded despite IPTW adjustment. Second, arterial blood gas data were missing for many cases, requiring imputation of P/F ratios from oxygen saturation (S/F ratio), which precluded the use of standard severity classification. Third, corticosteroid regimens were not standardized, as dosing and duration were determined by treating physicians, which may have influenced outcomes. Fourth, this study utilized all-cause mortality as the endpoint. Due to the retrospective design and the fact that part of the survival data was obtained via telephone follow-up, we were unable to accurately distinguish the specific causes of death (such as PJP itself, progression of the underlying disease, or other complications). Finally, outcomes were not compared between patients who did and did not receive corticosteroids, limiting conclusions about the absolute benefit of adjunctive corticosteroid therapy in this setting.
Conclusions
After adjustment for patient characteristics, no significant differences in clinical outcomes were observed between high- and low-dose adjunctive corticosteroid therapy, either in the overall cohort of HIV-negative patients with PJP or in the subgroup with respiratory failure. These findings suggest that high-dose adjunctive corticosteroid therapy offers no additional clinical benefit over low-dose therapy in this population, and that low-dose regimens may be adequate for treating PJP in HIV-negative individuals.
Supplementary
The article’s supplementary files as
Acknowledgments
The authors express gratitude to the clinical laboratory of Zhongnan Hospital of Wuhan University for technical support and to the patients and their families.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (approval No. 2025202K) and individual consent for this retrospective analysis was waived.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1984/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1984/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1984/dss
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