Prognostic analysis of Pneumocystis jirovecii pneumonia in interstitial lung disease patients: a retrospective clinical study

doi:10.21203/rs.3.rs-1454392/v1

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Research Article

Prognostic analysis of Pneumocystis jirovecii pneumonia in interstitial lung disease patients: a retrospective clinical study

https://doi.org/10.21203/rs.3.rs-1454392/v1

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Background

Pre-exiting chronic lung disease was a poor prognostic factor for pneumocystis jiroveci pneumonia (PJP). However, the clinical characteristics and the prognostic factors of HIV negative PJP patients (non-HIV-PJP) with interstitial lung disease (ILD) remains unclear.

Methods

This was a retrospective study of hospitalized patients with confirmed PJP and ILD at Peking Union Medical College Hospital between January 2014 and December 2020. The enrolled patients were stratified based on the presence or absence of ILD and the presence of fibrotic ILD (FILD) or nonfibrotic ILD (non-FILD). The log-rank test and Cox regression models were used to analyze the prognostic factors for PJP patients with different pre-existing statuses.

Results

Among 836 hospitalized individuals with PJP, there were 378 non-HIV-PJP with complete clinical-radiological-follow-up data. Among them, there were 133cases (35.2%) with non-HIV-ILD-PJP, and 70 patients were classified as fibrotic ILD-PJP. The all-cause mortality rate for ILD-PJP group was higher than that of non-ILD-PJP group (57.9% vs 38.4%, Log-rank = 12.2, p < 0.001, However, the all-cause mortality was similar between FILD-PJP and non-FILD-PJP (Log-rank = 0.03, p > 0.05). Co-infection with aspergillosis(HR = 2.89, χ2 = 5.0, p = 0.02, 95%CI:1.14–7.28), honeycomb in the chest HRCT(HR = 16.3, χ2 = 16.8, p < 0.001, 95%CI:4.3–62), invasive ventilation(HR = 3.02, χ2 = 7.1, p < 0.01, 95%CI:1.34–6.82) and non- invasive ventilation(HR = 6.2, χ2 = 16.7, p < 0.001, 95%CI:2.58–14.9 ) were independent survival risk factors for non-HIV-ILD-PJP. Non-invasive ventilation support (HR = 928.56, χ2 = 7.3, p < 0.01, 95%CI:6.6-130796.5) and the serum D-dimer (HR = 1.2, χ2 = 10.9, p < 0.001, 95%CI:1.01–1.34) were independent survival risk factors for fibrotic ILD-PJP patients.

Conclusions

Pre-exiting ILD is independently associated with poor survival of PJP patients. Co-infection with aspergillosis, honeycomb in the chest HRCT, invasive ventilation and non- invasive ventilation were independent survival risk factors for ILD patients complicated with PJP.

pneumocystis jiroveci pneumonia

human immunodeficiency virus negative

interstitial lung disease

prognosis

The prognosis of pneumocystis jiroveci pneumonia (PJP) in human immunodeficiency virus (HIV) (HIV-PJP) has improved with the standardized management and prevention of HIV-PJP. However, non-HIV-PJP is still a serious disease[1]. The mortality rate of non-HIV-PJP remains high, with a reported rate of 30–60%[2]. A higher serum lactate dehydrogenase (LDH), age, coinfection with cytomegalovirus (CMV), lower peripheral lymphocytes, pneumomediastinum, invasive ventilation, etc. have been reported to be associated risk factors for mortality in non-HIV-PJP patients[3–6]. Pre-existing chronic lung disease, especially interstitial lung disease (ILD), is a poor prognostic factor for PJP patients[7–9]. Corticosteroids and/or immunosuppressants are common medications for most ILD patients. These medications predispose non-HIV-infected patients to PJP[8, 10]. On the other hand, the prevalence of Pneumocystis jirovecii carriers was noted to be high in untreated ILD patients[11]. Clinicians should pay close attention to PJP in the treatment and follow-up of ILD patients.

Diffuse ground-glass opacities (GGOs), consolidations, architectural distortions, fine reticulations and/or traction bronchiolectasis are the classical chest high resolution CT (HRCT) manifestations of PJP, and these manifestations might mimic the chest HRCT shadows that are seen in ILD patients[12–15]. Both PJP and ILD patients have similar symptoms, i.e., dry cough, dyspnea and hypoxia. Therefore, it may be difficult to differentiate PJP from refractory ILD. PJP might be underdiagnosed or misdiagnosed. However, the delay in the initiation of anti-pneumocystis jirovecii (P. jirovecii) has been associated with the poor prognosis of non-HIV-PJP patients[16]. Few clinical studies to date have focused on exploring the prognostic factors for non-HIV-PJP in ILD patients (non-HIV-ILD-PJP).

Therefore, we conducted this retrospective analysis of non-HIV-PJP patients who were admitted to our hospital between January 2014 and December 2020. Our objectives were to describe the clinical characteristics and to explore the prognostic factors of non-HIV-ILD-PJP patients who had different radiological ILD patterns.

Study design

All patients who were discharged with a diagnosis of PJP from January 2014 to December 2020 were screened for eligibility from the electronic medical records bank at Peking Union Medical College Hospital (PUMCH). Eight hundred thirty-six patients were enrolled in this study. Their complete medical records and radiological imaging data were retrospectively reviewed through the hospital’s electronic banks. They were followed up from the day that the diagnosis PJP was confirmed. After discharge, they were followed up every 1 to 6 months, depending on the disease activity and severity. The final follow-up point was June 30, 2021. The mean follow-up period was 371.1 days, which ranged from 2 to 2548 days. The follow-up information was obtained through outpatient records or telephone conversations. The survival time was defined as the time when the patient was confirmed to have a diagnosis of PJP to death or the final follow-up point. The following information was reviewed and analyzed: age, sex, the clinical manifestations, the serological results, chest high-resolution CT, treatments, and outcomes.

Definitions

The criteria for the diagnosis of confirmed PJP were as follows: (1) the presence of relevant respiratory manifestations, i.e., cough, dyspnea, and/or hypoxia; (2) the presence of pulmonary shadows that were identified by chest high resolution computed tomography; (3) Identification of active P. jiroveci infection (ie. positive P. jiroveci DNA fragments in the respiratory samples, which was confirmed by polymerase chain reaction (PCR) and a serum 1,3-β-D-glucan (βDG)> 100 pg/ml, and/or ii. P. jirovecii asci were observed at direct microscopic examination with Grocott’s methenamine silver (GMS) stain in the respiratory samples. The respiratory samples included bronchoalveolar lavage fluid (BALF), aspirates, sputum or lung tissue.

ILD was defined by the presence of hallmark manifestations on chest HRCT¹⁴. Fibrotic ILD (FILD) was diagnosed with a pre-PJP chest HRCT, which showed traction bronchiolectasis, reticulation, architectural distortion, lung volume loss, and/or honeycombs, and the chest CT patterns were in accordance with the usual interstitial pneumonia (UIP) pattern, probable UIP pattern, possible UIP pattern, fibrosing non-specific interstitial pneumonia (NSIP) pattern[17] or fibrotic hypersensitivity pneumonitis (HP) pattern[18]. The findings in the PJP and pre-PJP HRCTs were reviewed by two pulmonologists (C.S. and H.H.) and one radiologist (K.X.). They were blinded to each other’s interpretations. The typical HRCT findings for non-ILD-PJPs, non-FILD-PJPs and FILD-PJPs are listed in Fig. 1.

CMV viremia was defined as having > 500 copies of peripheral CMV DNA.

Hospital acquired pneumonia (HAP) pathogen: patients were admitted > 48 h if they had positive BALF or bronchial aspiration cultures that yielded Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, or methicillin-resistant Staphylococcus aureus.

Aspergillosis was defined as: ≥1 host factor criterion, 1 microbiological criterion and 1 major clinical criterion (or 2 minor criteria) according to the EORTC/MSG Consensus

Respiratory failure was defined as: a room air pulse oxygenation of < 90% or a room air arterial partial pressure oxygen level of < 60 mmHg.

Inclusion and exclusion criteria

The inclusion criteria included the following: (1) Confirmed PJP diagnosis and (2) a negative HIV test.

The exclusion criteria included the following: (1) an active PJP infection in the respiratory samples was not confirmed; (2) the patient was less than 18 years old or was pregnant; (3) the patient had a positive HIV test; and (4) the patient’s complete clinical, chest HRCT, and/or follow-up data were missing.

This study was approved by the Ethics Committee PUMCH (JS-2517), in accordance with the Declaration of Helsinki. Our study was performed using anonymized health care data. The written informed consent from each patient was waived as this study met the IRB’s minimal risk waiver criteria.

Statistical analysis

The data were analyzed using the SAS version 9.4 software package (SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA.). GraphPad Prism version 8.0 was used for graphing. The quantitative variables were presented as the means ± standard deviation (SD), and the categorical data were presented as frequencies and percentages. The t-test or rank sum test was used for measured data, and the chi-square test was used for count data. The difference was statistically significant when p < 0.05. The log-rank test was used to compare the survival rates of different subgroups, and Kaplan-Meier survival curves were plotted. Cox regression models were used to identify factors associated with mortality for PJP with different pre-existing status. The statistically significant variables selected via univariate analysis were finally assessed by multivariate analysis.

General characteristics of the enrolled patients

Among the 836 enrolled patients, there were 48 HIV patients, 5 patients younger than 18 years, 16 patients without complete clinical-radiological-follow-up data, and 389 patients without a confirmed PJP diagnosis according to our detailed diagnostic criteria. Three hundred and seventy-eight patients with PJP were enrolled and were evaluated for the final analysis. The study flow chart is shown in Fig. 1.

Among the 378 enrolled PJP cases, there were 172 males and 206 females, who were (54.0 ± 16.1) years old (range from 18 y to 88 y). Most of them had different underlying diseases (Table 1). Hypoalbuminemia was common in the PJP patients (only 2 of the patients did not have serum albumin levels measured during PJP). There were 371 patients (98.7%) who had hypoalbuminemia, and the minimal serum albumin was 23.4 ± 5.1 g/L (range from 10 to 34 g/L, 325 cases/86.4%<30 g/L). Blood glucose was tested in all 378 patients during PJP. There were 110 patients who suffered from diabetes mellitus before PJP; however, more than half of the enrolled PJP patients (250/66.1%) showed hyperglycemia during PJP.

Most PJP patients were given corticosteroids and/or immunosuppressants before PJP: corticosteroids were given in 310 patients/82% (prednisone daily dosage > 1 mg/kg/d 266 patients/70.4%, methylprednisolone 500–1000 mg/d 58/15.3%); immunosuppressants were given in 233 patients/61.6% (including cyclophosphamide, tacrolimus, mycophenolate mofetil, etc.); and biological agents were given in 23/6.1% (including anti-tumor necrosis factor, rituximab, etc.). The management before PJP for 40 patients with malignancy included the following: chemotherapy (19/47.5%), chemotherapy and radiotherapy (4/10%), chemotherapy and immunotherapy (2/5%), chemotherapy, radiotherapy and immunotherapy (1/1.25%), EGFR-TKI (1/1.25%), and radiotherapy with no medical therapy (14/35%).

Some of the PJP patients were coinfected with cytomegalovirus (CMV, 210/55.6%), common HAP pathogens (114/30.2%), different species of aspergillosis (58/15.3%), oral candidiasis (37/9.8%), different species of mycobacteria (18/4.8%) and nocardia (7/0.2%).

There were 286 patients with PJP who were complicated with respiratory failure during hospitalization, and 192 patients were transferred to the ICU wards. Among them, 169 patients (44.7%) were supported with invasive ventilation, and 111 patients (29.4%) were supported with noninvasive ventilation. The overall mortality rate for all of the enrolled patients was 45.2%. Half of them (51.5%) died within 30 days after the diagnosis of PJP. A total of 84.2% patients died within 60 days after PJP, and 93.0% patients died within 3 months after PJP.

ILD-PJP vs. non-ILD-PJP

The clinical manifestations, laboratory tests, radiological features, treatments and prognostic factors of the ILD-PJP group versus the non-ILD-PJP group are described in Table 2. The non-ILD-PJP group was younger than ILD-PJP: 51.5 ± 16.7 years vs. 58.8 ± 13.9 years. The non-ILD-PJP group were more likely to have corticosteroid therapy (211/86.1% vs 9/74.4%, p = 0.005); however, the ILD-PJP group was more likely to have a higher dose of corticosteroid medication (≥ 500 mg/d methylprednisolone) (29/21.8% vs. 29/11.8%, p = 0.01). For the clinical manifestations, cough, expectoration, dyspnea, weight body loss and severe hypoxia [room air pulse oxygenation ([email protected]) < 90%] were more common in the ILD-PJP group: 93.2% vs 75.5%, 84.2% vs 57.1%, 94.0% vs 78.4%, and 85.7% vs 70.2% (every p < 0.001).

A low peripheral lymphocyte percentage (< 20%) was common in both the ILD-PJP and non-ILD-PJP groups (89.5% vs. 85.2%). The lymphocyte percentage and the absolute lymphocyte count were [(9.4 ± 7.8)% vs. (11.7 ± 10.9)%] and [(0.79 ± 0.82) ×10⁹/L vs. (0.86 ± 0.89) ×10⁹/L] for the ILD-PJP vs. non-ILD-PJP groups, respectively. There were 94 patients/70.7% with ILD-PJP and 150 patients/61.5% with non-ILD-PJP who had lymphocytopenia. The serum immunoglobin (Ig)G was lower in the non-ILD-PJP group [(8.4 ± 5.6)g/L vs (10.3 ± 5.6) g/L, p < 0.001], and there were more patients in the non-ILD-PJP group with hypo-IgG (52.6% vs 35.3%, p = 0.003 ).

The T-lymphocyte subset analysis was available for most of the enrolled PJP cases (Table 3): 111 patients (83.5%) with ILD-PJP and 205 patients (83.7%) with non-PJP. The percentages of B cells, NK cells and CD4⁺ T cells were less than normal among almost half of the enrolled PJP cases; however, the percentages of CD3⁺ T cells and CD8⁺ T cells were normal for most of the enrolled PJP patients. There was no significant difference between the ILD-PJP and non-ILD-PJP groups in the abnormal peripheral lymphocyte subset analysis.

The ILD-PJP patients were more likely to suffer from pneumomediastinum than the non-ILD-PJP patients (19.6% vs 8.6%, p = 0.002). Although the ILD-PJP patients were more likely to be complicated with respiratory failure than the non-ILD-PJP patients (85.7% vs. 70.2%, p < 0.001), the requirements for ICU admission, invasive ventilation and noninvasive ventilation were similar in the ILD-PJP group and the non-ILD-PJP group (48.9% vs. 51.8%, 45.1% vs. 44.5%, 29.3% vs. 29.4%, respectively, p > 0.05 for all). The interval between the onset and the diagnosis of ILD-PJP patients was longer than that of non-ILD-PJP patients [(31.1 ± 94.9)days vs (21.0 ± 75.1)days, p = 0.047].

A Kaplan–Meier survival analysis and a Cox regression multivariate analysis were performed to identify the potential confounding prognostic factors with hospital mortality for the ILD-PJP patients (Fig. 2, Table 4). The all-cause mortality rate for the ILD-PJP group was higher than that of the non-ILD-PJP group. Approximately half of the PJP patients, both the ILD-PJP group (49.4%) and non-ILD-PJP group (53.2%), died within 30 days after the diagnosis of PJP, and more than 90% of the PJP patients died within 3 months after PJP (90.9% ILD-PJP patients vs. 96.7% non-ILD-PJP patients). Coinfection with aspergillosis, honeycombs in the chest HRCT, invasive ventilation and noninvasive ventilation were the significant and independent risk factors for the ILD-PJP patients who did not survive. However, respiratory failure, hyperglycemia, decreased Ly%, albumin_min, consolidation in the chest HRCT and pleural effusion were protective factors.

FILD-PJP vs. non-FILD-PJP

After reviewing the chest HRCT, the ILD-PJP patients were subdivided into the F-ILD-PJP group (70 patients) and the non-F-ILD-PJP group (63 patients). The clinical, laboratory, radiological, and prognostic characteristics were compared between them (Table 5). Invasive ventilation support was more likely to be performed for non-FILD-PJP patients; however, noninvasive ventilation was more likely to be performed for FILD-PJP patients. Both the serum LDH and βDG were higher for non-FILD-PJP patients. The non-FILD-PJP patients were more likely to show elevated serum βDG than the FILD-PJP patients. However, the all-cause mortality was similar between them (Fig. 3). The Cox regression multivariate model indicated that noninvasive ventilation support and serum D-dimer were the significant independent risk factors for non-survival FILD-PJP patients.

In our study, we found that hypoalbuminemia and hyperglycemia were common in PJP patients. Most of these patients had suffered from an underlying disease that required immunosuppressive therapies. The serum IgG was lower in the non-ILD-PJP patients, and there were more non-ILD-PJP patients with hypo-IgG than in the ILD-PJP patients. The ILD-PJP patients were more likely to be complicated with pneumomediastinum and respiratory failure than the non-ILD-PJP patients. The all-cause mortality rate of the ILD-PJP patients was higher than that in the non-ILD-PJP patients. Coinfection with aspergillosis, honeycombs in the chest HRCT, invasive ventilation and noninvasive ventilation were the independent risk factors for non-survival in the ILD-PJP patients. However, there was no significant difference in the all-cause mortality rate between the FILD-PJPs and non-FILD-PJP patients.

Corticosteroids are the most commonly reported risk factors for non-HIV-PJP, but the association of the daily dose threshold, the cumulative dose and the kinds of corticosteroids used for PJP is still unknown[10]. In our study, although there were more non-ILD-PJP patients who were administered corticosteroids, methylprednisolone pulse therapy was more common in ILD-PJP patients before PJP. Almost most of our PJP patients had hypoalbuminemia and hyperglycemia during PJP, regardless of the presence of basic diabetes mellitus. With the resolution of PJP, the serum albumin of the patients gradually increased to normal. Decreased serum albumin was reported as a poor prognostic factor for PJP[19–21] and as a risk factor for acute lung injury/acute respiratory distress syndrome[22]. The administration of treatment for diabetes mellitus was associated with PJP for kidney transplantation patients but was not a prognostic factor[23]. However, both hyperglycemia and the serum minimal albumin values were independent protective factors for ILD-PJP patients in our study. Hypoalbuminemia has been a major focus since Chen’s and Li’s studies in our hospital[21, 24]. The active treatment of the abnormal blood glucose levels and hypoalbuminemia in our PJP patients might contribute to this association.

Although peripheral lymphocytopenia, especially a low CD4⁺ T cell count, was a recognized risk factor for HIV-PJP, the peripheral lymphocyte percentage, absolute lymphocyte count and subtype features have been variable among the different studies of non-HIV-PJP patients who were administered corticosteroids[4, 10, 25–27]. A low peripheral lymphocyte percentage was more common than a low lymphocyte count for our PJP patients, which might be caused by the elevation of the WBC count after corticosteroid administration. There have been few prospective studies that have evaluated the lymphocyte subtype analysis for non-HIV-PJP patients, and the lymphocyte subtype characteristics have varied significantly among the different studies[28, 29]. The percentages of CD3⁺ T cells and CD8⁺ T cells were normal for most of our enrolled PJP patients. This might be associated with the different pre-existing diseases and previous medications that the patients had before PJP.

There are several reported diagnostic and/or prognostic serum biomarkers for PJP patients. Serum LDH levels could be an adjunctive diagnostic biomarker for non-HIV-PJP, and elevated serum D-dimer and C-reactive protein and lymphopenia were reported to be associated with the prognosis of PJP patients[10, 30–31]. Elevated serum D-dimer and/or fibrinogen are a concern in coronavirus disease 2019 (COVID-19) and other severe viral pneumonia diseases[26–27]. Severe pulmonary inflammation might trigger the activation of and cause damage to the pulmonary endothelia and can cause thrombosis during severe pneumonia. Many of our enrolled PJP patients presented with respiratory failure and/or severe hypoxia. Elevations of D-dimer and fibrinogen were common both in the ILD-PJP and non-ILD-PJP patients. Both the serum LDH and βDG were higher for non-FILD-PJP patients than for FILD-PJP patients. Furthermore, elevations in D-dimer might be associated with the poor prognosis of FILD-PJP patients in our study. Hyperinflammatory characteristics, including elevations in ESR, CRP, D-dimer and/or fibrinogen, should be focused if present in ILD-PJP patients, especially FILD-PJP patients, as they might be poor prognostic factors.

The HRCT manifestations of PJPs were similar to those of ILDs[12–15], and it was more difficult to differentiate PJP from worsening of a pre-existing ILD in ILD-PJP patients than non-ILD-PJP patients. Extensive diffuse GGO was the main CT feature for early PJP, and it was usually symmetric and apical and had a perihilar distribution[12–13]. Reversible architectural distortions, including irregular linear opacities, reticulations and traction bronchiolectasis, appeared during the follow-up chest CTs in the non-HIV-PJP patients. A variable amount of pulmonary fibrosis could be beneficial for HIV-PJP patients; however, it rarely occurs in non-HIV-PJP patients[13]. GGOs, reticulation, traction bronchiolectasis, and honeycombs are also common chest manifestations of ILD[14–15, 34]. Therefore, the complications associated with PJP might be neglected or misdiagnosed in ILD patients. Concomitant ILD was associated with a poor prognosis for non-immunocompromised PJP patients[35]. The interval between the onset and the diagnosis of the ILD-PJP patients was longer than that of the non-ILD-PJP patients in our study. It has also been reported that a delayed diagnosis and the initiation of anti-PJP treatment were risk factors for the mortality in non-HIV-PJP patients[16]. PJP patients should be monitored for ILDs, especially for those patients who are administered corticosteroids and/or immunosuppressants.

The all-cause mortality rate of the ILD-PJP patients was higher than that of the non-ILD-PJP patients in our study. Coinfection with aspergillosis, honeycombs in the chest HRCT, invasive ventilation and noninvasive ventilation were significantly independent risk factors for non-survival in the ILD-PJP patients. The application of mechanical ventilation, a decreased serum albumin, coinfection with aspergillosis or CMV, and an underlying chronic pulmonary disease were reported as poor prognostic factors for PJP patients[4, 5, 20, 36]. Few studies have focused on the fibrosing characteristics in chest CTs within PJP patients. We found that the presence of honeycombs was a poor prognostic factor for non-HIV-PJP patients. It is necessary to pay attention to ILD-PJP patients who have honeycombs. Fortunately, although honeycombs were an independent risk factor for non-survival in ILD-PJP patients, there were no significant differences in all-cause mortality rate between the FILD-PJP patients and the non-FILD-PJP patients.

There were several limitations in our retrospective study. First, all patients were diagnosed with confirmed PJP and they were admitted to a tertiary hospital, which would lead to selection bias. Second, it was a retrospective study and almost more than half of the enrolled PJP cases were admitted or transferred to ICU, several information couldn’t be collected completely and homologously, eg, the detailed prophylaxis data for PJP, the date of the lymphocyte subtype analysis, the interval period of repeated chest HRCT frequency, etc. However, the role of PJP prophylaxis in HIV negative patients with long-term corticosteroids and the detailed prophylaxic project (when and how) remained controversial. A multi-center, well-designed prospective study was expected in future. Third, although all enrolled PJP cases were administrated with adjunctive corticosteroids, the detailed adjunctive corticosteroids protocol, especially the tapering protocol were not the same because of the various underlying disease.

Pre-exiting ILD is independently associated with poor survival of PJP patients. Co-infection with aspergillosis, honeycomb in the chest HRCT and ventilation support were independent survival risk factors for ILD patients complicated with PJP.

PJP: pneumocystis jiroveci pneumonia

HIV: human immunodeficiency virus

LDH: lactate dehydrogenase

CMV: cytomegalovirus

ILD: interstitial lung disease

GGO: ground-glass opacity

HRCT: high resolution CT

PUMCH: Peking Union Medical College Hospital

PCR: polymerase chain reaction

βDG: 1,3-β-D-glucan

GMS: Grocott’s methenamine silver

BALF: bronchoalveolar lavage fluid

FILD: fibrotic ILD

UIP: usual interstitial pneumonia

NSIP: non-specific interstitial pneumonia

HP: hypersensitivity pneumonitis

HAP: hospital acquired pneumonia

SD: standard deviation

EGFR-TKI: epidermal growth factor receptor-tyrosine kinase inhibitor

ICU: intensive care unit

[email protected]: room air pulse oxygenation

ESR: erythrocyte sedimentation rate

CRP: C-reactive protein

Ig: immunoglobin

NK: natural killer

CD: cluster of differentiation

HR: hazard ratio

CI: confidence interval

Ethics approval and consent to participate

The study was approved by the institutional review board of Peking Union Medical College Hospital (No. JS-2517). Our study was performed using anonymized health care data. The written informed consent from each patient was waived as this study met the IRB’s minimal risk waiver criteria.

Consent for publication

As any identifiable information (image, face, name etc.) of all enrolled cases is not revealed in the submission, for that Consent is not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article. Besides, any additional data/files may be obtained from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

The study was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [grant number 2019XK320037].

Authors' contributions

H.H is the guarantor of the content of the manuscript including the data and analysis. H.H, YX.S, C.S and ZJ.X conceived and designed the study; YX.S, C.S, K.X, and X.Z performed the study; YX.S, M.L, K.X and H.H analyzed the data; H.H and YX.S wrote the paper. All the authors have read and approved the final version of the manuscript. And the authors do not have any competing interests and/or bias with regard to this publication.

Acknowledgements

We would like to thank the patients and/or their relatives for their assistance.

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Table 1. The underlying diseases for enrolled PJP cases.

underlying disease (n=374)

connective tissue disease (CTD, n=184)

systemic vasculitis (n=48)

systemic lupus erythematosus (n=45)

idiopathic inflammatory myositis (n=40)

rheumatoid arthritis (n=17)

primary Sjögren syndrome (n=12)

other kinds of CTDs (n=22)

kidney diseases (n=59)

primary glomerulonephritis (n=56)

renal failure (n=3)

malignant (n=58)

hematological malignant (n=33)

other malignant (n=25)

pulmonary disease(n=28)

idiopathic interstitial pneumonia (n=24)

emphysema (n=3)

sarcoidosis (n=1)

non-malignant hematological disease(n=18)

dermatologic disease (n=13)

neurological disease(n=4)

Table 1. The underlying diseases for enrolled PJP cases (continued 1)

underlying disease (n=374)

transplantations (n=4)

kidney transplantation (n=3)

heart transplantation (n=1)

endocrinologic disease (n=3)

inflammatory bowel disease (n=2)

severe drug-induced liver injury (n=1)

PJP: pneumocystis jiroveci pneumonia, CTD: connective tissue disease

Table 2. The characters of ILD-PJP patients vs non-ILD-PJP patients

variables	ILD-PJP(n=133)	non-ILD-PJP(n=245)	P value
age (mean±SD)y	54.1±16.3	63.2±9.6	<0.001
gender (male, n/%)	67/50.4%	105/42.9%	0.16
underlying conditions (n/%) diabetes hyperglycemia malignant previous glucocorticosteroids administration prednisone(>1mg/kg/d) methylprednisolone (>500mg/d) previous immunosuppressant administration	44/33% 90/67.7% 16/12% 99/74.4% 99/76.7% 29/21.8% 77/57.9%	66/26.9% 160/65.3% 44/18% 211/86.1% 167/72.9% 29/11.8% 156/63.9%	0.21 0.64 0.13 <0.01 0.43 0.01 0.25
respiratory failure (n/%)	114/85.7%	172/70.2%	0.01

Table 2 The characters of enrolled ILD-PJP vs non-ILD-PJP cases (continued 1)

variables	ILD-PJP(n=133)	non-ILD-PJP(n=245)	P value
ventilation(n/%) invasive ventilation noninvasive ventilation	60/45.1% 39/29.3%	109/44.5% 72/29.4%	0.91 0.99
ICU admission(n/%)	65/48.9%	127/51.8%	0.58
pneumomediastinum(n/%)	26/19.56%	21/8.6%	<0.01
clinical manifestation (n/%) fever cough expectoration dyspnea haemoptysis	114/85.7% 124/93.3% 112/84.2% 125/94% 10/7.5%	220/89.8% 185/75.5% 140/57.1% 192/78.4% 19/7.8%	0.24 <0.001 <0.001 <0.001 0.93

Table 2 The characters of enrolled ILD-PJP vs non-ILD-PJP cases (continued 2)

variables	ILD-PJP(n=133)	non-ILD-PJP(n=245)	P value
body weight loss	50/37.6%	19/7.8%	<0.01
death during PJP (n/%) die from respiratory failure	77/57.9% 45/33.8%	94/38.4% 48/19.6%	<0.01 <0.01
co-infection(n/%) oral candidiasis mycobacteria nocardiasis aspergillosis HAP CMV viremia	13/9.8% 4/3.0% 3/2.3% 24/18% 42/31.6% 76/57.1%	24/9.8% 14/5.7% 4/1.6% 34/13.9% 72/29.4% 134/54.7%	0.99 0.24 0.97 0.28 0.66 0.65

Table 2 The characters of enrolled ILD-PJP vs non-ILD-PJP cases (continued 3)

variables

ILD-PJP(n=133)

non-ILD-PJP(n=245)

P value

laboratory tests

WBC(10⁹/L)(mean±SD)

Lymphocyte%

Lymphocyte count(10⁹/L)(mean±SD)

Hb (g/L) (mean±SD)

ESR elevation (n/%)

hsCRP elevation (n/%)

LDH (U/L) (mean±SD)

LDH elevation (n/%)

hypo-immunoglobin G %(n/%)

14.3±66.6

9.4±7.8

0.8±0.8

115.4±21.8

97/78.9%

112/88.2%

614.4±530

120/94.5%

41/35.3%

9.66±20.1

11.7±10.9

0.9±0.9

101.9±24.3

149/76%

180/83.0%

580.8±351.0

206/90.4%

100/52.6%

0.44

0.1

0.22

<0.001

0.56

0.19

0.46

0.17

0.003

Table 2 The characters of enrolled ILD-PJP vs non-ILD-PJP cases (continued 4)

variables	ILD-PJP(n=133)	non-ILD-PJP(n=245)	P value
D-dimer(mg/L) D-dimer elevation(n/%) Fbg(g/L) Fbg elevation(n/%) ferritin (ng/ml) ferritin elevation(%) βDG(pg/ml, n=355)	9.1±21.8 109/84.5% 4.0±1.9 118/90.1% 692.5±963.3 96/76.8% 1497.8±1922.2	7.9±19.2 191/82.3% 4.3±2.5 222/94.5% 1129±1266.7 208/88.5% 1836.0±3896.8	0.83 0.6 0.12 0.12 <0.001 <0.01 0.24
chest HRCT features
sub-pleural distribution (n/%) peri-bronchial distribution (n/%)	68/51.3% 13/9.8%	48/19.6% 22/9.0%	<0.001 0.8
GGO (n/%)	106/79.7%	176/71.8%	0.09

Table 2 The characters of enrolled ILD-PJP vs non-ILD-PJP cases (continued 5)

variables	ILD-PJP(n=133)	non-ILD-PJP(n=245)	P value
consolidation (n/%) reticular (n/%) honeycomb (n/%) nodular (n/%) septal thickening (n/%)	36/27.1% 50/37.6% 19/14.3% 46/34.6% 39/29.3%	106/43.3% 17/6.9% 1/0.4% 112/45.7% 16/6.5%	0.002 <0.001 <0.001 0.036 <0.001
pleural thickening (n/%) pleural effusion (n/%)	92/69.2% 43/32.3%	120/49.0% 101/41.2%	<0.001 0.09
lymphadenopathy (n/%)	79/59.4%	97/39.6%	<0.001
the interval between onset and diagnosis of PJP(days)	31.1±94.9	21.0±75.1	0.047

PJP: pneumocystis jiroveci pneumonia, ILD: interstitial lung disease, HAP: hospital acquired pneumonia, CMV: cytomegalovirus

Hb: hemoglobin, LDH: lactate dehydrogenase, Fbg: fibrinogen, GGO: ground glass opacity. βDG: 1,3-β-D-glucan

CMV viremia: peripheral blood CMV DNA copy >500, hypo-immunoglobin: immunoglobin G<7g/dl, Lymphadenopathy: the shorter diameter of the lymphanode≥10mm.

Table 3. Peripheral lymphocyte subset analysis

Variables	ILD-PJP (n=111)	non-ILD-PJP (n=205)	t or χ2 value	P value
Ly count(×10⁹/L)	818.6±2295.6	693.6±695.3	-0.27	0.79
Lymphocytopenia(n/%)	105/94.6%	192/93.7%	0.11	0.74
B cell count^* (×10⁹/L)	289.0±2247.0	80.1±115.1	0.2	0.84
B Lymphocytopenia^*(n/%)	97/90.7%	173/91.1%	0.01	0.91
B cell percent^*	13.1±14.3	11.7±11.3	0.61	0.54
Lower B cell percent^*(n/%)	51(47.7)	98(51.3)	0.36	0.55
NK cell count^#(×10⁹/L)	72.6±128.2	64.9±74.8	-0.55	0.59
NK Lymphocytopenia^#(n/%)	100/91.7%	182/92.4%	0.04	0.84
NK cell percent^#	13.8±34.8	11.2±9.9	-0.46	0.65
Lower NK cell percent^#(n/%)	64/58.7%	108/54.6%	0.5	0.48
T cell count(×10⁹/L)	460.0±449.4	546.0±590.6	-0.45	0.65
T Lymphocytopenia(n/%)	106/95.5%	185/90.2%	2.73	0.1
T cell percent	75.1±15.9	75.6±14.5	0.11	0.91
Lower T cell percent(n/%)	20/18.0%	38/18.5%	0.01	0.93
CD4⁺ T cell count(×10⁹/L)	197.5±219.6	232.9±281.8	-0.58	0.57
CD4⁺T Lymphocytopenia(n/%)	104/93.7%	184/89.8%	1.38	0.24
CD4⁺T cell percent	31.3±15.9	40.2±85.3	-1.17	0.24
Lower CD4⁺T cell percent(n/%)	58/52.3%	98/47.6%	0.63	0.43
CD8⁺ T cell count (×10⁹/L)	236.9±266.7	277.3±353.8	-0.53	0.60

Table 3. Peripheral lymphocyte subset analysis (continued)

Variables	ILD-PJP (n=111)	non-ILD-PJP (n=205)	t or χ2 value	p value
CD8⁺T Lymphocytopenia(n/%)	92/82.9%	160/78.1%	1.04	0.31
CD8⁺T cell percent	40.2±18.4	43.5±41.1	0.05	0.96
Lower CD8⁺T cellpercent(n/%)	13/11.7%	24/11.7%	0	0.99
CD4⁺T /CD8⁺T	1.3±1.7	1.2±1.1	-0.68	0.50

Ly: Lymphocyte, PJP: pneumocystis jiroveci pneumonia, ILD: interstitial lung disease

CD: cluster determinant.

^*:ILD-PJP 107cases, non-ILD-PJP:190, ^#: ILD-PJP 109cases, non-ILD-PJP:197

Table 4. The significant prognostic factors from the univariable and multivariable analysis

Variables	univariable analysis χ2 P OR 95%CI				multivariable analysis χ2 P OR 95%CI
age	8.9	0.003	1.01	1.0, 1.03
with ILD	11.8	<0.001	1.70	1.26, 2.30
pneumomediastinum	29.5	<0.001	2.71	1.90, 3.90
with aspergillosis	6.9	0.009	1.65	1.14, 2.39	5.0	0.02	2.89	1.14, 7.28
with HAP	24.6	<0.001	2.16	1.59, 2.92
with CMV	5.5	0.02	1.45	1.06, 1.98
cough	6.4	0.01	1.82	1.14, 2.85
dyspnea	5.83	0.02	1.82	1.12, 2.98
respiratory failure	31.7	<0.001	4.84	2.80, 8.38	7.6	0.006	0.001	0, 0.13
ICU admission	54.8	0.001	3.60	2.57, 5.06

Table 4. The significant prognostic factors from the univariable and multivariable analysis (continued 1)

Variables	univariable analysis χ2 P OR 95%CI				multivariable analysis χ2 P OR 95%CI
invasive ventilation	84.9	<0.001	4.90	3.50, 6.88	7.1	0.007	3.02	1.34, 6.82
noninvasive ventilation	30.7	<0.001	2.36	1.74, 3.19	16.7	<0.001	6.20	2.58, 14.9
ly count	31.4	<0.001	3.10	2.09, 4.60
ly%	31.7	<0.001	0.93	0.91, 0.95
decreased ly%	15.9	<0.001	3.94	2.01, 4.60	9.1	<0.001	0.003	0, 0.05
D-dimer	35.8	<0.001	1.02	1.01,1.02
D-dimer elevation	17.3	<0.001	3.49	1.93, 6.28
hyperglycemia	16.6	<0.001	2.12	1.48, 3.04	11.2	<0.001	0.004	0, 0.10
fibrinogen elevation	5.71	0.02	0.55	0.34, 0.90

Table 4. The significant prognostic factors from the univariable and multivariable analysis (continued 2)

Variables	univariable analysis χ2 P OR 95%CI				multivariable analysis χ2 P OR 95%CI
LDH	9.14	0.003	4.63	1.72, 12.52
hsCRP	6.6	0.01	2.06	1.19, 3.57
lymphacytopenia	5.2	0.02	3.79	1.20, 11.93
B%	7.5	0.006	1.02	1.01, 1.03
NKcytopenia	7.6	0.006	5.01	1.60, 15.76
T lymphacytopenia	8.3	0.004	5.42	1.72, 17.09
CD4⁺T lymphacytopenia	5.5	0.02	2.67	1.17, 6.03
CD4⁺ Ly <0.4/ul	14.4	<0.001	4.37	2.04, 9.36
consolidation	6.5	0.01	1.48	1.10, 2.01	15.9	<0.001	0.01	0, 0.20
honeycomb	8.6	0.003	2.27	1.31, 3.92	16.8	<0.001	16.33	4.30, 62.0

Table 4. The significant prognostic factors from the univariable and multivariable analysis (continued 3)

Variables	univariable analysis χ2 P OR 95%CI				multivariable analysis χ2 P OR 95%CI
pleural effusion	7.75	0.005	1.54	1.14, 2.08	4.4	0.04	0.13	0.02, 0.88
caspofungin	22.0	<0.001	2.07	1.53, 2.80
clindamycin	9.3	0.002	1.70	1.21, 2.38
primaquine	4.83	0.03	1.94	1.07, 3.49

OR: odds ratio, ILD: interstitial lung disease, HAP: hospital acquired pneumonia, CMV: cytomegalovirus, ICU: intensive care unit,

CD: cluster determinant, NK: natural kill

Table 5. The differences between FILD-PJP group and non-FILD-PJP group.

Variables	FILD-PJP (n=70)	non-FILD-PJP (n=63)	t or χ2 value	p value
age(y)	63.2±9.5	54±16.2	-3.1	0.002
diabetes mellitus (n/%)	30/42.9%	14/22.2%	6.4	0.01
invasive ventilation(n/%)	25/35.7%	35/55.6%	5.3	0.02
non-invasive ventilation(n/%)	26/37.1%	13/20.6%	4.4	0.04
hemoptysis(n/%)	9/12.9%	1/1.6%	4.5	0.03
LDH(U/L)	589.1±654.2	643.5±337.8	2.5	0.01
1,3-β-D-glucan (βDG, pg/ml)	592.1±929.2	804.7±995.9	2.6	0.01
elevated βDG (n/%)	43/65.2%	53/89.8%	10.7	0.001

FILD: fibrosing interstitial lung disease, LDH: lactate dehydrogenase

No competing interests reported.

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Prognostic analysis of Pneumocystis jirovecii pneumonia in interstitial lung disease patients: a retrospective clinical study

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