We conducted a retrospective study at Peking Union Medical College Hospital (PUMCH). The study cohort comprised all non-HIV immunocompromised patients who had confirmed PCP and were treated at PUMCH between April 1st, 2013, and December 31st, 2020.
From the patients’ medical records, we collected their information, including age, sex, underlying diseases (autoimmune disease, hematological malignancies, solid tumor, organ transplantation and others), treatment history (glucocorticoid, immunosuppressant and preventive dose of sulfanilamide, PCP prophylaxis), clinical manifestations (fever, cough, wheeze), level of white blood cells (WBC), lymphocyte (LY#), lactate dehydrogenase (LDH) and (1–3)-beta-D-glucan (BDG), need for ICU and mechanical ventilation, dates of treatment initiation and cessation, treatment switches, complications [bacteremia, cytomegalovirus (CMV) infection] and outcome.
During this 8-year period, primary PCP episodes in non-HIV immunocompromised patients were treated with TMP/SMX initiated at a standard dosage of 15–20 mg/kg/day of TMP equivalent in 3–4 doses per day. The duration of TMP/SMX treatment was 21 days for patients who responded. If the patient was previously allergic to sulfonamides, desensitization therapy would be adopted. If acute kidney injury appeared, the dose of TMP/SMX was adjusted according to the renal function.
In cases of treatment failure, a second-line regimen could be used according to the clinician’s consideration. Because of the unavailability of most regimens and the lack of clinical experience, the second-line treatments used are shown in Fig. 1, including clindamycin (1200 mg, intravenous infusion, 2 times daily) (C), clindamycin (600 mg, oral, 3 times daily) plus primaquine (30 mg, oral, once daily) (C-P), clindamycin (1200 mg, intravenous infusion, 2 times daily) plus caspofungin (50 mg, intravenous infusion, once daily) (C-Ca), and clindamycin (1200mg, intravenous infusion, 2 times daily) plus primaquine (30 mg, oral, once daily) plus caspofungin (50 mg, intravenous infusion, once daily) (C-P-Ca).
For patients with severe infection, adjunctive corticosteroids (40–80 mg daily) were given until PCP improvement. Except for steroids, other disease-related immunosuppressive drugs were stopped.
The eligible patients had clinical manifestations of PCP, such as dyspnea, cough, fever, or abnormal chest radiographs. The mycological and morphological diagnoses were confirmed by real-time fluorescence quantitative polymerase chain reaction (qPCR) and Grocott's methenamine silver (GMS) staining of respiratory samples, respectively . Based on the criteria used in previous studies [5, 9, 10], the diagnosis of PCP was considered definitive if a positive PCR test for Pneumocystis jirovecii (P. jirovecii) DNA in bronchoalveolar lavage fluid (BALF) or GMS staining positive on BALF or sputum or a positive PCR test for P. jirovecii DNA in sputum was confirmed, combined with an increased level of BDG from patients with clinical manifestations (fever, dry cough, or dyspnea), hypoxemia, and radiologic findings compatible with PCP. The diagnosis of PCP was considered presumptive if patients met all clinical criteria and had either a positive PCR test for P. jirovecii DNA in sputum or an increased level of BDG, after excluding other fungal infections . In our study, both definitive and presumptive cases were included.
Treatment success was defined as a clinical cure or showing definitive clinical improvement with resolution of dyspnea and chest infiltrates. Treatment failure was defined as clinical deterioration occurring 4–8 days after TMP/SMX treatment: (1) progressive clinical deterioration characterized by an inability to maintain a stable PaO2 despite an increased proportion of FiO2 and/or persistent fever; and (2) progressive deterioration of vital signs and/or radiographic worsening . The classification of the PCP severity is based on clinical symptoms, arterial blood gases and oxygen saturation, and radiological findings . CMV infection was defined as having CMV blood viral load of over 500 copies/ml, and all such patients received ganciclovir treatment.
The primary outcome was 90-day mortality, and the secondary outcomes included in-hospital mortality, 28-day mortality and overall survival, defined as the time from diagnosis to death or last follow-up.
Risk factors associated with TMP/SMX treatment failure were analyzed by Mann–Whitney U or Fisher’s exact tests as appropriate. To identify independent risk factors, parameters with P < 0.05 in the univariate analysis were analyzed using a multivariate logistic regression model. Categorical variables were compared using the chi-square test. Kaplan–Meier analysis was used for survival analysis, and survival curves of different groups were compared using the log-rank test. P < 0.05 was considered statistically significant. Considering the limited sample size of our study, the standardized mean difference (SMD) was used to describe the effect after controlling the baseline confounding factors and to reflect the differences between groups if the p-value was > 0.05. SPSS version 22.0 (IBM Corporation, Armonk, New York, USA) was used for the statistical analysis.