A total of 622 adult patients with a first episode of PJP were screened in the computer system from 2010 to 2019. Among these, 202 patients had probable PJP without microbiological results. Sixty patients were excluded: 26 for a sulfa drug allergy and 34 for hospitalization less than 1 week. Finally, 360 patients were included in the study: 167 patients in the NHIV-PJP group and 193 patients in the HIV-PJP group.
We compared demographics, clinical characteristics, and auxiliary examinations of the two groups (Table 1) and recorded the underlying diseases in the NHIV-PJP group (Table 2). HIV-PJP patients were predominantly men (97.4% vs. 61.7%, P<0.001), were less often smokers (22.80% vs. 35.3%, P=0.009), and were younger (38.12±10.53 vs. 53.69±16.32 years, P<0.001) than NHIV-PJP patients. There was no difference in blood type between the NHIV-PJP and HIV-PJP groups except for the O type. One NHIV-PJP patient was Rh-negative (rhesus factor). Underlying diseases/conditions in the NHIV-PJP group included solid organ transplantation (n=49, kidney 43, liver 5, cornea 1), connective tissue diseases (n=46, systemic vasculitis 11, rheumatoid arthritis 8, glomerulonephritis 3, Wegener's granulomatosis 1, systemic lupus erythematosus 8, Sjögren syndrome 1, pemphigus 1, Bechet's disease 1, IgA nephropathy 2, dermatomyositis or polymyositis 4, adult onset still’s disease 3, pemphigus 1, giant cell arteritis 1 and nonspecific optic neuritis 1), haematological malignancies (n=8, non-Hodgkin lymphoma 4, myelodysplastic syndrome 1, multiple myeloma 1, chronic lymphocytic leukaemia 1 and autologous haematopoietic stem cell transplantation 1), solid tumours (n=14, lung cancer 6, oesophageal cancer 2, malignant thymoma 2, breast cancer 2, cervical sarcoma 1, hepatic carcinoma 1), nephrotic syndrome (n=14), chronic lung diseases (n=53, interstitial lung disease 32, chronic obstructive pulmonary disease 8, chronic bronchiectasis 8, chronic bronchitis 4 and pneumoconiosis 1), and other chronic diseases (n =89, cardiovascular disease 49, diabetes mellitus 13, diabetes and cardiovascular disease 27). In the HIV-PJP group, past diseases included cardiovascular disease (10), diabetes mellitus (2), asthma (2), chronic hepatitis B (1) and schizophrenia (1).
Both NHIV-PJP and HIV-PJP patients had symptoms of fever (the most common) (89.8% vs. 86.0%, P=0.271), chest pain (3.60% vs. 3.10%, P=0.799), and the triad fever, cough, and dyspnoea (59.3% vs. 51.3%, P=0.129). These manifestations were not different between the two groups. However, there were an obviously shorter duration of fever before admission [7 (3-10) vs. 10 (4-15) days, P=0.004], higher temperature [39.0 (38.3-39.5) vs. 38.5 (37.6-39.0) °C, P<0.001], more cases of lung rales (54.5% vs. 15.0%, P<0.001), and a lower incidence of weight loss (18.6% vs. 69.4%, P<0.001) in the NHIV-PJP group.
A total of 154 (92.2%) of the NHIV-PJP patients were receiving immunosuppressants for their underlying diseases. Glucocorticoids alone were administered in 147 patients (88.0%), chemotherapeutic agents alone were administered in 19 patients (11.4%), and glucocorticoids combined with immunosuppressive or chemotherapeutic agents were administered in 115 patients (68.9%). The median time from beginning immunosuppressive medication to the PJP diagnosis was 186 days (range: 99-372 days). Laboratory data, including routine blood tests, β-D-glucan, CD4+ T cells, CD8+ T cells, the CD4/CD8 ratio, procalcitonin (PCT), C-reactive protein (CRP), lactic dehydrogenase, ALB and oxygenation index, were available from 360 patients. The PLT count, HGB level, CD8+ cell count, CRP level, ALB level and oxygenation index were significantly lower in the NHIV-PJP group than the HIV-PJP group. In contrast, CD4+ T cells, the CD4/CD8 ratio, PCT and lactic dehydrogenase were significantly higher in the NHIV-PJP group. Using a multivariate logistic regression model, febrile days after admission, CD4+ T cells ≤100/µl, pneumothorax, and sulfa combined with CAS treatment were identified as significantly associated with mortality in the NHIV-PJP group. Six parameters were identified as significantly associated with mortality in the HIV-PJP group: PLT≤80 (x109/L), HGB≤90 g/L, ALB, CMV coinfection, pneumothorax and sulfa combined with CAS treatment.
Coinfections in the respiratory tract were detected in both NHIV-PJP and HIV-PJP patients [87 (52.0%) vs. 136 (70.4%), p<0.001], with 54 patients infected by 2 or more pathogens simultaneously. A positive serum assay for CMV was identified in 241 patients altogether in the NHIV-PJP and HIV-PJP groups [112 (67.1%) vs. 129 (66.5%)], EBV in 101 patients [97 (58.1%) vs. 4 (2.1%)], and H1N1 virus in 3 patients [2 (1.2%) vs. 1 (0.5%)]. Other pathogens found in respiratory samples were Mycobacterium tuberculosis [n=5, 1(0.5%) vs. 4(2.1%)], Pseudomonas aeruginosa [n=19, 13(7.8%) vs. 6(3.1%)], Klebsiella pneumoniae [n=4, 4(2.4%) vs. 0 (0.0%)], Escherichia coli [n =9, 5(3.0%) vs. 4(2.1%)], fungi [n=80,60 (35.9%)vs. 20 (10.3%)], Acinetobacter baumannii [n=7, 5(3.0%) vs. 2(1.0%)], and atypical pathogens [n=4, 2(2.1%) vs. 2(1.0%)]. Coinfections in blood: Cytomegalovirus virusemia [n = 6, 0 (0.0%) vs. 6 (3.1%)], Gram-positive coccus septicemia [n = 14, 9 (5.4%) vs. 5 (2.6%)], Gram-negative bacillus septicemia [n = 9, 7 (4.2%) vs. 2 (1.0%)].
Treatment and outcome
A total of 354 patients received TMP-SMX (720 mg of trimethoprim, 3600 mg of sulfamethoxazole daily), and 125 patients received TMP-SMX (720 mg of trimethoprim, 3600 mg of sulfamethoxazole daily) combined with caspofungin (50 mg daily). Adverse effects of TMP-SMX included liver dysfunction (n=10), gastrointestinal reaction (n=3), minor myelosuppression (n=10), rash (n=22), and minor renal dysfunction (n=11). Adverse effects of TMP-SMX were more common in NHIV-PJP patients [22 (13.2%) vs. 21 (10.8%), p=0.504], but this difference did not reach statistical significance. Fifteen patients stopped taking TMP-SMX due to drug intolerance. A total of 351 patients received suitable antibiotic treatment based on antimicrobial susceptibility tests of respiratory samples or empiric antibiotic therapy. A total of 275 patients received systemic corticosteroids as adjunctive therapy.
NHIV-PJP caused more severe oxygenation impairment (oxygenation index, 287.57±119.28 vs. 310.78±100.68 mmHg, p=0.046), more transfers to the ICU [93 (55.69%) vs. 53 (27.46%), p<0.001], and more need for extracorporeal membrane oxygenation therapy [12 (7.2%) vs. 2 (1.0%), p = 0.040]. The mortality rate was higher in the NHIV-PJP group than in the HIV-PJP group [49 (29.3%) vs. 35 (18.1%), p=0.012], and this difference reached statistical significance.
Nomogram for mortality prediction
We investigated the association between clinical factors and all-cause mortality by univariate analysis in both groups. Febrile days after admission, PLT≤80(x109/L), HGB≤90 g/L, CD4+ T cells ≤100/µl, PCT, LDH≥500 U/L, ALB, CMV co-infection, EBV co-infection, pneumothorax, sulfa combined with CAS, ICU days, and ECMO were significantly associated with mortality in the NHIV-PJP group (Table 3). We then performed multivariate logistic regression analysis with these associated factors. We identified febrile days after admission, CD4+ cells ≤100/µl, pneumothorax and sulfa combined with CAS as independent risk factors. We found that a combination of these factors most precisely predicted mortality (Table 4). We then created a nomogram for mortality including all of these factors (Fig. 1). The area under the curve (AUC) was 0.865 (95% confidence interval 0.799-0.931, Fig. 2). The nomogram had a bootstrapped concordance index of 0.865 and was well calibrated (Fig. 3). In the same way, we created a nomogram for mortality in the HIV-PJP group (Fig. 4). The area under the curve (AUC) was 0.910 (95% confidence interval 0.850-0.970, Fig. 5). The nomogram had a bootstrapped concordance index of 0.904 and was well calibrated (Fig. 6).