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 were probable PJP without microbiological results. The following 40 patients were excluded: sulfa drug allergy in 26,hospitalized less than 1 week in 34. Finally, 360 cases were eventually included in the study, 167 cases in the NHIV-PJP group and 193 cases in the HIV-PJP group.
Patient Characteristics
We compared demographics, clinical characteristics, and auxiliary examination of both groups (Table 1), and recorded the underlying diseases in NHIV-PJP group (Table 2). HIV-PJP patients were predominantly men (97.4% vs. 61.7%; P < 0.001), less smoking (22.80% vs. 35.3%; P = 0.009) and younger (38.12 ± 10.53 vs. 53.69 ± 16.32 years; P < 0.001) compared to NHIV-PJP patients. There was no difference in blood type between NHIV-PJP and HIV-PJP group except O type. One NHIV-PJP patient was Rh-negative (rhesus factor). Underlying diseases in the NHIV-PJP group, included SOT (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), hematological malignancy (n = 8; non-Hodgkin’s lymphoma 4, myelodysplastic syndrome 1, multiple myeloma 1, Chronic Lymphocytic Leukemia 1 and autologous hematopoietic stem cell transplantation 1), solid tumor (n = 14; lung cancer 6, esophageal 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, the past diseases included cardiovascular disease 10, diabetes mellitus 2, asthma 2, chronic hepatitis B 1 and schizophrenia 1.
Table 1
Demographics characteristics of NHIV-PJP and HIV-PJP patients
Characteristic
|
NHIV-PJP( n = 167)
|
HIV-PJP(n = 193)
|
P-Values
|
Male sex
|
103(61.70)
|
188(97.4)
|
< 0.001
|
Age, y
|
53.69 ± 16.32
|
38.12 ± 10.53
|
< 0.001
|
BMI, kg/m2
|
24.29 ± 3.25
|
20.29 ± 2.86
|
< 0.001
|
Blood type, Rh+
|
|
|
|
A
|
51(30.50)
|
69(35.8)
|
0.295
|
B
|
50(29.9)
|
67(34.7)
|
0.335
|
O
|
50(29.9)
|
36(18.7)
|
0.012
|
AB
|
16(9.6)
|
21(10.9)
|
0.685
|
Smoking history
|
59(35.3)
|
44(22.80)
|
0.009
|
Clinical manifestations
|
|
|
|
Fever
|
150(89.8)
|
166(86.0)
|
0.271
|
Chest pain
|
6(3.6)
|
6(3.1)
|
0.799
|
Fever, cough, dyspnea
|
99(59.3)
|
99(51.3)
|
0.129
|
Febrile days before admission, d
|
7(3–10)
|
10(4–15)
|
0.004
|
Highest temperature, ℃
|
39(38.3–39.5)
|
38.5(37.6–39.0)
|
< 0.001
|
Febrile days after admission, d
|
27(16.2)
|
14(7.3)
|
0.008
|
Loss of weight
|
31(18.6)
|
134(69.4)
|
< 0.001
|
lung rale
|
91(54.5)
|
29(15)
|
< 0.001
|
Laboratory examination
|
|
|
|
WBC count (x109/L)
|
8.43 ± 3.88
|
6.64 ± 3.31
|
< 0.001
|
Lymphocyte count (x109/L)
|
0.81 ± 0.55
|
0.78 ± 0.48
|
0.475
|
Platelet (x109/L)
|
179.31 ± 79.68
|
251.71 ± 89.03
|
< 0.001
|
HGB, g/L
|
112.73 ± 26.22
|
123.34 ± 21.94
|
< 0.001
|
(1,3)-β-D-glucan, pg/mL
|
77.06(10.00-262.70)
|
88(27.5-210.5)
|
0.998
|
CD4 + T cell, cells/ml
|
140.00(69–258)
|
88(27.5-210.5)
|
< 0.001
|
CD8 + T cell, cells/ml
|
132.00(73–270)
|
397.00(241–622)
|
< 0.001
|
CD4/CD8
|
1.10(0.59–1.98)
|
0.05(0.02–0.10)
|
< 0.001
|
PCT, ng/ml
|
0.24(0.06–1.52)
|
0.09(0.05–0.25)
|
< 0.001
|
CRP, mg/dl
|
7.66(2.64–13.7)
|
39.2(15-78.2)
|
< 0.001
|
LDH, u/L
|
435(323–599)
|
402(289–489)
|
0.002
|
ALB, g/L
|
28.9(24.2–33.1)
|
32.2(28.25–35.40)
|
< 0.001
|
OI
|
287.57 ± 119.28
|
310.78 ± 100.68
|
0.046
|
EBV co-infection
|
97(58.1)
|
4(2.1)
|
< 0.001
|
CMV co-infection
|
112(67.1)
|
129(66.8)
|
0.964
|
Chest imaging
|
|
|
|
GGO
|
100(59.9)
|
170(88.1)
|
< 0.001
|
Interstitial infiltrates
|
63(37.7)
|
12(6.2)
|
< 0.001
|
Cyst
|
2(1.2)
|
1 (0.5)
|
0.599
|
Nodules
|
2(1.2)
|
10(5.2)
|
0.041
|
Pneumothorax
|
17(10.2)
|
9(4.7)
|
0.044
|
Treatment and result
|
|
|
|
TMP-SMZ within 24h
|
92(55.1)
|
171(88.6)
|
< 0.001
|
Sulfa combine CAS
|
102(61.1)
|
23(11.9)
|
< 0.001
|
TMP-SMZ adverse events
|
22(13.2)
|
21(10.9)
|
0.504
|
ICU, d
|
6(0–16)
|
0(0-3.5)
|
< 0.001
|
HFNC
|
7(4.2)
|
4(2.1)
|
0.244
|
NIMV
|
39(23.4)
|
2(1)
|
< 0.001
|
IMV
|
47(28.1)
|
49(25.4)
|
0.556
|
ECMO
|
12(7.2)
|
2(1)
|
0.003
|
Mortality rate
|
49(29.3)
|
35(18.1)
|
0.012
|
Data are presented as mean ± standard deviation, medians (interquartile ranges) or No. (%). BMI body mass index, Rh Rhesus, WBC white blood cells, HGB hemoglobin, PCT procalcitonin, CRP C-reactive protein, LDH lactate dehydrogenase, ALB albumin, OI oxygenation index, EBV Epstein-Barr virus, CMV cytomegalovirus, CAS caspofungine, GGO ground-glass opacity, TMP-SMZ trimethoprim-sulfamethoxazole, ICU intensive care unit, HFNC high-flow nasal cannula, NIMV non-invasive mechanical ventilation, IMV invasive mechanical ventilation, ECMO extracorporeal membrane oxygenation
Table 2
Underlying diseases at diagnosis of NHIV-PJP
Underlying disease
|
Number of patients
|
Hematological malignancy
|
8
|
(4.79)
|
Solid tumors
|
14
|
(8.38)
|
SOT
|
49
|
(29.34)
|
Cornea
|
1
|
|
Renal
|
43
|
|
Liver
|
5
|
|
Connective tissue diseases
|
46
|
(27.55)
|
ILD
|
32
|
(19.16)
|
Nephrotic syndrome
|
14
|
(8.38)
|
Others
|
4
|
(2.40)
|
Treatment before PJP
|
|
|
CS + IS
|
115
|
(68.90)
|
CS
|
147
|
(88.00)
|
Data are presented as No. (%). SOT solid organ transplantation, ILD interstitial lung disease, CS corticosteroid, IS immunosuppressor |
Both NHIV-PJP and HIV-PJP patients had symptoms of the commonest fever (89.8% vs. 86.0%, P = 0.27), the rarer chest pain (3.60% vs. 3.10%, P = 0.79), the triad of symptoms: fever, cough, dyspnea (59.3% vs. 51.3%, P = 0.12). These manifestations were no differences between two groups. However, obviously shorter duration of fever before admission [7(3–10) vs. 10(4–15) days, P = 0.004], higher temperature [39(38.3–39.5) vs. 38.5(37.6–39.0)℃,P < 0.001], much more patients had lung rale (54.5% vs. 15.0%, P < 0.001), and fewer patients loss of weight (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. Glucocorticoid alone was 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 PJP diagnosis was 186 days (range: 99–372 days). Laboratory data including blood routine, β-D-Glucan, CD4 + T cells, CD8 + T cells, CD4/CD8 ratio, procalcitonin (PCT), C-reactive protein (CRP), lactic dehydrogenase, albumin (ALB) and oxygenation index were available from all 360 patients. The value of platelet (PLT), hemoglobin (HGB), CD8 + cell counts, CRP, ALB and oxygenation index were much lower in the NHIV-PJP group than in the HIV-PJP group, the difference was statistically significant. Oppositely these variants of CD4 + T cells, 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 ≤ 100cells/ul, pneumothorax, and sulfa combine caspofungine (CAS) 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 ≤ 90g/L, ALB, CMV co-infection, pneumothorax and sulfa combine CAS.
Co-infections 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. Positive serum assay for CMV was identified in 241 patients in both NHIV-PJP and HIV-PJP groups [112(67.1%) vs.129(66.5%)], EBV in 101 patients [97(58.1%) vs. 4(2.1%)], respectively. 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 pneumonia [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%)], atypical pathogens [n = 4; 2(2.1%) vs. 2(1.0%)], and H1N1 virus [n = 3; 2(1.2%) vs.1(0.5%)], respectively. Co-infections in blood: Cytomegalovirus virusemia [n = 6, 0 (0.0%) vs. 6 (3.1%)], Gram-positive cocci septicemia [n = 14, 9 (5.4%) vs. 5 (2.6%)], Gram-negative bacilli septicemia [n = 9, 7 (4.2%) vs. 2 (1.0%)].
Treatment and outcome
354 patients received TMP-SMX (720 mg of trimethoprim, 3600 mg of sulfamethoxazole daily), 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 = 0.50], but this difference did not reach statistical significance. 15 patients stopped taking TMP-SMX due to drug intolerance. 351 patients received suitable antibiotic treatment according to antimicrobial susceptibility tests of respiratory samples or empiric antibiotic therapy. 275 patients received systemic corticosteroids as adjunctive therapy.
NHIV-PJP caused more severe oxygenation impairment (oxygenation index, 287.57 ± 119.28vs. 310.78 ± 100.68mmHg, p = 0.046), and transfer to the ICU [93 (55.69%) vs. 53(27.46%), p < 0.001], even extracorporeal membrane oxygenation therapy [12 (7.2%) vs. 2 (1.0%), p = 0.04].