Viral pneumonia has recently been defined as a risk factor for invasive pulmonary aspergillosis (IPA). Wauters et al[1] reported that 23% of critically ill patients who were admitted to the intensive care unit (ICU) with swine-origin influenza A (H1N1) viral infection had developed invasive aspergillosis. IPA was diagnosed in 83 of 432 (19%) patients who were admitted with influenza; for patients with influenza who were immunocompromised, the incidence of IPA reached up to 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, the incidence was 14% (45 of 315 patients).[2] The 90-day mortality was 51% in patients in the influenza cohort with IPA and 28% in the influenza cohort without IPA.[2] The prevalence of IPA is reported between 4% and 9% in critically ill patients of coronavirus disease.[3] Magira et al[4] found that respiratory viral infections caused by both parainfluenza virus and respiratory syncytial virus frequently preceded IPA in patients with leukemia and those who underwent hematopoietic stem cell transplantation. Considering the high incidence and mortality of viral pneumonia complicated with IPA, and the risk factors for it should be identified. Hence, we performed a study to explore the risk factors for viral pneumonia complicated with IPA.
We retrospectively screened data of hospitalized patients with viral pneumonia from the microbiology laboratories of six hospitals in China between August 2016 and December 2019. The inclusion criteria were as follows: (1) All patients were defined as the presence of a new or progressive infiltrate using chest radiography complicated with two or more of the following symptoms: fever, cough, expectoration, rhinorrhoea, sore throat, or dyspnea, or a diagnosis of pneumonia by the attending physician. (2) Patients who had a positive result of reverse transcription polymerase chain reaction (PCR) for respiratory virus nucleic acids in nasopharyngeal swab, sputum, or bronchoalveolar lavage (BAL) fluid. (3) Patients who received galactomannan (GM) test or sputum fungal culture. The following patients were excluded from this study: (1) aged <18 years; (2) patients who had no symptoms of infection; (3) non-pneumonic patient (such as upper respiratory tract infections); and (4) the GM or sputum fungal culture result was not available. The Ethics Committee of China-Japan Friendship Hospital (No. 2015-86) approved this retrospective study and orchestrated centralized collaboration and approval of all participating institutions. The written informed consent was waived.
Diagnostic criteria were set according to the revised definitions of invasive fungal diseases by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.[5] IPA diagnosis was defined as having clinical features and microbiological evidence of IPA. Clinical features included any of the following computed tomography (CT) or chest X-ray manifestations: (1) consolidation with or without a halo sign; (2) air crescent sign; (3) cavity; and (4) wedge-shaped, segmental, peribronchial, or lobar consolidation. Microbiological evidence included either (1) positive result from Aspergillus culture or microscopic examination with lower respiratory tract specimens, or (2) positive result from GM test of serum or BAL specimens. All patients with IPA were given antifungal treatment, such as voriconazole, caspofungin, or amphotericin B.
Respiratory viruses such as respiratory syncytial virus, influenza virus type A, influenza virus type B, parainfluenza virus, human rhinovirus, human metapneumovirus, and adenovirus were tested using nasopharyngeal swabs, sputum, endotracheal aspirate (ETA), or BAL fluid by reverse-transcription real-time PCR (Shanghai Zhijiang Biological Technology, Shanghai, China). Besides, the bacterial and fungal pathogens in sputum, ETA, and BAL fluid were also tested. The Aspergillus GM antigen in the samples was detected by the platelia Aspergillus test (Bio-Rad Laboratories, Marnes-la-Coquette, France).
Data were analyzed using SPSS (SPSS Inc., Version 23.0, Chicago, IL, USA). In univariable analysis, we compared categorical variables by Fisher's exact test or chi-square test; continuous variables were compared by the Student's t-test or Mann-Whitney U-test, as appropriate. Binary analysis was performed using backward and forward stepwise logistic regression, with explanatory variables including known risk factors for IPA, and baseline factor significantly different between the IPA and non-IPA groups. Two-tailed P value less than 0.05 was considered of statistical significance.
Among the six hospitals, 2500 inpatients were positive for viral nucleic acid, of which 1883 patients were excluded for not having pneumonia or unavailable results of GM test or sputum fungal culture. A total of 617 adult patients with viral pneumonia were included in the final analysis, and the IPA and non-IPA groups had 91 and 526 cases, respectively.
Compared with non-IPA group, IPA group had higher incidence of dyspnea (79.1% [72/91] vs. 65.8% [346/526]; χ2 = 6.320; P = 0.012), white blood count (10.7 [6.9, 13.8] × 109/L vs. 7.5 [5.4, 10.8] × 109/L; U = 4.811; P < 0.001), neutrophil count (8.0 [5.4, 12.3] × 109/L vs. 5.5 [3.5, 8.9] × 109/L; U = 5.106; P < 0.001), percentage of patients with diabetes mellitus (35.1% [32/91] vs. 21.9% [115/526]; χ2 = 7.563; P = 0.006); proportion of solid organ transplant recipients (18.7% [17/91] vs. 6.3% [33/526]; χ2 = 16.037; P < 0.001), pneumonia severity index score (86.0 [64.0, 107.0] vs. 74.0 [56.8, 99.0]; U = 2.843; P = 0.004). And compared with non-IPA group, the CT result of IPA group showed higher manifestation of halo sign (4.4% [4/91] vs. 0% [0/526]; χ2 = 23.041; P < 0.001), air crescent sign (4.4% [4/91] vs. 0.4% [2/526]; χ2 = 12.836; P < 0.001), cavity (15.4% [14/91] vs. 4.4% [23/526]; χ2 = 16.409; P < 0.001), peribronchial consolidation or nodular opacities (19.8% [18/91] vs. 1.9% [10/526]; χ2 = 56.601; P < 0.001), and tree-in-bud (13.2% [12/91] vs. 3.8% [20/526]; χ2 = 13.657; P < 0.001). Besides, the rates of glucocorticoid use before admission (49.5% [45/91] vs. 30.0% [158/526]; χ2 = 13.150; P < 0.001), glucocorticoid use after admission (49.5% [45/91] vs. 28.5% [150/526]; χ2 = 15.727; P < 0.001), non-invasive ventilation (24.2% [22/91] vs. 13.3% [70/526]; χ2 = 7.222; P = 0.007), invasive ventilation (51.6% [47/91] vs. 26.6% [140/526]; χ2 = 23.015; P < 0.001), respiratory failure (69.2% [63/91] vs. 44.5% [234/526]; χ2 = 19.026; P < 0.001), and in-hospital mortality (34.1% [31/91] vs. 18.4% [97/526]; χ2 = 11.519; P = 0.001) were significantly higher in IPA group compared with non-IPA group [Table 1].
Table 1 -
Clinical characteristics of viral pneumonia with invasive pulmonary aspergillosis or without invasive pulmonary aspergillosis.
| Variables |
IPA group (n = 91) |
Non-IPA group (n = 526) |
χ
2/U
∗
|
P values |
| Sex (female) |
24 (26.4) |
201 (38.2) |
4.693 |
0.030 |
| Age (years) |
62.0 (54.0, 68.0) |
62.0 (49.0, 72.0) |
−0.186∗
|
0.852 |
| Current smoker or ex-smoker |
49 (53.8) |
195 (37.1) |
9.696 |
0.002 |
| Symptoms and signs |
|
|
|
|
|  Fever |
67 (73.6) |
385 (73.2) |
0.007 |
0.931 |
|  Expectoration |
91 (100.0) |
494 (93.9) |
5.839 |
0.016 |
|  Dyspnea |
72 (79.1) |
346 (65.8) |
6.320 |
0.012 |
| Laboratory examinations |
|
|
|
|
|  White blood cell (×109/L) |
10.7 (6.9, 13.8) |
7.5 (5.4, 10.8) |
4.811∗
|
<0.001 |
|  Neutrophils (×109/L) |
8.0 (5.4, 12.3) |
5.5 (3.5, 8.9) |
5.106∗
|
<0.001 |
|  Lymphocyte (×109/L) |
0.9 (0.5, 1.5) |
1.0 (0.6, 1.6) |
−0.851∗
|
0.395 |
| Procalcitonin (ng/mL) |
0.4 (0.2, 1.2) |
0.3 (0.2, 0.7) |
1.572∗
|
0.116 |
| Severe pneumonia index score |
86.0 (64.0, 107.0) |
74.0 (56.8, 99.0) |
2.843∗
|
0.004 |
| CURB65 score>1 |
35 (38.5) |
161 (30.6) |
2.207 |
0.137 |
| Comorbidities |
|
|
|
|
|  Interstitial lung disease |
32 (35.2) |
116 (22.1) |
7.315 |
0.007 |
|  Chronic obstructive pulmonary disease |
15 (16.5) |
45 (8.6) |
5.555 |
0.018 |
|  Diabetes mellitus |
32 (35.1) |
115 (21.9) |
7.563 |
0.006 |
|  Kidney disease |
1 (1.1) |
12 (2.3) |
|
0.833â€
|
|  Connective tissue disease |
11 (12.1) |
59 (11.2) |
0.059 |
0.809 |
|  Tumor |
4 (4.4) |
37 (7.0) |
0.871 |
0.351 |
|  Solid organ transplantation |
17 (18.7) |
33 (6.3) |
16.037 |
<0.001 |
|  Immune deficiency |
41 (45.1) |
161 (30.6) |
7.353 |
0.007 |
| Imaging features |
|
|
|
|
|  Multi-lobe or segment infiltrates |
89 (97.8) |
492 (93.5) |
2.263 |
0.132 |
|  Pleural effusion |
17 (18.7) |
74 (14.1) |
1.225 |
0.268 |
|  Ground-glass opacity |
46 (50.5) |
216 (41.1) |
2.624 |
0.105 |
|  Consolidation |
54 (59.3) |
298 (56.7) |
0.144 |
0.705 |
|  Reticular pattern |
25 (27.5) |
108 (20.5) |
2.070 |
0.150 |
|  Halo sign |
4 (4.4) |
0 (0) |
|
<0.001â€
|
|  Cavity |
14 (15.4) |
23 (4.4) |
16.409 |
<0.001 |
|  Air crescent sign |
4 (4.4) |
2 (0.4) |
|
<0.001â€
|
|  Peribronchial consolidation or nodular opacities |
18 (19.8) |
10 (1.9) |
56.601 |
<0.001 |
|  Tree-in-bud |
12 (13.2) |
20 (3.8) |
13.657 |
<0.001 |
| Treatment measures |
|
|
|
|
|  Bronchoalveolar lavage |
82 (90.1) |
391 (74.3) |
10.790 |
0.001 |
|  Glucocorticoids use before admission |
45 (49.5) |
158 (30.0) |
13.150 |
<0.001 |
|  Immunosuppressants before admission |
18 (19.8) |
87 (16.5) |
0.577 |
0.448 |
|  Glucocorticoids use after admission |
45 (49.5) |
150 (28.5) |
15.727 |
<0.001 |
|  Noninvasive ventilation |
22 (24.2) |
70 (13.3) |
7.222 |
0.007 |
|  Invasive ventilation |
47 (51.6) |
140 (26.6) |
23.015 |
<0.001 |
| Complications |
|
|
|
|
|  Respiratory failure |
63 (69.2) |
234 (44.5) |
19.026 |
<0.001 |
|  Septic shock |
37 (40.7) |
91 (17.3) |
25.745 |
<0.001 |
|  ICU admission |
54 (59.3) |
213 (40.5) |
11.027 |
0.001 |
|  In-hospital mortality |
31 (34.1) |
97 (18.4) |
11.519 |
0.001 |
Data are presented as n (%) or median (Q1, Q3). ∗U values; †Fisher's exact test. CURB-65: Confusion, Urea, Respiratory Rate, blood pressure, Age≥65 years; ICU: Intensive care unit; IPA: Invasive pulmonary aspergillosis.
The risk for viral pneumonia complicated with IPA include glucocorticoid use after admission (odd ratio [OR], 1.981; 95% confidence interval [CI]: 1.194–3.286; P = 0.008), invasive ventilation (OR, 3.115; 95% CI: 1.905–5.094; P < 0.001), solid organ transplantation (OR, 3.142; 95% CI: 1.506–6.554; P = 0.002), diabetes (OR, 1.755; 95% CI: 1.048–2.938; P = 0.032), chronic obstructive pulmonary disease (COPD) (OR, 2.084; 95% CI: 1.055–4.117; P = 0.034), and influenza virus (IFV) infection (OR, 1.981; 95% CI: 1.194–3.286; P = 0.008).
In general, glucocorticoid use, invasive mechanical ventilation, COPD, solid organ transplantation, and diabetes mellitus are classic risk factors for IPA. Corticosteroid use prior to influenza infection has been evidenced to be associated with IPA.[2] The use of corticosteroids before admitting to ICU was considered as an independent risk factor for viral pneumonia complicated with IPA.[3] Apostolopoulou et al[5] evidenced that cumulative prednisone doses >140 mg within 7 days and pneumonia were independent risk factors for IPA with non-influenza respiratory viral infections. Respiratory viruses can damage the epithelial layer, leading to denudation, basement membrane exposure, and subsequent pathogen adherence and invasion. Steroids, particularly at higher doses, can compromise alveolar macrophage phagocytosis, predisposing patients to Aspergillus invasion.[5] Our study showed the incidence of IPA in adult patients with IFV pneumonia was higher than that in non-IFV patients, it is unclear why influenza patients have higher risk for IPA than patients with other virus infection; respiratory epithelium damage and mucociliary clearance dysfunction might facilitate the invasion of Aspergillus. Moreover, influenza-induced acute respiratory distress syndrome and hypoxia might cause immune paralysis.[2]
In conclusion, the incidence of IPA in IFV pneumonia patients was higher than non-IFV pneumonia patients. The risk factors for IPA in adult patients with viral pneumonia are glucocorticoid use after admission, invasive ventilation, solid organ transplantation, diabetes, COPD, and IFV infection.
Funding
This work was supported by a grant from the China National Key Research and Development Program (No. 2018YFE0102100).
Conflicts of interest
None.
References
1. Wauters J, Baar I, Meersseman P, Meersseman W, Dams K, De Paep R, et al. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med 2012;38:1761–1768. doi: 10.1007/s00134-012-2673-2.
2. Schauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med 2018;6:782–792. doi: 10.1016/S2213-2600(18)30274-1.
3. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-associated pulmonary aspergillosis. Am J Respir Crit Care Med 2020;202:132–135. doi: 10.1164/rccm.202004-1038LE.
4. Magira EE, Chemaly RF, Jiang Y, Tarrand J, Kontoyiannis DP. Outcomes in invasive pulmonary aspergillosis infections complicated by respiratory viral infections in patients with hematologic malignancies: A case-control study. Open Forum Infect Dis 2019;6:ofz247. doi: 10.1093/ofid/ofz247.
5. Apostolopoulou A, Clancy CJ, Skeel A, Nguyen MH. Invasive pulmonary aspergillosis complicating noninfluenza respiratory viral infections in solid organ transplant recipients. Open Forum Infect Dis 2021;2 8:ofab478. doi: 10.1093/ofid/ofab478.
