Patient characteristics
227 COVID-19 adult inpatients were tested for influenza serology admitted to Wuhan Tongji Hospital from the 10th of February 10 to 20th of March, 2020. 27 patients were excluded (25 were transferred from other hospitals with missing clinical data, two were admitted with critical type and died on admission day). A total of 200 adult inpatients diagnosed with severe COVID-19 were included in this study (Fig. 1). The median age was 63 years old (IQR, 52.0–72.0), 48.5% were male, 13.5% progressed to critical illness, 76.5% had clinical improvement, and 10.5% died during hospitalization (Tables 1 and 2). The most common symptoms were cough (78.5%), fever (76.5%), fatigue (48.5%), sputum (44.0%), and dyspnea (42.5%); ground glass opacity was the most common chest CT feature (67.5%) (Table 1).
Table 1
Demographic, clinical, laboratory, and radiographic findings of severe COVID-19 in-patients with and without influenza A virus recent infection.
Characteristics | All patients (n = 200) | Influenza A Recent infection (n = 103) | Influenza A Non- infection (n = 97) | p value |
Age, median (IQR), yr | 63.0 (52.0–72.0) | 62.0 (52.0–69.0) | 63.0 (52.0-74.5) | 0.106 |
Male, n (%) | 97 (48.5) | 36 (35.0) | 61 (62.9) | < 0.001 |
Current smokers, n (%) | 7 (3.5) | 2 (1.9) | 5 (5.2) | 0.268 c |
Pre-existing condition, n (%) | | | | |
Hypertension | 71 (35.5) | 39 (37.9) | 32 (33.0) | 0.472 |
Cardiovascular disease a | 22 (11.0) | 7 (6.8) | 15 (15.5) | 0.050 |
Cerebrovascular disease b | 10 (5.0) | 4 (3.9) | 6 (6.2) | 0.673 d |
COPD | 10 (5.0) | 5 (4.9) | 5 (5.2) | 1.000 d |
Diabetes | 32 (16.0) | 20 (19.4) | 12 (12.4) | 0.174 |
Symptoms, n (%) | | | | |
Fever | 153 (76.5) | 73 (70.9) | 80 (82.5) | 0.053 |
Cough | 157 (78.5) | 80 (77.7) | 77 (79.4) | 0.768 |
Sputum | 88 (44.0) | 46 (44.7) | 42 (43.3) | 0.846 |
Dyspnea | 85 (42.5) | 43 (41.7) | 42 (43.3) | 0.824 |
Palpitation | 32 (16.0) | 17 (16.5) | 15 (15.5) | 0.841 |
Fatigue | 97 (48.5) | 47 (45.6) | 50 (51.5) | 0.403 |
Diarrhea | 44 (22.0) | 21 (20.4) | 23 (23.7) | 0.571 |
Nausea and vomiting | 32 (16.0) | 17 (16.5) | 15 (15.5) | 0.841 |
Laboratory findings on admission, median (IQR) | | | | |
WBC count, × 109/L | 6.4 (5.2-8.0) | 6.4 (5.0-7.9) | 6.6 (5.3–8.1) | 0.356 |
Neutrophil count, × 109/L | 4.1 (3.2–5.7) | 3.9 (2.9–5.5) | 4.2 (3.2–6.1) | 0.251 |
Lymphocyte count, × 109/L | 1.3 (0.9–1.8) | 1.3 (0.9–1.9) | 1.1 (0.8–1.7) | 0.110 |
Platelet count, × 109/L | 235.0 (186.5–298.0) | 234.0 (187.3–292.0) | 236.5 (181.8-301.5) | 0.733 |
hsCRP, mg/L | 8.1 (1.4–44.3) | 5.3 (1.1–32.3) | 13.1 (2.2–56.3) | 0.045 |
PCT, ng/ml | 0.07 (0.05–0.12) | 0.06 (0.05–0.08) | 0.08 (0.06–0.15) | 0.018 |
AST, U/L | 23.0 (17.0-35.8) | 22.0 (16.0-36.5) | 24.0 (18.0–34.0) | 0.743 |
ALT, U/L | 22.0 (13.0-39.8) | 20.0 (12.8–34.8) | 25.0 (15.8–41.0) | 0.120 |
LDH, U/L | 222.5 (176.3–302.0) | 221.5 (180.0-303.5) | 232.5 (173.0-302.5) | 0.635 |
BUN, mmol/L | 4.5 (3.8–5.9) | 4.5 (3.7–5.8) | 4.7 (3.9-6.0) | 0.670 |
Creatinine, µmol/L | 74.7 (59.0-93.6) | 74.0 (60.0-90.5) | 77.0 (59.0–99.0) | 0.741 |
PaO2/FiO2, mmHg | 227.3 (158.5-305.9) | 213.8 (158.5-298.9) | 234.0 (160.6-326.5) | 0.549 |
IL-6, pg/ml | 5.4 (2.4–23.9) | 3.5 (1.9–10.3) | 10.0 (3.6–36.7) | 0.001 |
TNF-α, pg/ml | 8.7 (6.6–11.2) | 7.6 (6.2–10.4) | 9.7 (7.7–12.1) | 0.002 |
D-dimer, µg/ml | 0.7 (0.3–1.8) | 0.6 (0.3–1.6) | 0.8 (0.3–2.1) | 0.315 |
Radiographic findings on admission, n (%) | | | | |
Ground glass opacity | 135 (67.5) | 66 (64.1) | 69 (71.1) | 0.287 |
Diffuse bilateral pulmonary infiltration | 72 (36.0) | 37 (35.9) | 35 (36.1) | 0.981 |
Consolidation | 20 (10.0) | 11 (10.7) | 9 (9.3) | 0.741 |
a Cardiovascular disease were defined as congestive heart failure, known conduction system abnormality or ischemic heart disease. |
b Cerebrovascular disease were defined as intracerebral hemorrhage and ischemic strokes. |
c Fisher’s exact test was used. |
d Yates’s correction was used. |
Abbreviations: IQR = interquartile range. COPD = chronic obstructive pulmonary disease. WBC = white blood cell. hs-CRP = high-sensitivity C-reactive protein. PCT = procalcitonin. AST = aspartate aminotransferase. ALT = alanine aminotransferase. LDH = lactate dehydrogenase. BUN = blood urea nitrogen. eGFR = estimated glomerular filtration rate. IL-6 = interleukin-6. TNF-α = tumor necrosis factor-α. |
Table 2
Disease severity, complications, treatments and outcomes of severe COVID-19 in-patients with and without influenza A virus recent infection.
Characteristics | All patients (n = 200) | Influenza A Recent infection (n = 103) | Influenza A Non-infection (n = 97) | p value |
CURB-65 score ≥ 3 on admission, n (%) | 11 (5.5) | 7 (6.8) | 4 (4.1) | 0.407 |
Seven-category scale on admission, n (%) | | | | 0.925 |
4: Hospitalization, requiring supplemental oxygen | 188 (94.0) | 97 (94.2) | 91 (93.8) | |
5: Hospitalization, requiring HFNC or NIMV a | 12 (6.0) | 6 (5.8) | 6 (6.2) | |
Treatments, n (%) | | | | |
Admission to an ICU | 18 (9.0) | 8 (7.8) | 10 (10.3) | 0.530 |
Use of IMV | 15 (7.5) | 5 (4.9) | 10 (10.3) | 0.143 |
Use of CRRT | 6 (3.0) | 2 (1.9) | 4 (4.1) | 0.434 d |
Use of oseltamivir | 70 (35.0) | 52 (50.5) | 18 (18.6) | < 0.001 |
Use of arbidol | 170 (85.0) | 90 (87.4) | 80 (82.5) | 0.332 |
Use of lopinavir/ritonavir | 22 (11.0) | 10 (9.7) | 12 (12.4) | 0.548 |
Use of Lianhuaqingwen | 157 (78.5) | 84 (81.6) | 73 (75.3) | 0.279 |
Received antibiotic treatment | 136 (68.0) | 65 (63.1) | 71 (73.2) | 0.126 |
Use of corticosteroid b | 49 (24.5) | 22 (21.4) | 27 (27.8) | 0.287 |
Complications during hospitalization, n (%) | | | | |
ARDS c | 25 (12.5) | 11 (10.7) | 14 (14.4) | 0.422 |
Myocardial injury | 29 (14.5) | 9 (8.7) | 20 (20.6) | 0.017 |
AKI | 14 (7.0) | 8 (7.8) | 6 (6.2) | 0.661 |
Liver injury | 26 (13.0) | 16 (15.5) | 10 (10.3) | 0.272 |
Septic shock | 12 (6.0) | 6 (5.8) | 6 (6.2) | 0.915 |
Outcomes, n (%) | | | | |
Virus clearance | 173 (86.5) | 91 (88.3) | 82 (84.5) | 0.430 |
Progression to critical illness | 27 (13.5) | 10 (9.7) | 17 (17.5) | 0.106 |
Clinical improvement | 153 (76.5) | 81 (78.6) | 72 (74.2) | 0.462 |
In-hospital mortality | 21 (10.5) | 8 (7.8) | 13 (13.4) | 0.194 |
a HFNC was used in these 12 patients. |
b Corticosteroid treatment was defined as administration of at least a dose equivalent to ≥ 0.5 mgžkg− 1 of methylprednisolone during hospitalization. |
c Moderate-to-severe ARDS, was diagnosed according to the Berlin definition: PaO2/FiO2 ratio of less than or equal to 200 mmHg and a positive end-expiratory pressure of greater than or equal to 5 cmH2O. |
d Fisher’s exact test was used. |
Abbreviations: HFNC = high-flow nasal cannula for oxygen therapy. NIMV = noninvasive mechanical ventilation. ICU = intensive care unit. IMV = invasive mechanical ventilation. CRRT = continuous renal replacement therapy. ARDS = acute respiratory distress syndrome. AKI = acute kidney injury. IQR = interquartile range. |
51.5% (103/200) of the patients with recent influenza A virus infection. Recent infection group had a lower proportion of male sex than non-infection group (35.0% vs. 62.9%, P < 0.001). Compared with non-infection group, patients with influenza A virus recent infection presented with a prolonged duration of cough and sputum from illness onset (35.0 vs. 27.0 days, P = 0.018) and (33.0 vs. 26.0 days, P = 0.015), respectively (Fig. 2A). Recent infection group showed lower median high-sensitive C-reactive protein (hsCRP) (5.3 vs. 13.1 mg/L, P = 0.045), procalcitonin (PCT) (0.06 vs. 0.08 ng/ml, P = 0.018), interleukin-6 (IL-6) (3.5 vs. 10.0 pg/ml, P = 0.001) and tumor necrosis factor-α (TNF-α) (7.6 vs. 9.7 pg/ml, P = 0.002) at the time of admission (Table 1). No significant difference was found between these two cohorts in age, pre-existing conditions, symptoms, other laboratory findings, radiographic findings, and length of fever and dyspnea.
Disease severity, complications, treatments and outcomes of severe COVID-19 in-patients with and without recent influenza A virus infection
Proportions of patients with CURB-65 score equal and more than 3 was higher in recent infection group than that in non-infection group, while there was no significant difference (6.8% vs. 4.1%, P = 0.407). All the patients in our study tolerated antiviral therapy well after illness onset. A significant higher proportion of oseltamivir therapy was shown in recent infection group (50.5% vs. 18.6%, P < 0.001). Among 200 patients, incidence of myocardial injury was lower in recent infection group (8.7% vs. 20.6%, P = 0.017). In recent infection group, proportions of moderate-to-severe ARDS (10.7% vs. 14.4%, P = 0.422), AKI (7.8% vs. 6.2%, P = 0.422), liver injury (15.5% vs. 10.3%, P = 0.272), and septic shock (5.8% vs. 6.2%, P = 0.915) during hospitalization did not significantly differ from that in non-infection group (Table 2). Between the recent infection and non-infection cohorts, the occurrence of moderate-to-severe ARDS, myocardial injury, AKI and liver injury at a median of day (10.0 vs. 18.5, P = 0.380), (12.0 vs. 14.0, P = 0.555), (12.5 vs. 23.5, P = 0.330), and (19.0 vs. 19.5, P = 0.731) from illness onset, respectively (Fig. 2B).
Progression to critical illness from illness onset in recent infection patients at a median of day 11.5, was earlier than non-infection group (11.5 vs. 16.0, P = 0.034). Compared with the non-infection group, duration of viral shedding was longer in recent infection group without significant statistical difference (26.0 vs. 23.5 days, P = 0.051) (Fig. 3A). TTCI and length of hospital stay were longer in recent infection group (23.0 vs. 19.0 days, P = 0.044) and (22.0 vs. 18.0 days, P = 0.030), respectively (Fig. 3B). No difference was found in virus clearance rate, progression to critical illness rate, clinical improvement rate and mortality during hospitalization (Table 2). The two groups showed no significant difference neither in day-28 clinical improvement rate nor in day-28 mortality (Fig. 3C and D).