Abstract
Background
The high case fatality rate of influenza A(H7N9)-infected patients has been a major clinical concern.
Methods
To identify the common causes of death due to H7N9 as well as identify risk factors associated with the high inpatient mortality, we retrospectively collected clinical treatment information from 350 hospitalized human cases of H7N9 virus in mainland China during 2013–2017, of which 109 (31.1%) had died, and systematically analyzed the patients’ clinical characteristics and risk factors for death.
Results
The median age at time of infection was 57 years, whereas the median age at time of death was 61 years, significantly older than those who survived. In contrast to previous studies, we found nosocomial infections comprising Acinetobacter baumannii and Klebsiella most commonly associated with secondary bacterial infections, which was likely due to the high utilization of supportive therapies, including mechanical ventilation (52.6%), extracorporeal membrane oxygenation (14%), continuous renal replacement therapy (19.1%), and artificial liver therapy (9.7%). Age, time from illness onset to antiviral therapy initiation, and secondary bacterial infection were independent risk factors for death. Age >65 years, secondary bacterial infections, and initiation of neuraminidase-inhibitor therapy after 5 days from symptom onset were associated with increased risk of death.
Conclusions
Death among H7N9 virus–infected patients occurred rapidly after hospital admission, especially among older patients, followed by severe hypoxemia and multisystem organ failure. Our results show that early neuraminidase-inhibitor therapy and reduction of secondary bacterial infections can help reduce mortality.
Characterization of 350 hospitalized avian influenza A(H7N9)-infected patients in China shows that age >65 years, secondary bacterial infections, and initiation of neuraminidase-inhibitor therapy after 5 days from symptom onset were associated with increased risk of death.
Keywords: influenza, H7N9, zoonotic infection, risk factors
In the spring of 2013, a novel avian influenza A(H7N9) virus was discovered in the Yangtze River Delta region of China [1], with patients presenting with rapid progression to acute respiratory distress syndrome (ARDS), septic shock, and even multiple organ failure, with high mortality [2–4]. To date, 6 annual waves of an H7N9 virus epidemic have occurred in China, with 1568 laboratory-confirmed cases and a fatality rate of about 40% [5]. Global health and safety continue to be threatened by the H7N9 virus, with the most recent case reported on 31 March 2019 from Gansu, China [5].
The mortality rates due to H7N9 among the first 5 waves were 34%, 43%, 47%, 41%, and 38%, respectively [6, 7], showing that the mortality rate remained at a high level and indicating that an effective treatment for H7N9 infection was needed urgently. Thus, there is a great necessity to identify strategies for effective clinical treatment. Here, we systematically analyzed the clinical features, treatment, and prognosis of 350 confirmed cases of H7N9 virus infection during 2013–2017, evaluated the risk factors that affect the mortality rate, and report the high-risk factors directly related to mortality.
METHODS
Study Design
In this study, we retrospectively collected information about 350 patients who were clinically confirmed with H7N9 virus infection and hospitalized from different areas of China, including Zhejiang (186), Guangdong (61), Shanghai (30), Jiangsu (26), Hunan (22), Fujian (11), Anhui (3), Shandong (3), Henan (3), Guizhou (2), Beijing (2), and Hebei (1). The patients’ medical records were sent to our data collection center in Hangzhou, Zhejiang, where a team of physicians who had been caring for patients with H7N9 virus infection reviewed the data. This study conformed to the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the institutional review board of the First Affiliated Hospital of Zhejiang University, Hangzhou.
Data Collection
The clinical data included demography, medical comorbidities, date of symptom onset, symptoms and signs, timing of antiviral therapy, progression, and resolution of clinical illness. Documented medical comorbidities included diabetes mellitus, heart disease, chronic lung disease, renal failure, liver disease, human immunodeficiency virus infection, cancer, and receipt of immunosuppressive therapy, including corticosteroids. We considered that the symptoms started when any of fever, cough, chills, dizziness, headache, and fatigue appeared. Moderate to severe ARDS was diagnosed by definition of ARDS Berlin [8], severe hypoxemia (PaO2/FiO2 ≤200 mm Hg with positive end-expiratory pressure ≥5 cm H2O), in addition to bilateral opacities on chest X ray that could not be fully explained by cardiac failure or fluid overload.
Laboratory Confirmation
After admission, respiratory specimens (nasopharyngeal swabs, sputum, or endotracheal aspirates) were collected daily to determine the amount of H7N9 viral RNA by polymerase chain reaction analysis, as previously described [4]. Secondary infection was defined as recurrence of symptoms and signs of infection along with positive bacterial/fungal cultures from lower respiratory tract specimens and/or blood 48 hours after admission.
Statistical Analyses
For most variables, descriptive statistics such as mean standard deviation (SD; for data with normal distribution), median with interquartile range (IQR; for data with skewed distribution), and proportion (%) were calculated. The t test, analysis of variance, Mann-Whitney U test, Kruskal-Wallis test were used for continuous variables. The χ 2 test and Fisher exact test were used for categorical variables. Kaplan-Meier curves were used to analyze survival, and logistic regression was used for multivariable analysis. Statistical analyses were performed using SPSS software, version 16.0. In all analyses, a P value < .05 was considered significant. All probabilities were 2-tailed.
RESULTS
Patient Characteristics
Of 350 hospitalized H7N9 virus–infected patients during 2013–2017, 109 (31.1%) died. The demographic and clinical characteristics of H7N9 virus–infected patients are shown in Table 1. The median age was 57 years (IQR, 46–67), and 28.6% of the patients were aged >65 years. The median age of patients in the death group was significantly greater than of those in the survival group (61 [55–71.5] vs 55 [42–65]; P < .001]. There were 234 males (66.9%), and no statistical difference in gender existed between the 2 groups. A total of 209 cases (59.7%) had at least 1 underlying disease. Hypertension (n = 149) and diabetes mellitus (n = 67) were the most common underlying medical conditions among H7N9 patients. The occurrence of both conditions was found to be significantly higher in the death group than in the survival group (50.5% vs 39%, P = .045; 25.7% vs 16.2%, P = .036, respectively), whereas 34 or fewer patients had cardiac, lung, kidney, or liver disease; tumor; or were pregnant or immunosuppressed, with no statistical difference between the death and survival groups.
Table 1.
Clinical Characteristics of 350 Patients With Avian Influenza A(H7N9) Infection
| Characteristic | Total (N = 350) | Survived (n = 241) | Died (n = 109) | P Value |
|---|---|---|---|---|
| Demographics, n (%) | ||||
| Age, median (IQR), y | 57 (46–67) | 55 (42–65) | 61 (55–71.5) | <.001 |
| >65 | 100 (28.6) | 59 (24.5) | 41 (37.6) | .012 |
| Male sex | 234 (66.9) | 164 (68) | 70 (64.2) | .481 |
| Current smoker | 77 (22) | 51 (21.2) | 26 (23.9) | .600 |
| Underlying conditions, n (%) | ||||
| Any | 209 (59.7) | 139 (57.7) | 70 (64.2) | .248 |
| Hypertension | 149 (42.6) | 94 (39) | 55 (50.5) | .045 |
| Diabetes mellitus | 67 (19.1) | 39 (16.2) | 28 (25.7) | .036 |
| Cardiac diseasea | 34 (9.7) | 21 (8.7) | 13 (11.9) | .347 |
| Chronic lung diseaseb | 25 (7.1) | 14 (5.8) | 11 (10.1) | .150 |
| Tumor | 14 (4) | 10 (4.1) | 4 (3.7) | 1.000 |
| Chronic kidney disease | 13 (3.7) | 7 (2.9) | 6 (5.5) | .380 |
| Chronic liver disease | 12 (3.4) | 9 (3.7) | 3 (2.8) | .880 |
| Immunosuppressionc | 6 (1.7) | 6 (2.5) | 0 (0) | .183 |
| Pregnancy | 6 (1.7) | 3 (1.2) | 3 (2.8) | .314 |
| Presenting symptoms, n (%) | ||||
| Fever | 340 (97.1) | 234 (97.1) | 106 (97.2) | 1.000 |
| Cough | 318 (90.9) | 221 (91.7) | 97 (89) | .415 |
| Sputum | 250 (71.4) | 177 (73.4) | 73 (67) | .215 |
| Weakness | 134 (38.3) | 98 (40.7) | 36 (33) | .174 |
| Muscle soreness | 81 (23.1) | 62 (25.7) | 19 (17.4) | .088 |
| Hemoptysis | 53 (15.1) | 38 (15.8) | 15 (13.8) | .628 |
| Gastrointestinal symptomd | 55 (15.7) | 39 (16.2) | 16 (14.7) | .653 |
| Initial laboratory findings, median (IQR) | ||||
| PaO2, mm Hg | 67 (55–81) | 69.8 (58–85) | 58.1 (59.3–134.7) | <.001 |
| PaO2/FiO2 | 128.3 (80–199.2) | 149.22 (92.6–231.6) | 86.7 (59.25–134.2) | <.001 |
| Leukocyte count, 109/L | 4.6 (3–7) | 4.4 (3–6.9) | 5 (3.1–7.8) | .269 |
| Lymphocyte count, 109/L | 0.5 (0.3–0.7) | 0.5 (0.4–0.7) | 0.4 (0.3–0.6) | .010 |
| Hemoglobin, g/L | 129 (115–143) | 130 (117–142) | 128 (111.3–143) | .487 |
| Platelet count, 109/L | 123.5 (90.3–161.5) | 128 (94–170.5) | 114.5 (78.3–155.8) | .024 |
| K+, mmol/L | 3.8 (3.5–4.2) | 3.8 (3.4–4.1) | 3.96 (3.6–4.5) | .001 |
| Na+, mmol/L | 137 (133–140) | 137 (133–140) | 138 (134.8–142) | .076 |
| Aspartate aminotransferase, UI/L | 66 (40–119) | 61 (37–100) | 86.7 (49–149) | <.001 |
| Lactate dehydrogenase, UI/L | 570 (399.5–831.5) | 511.5 (365–722.5) | 684 (493–963) | <.001 |
| Creatine kinase, UI/L | 226 (92–611) | 200 (85–547.9) | 341.5 (127.3–802) | .008 |
| Creatinine, μmol/L | 70 (55.2–89.2) | 67.8 (55–84.2) | 79 (58.1–115) | .007 |
| Procalcitonin, ng/mL | 0.4 (0.2–1.9) | 0.3 (0.1–0.8) | 1.3 (0.4–6.1) | <.001 |
| C-reactive protein, mg/L | 81.7 (40.6–129) | 73.9 (33.1–121.3) | 97.2 (61.4–144.9) | .001 |
| Initial radiology findings, n (%) | ||||
| ≥2 quadrants with infiltrate | 243 (69.4) | 169 (70.1) | 74 (67.9) | .674 |
Bold texts indicate P <.05.
Abbreviation: IQR, interquartile range.
aCardiac disease included coronary heart disease, valvular heart disease, and congestive heart disease.
bChronic lung disease included chronic obstructive pulmonary disease and interstitial lung disease.
cImmunosuppression defined as the receipt of chemotherapy, radiotherapy, or corticosteroid therapy within 1 month before illness onset.
dGastrointestinal symptoms were any of the following: nausea, vomiting, abdominal pain, or diarrhea.
Clinical Features and Laboratory Abnormalities
Fever (97.1%), cough (90.9%), and expectoration (71.4%) were the most common clinical manifestations. In addition, 15.7% of patients developed gastrointestinal symptoms; however, there was no significant difference between the survival group and the death group. Among laboratory indicators at admission, the oxygenation index (P < .001), lymphocyte count (P = .010), and platelet count (P = .024) of those who died were significantly lower than of those who survived, while K+ (P = .001), aspartate aminotransferase (P < .001), lactate dehydrogenase (P < .001), creatine kinase (P = .008), creatinine (P = .007), calcitonin (P < .001), and C-reactive protein (P = .001) were significantly higher in those who died than in those who survived. There was inflammation involving both lungs in 243 cases (69.4%); however, there was no significant difference in lung imaging between the 2 groups (Table 1).
Treatment and Clinical Outcomes
All 350 patients received supportive treatments, including mechanical ventilation (52.6%), extracorporeal membrane oxygenation (ECMO) (14%), continuous renal replacement therapy (19.1%), and artificial liver therapy (9.7%); the proportion of death cases who received these treatments was significantly higher than of survival cases (Table 2). A total of 129 (36.9%) patients received intravenous infusion of gamma globulin. The proportion of corticosteroid usage was 79.1% among all patients and was significantly higher in the death group than in the survival group (93.6% vs 72.6%, P < .001), and the largest dosage of corticosteroid in the death group was significantly higher than that in the survival group (80 [40–140] vs 80 [40–80], P = .003). All patients in the survival group received neuraminidase inhibitor (NAI) treatment. The NAI treatment rate in the death group was 97.2%, and the difference was statistically significant (P = .030). In addition, 40.7% of patients in the survival group received oseltamivir-peramivir treatment, with a statistically significant difference compared with the death group (P = .004).
Table 2.
Treatments and Clinical Outcomes of 350 Patients With Avian Influenza A(H7N9)
| Variable | Total (N = 350) | Survived (n = 241) | Died (n = 109) | P Value |
|---|---|---|---|---|
| Treatment, n (%) | ||||
| MV | 184 (52.6) | 81 (33.6) | 103 (94.5) | <.001 |
| Time from illness onset to MV start, median (IQR), days | 7 (5–9) | 7 (6–10) | 7 (5–9) | .598 |
| Duration of MV treatment, median (IQR), days | 17.1 (7–36.1) | 20 (11–47) | 13 (5.2–27) | .004 |
| Extracorporeal membrane oxygenation | 49 (14) | 22 (9.1) | 27 (24.8) | <.001 |
| Continuous renal replacement therapy | 67 (19.1) | 25 (10.4) | 42 (38.5) | <.001 |
| Artificial liver support | 34 (9.7) | 17 (7.1) | 17 (15.6) | .012 |
| Intravenous immunoglobulin | 129 (36.9) | 86 (35.7) | 43 (39.4) | .477 |
| Antibiotic treatment | 325 (92.9) | 216 (89.6) | 109 (100) | .001 |
| Time from illness onset to antibiotic start, median (IQR), days | 6 (4–8) | 6.09 (4–9) | 6 (2–7) | .015 |
| Duration of antibiotic treatment, median (IQR), days | 17 (9–27.5) | 18 (10–28) | 15 (5–27) | .115 |
| Types of antibiotics used, median (IQR), no. | 2 (1–4) | 2 (1–4) | 3 (2–5) | <.001 |
| Antibiotic ≥3 classes | 149 (42.6) | 96 (39.8) | 53 (48.6) | .124 |
| Corticosteroid treatment | 277 (79.1) | 175 (72.6) | 102 (93.6) | <.001 |
| Time from illness onset to corticosteroid start, median (IQR), days | 7 (5–10) | 7 (5–10) | 7 (5–10) | .996 |
| Duration of corticosteroid treatment, median (IQR), days | 7 (4–12) | 8 (4–12) | 6 (3–12.5) | .134 |
| Initial dosage (equivalent methylprednisolone), median (IQR), mg/d | 60 (40–80) | 60 (40–80) | 80 (40–120) | .104 |
| Maximum dosage (equivalent methylprednisolone), median (IQR), mg/d | 80 (40–115) | 80 (40–80) | 80 (40–140) | .003 |
| NAI treatment | 347 (99.1) | 241 (100) | 106 (97.2) | .030 |
| Time from illness onset to NAI start, median (IQR), days | 6 (4–8) | 6 (4–8) | 6 (5–8) | .256 |
| Oseltamivir-peramivir combination therapy | 125 (35.7) | 98 (40.7) | 27 (24.8) | .004 |
| Clinical outcomes, n (%) | ||||
| Shock | 121 (34.6) | 42 (17.4) | 79 (72.5) | <.001 |
| Secondary infection | 141 (40.3) | 82 (34) | 59 (54.1) | <.001 |
| Time from hospitalization to secondary infection start, weeksa | ||||
| 1 | 80 (22.9) | 41 (17) | 39 (35.8) | <.001 |
| 2 | 35 (10) | 26 (10.8) | 9 (8.3) | .465 |
| 3 | 6 (1.7) | 4 (1.7) | 2 (1.8) | 1.000 |
| 4 | 1 (0.3) | 1 (0.4) | 0 | 1.000 |
| More than 4 | 3 (0.9) | 3 (1.2) | 0 | .555 |
| ICU admission | 250 (71.4) | 149 (61.8) | 101 (92.7) | <.001 |
| Time from illness onset to ICU admission, median (IQR), days | 7 (5–10) | 7 (5–10) | 7 (5–10) | .800 |
| ICU length of stay, median (IQR), days | 15 (7–32.8) | 15 (9–36.8) | 14.5 (4–27) | .093 |
| Length of hospital stay, median (IQR), days | 18 (10.6–30.5) | 18 (12–31) | 15 (5–28.5) | .002 |
Bold texts indicate P <.05.
Abbreviations: ICU, intensive care unit; IQR, interquartile range; MV, mechanical ventilation; NAI, neuraminidase inhibitor.
aSixteen strains without culture time recorded.
A majority of patients (325; 92.9%) were treated with antibiotics. The median time from symptom onset to antibiotic use was 6 days (IQR, 4–8), and the median duration of antibiotic therapy was 17 days (9–27.5). The proportion of patients treated with more than 3 antibiotics in the death group was significantly higher than in those who survived (P < .001). Of 266 patients for whom a date of beginning antibiotic use was available, 181 used antibiotics before hospitalization and 74 (40.9%) developed a secondary infection. A similar proportion of patients who received antibiotics after hospitalization (37.6%) developed a secondary infection (P = .834).
The intensive care unit (ICU) admission rate was 71.4%, the median time from symptom onset to ICU admission was 7 days (IQR, 5–10), and the median length of ICU stay was 15 days (IQR, 7–35.8). Compared with the survival group, the death group had a higher rate of ICU admission (92.7% vs 61.8%, P < .001). The proportion of concurrent shock and secondary infection in the death group was 72.5% and 54.1%, respectively, significantly higher than for those in the survival group (Table 2). Among the 109 deaths, refractory hypoxemia was the most common cause of death, accounting for 59 cases, followed by 20 cases of multiple organ dysfunction syndrome (MODS), 18 cases of septic shock, 5 cases of acute heart failure, 1 case of arrhythmia, and 1 case of pulmonary embolism (Figure 1). The causes of the remaining 3 deaths were unknown.
Figure 1.
Causes of death in patients with H7N9 virus infection. Abbreviation: MODS, multiple organ dysfunction syndrome.
Secondary Bacterial Infections
Secondary infection was present in 141 (40.3%) patients, among whom 47 (33.3%) were positive in blood culture, 137 (97.2%) were positive in sputum and/or bronchoalveolar lavage fluid (BALF), and 10 (7.1%) were positive in pleural effusion culture. The most common pathogen in blood culture was Acinetobacter baumannii, accounting for 19 cases (40.4%). Other common pathogens were Klebsiella pneumoniae in 11 cases (23.4%), Enterococcus in 9 cases (19.2%), and Burkholderia cepacia in 7 cases (14.9%). Acinetobacter baumannii was also the most common pathogen in sputum and/or BALF culture, accounting for 89 cases (65%), followed by 43 cases (24.8%) of K. pneumoniae, 24 cases (17.5%) of B. cepacia, 17 cases (12.4%) of Aspergillus, 15 cases (11%) of Pseudomonas aeruginosa, and 10 cases (7.3%) of Stenotrophomonas maltophilia. For pleural effusion, 4 cases (40%) of K. pneumoniae, 2 cases (20%) of A. baumannii, and 1 case (10%) of Candida were cultured (Table 3).
Table 3.
Secondary Bacterial Infections in the Study Population
| Pathogen, n (%) | Number of Patients (n = 141) | Blood Culture (n = 47) | Sputum/ Bronchoalveolar Lavage Fluid Culture (n = 137) | Pleural Effusion Culture (n = 10) |
|---|---|---|---|---|
| Acinetobacter baumannii | 91 (64.5) | 19 (40.4) | 89 (65) | 2 (20) |
| Klebsiella pneumoniae | 37 (26.2) | 11 (23.4) | 34 (24.8) | 4 (40) |
| Burkholderia cepacia | 27 (19.1) | 7 (14.9) | 24 (17.5) | 0 |
| Aspergillus spp. | 17 (12.1) | 0 | 17 (12.4) | 0 |
| Pseudomonas aeruginosa | 15 (10.6) | 1 (2.1) | 15 (11) | 0 |
| Enterococcus spp. | 13 (9.2) | 9 (19.2) | 4 (2.9) | 0 |
| Staphylococcus aureus | 11 (7.8) | 3 (6.4) | 9 (6.6) | 0 |
| Stenotrophomonas maltophilia | 10 (7.1) | 0 | 10 (7.3) | 0 |
| Enterobacter cloacae | 5 (3.5) | 1 (2.1) | 4 (2.9) | 0 |
| Escherichia coli | 5 (3.5) | 0 | 5 (3.7) | 0 |
| Ralstonia mannitolilytica | 5 (3.5) | 0 | 5 (3.7) | 0 |
| Haemophilus influenza | 2 (1.4) | 0 | 2 (1.5) | 0 |
| Candida | 5 (3.5) | 5 (10.6) | − a | 1 (10) |
| Others | 19 (13.5) | 4 (8.5)b | 15 (12)c | 0 |
a Candida is considered a colonizer of the airway.
bIncluding Streptococcus uberis (n = 1), Burkholderia pickettii (n = 1), Alcaligenes xylosoxidans (n = 1), Alcaugenes xylosoxidans (n = 1).
cIncluding Chryseobacterium meningosepticum (n = 3), Klebsiella oxytoca (n = 2), Serratia marcescens (n = 2), Enterobacter aerogenes (n = 1), Burkholderia pickettii (n = 1), Ralstonia pickettii (n = 1), Acinetobacter pittii (n = 1), Sphingomonas paucimobilis (n = 1), Pseudomonas putida (n = 1), Pseudomonas fluorescens (n = 1), Mucor (n = 1).
Risk Factors for H7N9-Related Hospitalization
We conducted multivariate logistic regression analysis to identify risk factors associated with hospitalization and mortality (Table 4). Age, time from illness onset to antiviral therapy initiation, and secondary infection were identified as predictors (independent factors) of fatality, whereas gender, currently smoking, hypertension, heart disease, diabetes, and chronic obstructive pulmonary disease were not independent factors.
Table 4.
Multivariate Logistic Regression Analysis of Risk Factors for Death from Avian Influenza A(H7N9) Virus in 350 Hospitalized Patients
| Variable | Odds Ratio (95% Confidence Interval) | P Value |
|---|---|---|
| Age | 1.030 (1.010–1.049) | .002 |
| Sex | 0.741 (.473–1.257) | .267 |
| Current smoking | 1.189 (.656–2.158) | .568 |
| Hypertension | 0.937 (.535–1.640) | .820 |
| Heart diseases | 0.783 (.349–1.758) | .553 |
| Diabetes | 1.706 (.912–3.190) | .095 |
| Chronic obstructive pulmonary disease | 1.162 (.465–2.899) | .748 |
| Time from illness onset to antiviral therapy initiation in days | 1.069 (1.003–1.139) | .040 |
| Secondary infection | 1.978 (1.214–3.223) | .006 |
Bold texts indicate P <.05.
Using a Kaplan-Meier survival analysis, we found that the delayed mortality (90 days postsymptom onset) of H7N9-infected patients aged ≤65 years was significantly lower than of those aged >65 years. Delayed fatality was significantly greater among those with secondary bacterial infections (P < .05; Figure 2A). Furthermore, we found that mortality was significantly lower in patients treated with NAI <5 days from illness onset (P < .05; Figure 2C); however, the underlying disease had no significant effect (P > .05; Figure 2D).
Figure 2.
Kaplan–Meier survival curves of patients hospitalized for confirmed H7N9 influenza virus infections, censored at 90 days. Survival according to (A) age >65 years (log-rank test, P < .05), (B) secondary bacterial infections (log-rank test, P < .05), (C) NAI therapy within 5 days from symptom onset (log-rank test, P < .05), and (D) any underlying disease (log-rank test, P = .121). Abbreviations: CI, confidence interval; HR, hazard ratio; NAI, neuraminidase inhibitor.
DISCUSSION
The median age of patients hospitalized with H7N9 was 57 years; 28.6% patients were aged >65 years. These demographics were consistent with 1220 laboratory-confirmed human infections across China [6]. In contrast, >80% of H5N1 hospitalizations were among those aged >35 years, derived from a systematic review of H5N1 case data from 1997–2015 [9]. The key difference may be due to live-poultry markets being the main source of H7N9 infection, where the elderly are more likely to be exposed to the virus [10]. In addition, our results showed that age was an important risk factor for death in H7N9 since the elderly are at increased risk of having coexisting illnesses as well as a weak immune response [1, 11, 12].
Fever and cough were the most common symptoms of H7N9 hospitalizations, similar to previous reports in H7N9 [2]. However, there were no significant differences in clinical symptoms between the H7N9 survivors and fatalities, consistent with H7N9 data from Guangdong [11]. In contrast, there were significantly more symptoms, including fever, cough, and vomiting, among H5N1 fatalities than among survivors in Thailand during 2004–2006 [13].
Previous studies reported that underlying disease was one of the risk factors for death in H7N9-infected patients [12, 14]; however, we found no statistical differences between patients with and without an underlying disease. A high proportion of H7N9 patients had hypertension and diabetes, both of which were significantly higher among those who died, potentially identifying important risk factors in the prognosis of H7N9. Our study was underpowered to examine the relationship of other underlying medical conditions with H7N9 fatalities, as there were 35 or fewer patients who had any cardiac, lung, kidney, or liver disease; tumor; or were pregnant or immunosuppressed.
Despite substantial differences between studies, a decrease in white blood cells, lymphocytes, and platelet (PLT) as well as an increase in aspartate transaminase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) were similar to those reported among H1N1pdm09- and H5N1-infected patients [13, 15]. While clinical studies on H5N1 found that the degree of lymphopenia and thrombocytopenia were directly correlated with disease prognosis [16, 17], our research showed that lymphocyte and PLT counts in the death group were significantly lower than in the survival group, while the levels of AST, CK, and LDH were significantly higher in the death group than in the survival group. Further study of these indicators is warranted during clinical treatment.
We showed that the fatality rate among hospitalized H7N9-infected patients was 31.1%, which was lower than the fatality rate in H5N1-infected patients reported in Vietnam and Thailand where it ranged from 67% to 80% [16, 17] but was much higher than in pandemic H1N1 patients in 2009 [18]. We further analyzed the cause of death in H7N9-infected patients. Similar to the finding of Gao et al [2], 72.5% of death cases were associated with refractory hypoxemia or MODS. Upon H7N9 infection, the capillary endothelial cells and alveolar epithelial cells are damaged, and alveolar membrane permeability is increased, which leads to pulmonary interstitial and alveolar edema, lung surfactant decrease, small airway closure, and alveolar atelectasis [19, 20]. These changes in pathology and alveolar morphology can result in severe ventilation–perfusion imbalance and pulmonary shunt and dispersion disorders, causing refractory hypoxemia. Some patients may develop MODS, even death.
Corticosteroid treatment has been controversial in patients with severe pneumonia caused by influenza. On the one hand, administration of corticosteroids during critical illness may attenuate the state of adrenal insufficiency and help to maintain homeostasis and control dysregulation of the immune system [21]. On the other hand, the use of corticosteroid treatment during influenza virus infection can significantly prolong the virus’s survival time in the body [22]. Clinical studies in H1N1 have shown that corticosteroid treatment fails to benefit patients with severe influenza pneumonia and even increases the risk of death [23–25]. In the clinical treatment of H7N9, although neither the World Health Organization (WHO) nor the National Health and Family Planning Commission of China recommend the use of corticosteroid treatment, studies have shown that most H7N9 patients are treated with corticosteroids. Cao et al discovered that a low dosage (25–150 mg/day methylprednisolone or its equivalent) of corticosteroid had no effect on the duration of H7N9 virus, whereas a high dosage (>150 mg/day methylprednisolone or its equivalent) of corticosteroid could significantly increase the duration of H7N9 virus [26]. In our study, we found that 79.1% of patients were treated with corticosteroid, and the proportion of corticosteroid use in the death group was significantly higher than that in the survival group. The maximum dose of corticosteroid used in the death group was higher than in the survival group. There are a number of reasons for this, but the main reason is that illness within the death group is more severe. This interferes with our evaluation of the efficacy of corticosteroid treatment. Whether corticosteroids are effective in treating H7N9 patients remains to be studied.
The guideline for diagnosis and treatment of H7N9 issued by the WHO and the National Health and Family Planning Commission of China recommends that NAI antiviral therapy be administered at the early stage of infection. In our previous study, we confirmed that early administration of NAI can significantly shorten the duration of H7N9 infection and improve the patients’ prognosis [27]. Here, we found that the risk of death was 1.590 times higher for treatment post-5 days of symptom onset, further confirming that the early use of NAI can significantly reduce the risk of death. Interestingly, it has been reported that the combination of oseltamivir and peramivir does not improve efficacy in influenza virus infection [28]. However, we found that the proportion of oseltamivir and peramivir in the survival group was significantly higher. Whether a combination of oseltamivir and peramivir is better than a single antiviral treatment requires further and specific studies.
Secondary bacterial infection that follows influenza virus infection has been a key cause of severe illness and death. Influenza virus can directly destroy airway epithelial cells, induce apoptosis of epithelial cells, expose the epithelial basement membrane, and increase susceptibility to bacterial infection [29, 30]. Furthermore, during the early stages of infection, there is an increased secretion of proinflammatory cytokines in the lung that lead to a large number of inflammatory cells in the lung, causing alveolar epithelial cell injury and pulmonary edema, thus providing an invasive environment for bacterial infection [29, 30]. Martin et al found that the risk of death in patients with secondary bacterial infection after influenza A (H1N1) infection was twice as high as that in patients without secondary bacterial infection, and it was an important independent risk factor for severe disease and death [31]. We found that the risk of death in patients with A(H7N9) virus infection who had secondary bacterial infections was 1.686 times higher than that in patients without secondary bacterial infections. However, while Streptococcus pneumoniae and Staphylococcus aureus have been reported as the most common secondary bacterial infections [31, 32], we found A. baumannii and K. pneumoniae to be the most common causes of infection. This is likely due to the higher proportion of severe patients with H7N9 who were treated with mechanical ventilation and ECMO, increasing the risk of secondary infection during the interventional treatment. Notably, A. baumannii and K. pneumoniae are the main causes of nosocomial infections in China.
Several study limitations should be noted when interpreting the results. Although this study included cases from 12 Chinese provinces comprising more than 20 large hospitals, a unified therapeutic regimen was not followed; therefore, the patients were not guaranteed to receive the same solution. In addition, the level of treatment, care, and medical treatment equipment are different in different hospital and are likely to cause death factor analysis bias. This was despite the issuance of guidelines for diagnosis and treatment of H7N9 at the beginning of the outbreak by the National Health and Family Planning Commission of China. This study is a retrospective analysis; therefore, the possibility of recall bias cannot be completely ruled out. Also, the admission stage of all patients is not uniform, not all patients were included in the study from the beginning of their disease, and some patients may have been transferred to another hospital for treatment after treatment at a primary medical institution was ineffective, which may also have an impact on analysis.
In conclusion, A(H7N9) virus can cause high mortality induced by hypoxemia and multiple organ failure. Lung rescue therapies including both mechanical ventilation and ECMO are required. Some clinical laboratory indicators at admission were associated with disease progression. We analyzed the death factors of patients with H7N9 avian influenza and found that age, time from illness onset to antiviral therapy initiation, and secondary infection were the main risk factors for patient deaths. Therefore, it is recommended that antiviral drugs be used as early as possible and that attention be paid to reducing secondary bacterial infections during treatment.
Notes
Acknowledgments. The authors thank the staff at the hospitals in Zhejiang, Guangdong, Shanghai, Jiangsu, Hunan, Fujian, Anhui, Shandong, Henan, Guizhou, Beijing, and Hebei provinces for providing assistance with field investigation administration and data collection; Prof. Lanjuan Li from the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases for his advice regarding the clinical study, data analysis, and preparation of the manuscript; and Prof. Hongjie Yu from the Fudan University for comments on the manuscript.
Financial support. This work was supported by the China National Mega-Projects for Infectious Diseases (grants 2017ZX10204401002008, 2017ZX10103008, and 2018ZX10101001); the National Key Research and Development Program of China (grant 2016YFC1200204); and the National Natural Science Foundation of China (grants 81672014 and 81702079). D. V. is supported by contract HHSN272201400006C from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States Department of Health and Human Services.
Potential conflicts of interest. All authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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