Comparison of Hospitalized Patients with Severe Pneumonia Caused by COVID-19 and Highly Pathogenic Avian Influenza (H7N9): A Retrospective Study from A Designated Hospital

doi:10.21203/rs.3.rs-135753/v1

Download PDF

Research

Comparison of Hospitalized Patients with Severe Pneumonia Caused by COVID-19 and Highly Pathogenic Avian Influenza (H7N9): A Retrospective Study from A Designated Hospital

https://doi.org/10.21203/rs.3.rs-135753/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: Considerable attention has been focused on clinical features of Coronavirus Disease 2019 (COVID-19), it is also important for clinicians to differentiate it from influenza virus infections.

Methods: The clinical data of 23 cases of H7N9 and 23 cases of COVID-19 with severe pneumonia were collected. The comparisons were performed with the t test, Mann-Whitney U test, Fisher exact test or the chi-squared test, and multivariable logistic regression analysis.

Results: All of the cases were under the circumstance of sufficient medical staff and medical supplies. Radiologically, severe COVID-19 patients had less consolidation and pleural effusion, but more crazy-paving pattern than severe H7N9 patients (p<0.05). Clinically, compared to severe H7N9, severe COVID-19 patients were more inclined to surfer to relative better disease severity score, less secondary bacterial infection, a shorter time to beginning absorption on CT, but a longer duration of viral shedding from the admission (p<0.05). Although more severe H7N9 patients needed non-invasive respiratory support, these two groups ultimately yielded comparable mortality. Based on multiple logistic regression analysis, severe COVID-19 infection was associated with a lower risk of the presence of severe ARDS (OR 0.964, 95% [CI] 0.931-0.998, p=0.040), but exhibited longer duration of viral shedding (OR 0.734, 95% [CI] 0.550-0.980, p=0.036) than severe H7N9 infection.

Conclusion: Although the conditions of severe H7N9 patients seemed to be more critical than those of severe COVID-19 patients, the relatively lower mortality of these two severe cases is to be expected in context of sufficient medical supplies.

Health Economics & Outcomes Research

Infectious Diseases

Pneumonia

Avian influenza A (H7N9)

COVID-19

The coronavirus disease 2019 (COVID-19), which is caused by 2019 novel coronavirus (2019-nCoV) imposes a grand immediate challenge for global public health. So far, COVID-19 has spread to many other countries with thousands of infected cases.

Despite many articles have established the clinical features of COVID-19 patients [1–3], comparison of hospitalized patients with severe pneumonia caused by COVID-19 and highly pathogenic avian influenza (HPAI) has not been reported yet. Because of distinct treatments and prognoses, it is important for clinicians to accurately identify these two respiroviral infections via their differential clinical manifestations [4–5].

In this study, we systematically compared severe pneumonia patients infected with COVID-19 versus H7N9 viruses in terms of clinical presentations, laboratory tests, virologic shedding, image characteristics, complication and clinical outcome in context of critical bundle and intensive management, in order to provide some guidance for their differential consideration.

Patients

All of the severe COVID-19 pneumonia and severe H7N9-induced pneumonia subjects were confirmed by laboratory tests and were hospitalized at The Fifth People's Hospital of Suzhou. The date of disease onset and hospital admission date, as well as the severity of disease were recorded. The severe COVID-19 pneumonia cases were hospitalized from January 2020 to March 2020, who was defined according to the diagnostic and treatment guideline for COVID-19 pneumonia issued by the National Health and Family Planning Commission of P.R.China (Version 1–7). The severe H7N9 cases were hospitalized from 2014 to 2016, who met the following criteria published by the National Health and Family Planning Commission of P.R.China (the 2nd edition, 2013).

Data collection

The data of all patients were collected from an electronic case report form and included the following: demographic characteristics (age and sex), comorbidities, clinical symptoms, laboratory tests (blood routine test, arterial blood gas analysis (ABG), and blood chemistry), virologic test, microbiological findings and images of the lung (chest CT). Antimicrobiological therapy, respiratory support, complications and outcomes were also recorded. The Ethics Committee of The Fifth People's Hospital of Suzhou approved this study (2020-005).

Study design

This was a retrospective case-control study. We compared two independent cohorts of patients infected with either COVID-19 or H7N9 in terms of initial onset, further course and outcome, which included clinical presentations at diagnosis, virologic shedding, peak values of laboratory tests, time course of image characteristics, the worst SOFA and PSI score, extrapulmonary complication, secondary bacterial infection, intensive therapy, and clinical outcome.

Definitions

Septic shock was defined according to the 2016 Third International Consensus Definition for Sepsis and Septic Shock [6]. Secondary bacterial infection was diagnosed when patients showed clinical symptoms or signs of pneumonia or bacteraemia and a positive culture of a new pathogen was obtained from lower respiratory tract specimens (qualified sputum, endotracheal aspirate, or bronchoalveolar lavage fluid) or blood samples after admission [7]. Extrapulmonary complication was defined as: i acute kidney injury was diagnosed according to the KDIGO clinical practice guidelines; ii acute cardiac injury was diagnosed if serum levels of cardiac biomarkers (eg, high-sensitive cardiac troponin I) were above the 99th percentile upper reference limit; iii acute liver injury was diagnosed if serum levels of ALT or TBIL was above the 2-fold of upper reference limit; iv coagulopathy was defined as a 3-second extension of Prothrombin time (PT) [8–9]. RNA shedding duration was defined the interval from admission to the date of the first RNA negative result before discharge.

Statistical analysis

Data were described as the mean ± sd, median (interquartile range, IQR) or number (%). The comparisons of the features between the different subtypes of virus (H7N9 and COVID-19) were performed with the t test to compare the mean ± sd of continuous variables, Mann-Whitney U test to compare the medians of continuous variables, and Fisher exact test or the chi-squared test to compare proportions. To identify risk factors associated with severe COVID-19 infection, we performed a multivariable logistic regression analysis adjusted for baseline covariates. Statistical analyses were performed using SPSS, version 24.0 for Windows, probabilities were 2-tailed, and a 2-tailed p value of < 0.05 was considered significant.

Dermatologic feature

As shown in Table 1, the median age of severe COVID-19 patients was 49 years old, which was comparable to that of severe H7N9 patients (54 years old, p > 0.05). The proportion of males in severe COVID-19 patients was 69.57%, which was also comparable to that of severe H7N9 patients (65.22%, p > 0.05). 26.09% of severe COVID-19 patients has a history of underlying diseases, whereas that of severe H7N9 patients was significantly higher, at 56.52% (p = 0.04). The majority of severe H7N9 patients suffered to hypertension (p < 0.01). There was no significant difference in the history of diabetes, chronic-airway diseases between the two groups (p > 0.05).

Table 1

Characteristics of subjects.
	H7N9	COVID-19	p value
Age (median, ys)	54 (35–66)	49 (38–60)	0.38
Male (%)	65.22	69.57	0.75
Underlying disease (%) Hypertension HBV Diabetes Chronic-airway diseases Clinical manifestations (%)	56.52 52.17 8,70 13.04 0	26.09 8.70 0 13.04 4.34	0.04 < 0.01 0.47 1.00 1.00
Fever	100	100	NA
Cough	100	82.61	0.12
Dyspnea Myalgia Nasal congestion Pharyngodynia () Gastrointestinal symptoms	86.96 47.82 30.43 21.74 17.39	30.43 17.39 0 8.70 8.70	< 0.01 0.03 0.01 0.41 0.66
Hemoptysis	0	0	NA

Clinical manifestations at diagnosis

At admission (Table 1), almost all severe H7N9 and severe COVID-19 patients presented with fever and cough (100% vs 100%, 100% vs 82.61%, p > 0.05 for each). Furthermore, 86.96%, 47.82% and 30.43% of severe H7N9 patients had dyspnea, myalgia and nasal congestion, which was significantly more than those of severe COVID-19 patients (30.43%, 17.39%, 0, p < 0.05 for each). The proportions of pharyngodynia (21.74%) and gastrointestinal symptoms (17.39%) in with severe H7N9 patients were comparable to those of severe COVID-19 patients (8.70%, 8.70%), whereas hemoptysis was less common in both two groups.

Laboratory results

Over the course of the hospitalization (Table 2), acute kidney injury, acute liver injury occurred in 8.07% and 69.57% of patients with severe H7N9, which was comparable to those of severe COVID-19 patients (13.04%, 78.26%, p > 0.05 for each). However, 69.57% of severe H7N9 patients suffered to acute cardiac injury, which was significantly higher than the proportion of 4.34% in severe COVID-19 patients (p < 0.01). Following biochemical testing, the peak level of alanine aminotransferase (ALT), total bilirubin (TBIL), creatinine (Cr), and troponin I (TnI) in severe COVID-19 patients were comparable to those in severe H7N9 patients (140.9.7 ± 19.11 vs 132.7 ± 19.64 U/L, 22.18 ± 2.80 vs 21.19 ± 1.62 µmol/L, 79.52 ± 5.22 vs 71.74 ± 3.72 µmol/L, 18.65 ± 9.36 vs 286.50 ± 181.1 pg/ml, respectively, p > 0.05 for each).

Table 2 Over disease’s course between of severe H7N9 and COVID-19 patients.

*, minimal or peak value of the index over disease’s course.

Both severe COVID-19 and severe H7N9 patients exhibited impairments in coagulation. However, significantly increase of peak levels of D-dimer and Prothrombin time (PT) were associated with severe H7N9 patients compared to severe COVID-19 patients (5447 ± 1094 vs 1914 ± 426.5 mg/L, 14.67 ± 0.74 vs 12.47 ± 0.17 sec, p < 0.05 for each).

In terms of blood cell counting, lymphopenia was observed in most severe COVID-19 (86.96%) and severe H7N9 patients (100%, p > 0.05), but the minimal level of lymphocytes in severe COVID-19 patients were higher than those in severe H7N9 patients (0.71 ± 0.06 vs 0.44 ± 0.39 × 10⁹/L, p < 0.05). Thrombocytopenia was observed in 47.82% of severe COVID-19 and 65.28% of severe H7N9 patients (p < 0.05), but the minimal level of platelet in severe COVID-19 patients were comparable to those in severe H7N9 patients (157.80 ± 11.34 vs 149.20 ± 18.67 × 10⁹/L, p = 0.69).

Worst Oxygenation Index (OI) during the hospitalization predicts deteriorated respiratory failure. The minimal level of OI in severe COVID-19 patients was 228.30 ± 11.01 mmHg, which was significantly higher than the 113.7 ± 11.18 mmHg of severe H7N9 patients (p < 0.05).

Imaging findings

In terms of imaging characteristics (Table 2), ground-glass opacity in initial chest CTs was common in COVID-19 patients (43.48%) and in H7N9 patients (60.87%, p > 0.05). In contrast, consolidation and pleural effusion were more common in H7N9 patients than in COVID-19 patients (p < 0.05 for each), crazy-paving pattern was less seen in H7N9 patients (p < 0.05).

Further course and intensive treatment

Over the course of the viral infections (Table 3), septic shock occurred in 13.04% of patients with severe H7N9. There was no significant difference in the duration of onset to ARDS between severe H7N9 and severe COVID-19 patients (8.39 ± 0.59 days, 8.09 ± 0.72 days, p = 0.74). The highest sequential organ failure assessment (SOFA) score and pneumonia severity index (PSI) score of severe COVID-19 patients were 3.57 ± 0.31 and 61.22 ± 2.99, respectively, which were lower than the scores of 5.35 ± 0.77 (p = 0.04) and 89.96 ± 7.72 (p = 0.00) for severe H7N9 patients.

Table 3

Treatment and prognosis of two groups.
	H7N9	COVID-19	p value
Respiratory support (%) NPPV IMV Respiratory support failure (%) NPPV IMV CRRT (%)	69.57 13.04 4.35 13.04 13.04	21.74 0 0 0 0	< 0.01 0.23 1.00 0.23 0.23
Duration of virus shedding (d) The time to beginning absorption on CT (d) Glucocorticoid (%) LMWH (%)	9.86 ± 0.81 11.64 ± 0.83 95.65 34.78	13.91 ± 1.56 9.13 ± 0.70 82.61 43.48	0.03 0.02 0.34 0.55
Mortality (%)	13.04	0	0.23

All patients have received medical bundle intervention, including antimicrobial therapy, fluid administration, respiratory support, or steroid therapy.

The two groups presented with a variety of accompanying secondary bacterial infection. 39.13% of severe H7N9 patients had positive culture of pathogen isolated from qualified lower respiratory tract specimens, whereas that of severe COVID-19 patients was significantly lower (8.70%, p < 0.05).

In terms of respiratory support, during the entire process of treatment, the proportions of severe H7N9 patients who received non-invasive mechanical ventilation (NIV) was significantly higher than that of COVID-19 patients (69.57% vs 21.74%, p < 0.05). The failure rates of NIV in severe H7N9 patients were comparable to than those in COVID-19 patients (4.35% vs 0%, p > 0.05).

In addition to treatments above, 82.61% of COVID-19 patients received glucocorticoids, which was comparable to the proportion of 95.65% in H7N9 patients (p > 0.05). Low-molecular-weight Heparin was administered in 43.48% of COVID-19 patients, which also was comparable to that administered to H7N9 patients (34.78%, p < 0.001).

Virologic outcomes and prognosis

All of the patients received antiviral therapies. Oseltamivir was administered in all of the H7N9 patients. However, COVID-19 patients had a variety of antiviral treatments, included 43.48% with lopinavir/ritonavir, 8.70% with arbidol, and 47.83% with combination. The duration of severe COVID-19 RNA shedding from the admission was 13.91 ± 1.56 days, which was longer than that of severe H7N9 patients (9.86 ± 0.81 days, p = 0.03).

Based on the follow-up of chest CT, the time to beginning absorption on chest CT (TTBAC) was established. Severe H7N9 patients have longer TTBAC than that in severe COVID-19 patients (11.64 ± 0.83 vs 9.13 ± 0.70 days, p = 0.02).

In terms of prognoses, although the in-hospital mortality of H7N9 patients with ARDS was 13.04%, it did not reach the statistical significance when compared to COVID-19 patients (0, p < 0.001).

Multivariate analysis

Based on multiple logistic regression analysis, compared with parameters in severe H7N9 patients, severe COVID-19 patients were associated with a lower risk of the presence of severe ARDS (OR 0.964, 95% [CI] 0.931–0.998, p = 0.040), but exhibited longer duration of viral shedding (OR 0.734, 95% [CI] 0.550–0.980, p = 0.036) than severe H7N9 infection (Table 4).

Table 4 Multivariate analysis of independent risk factors for differentiating COVID-19 from H7N9.

In this study, we compared the clinical features and courses of patients with severe pneumonia caused by COVID-19 and highly pathogenic avian Influenza (H7N9). As sufficient medical staff and medical supplies have affected the treatments and prognoses of severe cases, this retrospective study was conducted in a resident designated hospital, where medical resources reached standardized respiratory support in accordance with related guidelines.

Because of different therapies, it is important to differentiate these two diseases via clinical presentations. We found that compared with features in H7N9 patients, COVID-19 patients were less inclined to exhibit dyspnea, myalgia, and nasal congestion. Therefore, we speculate from previous research that severe H7N9 infection may present as more systemic and catarrh symptoms compared with the COVID-19 infection. Furthermore, based on the proportions of underlying diseases in these two groups, it was indicated that the combination of underlying diseases had a significant effect on the severities of H7N9 infection [1–5].

The main manifestations on chest CT for both diseases were characterized by ground-glass opacities (GGOs) [10]. Additionally, we found that crazy-paving pattern was more common in severe COVID-19 patients than in H7N9 patients, whereas consolidation and pleural effusion were more frequent in severe H7N9 patients. It was suggested that the combination of radiologic findings might have a certain value in the differential diagnosis of the two diseases.

Clinically, although severe COVID-19 patients had similar extra-pulmonary complication to those observed in the severe H7N9 patients, they were less inclined to surfer to secondary bacterial infection, severe thrombocytopenia, acute cardiac injury and impairments in coagulation. The majority of patients had increased coagulation activity, marked by increased D-dimer concentrations. High levels of D-dimer have a reported association with 28-day mortality in patients with infection or sepsis [11]. These experimental indexes were considered to be closely related to the severities of the severe infections [9, 12].

In term of disease severity, duration from the onset to confirmed diagnosis of ARDS in severe H7N9 and COVID-19 patients was comparable. However, severe COVID-19 patients were more inclined to surfer to relative better disease severity score. Also, according to the PaO₂/FiO₂ in severe COVID-19 patients, the corresponding OI was significantly higher than that of severe H7N9 patients, suggesting the relatively moderate conditions of the severe COVID-19 patients. As supported, serial chest CT showed that the absorption of the lesions among the H7N9 patients was slow. The main cause might have been more severe damage to the lung tissue.

There are still no specific antiviral medicines or vaccines recommended for COVID-19 infection. Under the circumstances, comparison of duration of virus shedding between severe COVID-19 and H7N9 infection may produce more interesting findings. Surprisingly, the severe COVID-19 group had longer duration of viral shedding from the admission than the severe H7N9 group. This has important implications for the guidance around the length of antiviral treatment.

We also found that severe COVID-19 patients received a wider variety of treatments that were similar to severe H7N9 patients. The application of glucocorticoids and LMWH were both common in COVID-19 and H7N9 patients in our present study. The treatments for ARDS of the two groups were mainly based on NPPV. More of the patients with severe H7N9 needed NPPV and ultimately cured. However, additional prospective and comparative trials that address the need for intubation and the mortality rate are required [13–14].

Taken together, compared to COVID-19, patients with H7N9 complicated by severe pneumonia had much more severe disease. Given sufficient medical staff and medical supplies, the relatively lower mortality rate of these two severe cases is to be expected. However, there were some limitations of our present study. First, this was a retrospective study that included data from one independent single-center cohorts, which may have resulted in unavoidable bias. Second, more observations are needed to clarify further clinical features by a large scale of investigation.

ARDS: acute respiratory distress syndrome; CI: confidence interval; COVID-19: Coronavirus Disease 2019; CT: computed tomography; GGOs: ground-glass opacities; HAP: hospital-acquired pneumonia; HPAI: highly pathogenic avian influenza; ICU: intensive care unit; IQR: interquartile range; NPPV: noninvasive positive pressure ventilation; OR: odds ratio; PSI: pneumonia severity index; RT-PCR: reverse transcription polymerase chain reaction; SOFA: sequential organ failure assessment

Acknowledgment

We thank the patients, the nurses and clinical staff who are providing care for the patient, and staff at the local and state health departments.

Authors’ contributions

T.P.J and C.C. conceived the idea, designed, and supervised the study, drafted the manuscript. G.B.B. and Y.L. collected data and had full access to all of the data and took responsibility for the integrity of the data. Z.X.Y. analyzed data and performed statistical analysis. All of the authors reviewed and approved the final version of the manuscript.

Finding

This work was supported by Novel Coronavirus Pneumonia Technology Research and Development Funding of Suzhou city SYS2020017 (to PJT). Six Talent Peaks Project in Jiangsu Province WSN-101 (to CC), Provincial Health Committee grant LGY2019083 (to CC). Postgraduate Research & Practice Innovation Program of Jiangsu Province SJCX20_1075 (to XYZ). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

All data generated during this study are included in this article.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of our Institute of The Fifth People’s Hospital of Suzhou (2020–005).

Consent for publication

In this retrospective small-scale study, written informed consent from the patients were waived, which was approved by the Ethics Committee of our Institute of The Fifth People’s Hospital of Suzhou (2020–005).

Competing interests

The authors declare that they have no competing interests.

Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395(10223):497-506.
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020; doi: 10.1001/ jama.2020.1585. [Epub ahead of print].
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020, 395(10223):507-513.
Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013; 368(20):1888-1897.
Wang C, Yu H, Horby PW, et al. Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. Clin Infect Dis. 2014; 58(8):1095-1110.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-810.
Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016; 63(5): e61-e111.
Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012; 120(4): 179-184.
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229):1054-1062.
Pan F, Ye T, Sun P, et al. Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia. Radiology. 2020; 200370, doi: 10.1148/radiol.2020200370. [Epub ahead of print].
Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada. JAMA. 2009; 302(17):1872-1879.
Rodelo JR, De la Rosa G, Valencia ML, et al. D-dimer is a significant prognostic factor in patients with suspected infection and sepsis. Am J Emerg Med. 2012; 30(9): 1991-1999.
Antonelli M, Conti G, Esquinas A, et al. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. 2007; 35(1):18-25.
Zhan Q, Sun B, Liang L, et al. Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial. Crit Care Med. 2012; 40(2):455-460.

Download PDF

Version 1

posted

You are reading this latest preprint version

Comparison of Hospitalized Patients with Severe Pneumonia Caused by COVID-19 and Highly Pathogenic Avian Influenza (H7N9): A Retrospective Study from A Designated Hospital

Status:

Version 1

Abstract

Introduction

Methods

Patients

Data collection

Study design

Definitions

Statistical analysis

Results

Dermatologic feature

Clinical manifestations at diagnosis

Laboratory results

Imaging findings

Further course and intensive treatment

Virologic outcomes and prognosis

Multivariate analysis

Discussion

Abbreviations

Declarations

References

Status:

Version 1