key: cord-1030005-mspgvglz authors: Huang, Hong; Zhang, Ming; Chen, Can; Zhang, Huilan; Wei, Yanqiu; Tian, Jianbo; Shang, Jin; Deng, Yan; Du, Aihua; Dai, Huaping title: Clinical Characteristics of COVID‐19 in patients with pre‐existing ILD: A retrospective study in a single center in Wuhan, China date: 2020-06-13 journal: J Med Virol DOI: 10.1002/jmv.26174 sha: 57b68d3a67af6417f95ee5c4fc040bf8b2239100 doc_id: 1030005 cord_uid: mspgvglz BACKGROUND: Since the outbreak of 2019 novel coronavirus (SARS‐CoV‐2) pneumonia, many patients with underlying disease, such as interstitial lung disease (ILD), were admitted to Tongji hospital in Wuhan, China. To date, no data have ever been reported to reflect the clinical features of Corona Virus Disease 2019 (COVID‐19) among these patients with pre‐existing ILD. METHODS: We analyzed the incidence and severity of COVID‐19 patients with ILD among 3201 COVID‐19 inpatients, and compared two independent cohorts of COVID‐19 patients with pre‐existing ILD (n=28) and non‐ILD COVID‐19 patients (n=130). RESULTS: Among those 3201 COVID‐19 inpatients, 28 of whom were COVID‐19 with ILD (0.88%). Fever was the predominant symptom both in COVID‐19 with ILD (81.54%) and non‐ILD COVID‐19 patients (72.22%). However, COVID‐19 patients with ILD were more likely to have cough, sputum, fatigue, dyspnea, and diarrhea. Very significantly higher number of neutrophils, monocytes, IL‐8, IL‐10, IL‐1β and D‐Dimer was characterized in COVID‐19 with ILD as compared to those of non‐ILD COVID‐19 patients. Furthermore, logistic regression models showed neutrophils counts, pro‐inflammatory cytokines (TNF‐α, IL6, IL1β, IL2R), and coagulation dysfunction biomarkers (D‐Dimer, PT, Fbg) were significantly associated with the poor clinical outcomes of COVID‐19. CONCLUSION: ILD patients could be less vulnerable to SARS‐CoV‐2. However, ILD patients tend to severity condition after being infected with SARS‐CoV‐2. The prognosis of COVID‐19 patients with per‐existing ILD is significantly worse than that of non‐ILD patients. And more, aggravated inflammatory responses and coagulation dysfunction appear to be the critical mechanisms in the COVID‐19 patients with ILD. This article is protected by copyright. All rights reserved. COVID-19, full name is Coronavirus Disease 2019, is an infectious disease caused by a coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and first appeared in Wuhan, Hubei, and has rapidly spread throughout China and around the world [1] [2] [3] . Up to March 31, 2020, the total number of patients has risen to 82,547 in China, and 50,006 (60.58%) of whom were in Wuhan 4 . Previous studies have only described the general epidemiological findings, clinical presentation, and clinical outcomes from COVID patients with chronic underlying comorbidities 1,5-6 . To our knowledge, none of the fatal case report has been associated with interstitial lung disease (ILD), which is featured by variable degrees of inflammation and fibrosis. Similarity, specific information characterising COVID-19 patients with or without pre-existing ILD remains unknown. As a leading hospital in Wuhan, Tongji Hospital serves as one of the main designated hospitals to receive and treat COVID-19 patients. This study is designed to analyze the incidence and severity of COVID-19 patients with pre-existing ILD, and to compare the clinical features between COVID-19 patients with pre-existing ILD and COVID-19 in patients without pre-existing ILD based on the epidemiological, clinical, laboratory and CT scan results. This article is protected by copyright. All rights reserved. Tongji Hospital, as the the center of COVID-19 epidemic, received 3201 COVID-19 inpatients from February 7th to March 27th, 2020. Among those 3201 COVID-19 inpatients, 28 of whom were COVID-19 with pre-existing ILD. In this retrospective study, we recruited all COVID-19 patients with pre-existing ILD, and subsequently, a total of 130 non-ILD patients with COVID-19 that were statistically matched with COVID-19 patients with pre-existing ILD at an approximate ratio of 4:1 based on age, sex and illness severity were enrolled in this study. The clinical features, laboratory findings, CT imaging, patient outcomes and management data were obtained from each patient. All patients with ILD enrolled in this study were diagnosed on the basis of ILD guideline 7 . According to the COVID-19 Diagnosis and Treatment Protocol 8 , patients diagnosed as COVID-19 were classified based on their clinical manifestations. Mild case was defined as mild clinical manifestations, with or without pneumonia changes of CT scans. Severe case was defined as: 1) respiratory distress, RR≥30 times/min; 2) oxygen saturation ≤93% at rest; and 3) Pao 2 /Fio 2 ≤300mmHg (1mmHg=0.133kpa). Critical case was defined as: 1) respiratory failure requiring mechanical ventilation; 2) occurrence of shock; and 3) combined with failure of other organs and ICU care was required. The study was approved by the Human Assurance Committee (HAC) of Tongji Hospital, and an oral informed consent was obtained from each participant. In case some of the data were missed from the records or specific clarification was necessary, we obtained those data by directly communicating with the attending doctors and health-care providers. This article is protected by copyright. All rights reserved. The COVID-19 nucleic acid assays were conducted in Tongji Hospital. Throat-swab specimens from the upper respiratory tract were collected from all outpatients twice with a 24h interval. The throat swab was placed into a collection tube with virus preservation solution, and total RNA was extracted using two different respiratory sample RNA isolation kits approved by the Food and Drug All patients had undergone non-contrast CT scanning using the standard-dose chest CT protocols (GE Healthcare, Philips, or Toshiba Medical Systems) of the thorax in the supine position during end-inspiration (80-120 kVp, automated tube current modulation, mA ranges from 60 to 300, rotate time 0.5s, pitch 0.984:1, a slice thickness of 1.25mm. All patients did not conduct enhanced CT scanning. This article is protected by copyright. All rights reserved. Epidemiological data including patients' age and sex information, clinical symptoms, blood routine results, and CT scans were collected through the standardized data collection tables from the electronic medical records. Continuous variables were presented as median and interquartile range (IQR) for skewed distributed data or mean and standard deviation (SD) for normal distributed data. Categorical variables were expressed as number (%). Differences between ILD and non-ILD patients with COVID-19. For continuous variables, the Student's t-test was used for normal distributed data, whereas Mann-Whitney U non-parameter test was used for skewed distributed data. The Pearson's χ² test or Fisher's exact test were applied for categorical variables. Unconditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between factors and the clinical outcomes of COVID-19. A two-sided P value<0.05 was considered statistically significant. All statistical analyses were performed using SPSS (22.0). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Since Tongji Hospital is almost located in the center of COVID-19 epidemic, it received 3201 COVID-19 inpatients between February 7th to March 27th, 2020, This article is protected by copyright. All rights reserved. and 28 of whom were COVID-19 patients with pre-existing ILD, and thus the incidence of COVID-19 with pre-existing ILD was 0.88%. Specifically, 9 of 28 cases are idiopathic interstitial pneumonias (IIPs), 10 cases are connective tissue disease-interstitial lung disease (CTD-ILD), 3 cases are anti neutrophil cytoplasmic antibodies-associated vasculitis combined with pulmonary fibrosis, 2 cases are chronic hypersensitivity pneumonitis, 2 cases are sarcoidosis, 1 case is pneumoconiosis, and the last 1 case is radiation pneumonitis. We subsequently recruited a total of 130 non-ILD patients with COVID-19 that were statistically matched with COVID-19 patients with pre-existing ILD at an approximate ratio of 4:1 based on age, sex and illness severity in this study. In terms of age, genders and severity distribution, no significant difference was noted between the COVID-19 with pre-existing ILD and COVID-19 without pre-existing ILD patients (Table1). Fever was the predominant symptom both in COVID-19 with pre-existing ILD (81.54%) and COVID-19 without pre-existing ILD patients (72.22%). Similarly, the comparison of other symptoms between COVID-19 with pre-existing ILD and COVID-19 without pre-existing ILD patients also failed to detect a significant difference such as chill (5.56% vs. 0.77%), muscle ache (11.11% vs. 2.31%), nausea and vomiting (5.56% vs. 0.00%), dizziness (5.56% vs. 0.00%). However, higher proportion of COVID-19 with pre-existing ILD patients displayed cough (66.67% vs. 29.23%, P = 0.004), expectoration (38.89% vs. 2.31%, P < 0.001), fatigue (22.22% vs. 6.15%, P = 0.041), difficulty breathing (50.00% vs. 8.46%, P < 0.001), and diarrhea (33.33% vs. 6.15%, P = 0.002) as compared to those of COVID-19 without pre-existing ILD patients (Table 1) . All the COVID-19 with pre-existing ILD patients performed chest CT-scans at the time of admission, and 114 out of 130 COVID-19 patients without pre-existing ILD performed chest CT scans. It was noted that the typical CT This article is protected by copyright. All rights reserved. images derived either from COVID-19 with pre-existing ILD or COVID-19 without pre-existing ILD patients were all characterized by the ground glass-like shadows (42.86% vs. 49.12%), patchy shadow (78.57% vs. 63.16%), and pleural thickening (50.00% vs. 33.33%). Remarkably, COVID-19 with pre-existing ILD were featured by the higher severity of honeycomb shadow (7.14% vs. 0.00%, P = 0.038) and interlobular septum and intralobular interstitial thickening (78.57% vs. 0.88%, P < 0.001). Furthermore, analysis of the lesion sites in CT-scans revealed that no significant difference was noted between the COVID-19 with pre-existing ILD and COVID-19 without pre-existing ILD patients (Table1). To understand the clinical risk of COVID-19 with pre-existing ILD patients, we compared laboratory findings between two groups. The average number of lymphocytes in the COVID-19 with pre-existing ILD patients was 0.82×10 9 /L, while it was 0.85×10 9 /L for the COVID-19 without pre-existing ILD patients, and no significant difference was observed between the two groups (P = 0.972). Furthermore, we have compared the differences between the two groups based on the counts of eosinophils, NK cell, T+B+Nk cell, B cell, T cell, CD3+CD4+T cell and CD3+CD8+T cell, but failed to detect a significant difference. Similarly, no significant difference was noted in terms of renal function, liver function and heart function. In sharp contrast, COVID-19 with pre-existing ILD patients displayed significantly higher level of neutrophils counts (5.78×10 9 /L vs. 4.16×10 9 /L; P = 0.017), monocytes counts (0.59×10 9 /L vs. 0.41×10 9 /L; P = 0.005), IL-8 (31.90pg/L vs. 12.70pg/L; P = 0.015), IL-10 (71.55pg/mL vs. 5.00pg/mL; P < 0.001), IL-1β (20.85pg/mL vs. 5.00pg/mL; P < 0.001), D-Dimer (2.81ug/mL vs. 1.07ug/mL; P = 0.001), as compared to those of COVID-19 without pre-existing ILD patients (Table 1) . All patients received same protocol of anti-virus treatments during hospitalization. It is worth reminding that COVID-19 patients with pre-existing This article is protected by copyright. All rights reserved. ILD were more likely to have poor outcome (39.29%), a percentage much higher than COVID-19 without pre-existing ILD patients (15.38%), P = 0.004 ( Figure 1 (Table 1) , suggesting up-regulation of those factors might result in a poor outcomes of COVID-19 in ILD patients. This is the first retrospective study with comparison between COVID-19 patients with pre-existing ILD and COVID-19 in patients without pre-existing ILD. ILD, a group of diseases with impaired interstitial lungs, the incidence of which is increasing by years and it has increasingly captured attention from both clinicians and patients [9] [10] . Nevertheless, the incidence and severity of COVID-19 among ILD patients remain unknown. Given such facts, the clinical features of This article is protected by copyright. All rights reserved. COVID-19 patients with pre-existing ILD are worth exploring. Therefore, this study is designed to analyze the clinical features between COVID-19 and COVID-19 patients with pre-existing ILD based on the incidence, severity, clinical features, laboratory findings, CT imaging and patient outcomes. As a leading hospital in Hubei Province, Tongji Hospital serves as one of the main designated hospitals to carry out patient admission. In particular, From February 7th to March 27th of 2020, 3,201 COVID-19 cases were hospitalized, while 28 of which had ILD as the underlying disease, which accounted for a relatively low proportion (0.88%) of the total hospitalized cases. In general, however, based on the analysis of SARS-CoV-2 in previous studies, SARS-CoV-2 is highly transmissible in humans, especially in the elderly and people with underlying diseases 1,6,11 . The low incidence in our report could be caused by following reasons: First, the incidence of ILD is indeed not as high as other underlying diseases including hypertension, diabetes, cerebrovascular disease, etc. 9,12-14 ; Second, ILD has undergone significant evolution in recent years, with more complex, ever expanding disease classification. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and difficult diagnose 15 , meaning that some ILD patients may escape diagnosis in the clinical practice; Finally, and most important, it's known that SARS-CoV-2 infects cells with angiotensin-converting enzyme 2 (ACE2) as receptor, while previous studies suggested that decreased angiotensin II mRNA and its activity not only in the lung tissue of patients with idiopathic pulmonary fibrosis, but also in a mouse model of bleomycin-induced pulmonary fibrosis [16] [17] [18] . Therefore, we assume that the reduced infection rate of ILD could be caused by decreased angiotensin II mRNA and its biological activity. However, due to the lack of research data on this conclusion, more exploration is needed. This article is protected by copyright. All rights reserved. Among 28 cases included in this study, the median age was 68 years, this finding is different from the average age (55.5 years) of the entire hospitalized COVID-19 patients previously published in Lancet 6 , but consistent with the fact that ILD patients are mostly elderly 19 . In term of gender, 23 were males (82.1%), while 5 were females (17.9%), which is consistent the epidemiology that ILD is always encountered primarily among males. Furthermore, 9 cases were common cases (32.14%), while 19 cases were severe or critical (67.85%), suggesting that even through ILD patients could be less vulnerable to SARS-CoV-2, once SARS-CoV-2 infection occurs, COVID-19 patients with ILD tend to serious condition. Subsequently, 28 COVID-19 patients with ILD were statistically matched with 130 patients without ILD at a ratio of 1: 4 based on age, gender, and disease severity. The main symptom of COVID-19 patients with ILD is fever, which is similar to the clinical manifestations of patients with COVID-19 without ILD. Note that patients with COVID-19 who had pre-existing ILD are more likely to have cough, sputum, fatigue, dyspnea, and diarrhea, which is consistent with the characteristic that ILD patients. Given the fact that the number of COVID-19 patients with pre-existing ILD is limited, further investigations with large-scale of patients would be necessary. Intriguingly, we did not found a significant difference in terms of lymphocytes and lymphocyte subsets between COVID-19 patients with pre-existing ILD and COVID-19 patients without ILD, while the number of neutrophil, monocyte was significantly higher in COVID-19 patients with pre-existing ILD as compared to that of COVID-19 patients without ILD. Also, the levels of IL-8, IL-10, IL-1β and D-D dimer were significantly higher in COVID-19 patients with pre-existing ILD. Indeed, previous studies have confirmed that IL-8, IL-10, and IL-1β are related to the occurrence and development of ILD 20-22 . Also, mostly studied has been done This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Table 1 Continuous variables were described as median and interquartile range (IQR) or mean and standard deviation (SD). Categorical variables were described as number (%). a P values were calculated by Student's t test. b P values were calculated by Wilcoxon sum-rank test. c P values were calculated by Fisher's exact test. 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