key: cord-0828699-u8xa0tku authors: Abdel-Hamid, Hoda M.; Rizk, Hoda Ibrahim; Magdy, Sally title: Occurrence of pulmonary residuals as one of the sequelae of COVID-19 and it's predictors among moderate and severe cases date: 2021-02-03 journal: Indian J Tuberc DOI: 10.1016/j.ijtb.2021.01.006 sha: 22bd728b25b42e8a1d43270699400d93f06c6487 doc_id: 828699 cord_uid: u8xa0tku BACKGROUND: Moderate and severe COVID-19 patients typically present with pneumonia. In this study we aimed to detect the occurrence of pulmonary residuals as a late sequela of COVID-19 and to identify it's predictors among moderate and severe cases. METHODS: This observational prospective study involved 85 COVID-19 patients confirmed by real time polymerase chain reaction (RT-PCR) nasopharyngeal swab, patients were recruited in the period of 1 st of June to 1 st of July. Demographic and clinical data were obtained for each patient. Chest imaging was performed initially and after 3 weeks to detect post COVID pulmonary residuals. RESULTS: The study population included 74 (87.1%) moderate and 11 (12.9%) severe patients. Patients with older age, male gender, high BMI and initial chest CT of consolidation/mixed consolidation and ground glass opacities (GGOs) had more frequent post COVID-19 pulmonary residuals (P 0.003, 0.026, 0.031, 0.035) respectively. There was a statistically significant difference between patients who showed complete resolution and patients who developed pulmonary residuals regarding the lymphocyte count, serum CRP and ferritin levels (P 0.0001). After logistic regression, male gender, high BMI, initial chest CT of consolidation/mixed consolidation and GGOs, lymphocytopenia, high serum CRP and ferritin levels were the predictors of pulmonary residuals. While the age wasn't statistically significant. CONCLUSION: 38.5% of moderate and severe COVID-19 patients tend to have pulmonary residuals. Independent predictors of pulmonary residuals as a sequela of COVID-19 are male gender, high BMI, initial chest CT of consolidation and mixed consolidation/GGOs, lymphocytopenia, high serum CRP and ferritin levels. At the end of the year 2019, the world witnessed the emergence of the COVID-19 (coronavirus disease) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) [1] . It all started in Wuhan city, China. The disease crossed China's borders to several other countries and was declared as a pandemic [2] . Rapid disease progression as well as diversity of the disease's clinical presentation that ranges from mild flu like illness to fatal forms of the disease targeting mainly the lungs [3] , made it crucial to develop stratagems to identify early predictors of COVID-19. This assisted in prognosticating the disease course, helped in triaging patients along with implementing an efficient management approach to every one thus improving survival as well as conserving limited resources [4] . Residual pulmonary imaging abnormalities and breathing difficulties were reported in patients recovered from previous coronavirus diseases [5, 6] . Various mechanisms of lung injury in COVID-19 have been described, with both viral and immunemediated mechanisms being involved [7] . COVID-19 lung injury is followed by acute inflammation and an attempt at pulmonary tissue repair. This result in the restoration of normal pulmonary architecture or it may proceed to lung fibrosis with architectural distortion and irreversible lung dysfunction [8] . Persistent pulmonary lesions secondary to SARS-COV-2 infection was one of the disease outcomes that required research attention. Early identification of those patients and treatment not only hinders disease progression to progressive fibrosis, but might also advocates near complete resolution. The aim of this study was to identify the occurrence of persistent pulmonary lesions as one of the sequelae of COVID-19 and to detect clinical, laboratory and radiological predictors that could help in the early recognition of those who are likely to had pulmonary residuals. This observational prospective study was performed on COVID-19 patients who tested positive by the real time polymerase chain reaction (RT-PCR) of nasopharyngeal sample in the period from first of June to first of July 2020. Patients were enrolled from two quarantine-hospitals in Cairo government. According to the clinical management of COVID-19 as declared by the World Health Organization (WHO), the diagnosis and classification of severity of COVID-19 disease were established [9] . Mild COVID-19: patients with COVID-19 infection without clinical signs of pneumonia or hypoxia. Moderate COVID-19: patients with clinical signs of pneumonia (fever, cough, dyspnea, tachypnea) but no signs of severe pneumonia and oxygen saturation ≥ 90% on room air. Severe COVID-19: patients with clinical signs of pneumonia and one of the following: respiratory rate > 30 breaths/min; severe respiratory distress; or oxygen saturation < 90% on room air. Treatment protocol followed the National Institute of Health treatment guidelines [10] . Accordingly, steroids were used in treatment protocol of moderate cases requiring supplemental oxygen and in severe cases who requiring mechanical ventilation. J o u r n a l P r e -p r o o f Any adult patient suffering from moderate and severe COVID-19 disease was included in this study. While mild cases according to WHO classification and pediatric age group patients were excluded. All patients with moderate and severe COVID-19 infection who were recruited in the period from first of June to first of July 2020 and committed to the follow up visit, who fulfilled the eligibility criteria and accept to participate in the study were included (85 patients). A set of demographic and clinical data were obtained for each patient (age, gender, body mass index (BMI), smoking history and comorbid conditions). Each patient was subjected to a checklist of COVID-19 symptoms with yes/no response including the constitutional symptoms as fever, fatigue and bony aches as well as respiratory symptoms as cough, dyspnea and sore throat in addition to headache, anosmia and diarrhea. Laboratory assessment as complete blood picture, urea, creatinine, liver transaminases, serum Creactive protein (CRP), D-dimer and ferritin were collected within 24 hours of symptom onset and oxygen saturation was recorded. Analysis of initial chest CT findings is performed according to "Glossary of Terms for Thoracic Imaging" established by the Fleischner Society in 2008 [11] . CT findings including predominant Follow up of patient's symptoms and oxygen saturation were recorded together with follow up chest CT was performed to assess the disease prognosis after 3 weeks of symptom onset and was compared to the initial chest CT. As notable radiographic progression occurred within the first 4 weeks followed by stabilization of these shadows [12] . The data were analyzed using IBM SPSS (Statistical Package of Social Science) version 23. Normality distribution of the data was tested by using Shapiro-Wilk test. Clinical characteristics, and laboratory data of the patients were presented by using the median and inter quartile range (IQR) for not normally distributed numerical data and by using frequency and percentage for qualitative data. The difference between group I (included patients whose follow up chest CT improved after 3 weeks of symptom onset), and group II (whose follow up chest CT showed persistent pulmonary lesions) regarding the clinical characteristics of the patient, laboratory findings and chest CT findings were assessed through chi-squared test for categorical variables and through Mann-Whitney for quantitative variables. Binary logistic regression analysis was done to identify predictors of post COVID-19 persistent pulmonary lesions after being adjusted for their potential mutual confounding effect. The results are presented as odds ratios (OR) and 95% confidence intervals (CIs). P-value ≤ 0.05 was considered statistically significant. All tests were two-tailed. The aim and nature of the study was explained for patient's relatives before inclusion. An informed written consent was obtained from relatives of participants before enrollment. The The study population included 85 patients who had moderate and severe COVID-19 infection, they were 74 (87.1%) moderate and 11 (12.9%) severe according to WHO classification, 56.5% were males and 43.5% were females with median age of 52 and interquartile range (IQR) (37.5-59.5) years. Other clinical characteristics of the study population were summarized in Table (1) . The patients were divided into two groups according to their follow up chest CT after 3 weeks. Group I (n= 51) included patients whose follow up chest CT improved either complete resolution or residual linear opacities. While group II (n=32) whose follow up chest CT showed persistent pulmonary lesions to COVID-19 infection. 2 patients of the study population had severe COVID-19 disease and died of respiratory failure within first week of illness. The median age in group I was 45 (IQR= 35 -56) while in group II was 55 (IQR= 50.2-64.7) years with statistically significant difference between 2 groups (P= 0.003). Also there was statistically significant difference between the two groups in gender with more predilection to males in group II (P= 0.026). Patients who developed persistent pulmonary lesions recorded significantly higher median BMI than patients showed complete resolution (P = 0.031). Regarding the medical comorbidities (diabetes, hypertension, cardiovascular disease), 55.6 % of the patients in group II had medical comorbidities compared to 44.4% in group I with statistically significant difference between the two groups, (P value= 0.027) ( Table 2) . All patients in group I had moderate COVID-19 infection whereas group II included 23 (71.8%) patients of moderate infection and 9 (28.2%) with severe infection showing a statistical significance with p value (0.0001). There was statistically significant difference between the 2 groups in certain labs as NLR lymphocytic count, lymphocytes %, Neutrophil %, Urea (mg/dl), Creatinine, AST, CRP and ferritin as outlined in Table ( 2). Initial chest CT of pure consolidation/ mixed consolidation and GGOs pattern was statistically significant as regarding development of post COVID-19 persistent pulmonary lesions, (P= 0.035) Table ( 3) and Figure (1) . A logistic regression was performed to detect the effects of age, sex, BMI, CRP, ferritin, lymphocyte count as well as initial chest CT pattern on the probability of participants to progress to persistent pulmonary lesions as a sequela of COVID-19 disease. The logistic regression model was statistically significant, χ2 = 2.6, p < .0001. The model explained 64% (Nagelkerke R2) of the variance in persistent pulmonary lesions as a sequela of COVID-19 disease and correctly J o u r n a l P r e -p r o o f classified 86.7% of cases. Males were 7 times more likely to exhibit post COVID-19 persistent pulmonary lesions than females. Those with consolidation/ mixed consolidation and GGOs patterns was 5 times more likely to exhibit persistent pulmonary lesions than those with ground glass appearance. With one unit increase in the BMI, CRP, ferritin the odds of exhibiting persistent pulmonary lesions tend to increase by 12.5%, 1.2%, 0.3% respectively whereas decreasing lymphocytic count by one unit was associated with a 75% increase in the odds of exhibiting persistent pulmonary lesions while the age was not statistically significant. The aim of our study is to identify the occurrence of persistent pulmonary lesions as one of the sequelae of COVID-19 and to detect clinical, laboratory and radiological predictors of these persistent lesions. In our study, 38.5% of the study population had tendency to have persistent pulmonary lesions, persistent pulmonary symptoms and hypoxia after 3 weeks of follow up. It is worth mentioning that those patients were older, mostly males with higher BMI, and more prevalence of comorbid illness than patients who showed near complete resolution as evidenced by their chest CT. Several previous studies have already established that advanced age, male gender and the presence of comorbid illness are considered as risk factors associated with adverse COVID-19 disease outcome. [13] [14] [15] As this may be related to the fact that age advancement is associated with the reduction in both cell mediated function and humoral immune response as well as cellular homeostasis impairment thus reducing the body's capability to mount proper response to external stimuli including J o u r n a l P r e -p r o o f viruses [16, 17] . Our finding that older age was associated with adverse disease outcome was consistent with other reports [18] . Similarly those who have an already compromised functioning organ as in those with comorbid illness are not capable of maintaining proper viral response hence further loading the body and as COVID-19 disease progress body oxygen decreases, contributing to more organ dysfunction [19] . With regard to gender, our observation that the disease is more prevalent in males has already been reported by a previous study [20] , researchers assumed that the sex difference is possibly related to the higher ACE2 receptor expression that has been recognized as a receptor for SARS CoV-2 and the lack of estrogen and X chromosome protection, hence weakening immune responses in males to viral respiratory diseases, thus signifying that males are more susceptible to increased severity of infection [21, 22] . In our study, males were 6.7 times more likely to have persistent pulmonary lesions than females. Likewise, Obesity aggravates the severity of respiratory diseases through inducing a low grade chronic inflammatory state evidenced by the upregulated pro-inflammatory cytokines, adipokines and interleukin 6 (IL-6) levels over expression [23] [24] [25] , coupled with rapid severe disease progression through dysregulated immune response and impaired T cell memory function [26] . Our finding presuming that one unit increase in the BMI increase the risk of persistent pulmonary lesions by 12.5%. Using lymphocytopenia to stipulate insights regarding COVID-19 prognosis is reported in several studies [18] . Several possible mechanisms hypothesizing the occurrence of lymphocytopenia in COVID-19 patients were presumed as that SARS-COV-2 may either induce direct infection or cytokine-mediated lymphocyte destruction as well as increased lymphocytic J o u r n a l P r e -p r o o f migration to the lungs [27] . So, acknowledging lymphocytopenia as one of the potential predictors to severe inflammation and tissue injury was mandatory which in turn influenced the tissue reparative process explaining our finding that decreasing lymphocytic count by one unit was associated with a 75% increase in the odds of exhibiting post COVID-19 persistent pulmonary lesions. Similarly, other biomarkers that mirror the inflammatory state of the body and contribute to weakening the immune responses [28] are also potential predictors of the disease, CRP and ferritin should be the first in line to be considered. Acute inflammation is associated with an evident increase in the C-reactive protein (CRP) levels denotes tissue injury [29] . Also increased serum ferritin levels via inflammation triggers a sequence of events where higher ferritin levels signals more tissue damage [30] . The present study revealed that a unit increase in the CRP and ferritin levels increases the risk of progression to persistent pulmonary lesions development by 1.2%, 0.3% respectively. Authors of this study postulate that lymphopenia, high CRP and ferritin levels in patients who tend to have persistent pulmonary lesions imply an inflammatory profile that appears to be associated with consolidation present in their initial CT. This suggests more pronounced tissue injury and delayed healing process with a protracted disease course. These findings echo the latest report, that severe patients with affection of more than half of their lungs presented with higher CRP level and neutrophil count, lower lymphocyte count, and more • COVID-19 lung injury is followed by acute inflammation and an attempt at pulmonary tissue repair. This result in the restoration of normal pulmonary architecture or it may proceed to lung fibrosis with architectural distortion and irreversible lung dysfunction • Persistent pulmonary lesions secondary to SARS-COV-2 infection was one of the disease outcomes that required research attention. A novel coronavirus from patients with pneumonia in China Cheng Z Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet COVID-19 pneumonia: a review of typical CT findings and differential diagnosis. Diagnostic and interventional imaging Self-reported olfactory loss associates with outpatient clinical course in COVID-19 Acute Middle East respiratory syndrome coronavirus: temporal lung changes observed on the chest radiographs of 55 patients Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV Pulmonary fibrosis in COVID-19 survivors: Predictive factors and risk reduction strategies. Pulmonary Medicine World Health Organization. Clinical management of COVID-19: interim guidance COVID-19) Treatment Guidelines Fleischner Society: glossary of terms for thoracic imaging The pulmonary sequalae in discharged patients with COVID-19: a short-term observational study Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine Predictive factors for disease progression in hospitalized patients with coronavirus disease 2019 in Wuhan Crosstalk between P53 and DNA damage response in ageing The immunopathogenesis of sepsis in elderly patients Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan Predictors of coronavirus disease 19 (COVID-19) pneumonitis outcome based on computed tomography (CT) imaging obtained prior to hospitalization: a retrospective study Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study The X chromosome and sexspecific effects in infectious disease susceptibility Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent Obesity, inflammation and the immune system Microbes and obesity-interrelationship between infection, adipose tissue and the immune system LICORN and the Lille COVID-19 and Obesity study group. High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation Obesity: The "Achilles heel" for COVID-19 The immune system in critical illness Use of national pneumonia surveillance to describe influenza A (H7N9) virus epidemiology Neutrophils: multitasking first responders of immunity and tissue homeostasis Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells