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Table of Contents
SYSTEMATIC REVIEW
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 85-97

Pneumothorax as a complication of COVID-19: A systematic review of individual patients' characteristics


1 Department of Medicine and Surgery, College of Medicine, Umm Al-Qura University, Al-Abdia Main Campus, Makkah, Saudi Arabia
2 Department of Family and Community Medicine, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia
3 Department of Respiratory Medicine, Al-Noor Specialist Hospital, Makkah, Saudi Arabia

Date of Submission20-Jul-2021
Date of Decision07-Sep-2021
Date of Acceptance31-Oct-2021
Date of Web Publication28-Apr-2022

Correspondence Address:
Murouj Adnan Almaghrabi
Department of Medicine and Surgery, College of Medicine, Umm Al-Qura University, Al-Abdia Main Campus, Makkah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_87_21

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  Abstract 


Since the coronavirus disease-2019 (COVID-19) outbreak in December 2019, evidence suggests an association between COVID-19 and the onset of pneumothorax (PTX). Thus, the present study aimed to investigate the onset of PTX, the possible risk factors, clinical characteristics, management, prognosis, and mechanism of PTX formation in patients with COVID-19 infection. A systematic review was done using several databases for articles published from December 2019 to January 2021. One-hundred and thirty-nine patients in a total of 87 articles fulfilled our criteria. A broad age range was affected (mean and standard deviation of 57 ± 15.39) with male predominance (77.7%). Most patients (66.2%) developed PTX during the hospital stays. In those who developed PTX, the most recognized characteristics included male gender (77.7%), severe COVID-19 infection (41%), mechanical ventilation (43.2%), age >65 years (30.9%), other diseases (79.1%), and smoking (8.6%). A good prognosis was reported in more than half of the patients (83; 59.7%). Death was significantly associated with critical conditions of COVID-19, bilateral PTX, respiratory distress, and mechanical ventilation (P = 0.006, 0.001, 0.013, and 0.001, respectively). PTX is a potential complication of COVID-19 infections, commonly noticed in the right lung. Mechanical ventilation, COVID-19 severity, bilateral PTX, and acute respiratory distress were associated with worse outcomes in COVID-19 patients with PTX.

Keywords: Complication, coronavirus, coronavirus disease 2019, manifestations, pneumothorax


How to cite this article:
Almalki AM, Almaghrabi MA, Alharbi AH, Basahal AM, Alharbi BA, Alfelali M, Shabrawishi M. Pneumothorax as a complication of COVID-19: A systematic review of individual patients' characteristics. J Nat Sci Med 2022;5:85-97

How to cite this URL:
Almalki AM, Almaghrabi MA, Alharbi AH, Basahal AM, Alharbi BA, Alfelali M, Shabrawishi M. Pneumothorax as a complication of COVID-19: A systematic review of individual patients' characteristics. J Nat Sci Med [serial online] 2022 [cited 2023 Mar 27];5:85-97. Available from: https://www.jnsmonline.org/text.asp?2022/5/2/85/344214




  Introduction Top


Coronavirus disease-2019 (COVID-19) is a novel coronavirus caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) family.[1] It was identified in December 2019, in the city of Wuhan, China, from where it quickly spread across the world with a high infection rate, after which it was declared a global pandemic by the World Health Organization (WHO).[1] COVID-19 patients present mainly with fever, cough, sore throat, headache, and fatigue.[2] In severe cases, the infection may progress into pneumonia, acute respiratory distress syndrome (ARDS), acute cardiac problems, and multiple organ dysfunction.[3] In addition, elderly and patients with multiple comorbidities were shown to be more prone to severe lung injury.[4]

Pneumothorax (PTX) is defined as the presence of air between the visceral and parietal layers of the lung's pleura. Patients mainly complain of the sudden onset of shortness of breath and pleuritic chest pain. However, PTX may be asymptomatic in 10% of patients.[5] Based on the etiology, PTX is divided into two groups traumatic and atraumatic. Traumatic PTX can be due to a blunt or penetrating trauma that results in simple, tension, or open. Atraumatic PTX is subdivided into primary spontaneous pneumothorax, which has no obvious cause, and secondary spontaneous pneumothorax, which is caused by underlying lung diseases such as obstructive lung diseases, infection, or iatrogenic.[6] Although mechanical ventilation is known to be the most common cause of iatrogenic PTX some studies have found that mechanical ventilation is not the only culprit, and it is usually related to an underlying lung pathology.[7] Coronavirus infections have been associated with PTX as a rare respiratory complication that was reported to be approximately 1%.[8]

Robert J Mason reported that the mechanism of injury to the lungs occurs mainly via viral attack of type II alveolar cells, leading to apoptosis, death, and diffuse alveolar damage.[9] However, this process is not the only mechanism that may lead to damage to the lungs; Koichi Yuki et al. reported that pathological T-cells and neutrophils may also play a role in the process of lung injury.[10] All of these mechanisms lead to ARDS and/or respiratory failure seen in the patients with severe COVID-19 infections. However, studies of PTX in COVID-19 patients are still lacking. This study aimed to discover the onset of PTX, possible risk factors, clinical characteristics, management, prognosis, and mechanism of PTX formation in patients with COVID-19 infections.


  Methods Top


The present study is a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines that were followed.[11]

Data sources and search strategy

We systematically searched in PubMed, EMBASE, and Google Scholar for articles published from December 2019 until January 15, 2021. In consideration of the following keywords: pneumothorax AND COVID-19 OR coronavirus OR SARS-CoV-2. In addition, the following MeSH terms were used in PubMed: (”Pneumothorax”[Mesh]) AND “Coronavirus”[Mesh]. The search was limited by applying humans and English filters.

Inclusion and exclusion criteria

This study focused on patients presenting with PTX as either early or late complication or adverse effect of COVID-19. All other conditions, such as pneumomediastinum and pneumopericardium, were excluded. Our sample was focused on adults and teenagers (>12 years); accordingly, all neonatal and children's studies were excluded, and we excluded studies that were lacking enough data based on our predefined data collection sheet. All articles that were published from December 2019 to January 2021 were included. In addition, all types of study design, including case reports, case series, cohort, and randomized controlled studies in addition to prospective and retrospective observational studies were also enrolled.

Data extraction

A defined data collection sheet was developed under the supervision of an expert pulmonologist. Relevant data were extracted from articles, and authors were contacted for further information if needed. For each case, we gathered data concerning demographic variables (including the patients' country, age, and gender), possible risk factors (including smoking status, previous medical history, and requirement for ventilation during COVID-19 infection and/or PTX), the onset of PTX, clinical characteristics (initial clinical presentation and COVID-19 symptoms), assessment of COVID-19 severity, COVID-19 management, results of diagnostic investigations, management used for PTX, and the prognosis of a patient's condition. Finally, we inspected all the studies that put forth hypotheses of the possible causes of PTX in patients with COVID-19 infection. We categorized the onset of PTX into four groups: (1) initially with the presentation of COVID-19 (IWA), (2) during hospital course (DHC), (3) after COVID-19 recovery and posthospital discharge (PHD), and (4) after incomplete management of COVID-19 (AIM) in terms of whether the patient refused to stay in the hospital or due to limited capacity problems. The severity of COVID-19 was measured based on a guideline that was published by the National Institute of Health on October 9, 2020.[12] These criteria grouped the severity into five categories [Figure 1]. Two investigators separately performed the data extraction and cross-checked the data.
Figure 1: Criteria for determination coronavirus disease-2019 severity (Based on National Institute of Health guidelines)

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Data analysis

For data analysis, IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp was used. All statistical analysis was done using two-tailed tests. A P < 0.05 was statistically significant. Hence, all data were presented in this study by using descriptive statistics, for which continuous data were expressed as mean ± standard deviation or as median and range according to the type of distribution of each variable. Frequencies and percentages were used for categorical variables. A Chi-square test was performed for testing the relationships between categorical variables.

Risk of bias and quality assessment of studies

Two independent investigators used the Joanna Briggs Institute (JBI) 2017 Critical Appraisal checklist for the assessment of the case reports, case series, and cohort studies.[13] In case of inconsistency, a consensus was reached with a third investigator.


  Results Top


Literature search

Two independent investigators identified 1700 articles after searching the databases. The investigators intensively reviewed the titles and abstracts of all articles and excluded papers that did not meet the prespecified eligibility criteria (n = 1497). After that step, duplicates were excluded (n = 111). Finally, five articles were excluded as they were lacking individuals' data. The final number of enrolled articles was 87,[1],[14],[15],[16],[17],[18],[19],[20]A,[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99] which included 75 case reports, 10 case series, and two cohort studies [Table 1]. Detailed information on the citation selection process is shown in [Figure 2]. A total number of 139 patients were included in the final analysis. Aggregated data summary of the demographic variables, possible risk factors, clinical characteristics, investigation modalities, management, and prognosis of all patients were reported.
Table 1: Summary of the included studies and their risk of bias measurement

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Figure 2: Flowchart of Preferred Reporting Items for Systematic Reviews and Meta-Analyses search and selection process

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Quality assessment

[Table 1] provides a summary of the quality assessment of the risk of bias for all the included articles; a justification of each rating is provided in [Supplementary Appendix Table A]. On the JBI Critical Appraisal Checklist for Case Reports, we considered articles that score 5 or less out of 8 as high risk of bias. In which, four articles were considered as a high risk of bias.[15],[27],[43],[66] In case series quality assessment, we considered the score 7 or less out of 10 as high risk of bias. Out of 10 analyzed case series, only two articles have a score 7 or less on the JBI Critical Appraisal Checklist for Case Series and were considered as a high risk of bias.[47],[99]

Among the included cohort studies, we considered the score 8 or less out of 11 as high risk of bias. Moreover, our assessment revealed only one study as high risk of bias.[75]

Characteristics of individual participants' data

The median age of the patients was 58, ranging between 14 and 90 years. More than half of the patients were males (108; 77.7%) compared to female patients (28; 20.1%), with three sets of missing data as the study did not report the complete information. Regarding comorbidities and risk factors, most of the patients were nonsmokers (123; 88.5%) and <65 years (93; 66.9%). Only one patient was underweight (body mass index [BMI] <18.5; 0.7%), and only a few patients were overweight (BMI 25–29.9) and obese/morbid obesity (BMI >30) for rates of 4.3% and 10.8%, respectively. Only 60 patients (43.2%) were ventilated during their infection courses of COVID-19 or after the onset of PTX. A previous history of diseases, including hypertension (HTN) in 34 (24.5%), diabetes mellitus (DM) in 25 (18%), and respiratory conditions (21; 15.1%), was noted. About one-third of the patients (45, 32.4%) had no known risks. Other nonspecific diseases/conditions were marked in 20 patients (14.4%). The most common manifestations (symptoms) of COVID-19 were cough (78; 56.1%), dyspnea (75; 54%), and fever (72; 51.8%). Other symptoms are described within [Table 2]. However, 16 cases (11.5%) did not report patient symptoms.
Table 2: Data analysis summary of 139 patients included in the study

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Out of 139 patients, severe cases were recognized in 57 patients (41%) and moderate in 36 patients (25.9%). Regarding the onset of PTX, our results reported DHC (92; 66.2%), IWA (25; 18%), PHD (14; 10.1%), and AIM (3; 2.2%).

Imaging

Findings including right PTX in 53 patients, left PTX in 41 patients, and bilateral in 36 patients (38.1%, 29.5%, and 25.9%, respectively) were detected. Chest X-ray (CXR) was used alone in 35 patients (25.2%) to diagnose PTX, while computerized tomography (CT) scans were used in 51 patients (36.7%), and about 52 patients underwent both modalities for the diagnosis of PTX (37.4%).

Management and prognosis

Most patients were managed by chest tube (101; 72.6%), while conservative management was followed in 27 patients (19.4%). A good prognosis (recovered and discharged) was reported in more than half of the patients (83; 59.7%), while deceased patients numbered 39 (28.1%), and eight patients were still in the hospital at the time of writing this paper (5.8%).

Association of prognosis with other variables

[Table 3] represents the association between patient prognosis and other variables, including risk factors of PTX, for which more than half of the male patients had a good prognosis, recovered, and were discharged to home (70; 71.4%). In addition, most of the patients aged <65 years had a good prognosis (62; 72.9%). On the other hand, more than half of the ventilated patients had a poor prognosis and passed away (30; 54.5%). Similarly, the mortality rate was significantly higher among critical cases of COVID-19 and among those who had bilateral PTX (57.1% and 60%, respectively). Moreover, 57.1% of patients who presented with respiratory distress died.
Table 3: Association between patients' prognosis (outcome) and other variables

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  Discussion Top


We reviewed clinical features, diagnostic imaging, interventions, and outcomes in 139 COVID-19-associated with PTX patients. In those who developed PTX, characteristics included male gender (77.7%), severe COVID-19 infection (41%), mechanical ventilation (43.2%), age >65 years (30.9%), previous diseases (79.1%), and smoking (8.6%). A good prognosis was reported in more than half of the patients (83; 59.7%). Death was significantly associated with critical conditions of COVID-19, bilateral PTX, respiratory distress, and mechanical ventilation.

Pneumothorax risks

PTX is a well-established complication of invasive ventilation[8] and high-flow nasal cannula oxygen therapy[29],[42],[50] in addition to a previous PTX. Primary lung diseases, such as COVID-19, might also be a risk factor.[35] Infection[100] and diffuse alveolar damage[50] have also proposed to cause PTX.

The formation of PTX is closely related to pre-existing lung disorders and to the presence of bullae or pneumatoceles. Other risk factors include male gender, aging, prolonged coughing, smoking, tall/thin stature, and strenuous exercise.[78],[101] In a previous multicenter retrospective case series study that found 54 patients with PTX and 11 patients with both PTX and pneumomediastinum, a higher incidence of PTX in males was reported. In addition, a bad prognosis was detected in patients aged 70 years and above.[102] This finding is consistent with our findings, in which male gender, ventilation, age >65, and history of respiratory diseases were remarkably observed risks in the included cases (77.7%, 43.2%, 30.9%, and 15.1%, respectively). In contrast, smoking history has been only found in a few cases (8.6%), this is consistent with a previous study in which they only revealed 10% of smoker patients,[103] and it could be due to poor documentation of the reports. Hence, some studies consider smoking as a risk that increases the COVID-19 severity via an increase in the gene expression of the angiotensin-converting enzyme 2 (ACE-2) receptor in the airway and oral epithelium, which results in increases in coronavirus entry. In contrast, some studies suggest that smoking is a protective factor in which nicotine may cause a decrease in gene expression of the ACE-2 receptor;[104] however, the evidence from these studies is inconclusive. In the same realm, our results showed that less than half of PTX patients were ventilated, a finding that is consistent with a previous retrospective case series study that showed out of 139 (24.2%) adults diagnosed with COVID-19 and undergoing mechanical ventilation, only 13 (9.4%) developed barotrauma, and three of them were PTX.[105] However, in our results, some cases of PTX with no risks, in which they were nonventilated, had no history of pre-existing lung conditions, had no history of smoking, and/or had no presence of bullae or pneumatoceles, were observed. These patients were females under the age of 65 years.[42],[45],[47],[80],[82],[93[,]97] The authors speculate that PTX formation was possibly linked to COVID-19 infection in those patients.

Hypotheses of the possible etiology for pneumothorax

The exact mechanism of PTX in COVID-19 patients has not been well established yet. One of our aims in this study was to collect and summarize all of the hypotheses regarding the possible mechanisms of PTX appearance in COVID-19 patients in the literature to serve as a starting point for further research. It was difficult to reach a consensus about the specific mechanism of PTX etiology. The analysis of the included literature revealed several PTX-related mechanisms: (1) alveolar destruction due to direct viral invasion along with the immunological response, (2) hypercoagulable state, and (3) mechanical ventilation, all of which may induce the formation of PTX. The extensive alveolar destruction and the inflammatory response are the leading causes of bullae formation and rupture, and this is the most reported mechanism in the literature.[14],[15],[17],[18],[19],[20],[23],[26],[29],[30],[33],[38],[41],[43],[45],[47],[51],[55],[57],[60],[67],[68],[70],[75],[76],[77],[78],[79],[81],[82],[85],[88],[90],[92],[93],[94],[95],[99] Moreover, pronounced and severe cough is strongly linked to PTX in which increased intra-alveolar pressure leads to bullae rupture.[1],[15],[17],[18],[19],[23],[25],[26],[29],[30],[33],[35],[36],[38],[42],[43],[47],[48],[54],[55],[57],[60],[74],[77],[83],[88],[91],[99] Inconsistent with our results, cough was detected as the most common manifestation (symptom) in the patients with COVID-19 who developed PTX (78; 56.1%).

Prolonged mechanical ventilation may induce PTX as a result of an increase intra-alveolar pressure.[14],[16],[21],[27],[42],[45],[46],[52],[59],[68],[84] However, our results showed that only 60 (43.2%) of COVID-19 patients who developed PTX were placed on mechanical ventilation [Table 2]. Some of the literature studies indicate that alveolar microthrombosis and hypercoagulable states result in parenchymal ischemia, fibrosis, and low alveolar compliance[106] that eventually lead to bullae formation, which may contribute to the formation of PTX in COVID-19 patients.[14],[50],[56],[58],[61],[79],[82],[90],[94] Another hypothesis suggested that the use of glucocorticoids may delay the healing process after alveolar destruction.[59],[78],[97] Smoking and pre-existing lung disease may play a role in PTX formation.[1],[14],[31] Yet, in our results, only 33 (23.7%) reported a history of either smoking or pre-existing lung diseases [Table 2].

Onset of pneumothorax

As demonstrated in the results [Table 2], the onset of PTX was diversified. Since it may occur during any phase of the infection period, it is important to bear in mind the risk of PTX development during the hospital course of COVID-19 or even after recovery. Our analysis revealed a statistically significant relationship between the onset of PTX and COVID-19 severity (P = 0.02), for which most critical cases developed PTX during the hospital course. In addition, a statistically significant P = 0.02 was discovered between the onset of PTX and smoking history [Table 4]. A study published by Wang et al.[75] indicated that the development of PTX is more likely to occur 2 weeks after dyspnea begins. They also stipulated some PTX-associated factors, such as excessive cough.
Table 4: Association between onset of pneumothorax and risk factors

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Imaging modalities of pneumothorax

A CXR has been established as a screening modality of PTX;[107] however, this modality is insufficient to discover the cause of PTX.[108] A CT scan can detect any pulmonary diseases and help plan further management strategies;[109] further, it can detect the dystrophic lesion if done before discharge.[106] Lung ultrasound is sensitive for discovering PTX as this imaging method is similar to CT, and it has higher sensitivity than that of conventional anterior–posterior chest radiography.[110] On ultrasound, the findings of barcode signs and the absence of lung sliding on a point-of-care ultrasound have high sensitivity for diagnosing PTX in emergency and critical care settings and are considered a lifesaving modality.[19],[34],[99] In our review, a patient came with recurrence of PTX after symptom resolution without chest radiograph before discharge.[65] This finding is why we endorse the recommendation of additional chest imaging as part of discharge protocol.[80]

Management/treatment of pneumothorax

Regarding the management of adult patients with secondary spontaneous PTX, both the British Thoracic Society and American College of Chest Physicians promote supplemental oxygen administration and repeat CXR in cases of minor PTX, while in cases of symptomatic patients and/or those with major or bilateral PTX, thoracostomy tube or pleural catheter placement is recommended. Hence, observing the patients alone is not recommended since there is a greater risk of mortality in those cases.[111] PTX treatment in COVID-19 patients might be more challenging than usual. That finding could be attributable to the general PTX procedure during which tube thoracostomy is possibly an aerosol-generating technique. Medical staff providers are at risk of aerosols spreading from continuous air leakage, thus using a drainage device with viral filters and covering the patient's chest while insertion or removal of the chest tube is recommended by a guideline from the American Association for the Surgery of Trauma, Acute Care Surgery, and Critical Care Committees (AAST, ACS, and CCC, respectively).[112] In fact, aerosols may be produced by bulla resection, which would usually be the first option of treatment for intractable PTX.[113] The risk of exposure also increases with transportation to the operating room, especially in cases of air leakage in the drainage system of the tubing.[114] In the literature search, two cases of intractable PTX in COVID-19 patients who underwent bulla resection in the intensive care unit without transportation were found.[16] However, this practice cannot be generalized as it is a daunting approach for certain institutions.

Pneumothorax prognosis

Prompt recognition of early PTX signs and symptom in COVID-19 patients is necessary to minimize morbidity and mortality.[115] A previous study published by Takahashi et al. aimed to simplify the etiology and prognosis of spontaneous PTX in patients aged 50 years and above. They revealed that the mortality rate was highest in patients with interstitial pneumonia and was mostly associated with infectious complications. Death or worsened respiratory failure within 180 days from admission was associated with older age, systemic corticosteroid use, and interstitial pneumonia.[116] In COVID-19 patients with PTX, the outcomes and prognosis are not well known yet. However, our results demonstrated that most of the deceased group had been ventilated (30 patients) with a statically significant, P = 0.001, which indicates the importance of close monitoring in these patients. Notably, other risk factors of PTX were not associated with the patient prognosis [Table 3]; therefore, PTX could be a fatal complication in patients with COVID-19 despite the absence of PTX risk factors. In fact, critical conditions of COVID-19, bilateral PTX, and respiratory distress were remarkably associated with death (P = 0.006, 0.001, and 0.013, respectively).

Study strengths and limitations

In this study, some limitations regarding the homogeneity of the results were found because we were mostly limited to case reports and cases series that were published in the literature, and we did not have control over the origin of said cases, nor did we have control over the points on which each report commented (missing data) because of the focus of the original authors. Despite all of these drawbacks, our study summarizes all of the literature regarding COVID-19 and PTX in either case report or case series format up to January 1, 2021. To our knowledge, this report is the first to do so.

Recommendations

The authors recommend further studies be done in the future regarding the current topic. We suggest studies that focus more on inspecting laboratory parameters, such as inflammatory markers, D-dimer, and viral loads. Furthermore, we suggest that the upcoming systematic review should include clinical trials if any and enroll other related cases, such as those concerning the pneumomediastinum that coexist with PTX which was excluded in this study. Collecting further data, such as duration between COVID-19 infection and PTX formation, and factors associated with the beginning of PTX might be necessary to enlighten clinicians to pay attention to it. Regarding the recommendation of a chest radiograph before the discharge or recovered PTX patients, it needs a prospective design to measure the outcome with the relative risk of COVID-19 with PTX versus no PTX.


  Conclusion Top


After the emergence of many case reports around the world, PTX is a potential complication of COVID-19 infections. Despite the absence of risk factors, PTX should not be ruled out of the differential diagnosis in patients with COVID-19. The current study revealed that COVID-19–related PTX was remarkably noticed in the right side of the lung. Mechanical ventilation, COVID-19 severity, bilateral PTX, and acute respiratory distress were associated with worse outcomes in COVID-19 patients with PTX. Further studies are required to obtain more informative evidence and to determine the prevalence of PTX among COVID-19 patients.

Acknowledgment

The authors would like to thank Dr. Abdulmohsen Saad Alqurashi at the College of Medicine, Umm Al-Qura University, for his valuable comments and suggestions in developing this systematic review.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


[INLINE:1]



 
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