DOI: https://doi.org/10.21203/rs.3.rs-30388/v1
Objective: To conduct a systematic review and meta-analysis on the comorbidities, symptoms, clinical characteristics and treatment of COVID-19 patients.
Method: Epidemiological studies published in 2020 (from January-March) on the clinical presentation, laboratory findings and treatments of COVID-19 patients were identified from PubMed/MEDLINE and Embase databases. Studies published in English by 27th March, 2020 with original data were included. A random-effects model was used to aggregate estimates across eligible studies and produce meta-analytic estimates. Primary outcomes included comorbidities of COVID-19 patients, their symptoms presented on hospital admission, laboratory results and radiological outcomes, and pharmacological and in-patient treatments.
Results: 77 studies were included in this meta-analysis, accounting for a total of 11,028 COVID- 19 patients in multiple countries. The most common comorbidities were hypertension (18.1%, 95%CI: 15.4-20.8%). The most frequently identified symptoms were fever (72.4%, 95%CI: 67.2-77.7%) and cough (55.5%, 95%CI: 50.7-60.3%). For pharmacological treatment, 63.9% (95%CI: 52.5-75.3%), 62.4% (95%CI: 47.9-76.8%) and 29.7% (95%CI: 21.8-37.6%) of patients were given antibiotics, antiviral, and corticosteroid, respectively. Notably, 62.6% (95%CI: 39.9- 85.4%) and 20.2% (95%CI: 14.6-25.9%) of in-patients received oxygen therapy and non- invasive mechanical ventilation, respectively.
Conclusions: This meta-analysis informed healthcare providers about the timely status of characteristics and treatments of COVID-19 patients across different countries.
PROSPERO Registration Number: CRD42020176589
Following the possible patient zero of coronavirus infection identified in early December 2019 (1), the Coronavirus Disease 2019 (COVID-19) has been recognized as a pandemic in mid- March 2020 (2), after the increasing global attention to the exponential growth of confirmed cases (3). As on 29 March, 2020, around 690 thousand persons were confirmed infected, affecting 199 countries and territories around the world, in addition to 2 international conveyances: the Diamond Princess cruise ship harbored in Yokohama, Japan, and the Holland America's MS Zaandam cruise ship. Overall, more than 32 thousand died and about 146 thousand have recovered (4).
A novel bat-origin virus, 2019 novel coronavirus, was identified by means of deep sequencing analysis. SARS-CoV-2 was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%) (5), both of which were respectively responsible for two zoonotic human coronavirus epidemics in the early 21st century. Following a few initial human infections (6), the disease could easily be transmitted to a substantial number of individuals with increased social gathering (7) and population mobility during holidays in December and January (8). An early report has described its high infectivity (9) even before the infected becomes symptomatic (10). These natural and social factors have potentially influenced the general progression and trajectory of the COVID-19 epidemiology.
By the end of March 2020, there have been approximately 3,000 reports about COVID-19 (11). The number of COVID-19-related reports keeps growing everyday, yet it is still far from a clear picture on the spectrum of clinical conditions, transmissibility and mortality, alongside the limitation of medical reports associated with reporting in real time the evolution of an emerging pathogen in its early phase. Previous reports covered mostly the COVID-19 patients in China. With the spread of the virus to other continents, there is an imminent need to review the current knowledge on the clinical features and outcomes of the early patients, so that further research and measures on epidemic control could be developed in this epoch of the pandemic.
Search strategy and selection criteria
The systematic review was conducted according to the protocol registered in the PROSPERO database (CRD42020176589). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline throughout this review, data were identified by searches of MEDLINE, Embase and references from relevant articles using the search terms "COVID", “SARS-CoV-2”, and "novel coronavirus" (Appendix 1). Articles published in English up to 27th March, 2020 were included. Studies with original data including original articles, short and brief communication, letters, correspondences were included. Editorials, viewpoints, infographics, commentaries, reviews, or studies without original data were excluded. Studies were also excluded if they were animal studies, modelling studies, or did not measure symptoms presentation, laboratory findings, treatment and therapeutics during hospitalization.
After the removal of duplicate records, two reviewers (CW and CHA) independently screened the eligibility criteria of study titles, abstracts and full-texts, and reference lists of the studies retrieved by the literature search. Disagreements regarding the procedures of database search, study selection and eligibility were resolved by discussion. The second and the last authors (JW and AW) verified the eligibility of included studies.
Outcomes definitions
Signs and symptoms were defined as the presentation of fever, cough, sore throat, headache, dyspnea, muscle pain, diarrhea, and rhinorrhea at the hospital admission.
Laboratory findings included a complete blood count (white blood count, neutrophil, lymphocyte, platelet count), procalcitonin, prothrombin time, urea, and serum biochemical measurements (including electrolytes, renal-function and liver-function values, creatine kinase, lactate dehydrogenase, C-reactive protein, Erythrocyte sedimentation rate), and treatment measures (i.e. antiviral therapy, antibiotics, corticosteroid therapy, mechanical ventilation, intubation, respiratory support, and renal replacement therapy). Radiological outcomes included bilateral involvement identified and pneumonia identified by chest radiograph.
Comorbidities of patients evaluated in this study were hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, chronic kidney disease, liver disease and cancer.
In-patient treatment included intensive care unit admission, oxygen therapy, non-invasive ventilation, mechanical ventilation, Extracorporeal membrane oxygenation (ECMO), renal replacement therapy, and pharmacological treatment. Use of antiviral drugs (Lopinavir/ritonavirm, Ribavirin, Interferon-alpha, or Interferon-beta), antibiotic drugs, corticosteroid, and inotropes (Nor-adrenaline, Adrenaline, Vasopressin, Phenylephrine, Dopamine, or Dobutamine) were considered.
Data analysis
Three authors (CW, EHMT and CHA) extracted data using a standardized spreadsheet to record the article type, country of original, surname of first author, year of publications, sample size, demographics, comorbidities, symptoms, laboratory and radiology results, pharmacological and non-pharmacological treatments.
We aggregated estimates across 90 eligible studies to produce meta-analytic estimates using a random-effects model. For dichotomous outcomes, we estimated the proportion and its respective 95% confidence interval. For laboratory parameters as continuous outcomes, we estimated the mean and standard deviation from the median and interquartile range if the mean and standard deviation were not available from the study (12), and calculated the mean and its respective 95% confidence intervals. Random-effect models on DerSimonian and Laird method were adopted due to the significant heterogeneity, checked by the I2 statistics and the p-values. I2 statistic of <25%, 25-75% and ≥75% is considered as low, moderate, high likelihood of heterogeneity. Pooled estimates were calculated and presented by using forest plots. Publication bias was estimated by Egger’s regression test. Funnel plots of outcomes were also presented to assess publication bias.
All statistical analyses were conducted using the STATA Version 13.0 (Statacorp, College Station, TX). The random effects model was generated by the Stata packages ‘Metaprop’ for proportions (13) and ‘Metan’ for continuous variables (14).
Ethical approval
This study was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Long West Cluster (Reference Number: UW 20-112).
Role of the funding source
There was no funding source for this study.
The selection and screen process are presented in eFigure 1 in the Supplement. A total of 241 studies were found by our searching strategy (71 in PubMed and 170 in Embase). 46 records were excluded due to duplication. After screening the abstracts and titles, 100 English studies were with original data and included in full-text screening. By further excluding 10 studies with not reporting symptoms presentation, laboratory findings, treatment and therapeutics, 90 studies (15-104) and 77 studies (15-29, 32-38, 40-43, 47-52, 55-62, 65-77, 79-94, 96, 98-103) were included in the current systematic review and meta-analysis respectively. 73.3% (66) studies were conducted in China. The summary of the included study is shown in Table 1.
Of those 90 eligible studies, 11,028 COVID-19 patients were identified and included in the systematic review. More than half of patients (6,336, 57.5%) were from mainland China. The pooled mean age was 45.8 (95% CI: 38.6-52.5) years and 49.3% (pooled 95% CI: 45.6-53.0%) of them were male.
For specific comorbidity status, the most prevalent comorbidity was hypertension (18.1%, 95% CI: 15.4-20.8%), followed by cardiovascular disease (11.8%, 95% CI: 9.4-14.2%) and diabetes (10.4%, 95% CI: 8.7-12.1%). The pooled prevalence (95% CI) of COPD, chronic kidney disease, liver disease and cancer were 2.0% (1.3-2.7%), 5.2% (1.7-8.8%), 2.5% (1.7-3.4%) and 2.1% (1.3%-2.8%) respectively. Moderate to substantial heterogeneity between reviewed studies were found, with I2 statistics ranging from 39.4% to 95.9% (p-values between <0.001-0.041), except for liver disease (I2 statistics: 1.7%, p=0.433). Detailed results for comorbidity status are displayed in Figure 1.
Regarding the symptoms presented at hospital admission, the most frequent symptoms were fever (pooled prevalence: 72.4%, 95% CI: 67.2-77.7%) and cough (pooled prevalence: 55.5%, 95% CI: 50.7-60.3%). Sore throat (pooled prevalence: 16.2%, 95% CI: 12.7-19.7%), dyspnoea (pooled prevalence: 18.8%, 95% CI: 14.7-22.8%) and muscle pain (pooled prevalence: 22.1%, 95% CI: 18.6-25.5%) were also common symptoms found in COVID-19 patients, but headache (pooled prevalence: 10.5%, 95% CI: 8.7-12.4%), diarrhoea (pooled prevalence: 7.9%, 95% CI: 6.3-9.6%), rhinorrhoea (pooled prevalence: 9.2%, 95% CI: 5.6-12.8%) were less common. The I2 statistics varied from 68.5% to 97.1% (all p-values<0.001), indicating a high heterogeneity exists across studies. Figure 2 shows the pooled proportion of symptoms of patients presented at hospital.
For laboratory parameters, white blood cell (pooled mean: 5.31 ×109/L, 95% CI: 5.03- 5.58×109/L), neutrophil (pooled mean: 3.60×109/L, 95% CI: 3.31-3.89×109/L), lymphocyte (pooled mean: 1.11 ×109/L, 95% CI: 1.04-1.17×109/L), platelet count (pooled mean: 179.5 U/L, 95% CI: 172.6-186.3 U/L), aspartate aminotransferase (pooled mean: 30.3 U/L, 95% CI: 27.9-32.7 U/L), alanine aminotransferase (pooled mean: 27.0 U/L, 95% CI: 24.4-29.6 U/L) and C- reactive protein (CRP) (pooled mean: 22.0 mg/L, 95% CI: 18.3-25.8 mg/L) and D-dimer (0.93 mg/L, 95% CI: 0.68-1.18 mg/L) were the common laboratory test taken for COVID-19 patients. Above results and other clinical factors are depicted in Figure 3. Same with the comorbidity status and symptoms, high likelihood of heterogeneity was detected by I2 statistics for a majority of clinical parameters.
Figure 4 presents the distribution of the pharmacological treatments received for COVID-19 patients. 10.6% of patients admitted to intensive care units (pooled 95% CI: 8.1-13.2%). For drug treatment, 63.9% (pooled 95% CI: 52.5-75.3%), 62.4% (pooled 95% CI: 47.9-76.8%) and 29.7% (pooled 95% CI: 21.8-37.6%) patients used antibiotics, antiviral, and corticosteroid, respectively. 41.3% (pooled 95% CI: 14.3-68.3%) and 50.7% (pooled 95% CI: 9.2-92.3%) reported using Lopinavir/Ritonavir and interferon-alpha as antiviral drug treatment, respectively. No reviewed studies reported the proportion of patients receiving Ribavirin, Interferon-beta, or inotropes.
The prevalence of radiological outcomes and non-pharmacological treatments were presented in Figure 5. Radiology findings detected chest x-ray abnormalities, with 74.4% (95% CI: 67.6- 81.1%) of patients with bilateral involvement and 74.9% (95% CI: 68.0-81.8%) of patients with viral pneumonia. 62.6% (pooled 95% CI: 39.9-85.4%), 20.2% (pooled 95% CI: 14.6-25.9%), 15.3% (pooled 95% CI: 11.0-19.7%), 1.1% (pooled 95% CI: 0.4 -1.8%) and 4.7% (pooled 95% CI: 2.1-7.4%) took oxygen therapy, non-invasive ventilation, mechanical ventilation, ECMO and dialysis respectively.
The funnel plots and results Egger’s test of comorbidity status, symptoms presented, laboratory test and treatment were presented in eFigure 2-6 in the Supplement.
This meta-analysis reveals the condition of global medical community responding to COVID-19 in the early phase. During the past four months, a new major epidemic focus of COVID-19, some without traceable origin, has been identified. Following its first identification in Wuhan, China, the virus has been rapidly spreading to Europe, North America, Asia, and the Middle East, in addition to African and Latin American countries. Three months since Wuhan CDC admitted that there was a cluster of unknown pneumonia cases related to Huanan Seafood Market and a new coronavirus was identified as the cause of the pneumonia (105), as on 1 April, 2020, there have been 858,371 persons confirmed infected with COVID-19, affecting 202 countries and territories around the world. Although this rapid review is limited by the domination of reports from patients in China, and the patient population is of relative male dominance reflecting the gender imbalance of the Chinese population (106), it provides essential information and practical guidance for clinicians and policy makers.
In this review, the pooled mean age was 45.8 years. Similar to the MERS-CoV pandemic (107), middle-aged adults were the at-risk group for COVID-19 infections in the initial phase, which was different from the H1N1 influenza pandemic where children and adolescents were more frequently affected (108). Biological differences may affect the clinical presentations of infections; however, in this review, studies examining the asymptomatic COVID-19 infections or reporting any previous infections were not included. It is suggested that another systematic review should be conducted to compare the age-specific incidence rates between the pre- pandemic and post-pandemic periods, so as to understand the pattern and spread of the disease, and tailor specific strategies in infection control.
Both sexes exhibited clinical presentations similar in symptomatology and frequency to those noted in other severe acute respiratory infections, namely influenza A H1N1 (109) and SARS (110, 111). These generally included fever, new onset or exacerbation of cough, breathing difficulty, sore throat and muscle pain. Among critically ill patients usually presented with dyspnoea and chest tightness (20, 37, 69, 70), 141 (4.6%) of them with persistent or progressive hypoxia resultsed in the requirement of intubation and mechanical ventilation (112), while 194 (6.4%) of them required non-invasive ventilation, yielding a total of 11% of patients requiring ventilatory support, which was similar to SARS (113).
The major comorbidities identified in this review included hypertension, cardiovascular diseases and diabetes mellitus. Meanwhile, the percentages of patients with chronic renal diseases and cancer were relatively low. These chronic conditions influencing the severity of COVID-19 had also been noted to have similar effects in other respiratory illnesses such as SARS, MERS-CoV and influenza (114, 115). Higher mortality had been observed among older patients and those with comorbidities.
Early diagnosis of COVID-19 was based on recognition of epidemiological linkages; the presence of typical clinical, laboratory, and radiographic features; and the exclusion of other respiratory pathogens. The case definition had initially been narrow, but was gradually broadened to allow for the detection of more cases, as milder cases and those without epidemiological links to Wuhan or other known cases had been identified (116, 117). Laboratory investigations among COVID-19 patients did not reveal specific characteristics - lymphopenia and elevated inflammatory markers such as CRP are some of the most common haematological and biochemical abnormalities, which had also been noticed in SARS (118). None of these features were specific to COVID-19. Therefore, diagnosis should be confirmed by SARS-CoV–2 specific microbiological and serological studies, although initial management will continue to be based on a clinical and epidemiological assessment of the likelihood of a COVID-19 infection.
Radiology imaging often plays an important role in evaluating patients with acute respiratory distress; however, in this review, radiological findings of SARS-CoV-2 pneumonia were non- specific. Despite chest radiograph usually revealed bilateral involvement and Computed Tomography usually showed bilateral multiple ground-glass opacities or consolidation, there were also patients with normal chest radiograph, implying that chest radiograph might not have high specificity to rule out pneumonia in COVID-19.
Limited clinical data were available for asymptomatic COVID-19 infected persons. Nevertheless, asymptomatic infection could be unknowingly contagious (119). From some of the official figures, 6.4% of 150 non-travel-related COVID-19 infections in Singapore (120), 39.9% of cases from the Diamond Princess cruise ship in Japan (121), and up to 78% of cases in China as extracted on April 1st, 2020, were found to be asymptomatic (119). Asymptomatic infection intensifies the challenges of isolation measures. More global reports are crucially needed to give a better picture of the spectrum of presentations among all COVID-19 infected persons. Also, public health policies including social and physical distancing, monitoring and surveillance, as well as contact tracing, are necessary to reduce the spread of COVID-19.
Concerning potential treatment regime, 62.4% of patients received antivirals (including oseltamivir, lopinavir-ritonavir, interferon alfa), while 63.9% received antibiotics (such as moxifloxacin, and ceftriaxone). In this review, around one-third of patients were given steroid, suggestive as an adjunct to IFN, or sepsis management. Antiviral agents such as ribavirin, IFN-α, and lopinavir-ritonavir were used during SARS, and the initial uncontrolled reports then noted resolution of fever and improvement in oxygenation and radiographic appearance (110, 122, 123), without further evidence on its effectiveness. At the time of manuscript preparation, there has been no clear evidence guiding the use of antivirals (124). Further research is needed to inform clinicians of the appropriate use of antivirals for specific groups of infected patients.
Limitations of this meta-analysis should be considered. First, a high statistical heterogeneity was found, which could be related to the highly varied sample sizes (9 to 4,226 patients) and study designs. Second, variations of follow-up period may miss the event leading to heterogeneity. In fact, some patients were still hospitalized in the included studies. Third, since only a few studies had compared the comorbidities of severe and non-severe patients, sensitivity analysis and subgroup analysis were not conducted. Lastly, this meta-analysis reviewed only a limited number of reports, with a predominant patient population from China. This review is expected to inform clinicians of the epidemiology of COVID-19 at this early stage. A recent report estimated the number of confirmed cases in China could reach as high as 232,000 (95% CI: 161,000, 359,000) with the case definition adopted in 5th Edition. In this connection, further evidence on the epidemiology is in imminent need.
Biographical Sketch
Dr Carlos KH Wong is an Assistant Professor (Research) at the University of Hong Kong, Hong Kong SAR, China, and is a statistician and methodologist.
Contributors
CW, JW and AW contributed equally to all aspects of study design, conduct, data interpretation, and the writing of the manuscript. CW, ET and CHA contributed to eligibility screening, data extraction from eligible studies, and data analysis and interpretation.
Declaration of interests
Authors have nothing to disclose.
Acknowledgements
None
Due to technical limitations, Table 1 is only available as a download in the supplemental files section