The PRISMA diagram details the selection of articles in Fig 1. In total, eighty articles were evaluated for inclusion in the article, of which sixty-six are excluded as they were either systematic review articles, reviews, editorials, journal articles, perspectives, or correspondences. Some journal articles are not included in the quality analysis as they were not relevant to the primary outcome. A total of 14 articles were included for meta-analysis.
Fig 1: PRISMA flow diagram
In Fig 2, word clouds from abstracts and journals of recently published articles help visualize their frequency.
Fig 2 Wordclouds of (a) abstracts & (b) journals (c) Comorbidities considered in research
Among 3745 patients in China, mean age is 50.63 (95% CI: 36.84, 64.42) years, and 55.7 % (95% CI: 52.2, 59.2) were males. The common symptoms included fever 86.5% (82.7, 90.0), fatigue 41.9% (32.7, 51.4), dyspnea 29.0% (21.2, 37.5), cough 66.0% (61.3, 70.6), mucus 66% (61.3, 70.6), lymphopenia 18.9% (5.2, 38.0). Prevalent comorbidities were hypertension 16.4% (12.5, 20.8), diabetes 8.9% (7.0, 11.1), CVD 10.9% (6.1, 16.7), ARDS 14.6% (4.9, 27.8), malignancy 1.5% ( 0.05, 2.8), COPD 1.3% (0.08, 1.9). 63.5 % (33.5, 88.7) of covid-19 patients received oxygen therapy, 20.8% (8.9, 35.7) were in ventilation, 23.5% (5.9, 47.8) were at the ICU. 86.5% (76.8, 94) patients were treated with antiviral, 73.9% ( 55.3, 89.0) had antibiotics, 30% (20.6, 40.2) had corticosteroids treatment. 32.3% (21.3, 44.5) were discharged, 52.6% (43.1, 62) remained in hospital, and 7.5% (2.6, 14.4) died.
The next section provides a narrative review of the inception of the pandemic, focusing on specific comorbidities.
Origin of COVID-19
Coronaviruses are not new to human society. It has occurred previously in China in the form of Severe Acute Respiratory Syndrome (SARS) and infected over 8000 persons and 776 deaths in 2003 [6] and was named SARS-COV [7, 8]. The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was detected in Saudi Arabia in 2012 [9], infecting more than 2428 individuals and 838 deaths across 27 countries, as reported to WHO. Initial Coronavirus 2019 (COVID-19) cases began at the Huanan wholesale seafood market in China that traded live exotic animals, and since then, it has severely affected humanity. The virus was identified by genome sequencing as a coronavirus with 96.2% homology (genetic identity) with bat coronavirus (CoV RaTG13) and 79.5% similarity with SARS-CoV. Humans' transmission is through an unknown intermediate source, which scientists have suspected to be bat, swine, snake, civet, pangolin, or mouse, among others [10–12]. Identifying a potential intermediate host of SARS-CoV-2 from the SARS-CoV-2 genome features can lead us to the proximal origin of and spread of the virus, from animal species boundaries to human. It is not a laboratory construct virus. [13]. Recent research finds SARS-CoV-2 bat sarbecovirus RaTG13 as the origin, claims of pangolin [14] being the intermediate host, or the virus being laboratory construct have been discarded [15]. It has been estimated that the virus has a higher reproductive number (R0) compared to SARS [16], which is around 3.28, with a median of 2.79. Fig 3 gives an overview of the pandemic explaining its origin, transmission, and the recommended precautions.
Fig 3. COVID-19 Pandemic - A Graphical Representation
Clinical Features and Symptoms
The incubation period of the virus is 2–14 days; however, it is frequently 3–7 days [17, 18]. It is highly contagious and does get transmitted from human-to-human contact, which has led to a high number of deaths. The human-to-human spreading of the virus occurs due to proximity with an infected person or patients or an individual exposed to coughing, sneezing, and respiratory aerosols droplets. These aerosols penetrate the human body via inhalation through the mouth or nose. In the study by Guan et al., patients' median age was 47–59 years, and 41.9–45.7% were females in China [19]. The symptoms include fever, cough, fatigue, sputum production, shortness of breath, sore throat, headache, diarrhea, and nausea or vomiting [19, 20]. Cases that involve symptoms like breathing trouble, persistent pain, or pressure in the chest, confusion, bluish lips require emergency medical attention (www.cdc.gov). People over 65 years and those with underlying disorders (i.e., hypertension, chronic obstructive pulmonary disease, diabetes, cardiovascular disease) were more prone to rapidly develop acute respiratory distress syndrome, septic shock, metabolic acidosis, and coagulation dysfunction, often resulting in death [1]. The proportion of typical symptoms are represented in Fig 4.
Fig 4: Forest plot of the proportion of common symptoms
COVID-19 and Comorbidities
People with associated comorbidities and preexisting conditions, including heart failure, uncontrolled diabetes, COPD, asthma, and cancer, are the risk group who would require to be put on ventilator support or oxygen therapy due to the COVID-19 event of the hospitalization. The effects of COVID-19 and its adversity due to comorbidities are explained in Fig 5 with Table 1 comparing the proportions among three tremendously affected countries of China, India, and the US.
Fig 5: Forest plot of the proportion of Comorbidities
In all the forest plots, total patients differ for each outcome differ as there was missing data.
Table 1: Comparison of the proportion of comorbidities globally
Comorbidities
|
China (N)
|
China % (CI)
|
US (%)*
|
India (%)**
|
Hypertension
|
3356
|
16.4 (12.5,20.8)
|
21.6
|
42.5
|
Diabetes
|
3516
|
8.9 (7.0,11.1)
|
16.4
|
39.7
|
CVD
|
3587
|
10.9 (6.1,16.7)
|
34.3
|
NA
|
ARDS
|
1867
|
14.6 (4.9,27.8)
|
12.9
|
NA
|
Malignancy
|
2394
|
1.5 (0.5,2.8)
|
4.6
|
NA
|
COPD
|
2217
|
1.3 (0.8,1.9)
|
23.59
|
16.4
|
*US data from CDC website till October 24, 2020; **522 patients [21]
Acute Respiratory Distress Syndrome
Pre-clinical and clinical studies indicate that ARDS is a primary manifestation in COVID-19 patients [21]. Among a large group of hospitalized patients who died, three-fourth of them developed ARDS, a significant of them required ICU and invasive ventilation [22].
Diabetes
Patients with pre-diabetic conditions and severe metabolic complications are prone to an increased risk of severe outcome from COVID-19, thus requiring blood glucose control [23]. Also, COVID-19 may trigger diabetes in healthy people resulting in a bidirectional relationship between the two diseases; SARS-CoV-2 may cause pleiotropic alterations of glucose metabolism due as it binds with ACE2 expressed in essential metabolic organs, tissues, kidneys that could complicate conditions of preexisting diabetes or lead to new mechanisms of disease. [24]. Recent initiatives have been taken by an international group of leading diabetes researchers in the COVIDIAB project (covidiab.e-dendrite.com) to study the new-onset COVID-19 related diabetes, along with data collection on preexisting metabolic disturbances including diabetic ketoacidosis, hyperosmolarity. Diabetes mellitus was associated with the critical outcome of severe COVID-19 disease progression and mortality, which was also influenced by age, obesity, and hypertension [25, 26].
Obesity
The scarcity of Body Mass Index (BMI) data on COVID-19 patients' needs special attention in understanding the underlying relation of obesity to COVID-19 infection and its severity due to obesity-induced adipose tissue inflammation in type 2 diabetes, hypertension, cardiovascular disease[27]. Obesity can lead to decreased expiratory reserve volume, functional capacity, and respiratory system compliance. Also, previous hospitalizations due to the H1N1 virus were higher in obesity, prevalent populations of Americans Indians, Hispanics, African Americans. The adult obesity rate has increased since the time of H1N1 in 2009. Thus, indicating the severe course of COVID-19 in such groups than H1N1 [28]. This evidence draws the need for precautions, prioritizing testing, care, and expanding research in people with obesity and COVID-19 to develop an effective treatment. It is observed that most of the younger COVID-19 hospitalized population were suffering from obesity [29]. The presence of morbid obesity (BMI ≥ 35 kg/m2) aggravates the respiratory disease and can result in intensive care unit (ICU) admission [30].
Cancer
It is crucial to understand the effects of COVID-19 and its associated and potentially serious outcomes, high susceptibility, and treatment effects specifically for cancer patients. More data-driven and broad collaborative efforts are underway like TERAVOLT, CCC19, ASCO Registry, among others [31]. The significant risk for cancer patients lies in the inability to get necessary treatment, medications as the healthcare workforce being concentrated towards treating patients with COVID-19, delay in oncology clinical trials due to delayed or canceled enrollment appointments with two-hundred international trials suspended between March to April [32], and restrictions on hospital visits, delayed surgeries due to the present infection [33, 34]. Thus cancer treatments have been modified to align with the situation, such as delaying breast cancer screening and lung cancer screenings to decrease the risk of exposure, the use of personal protective equipment (PPE) in surgery rooms, and implementing the RADS (Remote visits, Avoid radiation, Defer radiation, Shorten radiation) principle [35]. Cancer patients show adverse outcomes after coronavirus infection than other healthy individuals [36]. For immunosuppressed patients, personal level control measures for COVID-19, vigorous and robust screening and monitoring, and health care improvement are the recommended strategies. There should be an emphasis on the precautionary principle, evidence-based prioritizing of treatments while treating cancer patients during this pandemic [37] since they are at increased risk of COVID-19 [38, 39]. There is a need for clear communication and education about hygiene, infection, and control measures, with consideration of postponing surgery in patient groups with the standard progression of cancer, recommending the use of telemedicine [38].
Thyroid
There is not enough significant data that suggests that patients with preexisting thyroid conditions are more susceptible to COVID-19, and there is no general guidance, unlike other comorbidities. There have been instances of thyroid dysfunction during SARS, and risks of anti-thyroid drugs resulting in agranulocytosis remain, as the symptoms resulting from agranulocytosis and COVID-19 are similar, making it difficult for doctors to distinguish between the two [40]. A study in China found that the decrease in TSH and TT3 levels positively correlated with the severity of the COVID-19 disease, with lower TSH levels present in more than half of the patients. This change in serum TSH and TT3 levels will help to diagnose the course of COVID-19 [41]. There is evidence of some COVID-19 patients suffering from ear pain, which may indicate a sign of subacute thyroiditis along with tachyarrhythmia as the most common cardiovascular disease, so monitoring of thyroid function in COVID-19 patients is essential [42]. Patients with thyroid eye disease and those undergoing treatment with immunosuppressive agents are at a very high risk of severe illness from coronavirus. Pregnant women with treated hypothyroidism should continue to follow the advice to increase levothyroxine dose and regularly check their thyroid levels [43].
Smoking
COVID-19 is mainly a disease of the respiratory tract characterized by severe acute respiratory syndrome. Studies showed that smokers are 1.4 times likely to have severe symptoms of COVID-19 and approximately 2.4 times more likely to be admitted to an ICU, need mechanical ventilation, or die compared to non-smokers [44].
Chronic Obstructive Pulmonary Disease
Preexisting chronic obstructive pulmonary disease (COPD) and ongoing smoking history are likely to worsen the progression of symptoms and treatment effectiveness for COVID-19 [45]. Compared to previous and non-smokers, current smokers are more susceptible to severe complications and higher mortality rates, requiring preventive measures [46].
Mental health
Research-based evidence suggests that anxiety and depression symptoms and self-reported stress (8%) are common psychological reactions to the COVID-19 pandemic, as there is limited interaction with the outside world. Due to the lockdown, social distancing people, financial loss, confinement within homes, mental health is likely to get impacted. There has been an increased domestic abuse rate and family violence reporting due to confinement by social isolation and quarantine measures [47]. It is very likely that the healthcare workers may experience mental health problems due to their work under nerve-wracking pressure, and need to make decisions under unprecedented conditions of scant resources, life-support and intensive care distribution to the ones those have a higher scope of survival over equally needy elderly patients[48]. Large and growing financial loss, conflicting messages and guidelines from authorities, travel and visa restrictions may be a possible cause of mental distress and anxiety and calls for immediate action[49, 50]. It is suggested that along with health care providers, children, residents of remote rural areas, immigrants, especially international student populations, should be explored. Few studies have suggested psychologists and psychiatrists' critical role in healing people's mental health affected by this pandemic and those who survive COVID-19 [51].
Blood Type and COVID-19
Several studies have identified that blood group is a risk factor for COVID-19 infection. People with blood groups A, B, and AB have an increased risk of infection, while people with blood group O have a decreased risk of infection, possibly due to less blood clotting. [52]. Table 2 provide the distribution of the blood group in the reference population and Covid-19 risk associated with the blood group in a few selected studies
Table 2: Distribution of Blood type in literature
Blood Group
|
Zhao et al. 2020[53] (China)
|
Wu et al. 2020 [54]
(China)
|
Li et al. 2020 [55]
(China)
|
Goker et al. 2020 [56]
(Turkey)
|
Barnkob et al. 2020 [52]
(Denmark)
|
|
%
|
OR
|
%
|
OR
|
%
|
OR
|
%
|
OR
|
%
|
RR
|
A
|
32.2
|
1.28
|
27.4
|
1.54
|
32.2
|
1.30
|
38.0
|
2.1
|
42.4
|
1.09
|
B
|
24.9
|
1.09
|
NA
|
NA
|
24.9
|
1.06
|
14.7
|
1.4
|
11.4
|
1.06
|
AB
|
9.1
|
1.11
|
NA
|
NA
|
9.1
|
1.13
|
10.0
|
1.3
|
4.2
|
1.15
|
O
|
33.8
|
0.68
|
30.2
|
0.65
|
33.8
|
0.68
|
37.2
|
1.8
|
41.7
|
0.87
|
OR=Odds Ratio, RR=Relative Risk, NA= Not available
It is interesting to note that the odds ratios for blood groups A, B, AB, and O in the three Chinese studies are similar. Based on these three studies, there is a 32%-35% chance reduction in the O group for Covid-19 patients. In the other two studies, the risk of getting Covid-19 infection in patients with blood group O is less than the other blood groups.
Pediatric Group and COVID-119
Children have represented 2% of diagnosed cases in China, 1.2% in Italy, and 5% of positive cases in the United States that increased to 12% as of December 19, 2020[57]. The proportion of infection among children may be milder compared to adults with better prognosis response and rare death rates [57]; however, SARS COVID-19 infections among children were occurring early in the pandemic [58], and better quality studies are required for judging increased risk for severe inflammation and multiorgan failure. Studies suggest that children of all ages are susceptible to the infection, with a significant role in community-based virus transmission [59], and the number of pediatric patients may increase in the future unless stringent measures are undertaken [60]. A recent meta-analysis based on 266 relevant articles and letters showed that children have milder than adults symptoms but with variable manifestations and significantly better mortality outcome [61].
Pregnancy during COVID-19
Based on a small group of cases, currently, there is minimal evidence for intrauterine infection caused by vertical transmission or transplacental transmission in women who develop COVID-19 pneumonia during late pregnancy with varied symptoms, including cough and fever [62]. A single case of severe maternal presentation makes it impossible to rule out the possibility of vertical transmission [63, 64]. Currently, there is no evidence to believe that pregnant women are at increased risk [65], but this group should be considered as a vulnerable population and may have more severe respiratory complications [66]. Immune, respiratory, and cardiovascular systems are affected in pregnancy due to physiological changes. COVID-19 infection during pregnancy may adversely affect these systems. A recent update on the direct and indirect effect of COVID-19 on pregnancy is provided by Wastnedge et al. 2021 [67].
Vaccines and Therapeutics development for COVID-19
Multiple pharmaceutical companies are working for the development of effective COVID-19 vaccines, such as Moderna Therapeutics, Inovio Pharmaceuticals, Novavax, Vir Biotechnology, Stermirna Therapeutics, Johnson & Johnson, Pfizer, Merck, Glaxo-smith Kline, VIDO-InterVac, GeoVax-BravoVax, Clover Biopharmaceuticals, CureVac, and Codagenix to mitigate the spread of this infectious disease.
Research institutes all over the world are working relentlessly to find a cure for COVID-19. According to the National Institute of Allergy and Infectious Diseases (NIAID) director Dr. Anthony S. Fauci, the idea of vaccine emerging by the end of the year is "aspirational, but it is certainly doable." A vaccine or any drug has to go through the four phases of clinical trials before it is approved by the US Food and Drug Administration's (FDA's) or similar authorities for human use, while continuously balancing the safety, efficacy, and side effects due to the vaccine exposure." The most significant risk concern is the transmission of infection to healthcare workers. The first case in the United States occurred on January 19. The patient's condition improved by remdesvir, an investigational broad-spectrum antiviral treatment developed by Gilead Sciences, Inc. [68]. A randomized, controlled clinical trial evaluating the safety and efficacy of treatment with antiviral remdesivir for coronavirus disease 2019 (COVID-19) was initiated by (NIAID) on February 15 via Adaptive COVID-19 Treatment Trial (ACTT) [69]. It has been statistically significant in shortening the recovery period for those who have received remdesivir rather than the placebo (median, 11 days, compared with 15 days) [70]. The next trial, ACTT2 with remdesivir with Baricitinib, a product licensed to Eli Lilly company by Incyte, will determine if this addition can benefit patient recovery [71]. Chloroquine has been used to treat malaria over the years. Chloroquine and hydroxychloroquine have a wide range of potential in treating SARS CoV [72]. A clinical trial is ongoing to establish its utilization in the treatment [73]. It was recommended to be included as a treatment due to its apparent efficacy and acceptable safety against COVID-19 associated pneumonia, improving lung image findings, shortening the recovery period, and blocking the infection in in-vitro studies according to multicenter clinical trials in China [74]. Finally, researchers from Brazil established no distinguished improvement due to the drug after 15 days from infection in a large-scale clinical trial consisting of 504 COVID-19 patients. They concluded that the safety and efficacy of using hydroxychloroquine in treating COVID-19 patients are limited [75]. Protease inhibitors lopinavir and ritonavir used to treat the infection with human immunodeficiency virus (HIV) [76] has been recommended by researchers to help in the recovery of MERS-CoV [77] and SARS-CoV [78]. Studies claim that after lopinavir/ritonavir (KALETRA®, AbbVie) was administered, β-coronavirus viral loads significantly decreased, and no or little coronavirus titers were observed in treating the index patient in Korea [79]. Recent clinical trials to identify the efficacy and safety of oral Lopinavir–Ritonavir for COVID-19 did not significantly benefit recovery, reducing mortality, or diminishing throat viral RNA in critically ill COVID-19 patients[80]. Others include traditional Chinese medicine, combined Chinese medicine Shufeng Jiedu capsule (SFJDC), and western medicine [81]. The use of traditional Chinese medicine in H1N1 influenza and SARS prevention based on historical records leads it to be a prospective alternative for preventing COVID-19 in a high-risk population. The most frequently used herbs included Radix astragali (Huangqi), Radix glycyrrhiza (Gancao), Radix saposhnikoviae (Fangfeng), Rhizoma Atractylodis Macrocephalae (Baizhu), Lonicerae Japonicae Flos (Jinyinhua), and Fructus forsythia (Lianqiao) [82, 83]. The chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) has extremely promising results with an acceptable safety profile and homologous boosting increased antibody responses developed by the Oxford- AstraZeneca vaccine group [84]. Given the race of finding a treatment for COVID-19 and the accelerated rate of clinical trials, a real-time dashboard is available to track the clinical trials and understand their importance [85]. Ongoing clinical trials for the prevention and successful intervention are recorded [86, 87]. Vaccine development is a lengthy process, and though unlikely, in the event of an abrupt ending of the pandemic, promising vaccine candidates should be developed as preparation for another possible outbreak [88].
Prediction Models and COVID-19
There has been an ocean of research articles on prediction and models supporting medical decision making, diagnostic and prognostic efforts. Prediction modelling efforts include standard epidemiological models like Susceptible-Infectious-Recovered-Dead (SIDR) [89], Susceptible-Exposed-Infectious-Removed (SEIR) [90], extended state-space SIR (eSIR) [91], artificial intelligence, machine learning [92], and deep learning [93]. A review of the current literature pool to assess the diagnostic and prognostic multivariable prediction models of COVID-19 found common predictors like age, temperature, signs and symptoms, blood pressure, sex, comorbidities, and creatinine. It also reflects that all models included in the study reported optimistic performance, with a high risk of bias with poor reporting and predictor description, thus requiring rigorous prediction models supported by methodology. Cautious use of these models in current practice is recommended [94].
Twenty-seven review articles were separated based on origin, symptoms, comorbidities like ARDS, COPD, mental health, diabetes, obesity, cancer, smoking, pregnancy, children, thyroid, vaccine, therapeutics, and prediction models. Additional file 1 provides the review category, primary outcomes, no. of included studies, sample size, and conclusion for all the 27 main review articles. Methodological quality assessment of the included literature reviews was performed using the AMSTAR tool [95]. The AMSTAR score consists of a total of 11 points. A study is considered high quality with a score (9-11), medium quality with a score (6- 8), and low quality with a score (0-5).