A systematic review was planned according to PRISMA guidelines. Literature search was conducted across various databases which included Pubmed, Web of Science, Embase, Scopus and Cochrane library. All articles published between November 1, 2019 to July 31, 2020 were searched. Keywords or MeSH used were “COVID-19” or “SARS CoV 2” or Coronavirus disease 19 and “comorbidities” or “risk factors”. Individual risk factors were also used as key words. Such as “Diabetes”, Hypertension”, “Chronic kidney disease”, “Elderly”, “Cardiovascular disease”, “Obesity”, “Malignancy”, “Lung disorders”. The citations were copied to end note. Two researchers performed the literature search independently to prevent missing any valid studies, the references of the selected articles.

Inclusion criteria:

Exclusion criteria:

Data collection: Data were extracted independently by both the investigators. Any dispute was solved by mutual consensus. The following data of the study was documented in Microsoft excel sheet: first author, place of study, number of participants, comorbidities, result of the effect of comorbidities.

Quality assessment: The quality of the methods used in each article was assessed two independent reviewers. The criteria evaluated by the quality assessment included clear presentation of inclusion/exclusion criteria, patient/clinical information, reliable testing for disease confirmation and inclusion of appropriate sample population. The quality assessment used was based on the Joanna Briggs Institute Critical Appraisal guidelines [7].

With the use of MeSH terms, 276 articles were found. A total of 203 articles were duplicated which were removed and thereafter, 73 articles were screened for title and abstract. Irrelevant articles and those with incomplete data, conference abstracts were further removed. Full text of 55 articles was read. All the references of these 55 articles were checked and two more articles were added from registries. These 57 articles were divided based on the comorbidities as mentioned in the flow chart 1 [Table Fig-1].

[Table/Fig-1]:

Flow Chart of number of studies screened and included.

The hospitalisation rate due to COVID-19 is 4.9 per 100,000 population. Approximately, 90% of the patients hospitalised have comorbidities according to the Center for Disease Control and prevention (CDC). COVID- NET is a newly created COVID-19 surveillance team in the United State America (USA). According to whom, the prevalence of co-morbidities was at 89.3% in hospitalised patients [8]. The most common and major comorbidities were hypertension, diabetes, obesity, CKD, cardiovascular disease, malignancies and pre-existing lung disorders [8]. Elderly (>65 years) patients were at higher risk of hospitalisation and death. A total of 94.4% of elderly patients had comorbidities. The most common underlying condition in elderly was hypertension with a prevalence of 72% followed by cardiovascular disease, obesity, diabetes and respiratory illness. Among the younger age group of patients, obesity was most common with prevalence of 49% in the age group of 50- to 64 years and 59% in those between 18 to 49 years [8].

Guan WJ et al., studied 1590 lab confirmed COVID-19 patients in China [9]. Out of 1590 patients, 25% had atleast one comorbidity. The prevalence of hypertension was most common (16%). Other significant co-morbidities were cardiovascular diseases, diabetes, respiratory diseases like Chronic Obstructive Pulmonary Disease (COPD), Chronic Kidney Disease (CKD), malignancy and immunodeficiency syndromes. Two or more co-morbidities were commonly seen in severe cases than in nonsevere cases. These patients were likely to be older, presenting more commonly with shortness of breath followed by nausea or vomiting, unconsciousness and less abnormal chest x-ray compared to patients with one comorbidity. Yang J et al conducted a meta-analysis [10], which included seven chinese observational studies, with a total of 1527 infected patients. On comparing severe and nonsevere cases, pooled odds ratio for hypertension, respiratory illness and cardiovascular disease were 2.36, 2.46 and 3.42, respectively. They concluded that patients with comorbidities may be at risk of severe disease compared to those without.

Liu Y et al., in China studied the association between age and clinical characteristics and outcome of COVID-19 illness [11]. They studied 221 COVID-19 positive patients. These patients were divided into two groups- less than 60 years of age and more than 60 years of age. The primary outcome of the disease course and secondary outcome of respiratory failure was compared between both the groups. Patients in older age group presented with higher severity of illness and higher levels of Blood Urea Nitrogen (BUN), Lactate Dehydrogenase (LDH), lymphopenia compared to those <60 years of age. Older patients had more lobes of lung involvement and secondary bacterial coinfection. The disease course was longer and respiratory failure rates were higher in this group.

Death and hospitalisation rates have been compiled by the CDC which is summarised in [Table/Fig-2] [12]. They have taken age group between 18 to 29 years as the comparison group because they have a strong immunity and compared the rest of the age groups with this particular group [Table/Fig-3] [11,13-18].

Few other case series have also showed that patients older than 65 had severe COVID-19 illness [13-15]. Initial reports showed an increase prevalence of COVID-19 in elderly population [16]. It is important to know that in the elderly, weight and muscle mass decline as age advances, but relative fat mass increases. Elderly are hypertensive and diabetic due to stiffer vessels and impaired metabolic efficiency, respectively. People who are older (>70 years of age), have less cardiorespiratory reserve to cope with COVID-19 infection just like the young obese people. Immune senescence and inflammageing is well known to increase the risk of disease severity in elderly [19].

A study by Jin JM et al., has showed that men developed more severe illness compared to women irrespective of the age group [17]. Among the deceased patients, men were 2.4 times more in number compared to women. Though males and females were equally susceptible to the disease, males died more than females. The reason for increase in mortality in males in unexplained [Table/Fig-3]. Few theories have been proposed. Males smoke and consume alcohol more than women. There are more Angiotensin Converting Enzyme 2 (ACE-2) receptors in men compared to women. Females have more resistance to infections than men maybe due to hormonal differences. Also, women are considered to be more responsible than men, hence they practice preventive measures such as hand washing, wearing masks, social distancing more carefully than men [20].

Many hypertensive patients are on Angiotensin Converting Enzyme (ACEi) inhibitors and Angiotensin Receptor Blockers (ARBs). These drugs can theoretically increase the levels of ACE-2 receptors [21], which are the entry point for the virus. Hence, increasing the severity of illness. Few other experimental studies have shown ACE-2 to be protective against lung injury. ACE-2 breakdown Angiotensin II to Angiotensin [1-7] which is anti-inflammatory in action. Hence, it reduces the inflammation and prevents damage to major organs [22]. Few other studies have shown that Increased ACE-2 levels bind to SARS-Coronavirus in circulation and in turn reduce the injury to lungs and other major organs like the heart and kidneys [23]. In fact, recombinant ACE-2 is being studied as treatment for COVID-19, it reduces organ damage by binding to circulating virus. Protecting major organs like lungs, heart and kidney. Thus, reducing the chances of acute lung injury, myocarditis, acute kidney injury [23]. More studies are required to assess the risks or benefits of ACEi or ARBs in COVID-19 disease. Current guidelines recommend not to withhold ACEi or ARBs in hypertensive patients with COVID [Table/Fig-4] [24-28].

Diabetes is another important risk factor for mortality in COVID-19. As such, mortality rates in people aged above 75 years was higher in diabetics with pneumonia when compared to mortality due to cardiovascular disease or cancer in the same age group [29]. Similar results hold good for the two earlier corona virus infections. SARS which started in 2002 and affected more than 8000 people mainly in Asia [30]. Middle East Respiratory Syndrome (MERS) affected more than 2000 people mainly in Saudi Arabia [31]. Diabetes compromises the innate immune system and creates a pro-inflammatory cytokine milieu. Theoretically, it reduces the expression of ACE-2 and use of ACEi or ARB may contribute to poor prognosis. On the other hand, direct beta cell damage, insulin resistance due to cytokines, hypokalemia and use of drugs such as corticosteroids, lopinavir/ritonavir can worsen the glucose control in patients with diabetes mellitus. The two-way interaction between diabetes and COVID-19 is like a vicious cycle. COVID-19 worsens dysglycaemia and diabetes exacerbates the severity of COVID-19. Hence, it is important to maintain good glycaemic control to prevent COVID-19 illness and its severity in people with diabetes mellitus [Table/Fig-5] [32-35].

Obesity is one of the pre-existing diseases associated with deaths in COVID-19. The increase in number of deaths in Italy and USA compared to China can be attributed to obesity [36]. Furthermore, the increase in prevalence of obesity in USA [37] and prior experience showing increase in mortality in obese patients with H1N1 influenza [38], should sensitise the clinicians to plan for an aggressive treatment for COVID-19 in obese patients. Obesity is associated with decreased functional capacity, expiratory reserve volume, and respiratory system compliance. When patients lie down in supine position, the diaphragm gets pushed up compromising the ventilatory capacity [38]. Also, increased pro-inflammatory cytokines associated with obesity may cause increased morbidity [38]. All these factors emphasise on the need for increased vigilance, priority for detection and testing and more aggressive treatment in this group of patients [Table/Fig-6] [39-42].

Patients on chronic dialysis are prone for increased risk of mortality. The severity of infection is high as they have suppressed immune response due to uremia. They are also exposed multiple number of times to the hospital environment and are at higher risk of acquiring infection as well. There is a huge burden on the dialysis facility as they have to ensure the safety of the staff, follow isolation procedures and prevent infection. Home dialysis or peritoneal dialysis is always preferred and tele-consultation can be provided for the same [43]. In a study conducted at a haemodialysis center at Wuhan, China found that the risk of acquiring infection was higher in haemodialysis patients. The centers for haemodialysis can be the source of spread of infection. However, they usually have mild illness and are unlikely to progress to severe illness as they have impaired cell mediated immunity and are less likely to mount a cytokine storm in response to infection. Mortality was mainly due to cardiovascular causes. Hence, the effect of COVID-19 on cardiovascular system needs to be studied [44]. Few studies found that the outcomes of COVID-19 in haemodialysis patients was not poor and attributed it to earlier detection and treatment with antivirals [44,45]. However, other studies have shown poor outcomes in patients with kidney disease [Table/Fig-7] [46-48].

A meta-analysis of six studies which included 1527 patients found an increase in morbidity and mortality in patients with underlying metabolic cardiovascular disease and COVID-19. An 8% of patients had acute cardiac injury. Also, cardiac injury was more commonly seen in patients admitted in ICU and in those with severe illness compared to mild illness and non-ICU patients [49]. Patients with underlying ST-Segment Elevation Myocardial Infarction (STEMI) or unstable angina have poor cardiac reserve and more susceptibility to infection. According to Shanghai health commission, the first COVID death was an 88-year-old with pre-existing hypertension and cardiac dysfunction. The patient died of cardiac failure and multi-organ dysfuction. Autopsy study showed that, COVID-19 infection precipitated the causes of death [50]. Many mechanisms of injury are proposed. First of all, the virus can cause direct cardiac myocyte injury as studied by Oudit GY et al., in Toronto, Canada during SARS outbreak. When mice were infected with SARS-Cov, it caused pneumonia and ACE-2 dependent cardiac infection [50]. Secondly, hypoxia causes myocardial injury. Pneumonia causes reduced gas exchange in the lungs leading to hypoxemia which in turn hampers cell metabolism. Anaerobic fermentation caused release of free radicals and lactic acidosis. Free radicals injury the phospholipid cell membranes causing cell apoptosis and organ damage [51]. Thirdly, patients with high inflammatory markers caused be cytokine storm had more severe illness [51]. Also, other factors such as anxiety and certain medications caused repeated increase in catecholamine levels causing myocardial cell damage [Table/Fig-8] [13,15,52, 53].

COPD is associated with increased risk of morbidity and mortality in COVID-19 infection [54]. Many mechanisms contribute to increased risk such as impaired host immunity, imbalance in microbiome, persistent mucus production, structural injury of the lung, altered local and systemic inflammatory response and use of steroid inhalation. Some studies have showed an increased level of ACE-2 in COPD patients with COVID-19. However, more studies are required to prove it [54,55].

The studies mentioned below showed that the cancer patients had higher severity of illness, higher risk of intubation and higher mortality rates compared to the general population. Most commonly elder patients (>65 years) were affected with malignancy. Patients who underwent chemotherapy or onco-surgery during the previous month were particularly at higher risk. Also, they deteriorated rapidly compared to the general population [56,57].

Hence, few strategies are proposed to protect these groups of patients. Firstly, any chemotherapy and onco-surgery should be postponed in stable malignancy patients. Secondly, they should wear personal protective equipment at all times. Thirdly, they should be treated for COVID-19 aggressively especially elderly patients [Table/Fig-9] [56-58].

A study was conducted in Beijing, China where they included all severely ill patients admitted in critical care ward. There were 69 patients included in the study. These patients were divided into three categories- Category A: Patients with only pneumonia, Category B: Patients with pneumonia and pre-existing comorbidities, Category C: Patients with severe illness due to worsening of either Category A or B.

Type A patients received basic treatment like steroids, antivirals, antibiotics and oxygen therapy. In Type B patients, they monitored the trend of the status of comorbidities while treating for pneumonia. Type C patients included those in type A and type B who deteriorated with multi-organ dysfunction. 22% in Group A, 55% in group B and 23% in Group C were present. They concluded that importance should be given to the organ function and supportive treatment in the form of ventilation and renal replacement therapy. Therapy should be individualised based on the organ involved. Aggravation of the underlying comorbid condition due to COVID was the main cause of death. Hence, it is important to emphasise on the treatment of underlying comorbidities while treating pneumonia. COVID-19 causes not only pneumonia but also multi-organ injury like cardiac arrythmias, acute myocardial injury, acute renal injury, acute hepatic dysfunction, coagulation abnormalities, lymphopenia, neutrophilia and so on. Patient may ultimately succumb to multi organ injuries [59].

Overall, circulatory and endocrine diseases were found to be the most common pre-existing condition in the form of hypertension and diabetes mellites, respectively. It should be noted that the observed frequency of comorbidity may be confounded by the transmission dynamics within particular age groups, case detection or testing protocols or hospital admission policies during the earlier phase of the epidemic. However, the percentage of COVID-19 patients with renal disease and malignancy were low. Immune dysregulation and prolonged inflammation caused by COVID-19 infection in patients with comorbidities are the key causes for increased risk of death in this population.

It is also well known that some of the comorbidities co-exist. For example, diabetes and COPD are frequently seen in patients with hypertension or cardiac disease. Hence, people with comorbidities have prior poor baseline health characteristics and are prone for more severe disease. Furthermore, as the number of comorbidities increased, the severity of the disease also proportionally increased. A meticulous triage of patients should be carried out after acquiring proper medical history because this will help to identify patients who are at an increased risk of poor outcome of the infection. Also, they should be given more aggressive treatment upon diagnosis of infection.