Discussion
The present study exhibited a pattern of association between the risk factors and the variants of SARS-CoV-2, showing significantly increased mortality amongst patients with comorbidities during the delta variant infection. The study also highlights the association of the Omicron infection with a substantially higher risk of adverse outcomes in comorbid adults than that of the previously dominant delta variant.
The odds of hospitalization in this study were decreased by 4% for patients with Omicron infection than with the Delta which was consistent with studies done in the United Kingdom and South Africa (25-29%) [7,8]. Compared to the Delta variant, Omicron is more likely to cause breakthrough infections of vaccinated individuals and reinfections [9], yet admissions were less frequent, due to the lesser severity of the disease. Hence, there was an increased risk of hospitalization of patients with comorbidities infected with the Delta variant.
The current study reveals that SARS-CoV-2 cases infected with the Omicron variant had a 2-fold decreased risk of death than the patients suffering from the Delta variant. Similar to studies performed by Kim et al. and Maslo et al. [10,11] in South Korea and South Africa, respectively, it was seen that the severity of the Omicron variant was milder. This could be due to vaccination, or previous infection, leading to a decrease in hospitalization and mortality [4,12].
Most of the patients in this study during the period of April 2021 had either taken just the first dose of vaccine if above 60 years of age or had not taken any vaccination; while the cases were mostly double vaccinated during the period of January 2022. [13] However, as the present study highlights, the patients with co-morbidities like hypertension and diabetes when admitted from the Omicron variant are more likely develop severe disease, compared to an infection by Delta variant to have adverse outcomes. This could be because both diabetes and hypertension are conditions associated with chronic systemic inflammation, where there are considerable alterations in all tissues and organs that may affect normal cell functions, including the immune response to vaccines [14,15]. Due to elevated levels of pro-inflammatory cytokines which correlates with hypo-responsiveness to vaccination [16] and perivascular inflammation [17] in hypertension, there is an impaired immune function, influencing the response to vaccination. The findings correlate with a study conducted in Indonesia by Soegiarto et al. [18] in 2021, on 2714 healthcare workers who received two doses of inactivated viral vaccine, showed that hypertension is associated with lower antibody titers and breakthrough infection following COVID-19 vaccination. Similarly in diabetic patients, dysregulation of antigen presentation and deteriorated complement function, followed by hyperglycemia and insulin resistance, could justify lower levels of antibodies in diabetes [15]. A systematic review by Boroumand et al. [19], reported the immunogenicity of vaccines (vector-based, inactivated) to be lower among patients with diabetes mellitus as compared to healthy controls.
As inferred from the current study, patients with hypertension have a significant risk of hospitalization and mortality irrespective of the variant they are infected with. This could be due to the ACE-2 receptor which mediates the entry of the virus into the lung, and patients with high blood pressure are administered drugs like ACE-2 inhibitors and angiotensin receptor blockers which lead to overexpression of ACE-2, thus increasing the fatal outcomes of COVID-19 [20]. Lippy et al. [21] demonstrated a 2.5-fold increased risk of mortality in patients with hypertension, predominantly in the geriatric age group.
Diabetes is a significant risk factor for mortality in patients infected with either Delta or Omicron variant as shown in this study. In a study of England, both type 1 and type 2 diabetes were independently associated with a significant increase in COVID-19–related mortality (adjusted odds of 2.86 for type 1 and 1.80 for type 2 diabetes) [22] which correlates with the present study. Patients with diabetes mellitus have poor innate immunity and being a proinflammatory condition with increased blood counts of IL-6, CRP, and ferritin; diabetic patients with COVID-19 are vulnerable to shock and acute respiratory distress syndrome [23]. Furthermore, the hypercoagulation cascade in COVID-19 results in catastrophic thromboembolism exacerbated by the presence of DM shown by greater D-dimer concentrations and increased risk of fatality [23]. Also, diabetic patients have impaired innate immunity, predisposing them to breakthrough COVID-19 infections [24].
There was a higher prevalence of patients with chronic obstructive pulmonary disease (COPD) in the Delta (24%) infection as compared to the Omicron (11%) infected patients. However, both showed significant odds (1.6-2.2) for mortality. The genome of the Omicron variant of SARS-CoV-2 has more than 30 mutations which have increased the transmissibility of the virus and affected binding affinity [9,25]. It has been also reported that Omicron replicates faster than all other SARS-CoV-2 variants in the bronchus but less efficiently in the lung parenchyma, and appears to enter human cells by a different route than other variants [26]. Hence, the decreased prevalence of COPD patients could be attributed to increased vaccination [13] as well as decreased severity of the disease during the Omicron variant.
Similarly, patients with chronic kidney disease also showed an increased risk of mortality during the Delta COVID-19 infection than in the Omicron variant. ACE-2 protein is expressed at high levels in the kidneys (proximal kidney tubules) [27], hence, kidney damage may be caused by SARS-CoV-2 entering cells by targeting ACE-2 receptors, leading to collapsing glomerulopathy by toxic viral effects on podocytes [28].
Moreover, the mortality of patients with Omicron was seen to be in the elderly age group as compared to the Delta variant (68 years vs 49 years). Patients admitted due to the infection by Omicron were elderly which correlated to previous studies [10,11,29]. This can be attributed to the fact that compromised immunity of elderly patients having comorbidity despite immunisation, confront the worst outcome with COVID-19. Although the mortality amongst males was higher during the Delta SARS-CoV-2 infections, no such significant association for gender was seen during the Omicron variant. This correlates with other studies [30,31] which reported that males were more affected than women during Delta variant infections. In the present study, smoking increased the mortality in both Delta and omicron variants (15.4%, 40%) as reported in previous studies [32,33]. In a systematic review by Vardavas et al. [34], smokers were 2.4 times more likely to be admitted to an ICU, need mechanical ventilation, or die compared to non-smokers.
Oxygen requirement as a treatment showed a significant correlation with the severity of the disease in the current study, irrespective of the disease variant. Acute hypoxemic respiratory failure is the most common complication in adult patients with COVID-19. Most patients are managed with enhanced respiratory support modalities such as high-flow nasal cannula (HFNC), non-invasive positive pressure ventilation (NIPPV), endotracheal intubation, and invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). [35]
The length of stay in the hospital was more than 7 days for majority of the patients who died with Omicron infection (80%) as compared to Delta variant infection (30.8%). According to the current study, patients with infections by the Delta variant, died mostly within 48 hours (30.8%), probably due to the delayed presentation of the patients to the hospital which was not seen in the Omicron variant infection. Along with increased risk of comorbidities leading to death in the Omicron variant infection, it can be perceived that vaccination of individuals and lesser severity of the Omicron variant could be a possible reason for the longer duration of stay in patients who died due to comorbidities in this period.
However, there were some limitations in the study. First, it might not reflect the scenario of the whole country as it was a single centred study with a minimum size of 100 patients each from each duration of infection with a variant. Second, could not compare the symptoms and risk of hospital acquired infection in these patients. Third, were unable to demonstrate the efficacy of vaccination in the patients during the delta infection, most of the patients were not vaccinated. Fourth, though the study shows increased odds of mortality with other risk factors such as chronic liver disease (OR:6.08) and malignancy (OR:4.89), however, were unable to compare amongst the variants for the same, due to fewer number of such patients. The findings in the study were consistent with other studies done in different countries [31,36]; hence, proving that comorbidity deteriorates the defensive mechanism of the patients and worsens the mortality outcome of COVID-19 patients, irrespective of the variant of infection. Finally, due to insufficient sample size, it was difficult to assess the role of previous infection on clinical presentation.
The overall reduction in the risk of death with newer variant has made it substantially easier to live with COVID-19 as an endemic disease. The study exhibited a pattern of association between the risk factors and the variants of SARS-CoV-2, showing that Omicron is associated with a substantially higher risk of adverse outcomes in comorbid adults than that of the previously dominant Delta variant. Hence, it is of crucial need for a sufficiently detailed and systematic surveillance, which will allow timely detection and characterization of new viral lineages with the emergence of newer variants of SARS-CoV-2; as Omicron is not a milder strain for patients with comorbidities.