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.