Methods
A search strategy was designed to retrieve all relevant articles. The search terms
“COVID-19 AND comorbidity” and “COVID-19 AND comorbidities, clinical characteristics,
epidemiology” were used. To avoid missing any relevant literature, we performed additional
searches using the reference lists of the included studies. The databases PubMed,
MEDLINE, EMBASE, SCOPUS, and Google Scholar were accessed to identify all relevant
articles published by May 7, 2020. Articles were screened using the abstracts, and
then the inclusion criteria were applied. The full texts of articles that appeared
relevant to the study topic were accessed for further screening.
The inclusion criteria were as follows: Articles about comorbidities and individuals
diagnosed with COVID-19 published in 2020 in English were included. The studies included
datasets of patients with COVID-19 and major comorbidities, including CVD, HTN, diabetes,
COPD, CKD, and malignancy. The exclusion criteria were as follows:[1] Articles that did not contain appropriate or sufficient data regarding the major
comorbidities listed above were excluded.[2] Studies limited to pediatric patients, pregnant patients, and disease-specific studies
were excluded.[3] Studies not written in English were excluded,[4] as were discussion summaries, abstracts, case reports, systematic reviews, editorials,
and letters.
COVID-19 Symptoms and Possible Outcomes
Recent reports indicate that the clinical manifestations of COVID-19 may include a
multitude of symptoms that vary in severity. The most common symptoms are fever, cough,
sputum, myalgia, fatigue, and shortness of breath. Most patients present without complications.
However, significant percentages of COVID-19 patients experience severe (35%) or critical
(28%) disease.[7] Critically ill patients may suffer from adverse outcomes that necessitate ICU admission,
such as sepsis, acute respiratory distress syndrome (ARDS), shock, heart failure,
respiratory failure, coagulopathy, acute kidney injury, and even death.[7] Everyone is susceptible to this virus, but the elderly and those with underlying
diseases have a higher risk of adverse outcomes.[8]
The Prevalence of Comorbidities in COVID-19 Patients
A nationwide analysis of the prevalence of comorbidities in patients with COVID-19
in China reports that almost 50% of patients hospitalized due to COVID-19 had at least
one of the following comorbidities: diabetes, HTN, CVD, or cerebrovascular disease.[9] This is supported by a study showing that severely afflicted patients had higher
rates of HTN, diabetes, and coronary heart disease. Moreover, COVID-19 patients with
concomitant CVD have a higher risk of mortality.[10] Another comparative study in Wuhan revealed that patients who were suffering from
severe illness had a higher prevalence of comorbid conditions than those with a non-severe
course. This suggests that comorbidities may increase the risk that an individual
will present with a severe case of COVID-19.[8]
In our meta-analysis of the prevalence of comorbidities in hospitalized COVID-19 patients,
HTN was the most common comorbidity, occurring in 16% of hospitalized patients, followed
by CVD, occurring in around 12%. Diabetes mellitus occurred in 7.8% of cases, and
COPD and CKD occurred in 0.95% and 0.83%, respectively.[11] Deficits in spirometric testing (a test of lung functionality) and a lack of awareness
due to lack of careful observation played important roles in the diagnosis of respiratory
disorders in this study.[12]
[13]
Early in an epidemic, the prevalence of comorbidities might reflect transmission dynamics
within certain age groups; it may also affect hospital admission policies and case
detection.
The Impact of Comorbidities on the Severity of COVID-19
Healthcare providers must pay careful attention to the treatment of original comorbidities
in COVID-19 patients, especially those with pneumonia and particularly when those
comorbidities include diabetes, CVD, COPD, CKD, HTN, or respiratory system disorders.
These guidelines are even more important for older patients with serious comorbidities.
It has been observed that COVID-19 is involved in the impairment of various organs
and systems, including the kidneys, heart, liver, immune system, and the blood vessel
system.[14]
[15]
[16] Patients with COVID-19 may die due to ARDS, multiple organ failure, heart and renal
failure, shock, or cardiac arrhythmia.[17] For this reason, the treatment of patients with COVID-19 must include protection
against and prevention of problems in multiple organs.
Diabetes
Patients with COVID-19 pneumonia and concurrent diabetes have been reported to have
a more severe course than those without diabetes. Severity is evaluated in terms
of organ damage, inflammatory factors, or hypercoagulability. These patients are also
more likely to progress to a worse prognosis. Therefore, diabetes might be considered
a risk factor for a poor outcome in patients with COVID-19 pneumonia.[18] Furthermore, endocrine diseases, such as diabetes, are common in patients diagnosed
with COVID-19, even apart from the likelihood of circulatory and endocrine comorbidities.
One study estimated that the prevalence of diabetes among patients with COVID-19 was
7.87% (95% CI: 6.57%–9.28%).[11]
Hypertension (HTN)
The current literature suggests that HTN may be associated with an up to 2.5-fold
increase in the risk of severe COVID-19, especially among older individuals. HTN is
also associated with higher mortality due to COVID-19.[13]
The present meta-analysis finds that HTN occurs in approximately 17% of patients hospitalized
with COVID-19.[19] Another study found that HTN is the most prevalent underlying disease in hospitalized
COVID-19 cases, occurring in 16% of such cases (95%: CI: 10.15–23.65%).[11]
Chronic Obstructive Pulmonary Disease (COPD)
COPD is associated with over a five-fold increase in the risk of severe COVID-19 infection.[14] A recent study suggested that, compared to patients with no comorbidities, patients
with severe cases of COVID-19 and COPD had the highest mortality risk (OR 1.49, 95%
CI: 1.10–2.01).[19] Another study found that COPD occurred in 0.95% of hospitalized COVID-19 patients
(95% CI: 0.43–1.61%).[11]
Furthermore, ongoing COPD and a history of smoking contribute to more severe cases
and poorer outcomes in patients with COVID-19. SARS-CoV-2 initially occupies the pulmonary
alveolar epithelial cells.[20] However, most infections are believed to cause only mild symptoms; ARDS is rare
but can lead to multi-organ dysfunction.[21]
The effects of COPD and of a history of smoking on the course of a COVID-19 infection
and on the disease’s clinical manifestation are, however, still uncertain.[22]
Cardiovascular Disease (CVD)
Patients with previous CVDs are more likely to experience a severe course of COVID-19.
COVID-19 may also expedite cardiac damage through multiple mechanisms, further worsening
the patient’s prognosis.[23]
One study suggested that, compared to patients with no comorbidities, patients with
severe cases of COVID-19 and with CVD have a higher risk of morbidity (OR 2.92, 95%
CI: 1.76–4.86).[24] In the present analysis, eight studies were evaluated to estimate the pooled prevalence
of CVD in COVID-19 patients; CVD occurred in approximately 5% of hospitalized COVID-19
cases.[11]
Malignancy (Malignant Tumor)
Immunocompromised people with a history of cancer are more susceptible to COVID-19
due to anti-cancer treatments and malignancies. Similarly, healthy individuals are
less susceptible to the infection than those suffering from gastro-intestinal (GI)
cancer.
In a recent nationwide analysis in China,[25] 18 of 1,590 (1%) COVID-19 cases had a history of cancer. Of those 18 cases, three
had a history of colorectal cancer, including one colorectal carcinoma, one colonic
tubular adenocarcinoma, and one rectal carcinoma.[26]
A recent study showed indicated that the prevalence of malignancy among hospitalized
COVID-19 patients is approximately 0.92% (95% CI: 0.56–1.34%).[11]
Chronic Kidney Disease (CKD)
A previous study found that approximately 13% of patients with COVID-19 had underlying
kidney disease.[11] Similarly, during hospitalization for COVID-19, up to 40% had signs of abnormal
kidney function, and 5.1% had acute kidney injury (AKI). A dose-dependent association
was observed between COVID-19 morbidity risk and the stage of AKI; patients with stage
three AKI had a four-fold increased risk of mortality. Furthermore, a major complication
of COVID-19 is a substantial morbidity risk increase by a kidney disease.[27]
The main symptoms of severe cases of COVID-19 are acute respiratory failure and alveolar
impairment; 24 the involvement of other organs needs to be explored. Subsequently, the virus accumulates
in the kidneys, destroying resident renal cells, and it might enter the blood after
causing a lung infection. Using real-time polymerase chain reaction analysis, COVID-19
RNA has been identified in the plasma of 15% of patients.[13] It is reported that 6.7% of SARS patients presented with AKI, and the mortality
rate among SARS patients with AKI was 91.7%.[28] Consequently, there is an urgent need to understand how the kidney is affected by
COVID-19.
A study that used Kaplan-Meier statistics found that patients with kidney disease
had a considerably higher risk of hospitalized death after adjusting for disease severity,
age, gender, leukocyte count, and other comorbidities. Therefore, the prevalence
of kidney disease and the development of AKI in patients with COVID-19 is high during
hospitalization and is associated with in-hospital mortality.[27] This means that physicians must be aware of kidney disease in patients with severe
COVID-19.[27]
According to our pooled analysis of hospitalized patients with COVID-19, the prevalence
of kidney disease is almost 0.83% (95% CI: 0.37%–1.43%).[11]
Smoking
Our analysis shows that, of patients hospitalized with COVID-19, 7.63% have a history
of smoking. However, the six studies included in this analysis show significant heterogeneity
(I2 = 90.19%, p < 0.001).[26]
The traditional interpretation of this finding is that the smokers are more susceptible
to respiratory viruses and that smoking can up-regulate the angiotensin-converting
enzyme-2 (ACE2) receptor, which is the receptor associated with human respiratory
coronavirus NL638 and with severe or acute COVID-19. Electronic smoking devices, such
as e-cigarettes, IQOS, and heat-not-burn devices, are considered less harmful than
traditional cigarettes, but these devices still cause respiratory damage. ACE2 could
play a unique role in COVID-19 as an adhesion molecule; it is also a potential target
of therapies to prevent infection. Therefore, to prioritize and facilitate investigation
into the role of this molecule, data on smoking status must be recorded for all diagnosed
cases of COVID-19.[29]
The evidence suggest that smokers’ lungs are injured because such patients are more
susceptible to pulmonary bacterial infections and viral infections.[30] Similarly, smokers have a 34% higher chance of infection with influenza than nonsmokers.[30] Han et al. found that smoking was consistently associated with an increased risk
of hospital admission due to post-influenza infections.[31]
Obesity
Obese individuals may also have a higher risk of severe COVID-19. However, metabolic
parameters, such as body mass index (BMI) and blood levels of insulin and glucose
(COVID-19) are insufficient to measure this effect. More attention to this issue is
needed to improve our understanding of the causes of COVID-19 and (equally important)
our ability to care for patients affected by it.[32]
In one study, almost 85% of obese patients hospitalized with COVID-19 required a mechanical
ventilator; 62% mortality was reported for COVID-19 patients with obesity.[32] Similarly, 64% of non-obese patients required mechanical ventilation, and the mortality
rate for non-obese patients was 36% percent.[33]
It has been repeatedly documented that comorbidities, such as diabetes mellitus, CVD,
and HTN, are associated with a more severe course of COVID-19. So far, obesity has
received less attention.[34] However, it is a key risk factor for these other comorbidities and is often associated
with poor metabolic health, such as dyslipidemia and insulin resistance. Obesity is
also associated with a higher risk of pneumonia. Thus, anthropometric features and
metabolic parameters must be evaluated to appropriately assess the risk of complications
in patients with COVID-19.[35]
Moreover, according to data reported by a university hospital in Lille, France, of
124 COVID-19 patients, the need for invasive mechanical ventilation was associated
with a BMI greater than35 kg/m2, independently of other comorbidities.[32]
Mode of Action of Comorbidities that Influence the Course/Severity of COVID-19
Perhaps chronic disorders gate the origin of the infection, specifically the attenuation
of the innate immune response and the pro-inflammatory state. For example, diabetes
mellitus occurs due to an accumulation of (activated) innate immune cells in the metabolic
tissues. This permits the release IL-1β and TNFα (inflammatory mediators), which cause
β-cell impairment and systemic insulin resistance. In addition,[36] through microphage damage and lymphocyte dysfunction, metabolic diseases might decrease
immune function,[37] which could make individuals more susceptible to COVID-19 complications.[38]
In a retrospective study, Guo et al.[39] analyzed clinical data from patients with a history of viral pneumonia and found
that the absolute levels of CD4+ T cells, CD3+ T cells, CD3+ cells, and CD3+ CD8+
T cells were considerably lower in patients who died than in those who survived. This
suggests that several measures indicating inflammation were lower in patients who
died.[8]
These comorbidities may also facilitate COVID-19 complications via multiple mechanisms,
leading to poorer outcomes. For example, diabetes mellitus is known to lead to a compromised
immune state by impairing macrophage and lymphocyte function.[37] This in turn makes the patient more likely to experience severe illness and develop
complications.
Another possible mechanism implicates ACE2 imbalance as the cause of severe disease
in patients with both COVID-19 and CVD. This can be explained by the fact that ACE2
is the main active peptide in the renin-angiotensin-aldosterone-system.[29] By targeting angiotensin, ACE2 acts as a protective compound for the cardiovascular
system; it even demonstrates protective effects against respiratory failure in some
infections.[29] Like SARS, SARS-CoV-2 is believed to invade the host through the cell entry receptor
ACE2.[40]
[41]
SARS-CoV-2 has been shown to bind to ACE2 with high affinity. This reduces the amount
of active ACE2, limiting its protective effect and aggravating CVD and COVID-19. This
may explain why patients with cardiovascular comorbidities are more likely to present
with a more severe disease course than those without CVD.[42]
Moreover, patients with diabetes and HTN who are treated with ACE inhibitors may be
at an increased risk of developing COVID-19.[42] This can be explicated by the fact that human pathogenic coronaviruses, like SARS-CoV-2,
bind to their target cells via ACE2.[43] ACE2 expression is substantially increased in patients with diabetes and HTN who
are treated with ACE inhibitors.[41] This increased expression of ACE2 may facilitate COVID-19 infection by increasing
its cellular binding and expediting its entry into cells.[43]
Glycolipid metabolic disorders such as hyperlipidemia, diabetes, and atherosclerotic
CVD may also play a role in increasing disease severity in COVID-19 patients.[40]
[41]
[42]
[43] These disorders are associated with chronic inflammation and elevated cytokine levels,
both of which are associated with more severe cases of COVID-19.[42]
Several studies have illustrated the fundamental mechanisms of these associations.
Similarly, Kulscar et al. found that MERS-CoV infections lead to immune cell dysfunction,
prolonged airway inflammation, and alteration expression profiles of inflammatory
mediators in diabetic mice models.[44]
Our analysis indicates that COVID-19 may lead to immune dysregulation; this might
contribute to the increased risk associated with CVD, malignancies, and bone diseases.[45] Prolonged inflammation and dysregulation of the immune system may be key drivers
of poor clinical results in patients with these comorbidities and COVID-19, but verification
via more mechanistic studies is needed.[46]
Patients with coexisting comorbidities are more likely to have poorer baseline health.
Therefore, patients with more than two comorbidities have an increased risk of a poor
prognosis.[9]
[10] This means that, when determining the prognosis for COVID-19 patients, the number
and type of comorbidities must be considered.[9] Disease severity partially depends on the ratio of comorbidities, and proper triage
requires a careful inquiry into a patient’s medical history, as this will help healthcare
providers identify patients who are more likely to develop a severe case. Early diagnosis
of potential problems will better protect patients with COVID-19 and other comorbidities.
However, underreporting of COVID-19 cases may result in an overestimation of the strength
of these associations and thus of severe outcomes; this is consistent with existing
literature.[13] Proper documentation of all patients at the time of hospital admission must include
a complete patient history.[48]
COVID-19 is Associated with Significant Morbidity
In patients hospitalized with COVID-19, the casualty rate is higher than ten percent,
regardless of treatment. In most cases, COVID-19 presents similarly to other respiratory
viral infectious agents (pathogens), with symptoms such as cough, dyspnea, and fever.
Unique elements include the rapid progression to ARDS and leukopenia observed in severe
cases of COVID-19. More research is needed to identify the natural host of SARS-CoV-2
and the viral factors in fatal and severe infections.[49]
Hong et al. found that CVD and diabetes mellitus are significantly associated with
COVID-19 complications; they also observed that diabetes did not depend on the risk
factor for chronic influenza. [38]
Another study found that, in patients with MERS-CoV, smoking, diabetes, and cardiac
disease were significantly associated with more severe illness.[50]
MERS-CoV, Avian Influenza, and SARS-CoV
Current literature indicates that avian influenza and SARS-CoV are more likely than
MERS-CoV[51]
[52] to lead to poor clinical outcomes.[53]
[54]
The function of the spike protein found on coronaviruses is similar to that of the
hemagglutinin (HA) protein in avian influenza viruses; the rapid replication and transmission
of avian influenza in compact chicken populations indicate that it is an acquirer
of polybasic cleavage sites.[55] Acquisition of polybasic cleavage sites in the hemagglutinin protein by recombination
or insertion transforms low-pathogenicity avian influenza viruses into highly pathogenic
forms;[51] this process has also been detected after repeated passages in animal cell cultures.[56]
Various Comorbidities their Association and Prognosis
Several comorbidities are associated with poor prognoses in COVID-19 patients; these
comorbidities include diabetes, respiratory diseases, HTN, malignancies, renal disease,
pregnancy, and cardiac diseases.[57]
[58] Comorbidities associated with poor outcomes in other outbreaks of severe acute respiratory
diseases, such as COPD, HTN, malignancies, and diabetes, may also predispose patients
with COVID-19 to more severe cases.[54]
[56]
[59]
[60] However, the strength of this association between COVID-19 prognosis and various
comorbidities is unclear as it varies in different reports[61]
[62]; for example, the association of CVD with poor clinical outcomes of SARS-CoV, MERS-CoV,
or influenza remains uncertain. Apart from diabetes, no other comorbidities have been
recognized as prognosticators of poor clinical outcomes in patients with MERS-CoV.[63]
