21 Comorbidities and COVID-19 Perspectives and Challenges


Since the earliest days of the pandemic, it became obvious that patients with pre-existing comorbidities were at high risk for developing severe COVID-19 disease, prolonged hospitalization, respiratory failure, and death. The major comorbidities included obesity, diabetes mellitus (DM), cancer patients hypertension (HTN), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and cardiovascular disease (CVD).13 Up to 25 to 60% of patients with severe COVID-19 have multiple pre-existing comorbidities.13 Guan and coworkers observed that the greater the amount of comorbidities the higher the risk for poorer clinical outcomes.3 Although somewhat of an oversimplification, an underlying common pathophysiologic finding in patients with these comorbidities is either a downregulation of angiotensin converting enzyme 2 (ACE2) or increase in ACE/ACE2 ratio (Fig. 21.1).46 In addition, patients on immunosuppression, such as solid organ transplant (SOT) and bone marrow transplant (BMT) recipients, present another spectrum of patients at increased risk of adverse outcomes and a poor response to vaccination.13,713 Patients with COPD, HTN, DM, and CVD have been noted to have a higher incidence of the acute respiratory distress syndrome (ARDS), acute kidney injury, shock, and multiorgan dysfunction syndrome (MODS).1,2,9,10,1216 Both the pre-COVID therapy of the disease and therapeutic management of these patients pose specific challenges.2 In this chapter, we present a brief overview of the challenges in managing patients with comorbidities afflicted with COVID-19 and provide some representative cases illustrating the challenges these patients face (with some of the most common comorbidities present).

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Fig. 21.1 Depiction of the critical balance between angiotensin-converting enzyme (ACE) and ACE2 products and clinical course of COVID-19. Patients with comorbidities may already have a baseline imbalance in ACE/ACE2 ratio in a proinflammatory, procoagulant vasoconstrictive state due to increased A2 which is further exacerbated by SARS-CoV-2 binding to ACE2 during infection. Pagliaro P, Penna C. ACE/ACE2 ratio: a key also in 2019 coronavirus disease (Covid-19). Front Med (Lausanne) 2020;7:335. Creative Commons Attribution License (CC BY Frontiers in Medicine).4


In most clinical studies of individuals with COVID-19, obesity has been highly associated with increased hospitalizations, morbidity, and mortality.17,18 A meta-analysis by Poly et al evaluated 17 studies and over 500,000 patients observed obesity to be associated with a 42% increased risk of mortality.18 In addition, obese individuals 65 years and older demonstrated a markedly (higher 150%) increased risk of death.19 Obesity increases the necessity of mechanical ventilation, and from a general respiratory standpoint, obesity poses significant challenges in management due to changes in airway mechanics, such as decreased compliance, airway resistance, increased work of breathing, and reduced gas exchange. In addition, ACE2, the primary receptor, is highly expressed in visceral adipose tissue.14,15,17,18,2022 Obesity results in alterations in T and B lymphocytes, and obese individuals have demonstrated poor antibody responses to immunization.21,23,24 Obese individuals have an increase in net visceral adipose tissue and thus an increased ACE2, possibly making them more prone to infection and increased viral shedding.10,2527 Furthermore, they have a higher ACE/ACE2 ratio at baseline, resulting in an unabated Angiotensin II (ANG II) effects.4,5,14,17,20,25,28,29 The SARS-CoV-2 infection causes downregulation of ACE2, further increasing the ACE/ACE2 ratio. The net effect is a dysregulated increase in ANG II expression, increase in circulating reactive oxygen species, a proinflammatory state, vasoconstriction, and the prothrombotic state, and increase in proinflammatory cytokine production which is characteristic of severe COVID-19 disease.4,6,14,17,20,21,24,27 Furthermore, obesity is a chronic proinflammatory state and coupled with increases in dysregulated ANG II production may enhance cytokine production and the development of the cytokine storm, cardiovascular dysfunction, and ARDS in infected individuals.14,17,20,25,29


Diabetes mellitus (DM) and poor glycemic control are independent risk factors of mortality in patients with COVID-19 disease.2,9,30 Furthermore, infection results marked insulin resistance and worsening glycemic control. A large percentage of type 2 diabetics afflicted with infection develop diabetic keto acidosis (DKA).3134 Hyperglycemia contributes to the dysregulated immune response and increases viral replication.30 Interestingly, Zhou reported in an observational study that 10% of type II diabetics developed at last one episode of hypoglycemia.35 Hypoglycemia also increases morbidity during the clinical course of infection by increasing proinflammatory monocytes phenotypes and inducing platelet dysfunction.30,3537 Similar to obesity, both type I and type II DMs are states of increase in ANG II expression which is further exacerbated in COVID-19, resulting in a marked prothrombotic, proinflammatory state, and endothelial injury which are harbingers of multiorgan failure.4,30,32,37,38 Hyperglycemia has been known to decrease the efficacy of tocilizumab in patients with severe COVID-19 disease.39

A variety of therapeutic agents used in the management of COVID-19 have variable effects on blood glucose. Glucocorticoids and protease inhibitors, such as lopinavir/ritonavir, increase blood glucose levels.2,30,32,38 Tocilizumab and remdesivir have been reported to decrease insulin resistance. Both chloroquine and hydroxychloroquine demonstrate the ability to induce hypoglycemia.2,30,32,38 Thus, potential drug–drug interactions between therapeutic agents used during the clinical course of COVID-19 infection and those used to treat DM need to be considered.2,30,32,38

Therapeutic agents that can be employed with reasonable safety in the management of DM during infection include insulin, metformin, and dipeptidylpeptidase-4 (DPP-4) inhibitors such as sitigliptin.2,30,32,38 In terms of metformin use, this agent should be discontinued if patients develop acute kidney injury or lactic acidosis. DPP-4 inhibitors have the potential to inhibit viral cell entry due to blockade of the DPP-4 receptor, a known SARS-CoV-2 receptor protein.30,32,4044 Furthermore, DPP-4 inhibitors possess immunomodulatory properties and thus may attenuate the dysregulated immune response commonly observed in severe infection.30,45,46 A recent case-control observational study showed that the use of sitigliptin was associated with a decrease in mortality and an improvement in clinical outcomes.47 Glucagon-like peptide-1 (GLP-1) agonists in combination with insulin have the potential of improving glucose control and decreasing proinflammatory cytokine expression.30,4850 The effects of GLP-1 agonists such as nausea, vomiting, and diarrhea result in volume depletion.30,32,38,50 Thus, caution must be taken when employing GLP-1 agonists in patients with worsening disease. Sodium glucose transporter-1 (SGLPT2) inhibitors, such as empagliflozin, possess natriuretic and diuretic properties which can lead to volume depletion. A noted side effect of SGLPT2 inhibitors is diabetic ketoacidosis; thus, the use of these agents in COVID-19 should be avoided.30,38

The sulfanylurea class of oral hypoglycemics should be used with caution in patients with poor oral intake as profound hypoglycemia may occur. Pioglitazone use may result in significant fluid retention, and cardiac compromise that can commonly occur in COVID-19 disease may result in congestive heart failure (CHF). Concurrent use of angiotensin receptor blockade (A2RB) or angiotensin-converting enzyme inhibitors (ACEIs) should not be discontinued unless hemodynamic instability, hyperkalemia, or acute kidney injury develops.2,30,38

Chronic Obstructive Pulmonary Disease

Multiple studies have observed that patients with COPD have an increased risk of hospitalization, intensive care unit (ICU) admission, and mortality.16,5153 Clearly, COPD patients have less pulmonary reserve; thus, any insult during infection such as COVID-19 tracheobronchitis or pneumonia will lead to severe decompensation in a shorter time period. Many patients with COPD are chronically on inhaled corticosteroids (ICS) and initially it was presumed that these agents would predispose patients to a higher risk of infection and worse outcomes.52,54,55 However, to date there has been no evidence to support that ICS leads to increase in infection rates and outcomes.52,54,55 COPD patients have a higher expression of ACE2 and transmembrane protease (TMPRS) in bronchial epithelial and lung tissue allowing for the potential increased viral entry into respiratory epithelial cells that results in a more rapid progression of infection into the lower respiratory tract.55,56 Patients with COPD have demonstrated an abnormal innate immune response to viral infection, possibly predisposing them to development of severe disease.57,58

Cardiovascular Disease and Hypertension

Throughout the period of the current pandemic, many observational studies have demonstrated an increased prevalence of hypertension (HTN) and cardiovascular disease (CVD) in individuals afflicted with COVID-19 disease.5967 Although many of the original studies were not adjusted for confounders, there is abundant data to suggest that individuals with HTN and CVD are at higher risk for the development of COVID-19 complications and death.5967 In a large meta-analysis involving over 15,000 patients, Barrera and collaborators demonstrated that HTN, even when adjusted for confounding risks, was associated with ICU admission and death.68 Initially, due to the mechanism of viral cellular entry involving interactions with the viral S protein and ACE2, it was thought that the employment of ACEIs or angiotensin 2 receptor blockers (ARBs) would place individuals treated with these agents at higher risk of infection and disease complications.66 Large observational studies by Rezel-Potts and coinvestigators, and others, have demonstrated that none of the use of ARBs, ACEI, or any of the major classes of antihypertensive agents commonly employed were associated with adverse outcomes or increased rate of infection.69 Thus, unless hemodynamic compromise exists, hyperkalemia develops, or acute renal failure occurs, recommendations are to continue ACEI or ARB use.

A myriad of observational studies have demonstrated that CVD can be associated with poor clinical outcomes and mortality.5967 This is perhaps due to SARS-CoV-2 S protein interaction with ACE2 during infection, which results in a proinflammatory and prothrombotic state, potentially leading to acute myocardial infarction, myocarditis, cardiac arrhythmias, and thromboembolic events.4,6,66 As myocarditis, elevated troponin I, and acute myocardial infarction are not uncommon, CVD complications such as CHF may occur.60,62,66 Thiazolidinediones used to treat DM have been known to precipitate CHF and should be discontinued. Many therapeutic agents that have been employed in the therapeutic arsenal against SARS-CoV-2 such as chloroquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir have cardiotoxic effects such as prolongation of the QTc interval (as is the case with hydroxychloroquine and chloroquine and azithromycin). Lopinavir/ritonavir have been reported to cause bundle branch block and prolonged QTc interval. The presumptive mechanism of these agents is that they block the human ether-a-go-go-related gene (hERG) potassium channel resulting in a risk for arrhythmogenesis.66,70,71 Therefore, therapy with these prodysrhythmic agents in the setting viral-induced myocardial injury, cytokine-mediated myocardial dysfunction, and electrolyte abnormalities poses a significant risk for the potential development of lethal dysrhythmias.

Chronic Liver Disease

The impact of chronic liver disease (CLD) regarding the risk of infection and clinical outcomes is poorly understood. Previous experience in patients with liver disease developing acute-on chronic hepatitis and ARDS resulting in clinical decompensation has been observed during infection with influenza.72 A small observational study demonstrated that in patients receiving corticosteroids, chronic hepatitis B was independently associated with delay in SARS-CoV-2 viral clearance.73 In an observational study including over a thousand patients, 2.1% of the patients had chronic hepatitis B.3 Investigators demonstrated no increased risk of decompensation in patients with chronic hepatitis B.3,74 Patients with chronic hepatitis C have an increased risk of hospitalization; however, there does not seem to be an increased risk of ICU admission or mortality.75 In patients with hepatitis C, hospitalization rates are higher in patients with a higher fibrosis score.75 Although the risk of mortality and morbidity associated with CLD was initially unclear, as we learn more about this disease it has become clear that the presence of CLD is associated with poor clinical outcomes particularly as the severity of CLD increases with patients with nonalcoholic hepatic steatosis, cirrhosis, hepatocellular carcinoma, and alcoholic liver disease.74,7682

Therapeutic agents used in the management of the COVID-19 disease have significant hepatotoxic side effect potential including tocilizumab, remdesivir, lopinavir/ritonavir, and azithromycin.83,84 Tocilizumab has been observed to cause elevated transaminases which are usually mild; however, when employed with other drugs it may become more pronounced. In most cases, elevated transaminases have not resulted in terminating therapy.83,84 Although tocilizumab has the potential to cause reactivation of hepatitis B, there appears to be very little risk of reactivation occurring during treatment for COVID-19.85 Remdesivir has been demonstrated to cause an elevation in transaminases, and in some studies, transaminitis is the most commonly cited side effects of treatment.83,86,87 The elevation of transaminases can be severe; however, discontinuation of therapy is usually not necessary. Generally, the current thinking is that most of the elevations in transaminases observed with remdesivir is related to the superimposed infection with SARS-CoV-2.81,86,87 It is currently not recommended to start therapy with this agent if transaminases are greater than five times normal.87 Elevated transaminase levels have occurred in patients with HIV treated with lopinavir/ritonavir which can also occur in patients with COVID-19 treated with these agents.8890 The potential hepatotoxicity of this agent is possibly due to its activation of caspases, oxidant stress, and toxic metabolites resulting in hepatocyte injury. The clinician should be constantly vigilant of drug–drug interactions, because many of these agents are inhibitors of the cytochrome p-450 system.8890

Chronic Kidney Disease

Patients with chronic kidney disease (CKD) usually have multiple superimposed comorbidities such as diabetes, CVD, and HTN. Thus, it is understandable from an epidemiological and pathophysiological standpoint that individuals with CKD would represent a group at high risk for increased morbidity and mortality in the setting of COVID-19. Large observational studies have demonstrated that patients with CKD and COVID-19 have a significantly worse prognosis and mortality than those individuals with and without CKD.91,92 Henry and Lippi performed a small unadjusted meta-analysis involving over 1,000 patients and observed an almost threefold risk for the development of severe COVID-19 in individuals with CKD.93 Pakhchania et al employing a large electronic medical record database observed that individuals with CKD demonstrated a significant increase in hospitalization, need for mechanical ventilation, requirement for dialysis, and mortality.92 When individuals were propensity matched for comorbidities, these significant differences in morbidity and mortality remained in patients with moderate to severe CKD.92 After propensity matching patients with mild disease, a significant difference in need for hospitalization remained.92 Drug dosing in the setting of impaired renal dysfunction needs to be considered. Although there is a paucity of information, attention should be paid to the timing and dosing of medications in patients requiring renal replacement therapy. Interestingly, patients with CKD in contrast to patients with SOTs demonstrate a better response to mRNA vaccines employed during the pandemic.9496 However, hemodialysis patients demonstrate a blunted response to vaccination.9496

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Jun 23, 2022 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on 21 Comorbidities and COVID-19 Perspectives and Challenges
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