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Answering Patient Questions About COVID-19, Part 2

AUTHORS

C.S. Solomon, BSPharm, RPh, CTTS, NCTTP, Clinical Associate Professor, Department of Internal Medicine and Neurology, Wright State University Boonshoft School
of Medicine, Dayton, OH

Glen D. Solomon, MD, MACP, FRCP (London), Chairman, Department of Internal Medicine and Neurology, Wright State University Boonshoft School
of Medicine, Dayton, OH

WSU-BSOM COVID-19 Education Task Force Members, Wright State University Boonshoft School of Medicine, Dayton, OH

PEER REVIEWER

Sary Beidas, MD, MBI, FACP, Associate Professor of Medicine, Florida State University, Sarasota, FL

EXECUTIVE SUMMARY

During the COVID-19 pandemic, one medical school initiated a task force to bring together answers to common questions by clinicians and the public regarding the pandemic. This issue summarizes the results of that effort and is presented in a different format, with references included for each section.

For more than two years, we have been struggling with finding the right answers to a host of issues that are changing constantly in complexity and applicability.

  • What should primary care physicians do if a patient tests positive?
  • Why is it so difficult to interpret the medical literature in the face of often contradictory and politically charged theater?
  • Where are the trusted sources of information?
  • How should we respond to new, mutated viral strains? How do we decide on appropriate therapy for individual patients, and how do we prepare for the apparently inevitable next wave of infection?

Vaccination vs. Naturally Acquired Immunity

If I already have had COVID-19, should I still be vaccinated?

Providers should encourage their previously infected patients to seek vaccination for COVID-19. Many patients infected with COVID-19, having not been vaccinated previously, may mistakenly believe they are equally protected from future reinfection by their natural immunity, compared to people already vaccinated. The duration of naturally acquired immunity differs by COVID-19 variant. Neutralizing antibodies after natural infection have a half-life of two to three months, while with messenger RNA (mRNA) vaccination, the half-life extends to three to six months.1 Both cellular and humoral immunity appears to be more durable after vaccination compared with infection. Studies have shown that vaccination, in combination with previous infection, reduces the frequency of reinfection.2,3 Individuals who have been both infected and vaccinated show a more robust immune response when compared to those who have naturally acquired immunity alone.4,5 Additionally, patients who have been infected previously with COVID-19 generate a stronger immune response from vaccination, compared with vaccinated individuals who have not been infected previously.6,7

Many studies have estimated that previous infection plus an mRNA vaccine dose produces an antibody response similar to two doses of vaccine in a person without a history of infection.1 Antibodies induced by vaccination have been shown to be more diverse and have greater reactivity against variants than antibodies from prior infection.8 Multiple studies have shown varying rates of seronegativity following confirmed COVID-19 infection, further suggesting that natural infection does not guarantee immunity.9-12 Patients with lower viral loads and less symptomatic disease were more likely to lack seroconversion and, conversely, severe disease did not guarantee a seroconversion.13 Vaccination against the SARS-CoV-2 virus after previous infection may amplify the immune response, provide broader protection against different strains of the virus, and provide protection to those who may have had an absent or low level of immunity created by natural infection.

References

  1. Centers for Disease Control and Prevention. Science Brief: SARS-CoV-2 infection-induced and vaccine-induced immunity. Updated Oct. 29, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/vaccine-induced-immunity.html#anchor_1635540136596
  2. Cavanaugh AM, Spicer KB, Thoroughman D, et al. Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination – Kentucky, May-June 2021. MMWR Morb Mortal Wkly Rep 2021;70:1081-1083.
  3. Nordstrom P, Ballin M, Nordstrom A. Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: A retrospective, total population cohort study in Sweden. Lancet Infect Dis 2022;22:781-790.
  4. Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N Engl J Med 2022;386:1207-1220.
  5. Milne G, Hames T, Scotton C, et al. Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity? Lancet Respir Med 2021;9:1450-1466.
  6. Bates TA, McBride SK, Leier HC, et al. Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants. Sci Immunol 2022;7:eabn8014.
  7. Kent SJ, Juno JA. Vaccination after prior COVID-19 infection: Implications for dose sparing and booster shots. EBioMedicine 2021;72:103586.
  8. Castro Dopico X, Ols S, Loré K, Karlsson Hedestam GB. Immunity to SARS-CoV-2 induced by infection or vaccination. J Intern Med 2022;291:32-50.
  9. Wellinghausen N, Plonné D, Voss M, et al. SARS-CoV-2-IgG response is different in COVID-19 outpatients and asymptomatic contact persons. J Clin Virol 2020;130:104542.
  10. Thiruvengadam R, Chattopadhyay S, Mehdi F, et al. Longitudinal serology of SARS-CoV-2-infected individuals in India: A prospective cohort study. Am J Trop Med Hyg 2021;105:66-72.
  11. Masiá M, Telenti G, Fernández M, et al. SARS-CoV-2 seroconversion and viral clearance in patients hospitalized with COVID-19: Viral load predicts antibody response. Open Forum Infect Dis 2021;8:ofab005.
  12. Oved K, Olmer L, Shemer-Avni Y, et al. Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation. EClinicalMedicine 2020;29:100651.
  13. Liu W, Russell RM, Bibollet-Ruche F, et al. Predictors of nonseroconversion after SARS-CoV-2 infection. Emerg Infect Dis 2021;27:2454-2458.


Treatment Strategies

What are some of the current treatment strategies for non-hospitalized COVID-19 patients?

Treatment of COVID-19 in outpatients generally is limited to patients at high risk of severe disease. Four available therapies are nirmatrelvir/ritonavir (Paxlovid), molnupiravir (Lagevrio), sotrovimab (Xevudy), and remdesivir (Veklury). Nirmatrelvir/ritonavir combination acts as an oral protease inhibitor. Used in patients with at least one risk factor for progression of disease, nirmatrelvir/ritonavir can be taken at home, lowering the risk of hospitalization by nearly 90%. Treatment needs to be started within five days of either the beginning of symptoms or a confirmed positive COVID-19 test. Because there are many potential drug interactions, drug reconciliation, with possible temporary therapeutic changes, is a necessity prior to dispensing the treatment.1 Patients with severe kidney or liver impairment should not be prescribed nirmatrelvir/ritonavir. Regimens of medications or dietary supplements significantly metabolized via cytochrome P450 enzyme reactions (see the University of Liverpool COVID-19 Drug Interactions resource at www.covid19-druginteractions.org/checker) must be thoroughly scrutinized for patient safety prior to prescription. The so-called “rebound effect,” recurrent symptoms or positive polymerase chain reaction (PCR) test occurring two to eight days post-nirmatrelvir/ritonavir treatment course, remains a concern. Recurring symptoms after completing the five-day course do not appear to represent reinfection or resistance to nirmatrelvir/ritonavir. Retreatment with nirmatrelvir/ritonavir is not recommended, nor is it part of the current emergency use authorization (EUA) for this medicine.

Sotrovimab is a monoclonal antibody given as a single infusion. It can be given within 10 days of symptom onset. Sotrovimab is not effective against the Omicron variant BA.2 and no longer is authorized for use in areas with high BA.2 frequency. Remdesivir injection was the first drug to receive FDA approval for use specifically in COVID-19. A prodrug of an adenosine analog, it is given once daily via intravenous infusion for up to 10 days.

Molnupiravir is an oral antiviral drug that works by preventing the SARS-CoV-2 virus from making more copies of itself. It appears to be less effective in preventing hospitalization and death than the other drugs, lowering the risk of hospitalization and death by about 30%. It is recommended for use only when the other three options are not available. It should be given within five days of symptom onset.

To improve access to these therapies, an online locator tool is available at https://covid-19-therapeutics-locator-dhhs.hub.arcgis.com.

For pre-exposure prophylaxis, the FDA has authorized, via EUA, the combination of tixagevimab plus cilgavimab (Evusheld). This is a long-acting anti-SARS-CoV-2 monoclonal antibody combination used for individuals who do not have SARS-CoV-2 infection and have not recently been exposed to an individual with SARS-CoV-2 infection, but who are at risk for inadequate immune response to COVID-19 vaccination or have a documented history of severe adverse reaction to an available COVID-19 vaccine or its components. It provides at least six months of protection. Information on each of these treatments can be found at:

What is the role of dietary supplements in treating COVID-19 infections?

Recent studies have evaluated several dietary supplements in the treatment of COVID-19-infected patients. Dietary supplements, as regulated currently, are not considered as medicines, nor are they intended to treat, diagnose, mitigate, prevent, or cure disease. Although limited evidence exists about the safety and effectiveness of using vitamin D and zinc for treating or preventing COVID-19, several studies have been conducted to assess in vitro antiviral properties and how this might translate into humans.

Current literature shows that people receiving vitamin D and zinc, either individually or combined, had no improvement in symptoms, and no faster recovery or change in intubation status nor outcome.2 Many individuals who were infected by COVID-19 were found to have low levels of vitamin D.3 Despite supplementation with vitamin D during COVID-19 infection, there was no change in outcomes for these patients.2,3 Patients with normal vitamin D levels had more favorable outcomes than patients with low vitamin D levels.2 This suggests that patients who are deficient in vitamin D may have less favorable health outcomes after COVID-19 infection than patients who have normal serum levels of vitamin D. However, there is no evidence that patients with normal vitamin D serum levels benefit from vitamin D supplementation during active COVID-19 infection. There are potential risks to over-supplementing with vitamin D. Current studies found that overzealous dosing with vitamin D led to side effects, including nausea, vomiting, altered sensorium, constipation, headaches, acute kidney injury, weight loss, and symptomatic hypercalcemia.4 In summary, vitamin D does not appear to be beneficial as a treatment for COVID-19-infected patients.

Because zinc may play a role in the immune response, it has been studied in COVID-19 patients.2 A recent meta-analysis of patients supplemented with zinc during active COVID-19 infection showed no evidence of benefit to patients.2 There is evidence that supra-physiologic supplementation with zinc may lead to irreversible loss of taste and smell.3 Because COVID-19 symptoms can include loss of taste and smell, zinc supplementation may cause providers a challenge in differentiating between COVID-19 symptoms and effects from consuming zinc.

Deficiencies of vitamin D and/or zinc have been associated with less favorable outcomes in COVID-19 patients.2,4 Neither supplementing vitamin D and/or zinc during a COVID-19 infection, nor treating low levels of either, has shown improved outcomes. Other supplements also have failed to show positive outcomes in COVID-19.

References

  1. National Institutes of Health. Ritonavir-boosted nirmatrelvir (Paxlovid). Updated May 13, 2022. https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/
  2. Speakman LL, Michienzi SM, Badowski ME. Vitamins, supplements and COVID-19: A review of currently available evidence. Drugs Context 2021;10:2021-6-2.
  3. Joachimiak MP. Zinc against COVID-19? Symptom surveillance and deficiency risk groups. PLoS Negl Trop Dis 2021;15:e0008895.
  4. Kaur P, Mishra SK, Mithal A. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf) 2015;83:327-331.


Long COVID

What is long COVID?

Because post-COVID-19 syndrome, also called long COVID or post-acute sequelae of COVID-19 (PASC), has no universal definition, it is difficult to compare studies. The World Health Organization (WHO) defines PASC as occurring in people with a history of probable or confirmed SARS-CoV-2 infection, usually within three months from the onset of COVID-19, with symptoms and effects lasting at least two months, unexplained by an alternative diagnosis.

Post-COVID-19 conditions are reported by individuals with both symptomatic and asymptomatic initial infection. Many people who experience mild or asymptomatic SARS-CoV-2 infections do not receive PCR or antigen testing at the time of acute infection, making it more challenging to attribute later symptoms to SARS-CoV-2 infection.1,2 Symptoms associated with post-COVID-19 conditions are heterogeneous and often non-specific, overlapping with many common medical conditions, and may be difficult to fully capture in any single data system.1,3,4 Long-term symptoms are common, occurring in one-quarter to one-half of all COVID-19 patients.

Commonly reported symptoms associated with long COVID are illustrated in Figure 1.

Figure 1. Long COVID Symptoms

Figure 1

Sources: Centers for Disease Control and Prevention. Long COVID or post-COVID conditions. Updated June 17, 2022. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html

Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: A systematic review and meta-analysis. Sci Rep 2021;11:16144.

Sanchez-Ramirez DC, Normand K, Zhaoyun Y, Torres-Castro R. Long-term impact of COVID-19: A systematic review of the literature and meta-analysis. Biomedicines 2021;9:900.

References

  1. Saydah SH, Brooks JT, Jackson BR. Surveillance of post-COVID conditions is necessary: Addressing the challenges with multiple approaches. J Gen Intern Med 2022;37:1786-1788.
  2. Kalish H, Klumpp-Thomas C, Hunsberger S, et al. Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States. Sci Transl Med 2021;13:eabh3826.
  3. Wanga V, Chevinsky JR, Dimitrov LV, et al. Long-term symptoms among adults tested for SARS-CoV-2 - United States, January 2020-April 2021. MMWR Morb Mortal Wkly Rep 2021;70:1235-1241.
  4. Jiang DH, Roy DJ, Gu BJ, et al. Postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection: A state-of-the-art review. JACC Basic Transl Sci 2021;6:796-811.


Neurologic Symptoms

How common are neurologic long COVID symptoms, such as brain fog and headache?

The five most common symptoms of long COVID are fatigue (58%), headache (44%), attention-deficit disorder (27%), hair loss (25%), and dyspnea (24%). Various neurologic symptoms of post-acute COVID syndrome (PACS) include headaches, memory deficits, difficulty concentrating, and cognitive impairment (brain fog).1

Post-COVID fatigue represents one of the most persistent and debilitating symptoms following infection. The multiple mechanisms for fatigue post-COVID should be considered in the patient’s differential diagnosis and treatment plan. Mechanisms for fatigue include:2

  • inflammation caused by the release of pro-inflammatory cytokines (cytokine storm);
  • mitochondrial dysfunction;
  • autonomic nervous system abnormalities;
  • reduced systemic oxygen extraction;
  • poor nutritional status related to loss of taste and smell;
  • obesity and physical inactivity;
  • muscle wasting (sarcopenia);
  • sleep alterations;
  • excessive respiratory effort related to respiratory complications;
  • depression.

Headache is the most common neurologic symptom. Many patients report headache during and after COVID-19 infection. The characteristics of the headache may resemble migraine or tension-type headache and are treated like the headaches they resemble. There are no symptoms specific for headache related to COVID-19. Headaches can occur in people with a history of prior headaches, but they also can occur in people without a previous headache history.

Neuropsychiatric symptoms also are common after COVID-19 infection, occurring in 30% to 40% of patients.3 Approximately one-third of COVID-19 survivors were diagnosed with generalized anxiety disorders, one-quarter with sleep disorders, 20% with depression, and 12% with post-traumatic stress disorder. The etiology of neuropsychiatric symptoms in COVID-19 patients is complex and multifactorial. Symptoms may be the result of direct effects from infection, including hospitalization and treatment, cerebrovascular disease (including micro-thrombosis), physiological compromise (hypoxia), side effects of medications, or social aspects of having a potentially fatal illness. New preliminary reports suggest that a biomarker, the SARS-CoV-2 spike protein, may further categorize this disorder, since it has been found in blood samples from more than half of the patients studied at Brigham and Women’s Hospital in Boston. Identifying such biomarkers would assist the work to further decipher post-acute sequelae of COVID-19.

Adults have an increased risk of being diagnosed with a new psychiatric disorder after COVID-19 infection. The most common psychiatric conditions presented were anxiety disorders, insomnia, and dementia. Sleep disturbances also may contribute to the presentation of psychiatric disorders.4

References

  1. Groff D, Sun A, Ssentongo AE, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 Infection: A systematic review. JAMA Netw Open 2021;4:e2128568.
  2. Azzolino D, Cesari M. Fatigue in the COVID-19 pandemic. Lancet Healthy Longev 2022;3:e128-e129.
  3. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med 2021;27:601-615.
  4. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: A systematic review and meta-analysis. Sci Rep 2021;11:16144.


Pulmonary Concerns

What are the common pulmonary concerns associated with long COVID?

The most common respiratory symptoms reported between 60 and 100 days after hospital discharge are dyspnea, in as many as two-thirds of patients, and cough, in approximately 16% to 18% of patients. At one year, the prevalence of both dyspnea (in 23% to 25%) and cough (in 2% to 13%) decreased, respectively.1-5 Female gender, number of comorbidities, number of symptoms at the time of admission, and length of admission have been identified as individual risk factors correlating with dyspnea seven months after discharge.6 Higher BMI is associated with persistent dyspnea at one year.7 Several recent studies investigated the effect of pulmonary rehabilitation programs (PRP) on dyspnea progression in these patients. Although more study is needed, findings appear to suggest improvement in respiratory function, exercise capacity, and dyspnea are possible with PRP.8

Pulmonary function tests (PFT) generally are normal in patients following mild or moderate COVID-19 infection.9 However, in patients with severe infection, impaired diffusing capacity of the lungs for carbon monoxide < 80% is the most common pulmonary function test abnormality, seen in almost half of the patients at three to four months, decreasing to 21% at one year. Risk factors for reduced diffusion capacity and poor recovery include female gender, preexisting lung disease, smoking, and ICU admission.7,10 Restrictive ventilatory defects with decreased total lung capacity (TLC) also are directly associated with disease severity.11 Reduced six-minute walk distance, also referred to as 6-MWD, assessed as
< 80% of predicted, was present in 20% of patients at three months, with significant improvement demonstrated at one year with prevalence of 7%.7,12

Radiographic abnormalities, including ground-glass opacities and fibrosis, are present in about one-third of patients six months after severe COVID-19 infection. This finding is directly correlated with age, length of admission, acute respiratory distress syndrome, mechanical ventilation, and the presence of cough.9,13,14 At one year, many patients show improvement, with only 10% having non-progressive fibrotic changes on computed tomography (CT) scan.7

Current recommendations are to perform a baseline assessment within three months after hospitalization by using PFTs, 6-MWDs, and chest radiography, followed serially at six months to one year. Further evaluation with high-resolution CT chest or echocardiogram may be needed for persistent symptoms or severe disease.15,16 There is growing evidence that pulmonary rehabilitation can improve 6-MWD and decrease fatigue and dyspnea, independent of disease severity.17,18 A course of corticosteroids also may be beneficial in a subset of patients with post-COVID-19 interstitial lung disease with organizing pneumonia.19,20 Lung transplantation is reserved for patients with significant debility or progressive disease failing medical therapy.15 Clinical trials currently are underway investigating the role of antifibrotic agents, such as pirfenidone or nintedanib, in the prevention of pulmonary fibrosis and other respiratory complications in COVID-19 survivors.21

References

  1. Chopra V, Flanders SA, O’Malley M, et al. Sixty-day outcomes among patients hospitalized with COVID-19. Ann Intern Med 2021;174:576-578.
  2. Garrigues E, Janvier P, Kherabi Y, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect 2020;81:e4-e6.
  3. Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA 2020;324:603-605.
  4. Millet C, Narvaneni S, Chaudhry S, et al. The long haul: A follow-up study of patients diagnosed with COVID-19 one year ago at an urban medical center in New Jersey. Chest 2021;160:A566-A567.
  5. Fernández-de-Las-Peñas C, Guijarro C, Plaza-Canteli S, et al. Prevalence of post-COVID-19 cough one year after SARS-CoV-2 infection: A multicenter study. Lung 2021;199:249-253.
  6. Fernández-de-Las-Peñas C, Palacios-Ceña D, Gómez-Mayordomo V, et al. Fatigue and dyspnoea as main persistent post-COVID-19 symptoms in previously hospitalized patients: Related functional limitations and disability. Respiration 2022;101:132-141.
  7. Lorent N, Vande Weygaerde Y, Claeys E, et al. Prospective longitudinal evaluation of hospitalised COVID-19 survivors 3 and 12 months after discharge. ERJ Open Res 2022;8:00004-2022.
  8. Esque AM, Arias PC, Lostes SS, et al. Impact of pulmonary rehabilitation on sequelae produced in critically ill patients by COVID-19. Eur Respir J 2021;58:PA2263
  9. Guler SA, Ebner L, Aubry-Beigelman C, et al. Pulmonary function and radiological features 4 months after COVID-19: First results from the national prospective observational Swiss COVID-19 lung study. Eur Respir J 2021 Apr 29;57:2003690.
  10. Bellan M, Soddu D, Balbo PE, et al. Respiratory and psychophysical sequelae among patients with COVID-19 four months after hospital discharge. JAMA Netw Open 2021;4:e2036142.
  11. Mo X, Jian W, Su Z, et al. Abnormal pulmonary function in COVID-19 patients at time of hospital discharge. Eur Respir J 2020;55:2001217.
  12. Wu X, Liu X, Zhou Y, et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: A prospective study. Lancet Respir Med 2021;9:747-754.
  13. Han X, Fan Y, Alwalid O, et al. Six-month follow-up chest CT findings after severe COVID-19 pneumonia. Radiology 2021;299:E177-E186.
  14. Mumoli N, Bonaventura A, Colombo A, et al. Lung function and symptoms in post-COVID-19 patients: A single-center experience. Mayo Clin Proc Innov Qual Outcomes 2021;5:907-915.
  15. King CS, Mannem H, Kukreja J, et al. Lung transplantation for patients with COVID-19. Chest 2022;161:169-178.
  16. Bai C, Chotirmall SH, Rello J, et al. Updated guidance on the management of COVID-19: From an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020). Eur Respir Rev 2020;29:200287.
  17. Büsching G, Zhang Z, Schmid JP, et al. Effectiveness of pulmonary rehabilitation in severe and critically ill COVID-19 patients: A controlled study. Int J Environ Res Public Health 2021;18:8956.
  18. Gloeckl R, Leitl D, Jarosch I, et al. Benefits of pulmonary rehabilitation in COVID-19: A prospective observational cohort study. ERJ Open Res 2021;7:00108-2021.
  19. Myall KJ, Mukherjee B, Castanheira AM, et al. Persistent post-COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Ann Am Thorac Soc 2021;18:799-806.
  20. Vadász I, Husain-Syed F, Dorfmüller P, et al. Severe organising pneumonia following COVID-19. Thorax 2021;76:201-204.
  21. ClinicalTrials.gov. A study to evaluate the efficacy and safety of pirfenidone with novel coronavirus infection. https://clinicaltrials.gov/ct2/show/NCT04282902


Cardiac Complications

What are some of the cardiac complications of post-acute sequelae of COVID-19?

Cardiovascular complications in acute and post-acute sequelae of COVID-19 (PASC) have been well documented in the literature. The COVID-19 outbreak affected 892 ongoing clinical trials in cardiology.1 Since then, more than 100 trials have been registered to investigate cardiovascular complications.2 The term PASC-CVD (post-acute sequelae of COVID-19 cardiovascular disease) describes the collection of cardiovascular diseases that emerge or persist four or more weeks after an acute COVID-19 infection.3 PASC may affect 10% to 30% of COVID-19 patients.4

As the prevalence of PASC increases, clinicians will need to be familiar with:

  • the spectrum of cardiovascular complications;
  • the pathophysiology of the complications;
  • current practice guidelines for the evolving management of these patients.

A study comparing 153,760 COVID-19 patients with contemporary and historical controls evaluated the risk and the 12-month burden of incident cardiovascular disease. Notably, PASC-CVD was observed in low-risk COVID-19 patients who had not been hospitalized and had no past medical history of CVD. The risk and burden of PASC-CVD increased as the severity of the acute COVID-19 infection increased and remained significant, after controlling for demographic and comorbidity variables.5 Cardiovascular manifestations of PASC were diverse and spanned the spectrum of cardiovascular pathology, including thromboembolic disease, inflammatory myocarditis/pericarditis, dysrhythmias, ischemic heart disease, and cerebrovascular disorders.5

The pathophysiological mechanisms underlying PASC-CVD are poorly characterized and multifactorial, potentially accounting for the diversity of its manifestations.6 Direct cardiomyocyte damage from viral invasion, fibrosis, and cardiac remodeling from cytokine upregulation, micro-angiopathy from complement activation, and autoimmunity from hyperactive immune response all have been implicated.7-12 Trials on pharmacotherapies targeting these pathways have been small, have been underpowered, or have had neutral outcomes.2

The American College of Cardiology (ACC) released an expert consensus document regarding the evaluation and management of PASC-CVD, noting that these best practices continue to evolve.3 In symptomatic patients, the ACC recommended advanced testing, guided by clinical circumstance, including laboratory testing, electrocardiograms, echocardiography, and ambulatory rhythm monitoring. It encouraged early cardiology involvement, symptom-guided management, and an emphasis on graded exercise regimens.3

Given the rising incidence of PASC-CVD even in low-risk patients with mild disease, primary COVID-19 prevention should be prioritized. Familiarity with the diagnosis and evolving management of these chronic complications will be a necessity for primary care clinicians.

References

  1. Selvaraj S, Greene SJ, Khatana SAM, et al. The landscape of cardiovascular clinical trials in the United States initiated before and during COVID-19. J Am Heart Assoc 2020;9:e018274.
  2. Satterfield BA, Bhatt DL, Gersh BJ. Cardiac involvement in the long-term implications of COVID-19. Nat Rev Cardiol 2021;19:332-341.
  3. Writing Committee; Gluckman TJ, Bhave NM, Allen LA, et al. 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS- CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2022;79:1717-1756.
  4. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open 2021;4:e210830.
  5. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022;28:583-590.
  6. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med 2021;27:601-615.
  7. Farshidfar F, Koleini N, Ardehali H. Cardiovascular complications of COVID-19. JCI Insight 2021;6:e148980.
  8. Nishiga M, Wang DW, Han Y, et al. COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543-558.
  9. Chung MK, Zidar DA, Bristow MR, et al. COVID-19 and cardiovascular disease: From bench to bedside. Circ Res 2021;128:1214-1236.
  10. Delorey TM, Ziegler CGK, Heimberg G, et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 2021;595:107-113.
  11. Song W-C, FitzGerald GA. COVID-19, microangiopathy, hemostatic activation, and complement. J Clin Invest 2020;130:3950-3953.
  12. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-1418.


Gastrointestinal Issues and COVID-19

What are the gastrointestinal issues with COVID-19?

Gastrointestinal complications from COVID-19 can occur during acute infection, continue after resolution of the infection (long COVID), or develop in the weeks or months after infection. Up to one-third of COVID-19 patients present with gastrointestinal complaints, such as nausea, vomiting, or diarrhea.1

Patients with severe COVID-19 are at high risk for developing gastrointestinal dysfunction, including acute liver injury with elevated transaminases, acute cholecystitis, acute pancreatitis, ileus and feeding intolerance, acute colonic pseudo-obstruction, and mesenteric ischemia. Mesenteric ischemia is the most serious gastrointestinal complication reported in critically ill COVID-19 patients and should be considered in a hospitalized patient complaining of severe abdominal pain.1

In about one-half of COVID-19 patients, SARS-CoV-2 RNA is shed in the feces in the week after diagnosis and, in some patients, can continue to shed for many months. The presence of fecal SARS-CoV-2 RNA is associated with gastrointestinal symptoms, suggesting that gastrointestinal tissues are directly infected or serve as a viral reservoir.2,3

Long COVID gastrointestinal symptoms include decreased appetite, nausea, weight loss, abdominal pain, heartburn, dysphagia, diarrhea or constipation, and irritable bowel syndrome.4 A personalized nutritional risk assessment should be completed in patients with sustained decreased appetite, particularly in the elderly and the immunocompromised. The use of antimotility agents to treat diarrhea should be avoided, since it may impair viral clearance.5

References

  1. The Coronavirus Visualization Team. COVID long-haulers: Gastrointestinal system. Harvard University. https://scholar.harvard.edu/cvt/covid-long-haulers-gastrointestinal-system%C2%A0
  2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nature Med 2021;27:601-615.
  3. Blackett JW, Wainberg M, Elkind MSV, Freedberg DE. Potential long coronavirus disease 2019 gastrointestinal symptoms 6 months after coronavirus infection are associated with mental health symptoms. Gastroenterology 2022;162:648-650.
  4. Meringer H, Mehandru S. Gastro-intestinal post-acute COVID-19 syndrome. Nat Rev Gastroenterol Hepatol 2022;19:345-346.
  5. Kow CS, Hasan SS. The use of antimotility drugs in COVID-19 associated diarrhea. J Infect 2021;82:e19.

Diabetes and COVID-19

How does diabetes fit into the COVID-19 picture?

In addition to blood clots, pneumonia, and other complications associated with a SARS-CoV-2 infection, recent studies have identified yet another worrisome association: new-onset diabetes.

Earlier findings had established the connection between diabetes patients and an increased risk of developing a COVID-19 infection, as well as a worsening of diabetes symptoms from the presence of a COVID-19 infection.1 More recent studies have suggested that non-diabetic individuals with COVID-19 may be at risk of receiving a new diabetes diagnosis shortly following infection.

A recent report in Morbidity and Mortality Weekly Report from the CDC demonstrates that persons younger than 18 years of age with COVID-19 were more likely to receive a new diabetes diagnosis greater than 30 days after infection than were those without COVID-19, based on health claims data. The diabetes risk for COVID-19 patients younger than 18 years of age was dramatically higher (31% to 166%) than for those never infected with the virus.2

Diabetes prevalence appears to rise as severity in COVID-19 disease increases, from 6.4% in non-hospitalized patients to 32.4% in intensive care unit patients.3 A study by Montefusco et al found that one-third of newly hyperglycemic individuals remained hyperglycemic for at least six months following their recovery from COVID-19.4 Whether the hyperglycemia causes the poor COVID-19 infection outcomes or if it reflects poor outcomes remains unclear.

Researchers have found that the SARS-CoV-2 virus can affect the pancreas in one of three ways.5-8 First, it may cause direct damage to pancreatic insulin-producing beta cells, inhibiting them from producing enough insulin to control blood sugar levels. Second, the viral replication within the pancreas can damage the cells that directly surround the beta cells, which are needed for appropriate insulin release. Finally, the virus may reprogram any surviving cells, causing them to malfunction and disrupt proper blood sugar regulation.

Additional work has shown another potential cause for newly acquired diabetes in COVID-19-infected patients. According to Zickler et al, SARS-CoV-2 can replicate in human adipose tissue.9 It may cause the adipocytes to send incorrect messages to other cells.

A study by Reiterer et al discovered that COVID-19-infected patients had low levels of adiponectin, a hormone produced by adipocytes that modulates glucose regulation and fatty acid oxidation.10 Therefore, new findings are suggesting that the hyperglycemia in COVID-19 patients is the result of insulin resistance from improper fat hormone levels rather than an inability of pancreatic cells to produce insulin.

Evidence suggests that insulin and dipeptidyl peptidase 4 inhibitors can be used safely in patients with diabetes mellitus and COVID-19. Metformin and sodium-glucose cotransporter 2 inhibitors might need to be withdrawn in patients at high risk of severe disease. Many pharmacological agents currently under investigation for the treatment of COVID-19 can affect glucose metabolism, especially in diabetes patients, requiring frequent blood glucose monitoring and adjustment of medications. Thiazolidinediones, such as pioglitazone, can mediate protective effects on the cardiovascular system. However, the use of this drug class remains unsupported in COVID-19 patients, since heart failure can be aggravated.11

References

  1. Guo W, Li M, Dong Y, et al. Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev 2020;36:e3319.
  2. Barrett CE, Koyama AK, Alvarez P, et al. Risk for newly diagnosed diabetes > 30 days after SARS-CoV-2 infection among persons aged < 18 years — United States, March 1, 2020-June 28, 2021. MMWR Morb Mortal Wkly Rep 2022;71:59-65.
  3. CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 – United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69:382-386.
  4. Montefusco L, Ben Nasr M, D’Addio F, et al. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection. Nat Metab 2021;3:774-785.
  5. Tang X, Uhl S, Zhang T, et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab 2021;33:1577-1591.e7.
  6. Wu CT, Lidsky PV, Xiao Y, et al. SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metab 2021;33:1565-1576.e5.
  7. Yang L, Han Y, Nilsson-Payant BE, et al. A human pluripotent stem cell-based platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 2020;27:125-136.e7.
  8. Müller JA, Groß R, Conzelmann C, et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab 2021;3:149-165.
  9. Zickler M, Stanelle-Bertram S, Ehret S, et al. Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans. Cell Metab 2022;34:1-2.
  10. Reiterer M, Rajan M, Gómez-Banoy N, et al. Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2. Cell Metab 2021;33:
    2174-2188.e5.
  11. Lim S, Bae JH, Kwon H-S, Nauck MA. COVID-19 and diabetes mellitus: From pathophysiology to clinical management. Nat Rev Endocrinol 2021;17:11-30.

Conclusion: The End of the Pandemic?

For more than two years, people around the world have asked this question:

When will COVID-19 end?

The pandemic has claimed more than 6 million lives worldwide, with more than 1 million documented in the United States.1 COVID-19 has brought increased stress, anxiety, frustration, and fear. Although people remain optimistic that things are improving, this pandemic is not yet over.

The American Psychological Association’s Stress in America survey sheds light on the effect the pandemic has had on the American population.2 More than 60% of people report their lives as permanently changed. The effects of the pandemic on individuals have included increased unhealthy habits, decreased sleep, and worsening mental health.2 Hospitals and their healthcare systems have reorganized patient care, introducing more telehealth options along with employee resource support. It has created a positive shift toward addressing mental health, including patient-, caregiver-, and child-focused needs, as well as rewarding healthcare professional heroes and providing programming to prevent healthcare professional burnout.

A recent survey from Axios/Ipsos shows that Americans no longer view the pandemic as a serious crisis.3 More people view the pandemic as “not a problem at all” vs. a “serious crisis.” Nearly 75% of people see the COVID-19 pandemic as a manageable problem moving forward.3 Data show how the American population has endured and is recovering from the adverse effects of this pandemic. Some Americans maintain resiliency and optimism; yet, education helping to limit misinformation remains a necessity in persevering through the pandemic’s effects.

Omicron variants of the coronavirus SARS-CoV-2 pose a daunting public health emergency. The COVID-19 virus is constantly changing and accumulating mutations in its genetic code over time, resulting in new variants with high transmissibility.4 As social distancing restrictions lessen and Americans reduce mask use, variants able to evade immunity continue to emerge. With vaccination rates still less than optimum, vaccine refusal has continued to be a barrier to bringing this virus under control.5 Second-generation vaccines, now deemed necessary, will be available soon, hopefully leading to less frequent calls for booster doses.

The pandemic continues to contribute to ever-present healthcare issues, such as inequality in access to safe, quality care.6 Patients continue to endure stressors caused by COVID-19, promoting the need for current and relevant education. Healthcare providers can use the educational tools provided in this article as a framework to promote the health and well-being of their patients.

References

  1. World Health Organization. United States of America situation. https://covid19.who.int/region/amro/country/us
  2. American Psychological Association. Stress in America: Money, inflation, war pile on to nation stuck in COVID-19 survival mode. https://www.apa.org/news/press/releases/stress/2022/march-2022-survival-mode?utm_source=twitter&utm_medium=social&utm_campaign=apa-stress&utm_content=sia-mar2022-parents#parents
  3. Jackson C, Newall M, Diamond J, et al. Americans divided over when to return “normal.” Ipsos. Published June 14, 2022. https://www.ipsos.com/en-us/news-polls/axios-ipsos-coronavirus-index
  4. Centers for Disease Control and Prevention. Variant proportions. http://covid.cdc.gov/covid-data-tracker/#variant-proportions
  5. Haque A, Pant AB. Mitigating Covid-19 in the face of emerging virus variants, breakthrough infections and vaccine hesitancy. J Autoimmun 2022;127:102792.
  6. Chowkwanyun M, Reed AL Jr. Racial health disparities and Covid-19—caution and context. N Engl J Med 2020;383:201-203

The members of the WSU-BSOM COVID-19 Education Task Force are: Maaz Arif, MD; Steven Borchers, MS4, MD Candidate; Leah Burke, MS4, MD Candidate; Jacob Butman, BS, MS4, MD Candidate; Lisa Aron Carter, MD; Katie L. Fletcher, BS, MS4, MD Candidate; We’am Hussain, MD; Ariel L. Lanier, MS4, MD Candidate; Deanne Darlene Locker, MS4, MD Candidate; Noah Parker, BA, MS2, MD Candidate; Melanie Alexandra Sich, MS4, MD Candidate; Miriam Malak Soliman, MS3, MD Candidate; Muhammad A. Soofi, MD; Tiffani R. Spaulding, MPH, MS3, MD Candidate; Daniel Von Der Vellen, MS3, MD Candidate; and Joy I. Wang, MD.