The intersection of increased chronic disease burden worldwide with the COVID-19 pandemic was called the “perfect storm”. This article discusses yet another perfect storm: Post COVID-19 (acute and non-acute) syndrome, high chronic disease burdens, advanced age, and polypharmacy. The expected hyper polypharmacy that should result from the added disease and symptom burden due to post COVID-19 syndrome is discussed, as well as the importance of studying the incidence and characteristics to be able to address avoidable medication-related problems

Antimisiaris, Demetra

English

University of Louisville

University of Louisville Journal of Respiratory InfectionsOPINION PIECEPost-Acute Sequelae of COVID-19 and Polypharmacy: If You ThinkThere’s Too Much Polypharmacy Now, Just WaitDemetra Antimisiaris, PharmD, BCGP, FASCP1∗1Center of Excellence for Research in Infectious Diseases, University of Louisville, Louisville, KY, USA∗demetra.antimisiaris@louisville.eduRecommended Citation: Antimisiaris D. Post-acute sequelae of COVID-19 and polypharmacy: if you think there’s too much polypharmacy now, just wait. UnivLouisville J Respir Infect 2021; 5(1):Article 19.The perfect stormThe editor-in-chief of the Lancet, Richard Horton, re-cently called the intersection of the COVID-19 pan-demic with the epidemic of increasing chronic diseaseburden an “acute-on-chronic health emergency”.[1]The Institute for Health Metrics and Evaluation at theUniversity of Washington describes the rising world-wide chronic disease burden and public health fail-ures as “fueling” the COVID-19 pandemic.[1, 2] Priorto the pandemic, polypharmacy per capita was steadilyincreasing over decades due to many factors, but es-pecially because of increased chronic disease burdenamong the general population worldwide.[3, 4]Chronic disease, and more post-COVID-19chronic diseaseWe are learning that post-acute sequelae of COVID-19 (PASC) in many ways parallel post-intensive caresyndrome (PICS), with persistent physical, cognitiveand psychological sequelae impacting quality of life.[5]This implies that many recovered COVID-19 patientswill live with increased disease burden and accompa-nying polypharmacy, in addition to their pre-COVID-19 conditions and medications. The wide variety ofPASC reported within the first year of the pandemicindicates that PASC patients will experience an abruptincrease in per patient burden of diagnoses in the nearterm and possibly permanently.[6]In addition to PASC patients, there are an unknownnumber of milder COVID-19 infection cases. Regard-less of the severity of infection, it is clear that prolongedafter-effects of COVID-19 after treatment or hospital-ization do exist.[7] Johansson et al. report that even out-patient COVID-19 infection cases can have non-specificsymptoms of autonomic dysfunction, blood pressuredysregulation, and orthostatic intolerance (postural or-thostatic tachycardia syndrome, or POTS).[8] Multi-ple neurological sequelae of COVID-19 infection havealso been reported, including cerebrovascular disor-ders (stroke, vasculitis), altered mental status (en-cephalitis, encephalopathy, seizures), peripheral ner-vous system problems (myositis, Guillain-Barre syn-drome), movement disorders (ataxia, myoclonus andopsoclonus), and neuropsychiatric problems (depres-sion, personality change, mania, psychosis, and cata-tonia).[9]In March 2021, results were published from an ongo-ing prospective study in the United Kingdom with acohort of 201 community-based low-risk post-COVID-19 patients (mean age 45; range 21–71). The patientsreported fatigue (98%), muscle aches (87%), breathless-ness (88%), and headaches (83%). Mild organ impair-ment was present in the heart (26%), lungs (11%), kid-neys (4%), liver (28%), pancreas (40%), and spleen (4%),with single organ (70%) and multiorgan (29%) impair-ment. In this study, severe PASC was associated withradiological evidence of cardiac damage.[10]Yet another perfect stormThe intersection of the COVID-19 pandemic with theepidemic of increasing chronic disease burden world-wide has been called “the perfect storm”.[1] The ex-pected burden of additional diagnosis in post-COVID-19 patients, with high antecedent chronic disease bur-dens and accompanying polypharmacy, is yet an-other perfect storm, especially for the most vulnera-ble COVID-19 patients: older persons.[11] Older adultstend to have multiple comorbidities and have the high-est level of polypharmacy use in society, even pre-COVID-19.[12] The prevalence of polypharmacy in-creases proportionally with increasing age.[12] OlderULJRI | https://ir.library.louisville.edu/jri/vol5/iss1/19 1ULJRI Post-Acute Sequelae of COVID-19 and Polypharmacypersons are seven times more likely to be hospital-ized for adverse drug events than younger persons.[13]In the United States and Europe, the number of peo-ple taking five or more prescription drugs (not count-ing over-the-counter medications, herbal supplements,and vitamins) is increasing rapidly. One study reportedthat 85% of older adults with cancer received five ormore prescription medications, and 43% received ten ormore.[14] Cancer.org reports the risk of living with can-cer in adults 85 years and older is 1 in 6 for men and 1 in8 for women, and this age cohort is expected to triple by2060.[15] Older adults typically live with chronic sub-clinical systemic inflammation, a heightened baselineinflammatory status termed “inflammaging.” Inflam-maging is thought to start in middle age and clinicallypresents as excessive chronic disease. Inflammagingis associated (causally in many cases) with age-relateddiseases, such as insulin resistance, cardiovascular dis-ease, osteoarthritis, COPD, emphysema, pulmonary ar-terial hypertension, Alzheimer’s disease, Parkinson’sdisease, macular degeneration, sarcopenia, immunose-nescence, and frailty.[16]Hyperinflammatory syndromes—such as SARS-CoV-2 (COVID-19), ARDS, cytokine storm syndrome, andPICS—are associated with short- and long-term seque-lae following recovery. These syndromes lead to an ac-celerated state of chronic subclinical inflammation andan increase or worsening of age-related conditions, in-cluding frailty in older (as well as potentially younger)persons with PASC who are already living with highchronic disease burden.[16] Medical scholars expectpost-COVID-19 patients to experience accelerated in-flammaging.It is not difficult to see how polypharmacy levels willdramatically increase due to the COVID-19 pandemic,given the anticipated burden of PASC conditions andthe potential for accelerated inflammaging. Cliniciansare already anxious about the impact of added neu-rocognitive and psychiatric conditions that result fromheavy burdens of medical comorbidities. Layeringneuropsychiatric problems on top of chronic metabolicand inflammatory disease presents a difficult and com-plicated medication management challenge.[17] Addi-tionally, medications can interfere with clinical testsand outcomes.[18, 19]Consider the case scenario of polypharmacy in anolder male patient with multiple chronic diseases, dis-charged from hospital after acute COVID-19 infection,who now has seizures and survived an acute myocar-dial infarction due to the COVID-19 infection. The pa-tient now lives with anxiety, insomnia, and depressionbecause of post–acute COVID-19 change in functionalstatus and an increased level of frailty (Figure 1).[20,21]This patient was discharged with a new prescriptionsfor a beta blocker (metoprolol), because he had an acutemyocardial infarction, and levetiracetam for new-onsetseizures also caused by the acute COVID-19 infection.The patient was also discharged with a tramadol pre-scription for persistent pain. Two months after hospitaldischarge, because the patient became depressed aboutdiminished post–acute COVID-19 functional status, hewas prescribed fluoxetine by his community physician.The levetiracetam was dosed too high for the patient’srenal function, resulting in restlessness and psychiatricadverse effects. The patient’s family took the patient tothe grocery store easy-access clinic for symptoms of in-somnia, where he was prescribed trazodone. An acuteCOVID-19 episode can cause post-COVID-19 seque-lae that significantly increase a patient’s polypharmacyburden. Increased polypharmacy burden increases therisk of adverse events, and for this patient, there areseveral new medication burden–related threats. Thetramadol may not be effective because fluoxetine in-hibits conversion to active drug; fluoxetine also inhibitsmetabolism of active metoprolol, which may put thepatient at risk of bradycardia and hypotension. The flu-oxetine may interact with the patient’s existing simvas-tatin prescription and cause muscle pain or rhabdomy-olysis. Furthermore, levetiracetam toxicity may be un-recognized and misdiagnosed as new-onset psychosisor dementia and start a prescribing cascade to addressmedication-induced symptoms.Significance of expected post COVID-19syndrome hyper-polypharmacyThe potential for hyper-polypharmacy worldwide dueto the COVID-19 pandemic is significant. At a timewhen societies are trying to gain control over ram-pant polypharmacy with large government-sponsoredprograms, such as “Polypharmacy Management by2030” in the European Union, the “Canadian Depre-scribing Network,” the “US Deprescribing ResearchNetwork,” and Australia’s “National Prescribing Ser-vice Medicinewise,” it is daunting to think aboutthe potential for added medication load per capitaaround the world due to PASC and post–outpatientCOVID-19 syndrome.[12, 22-24] Well-intentioned med-ication use in 2016 was responsible for 275,689 deathsand cost $528.4 billion dollars.[25] This means that ifmedication-related problems were a disease countedby the Centers for Disease Control as a cause of deathin the United States, it would rank as the third lead-ing cause of death behind cancer and heart disease, butahead of diabetes, Alzheimer’s disease and others.[26]Most medication-related problems are avoidable withthe optimization of adherence, prescribing practices,and, most importantly, monitoring.[27, 28] The morecomplex the patient and the higher the number ofmedications, supplements and vitamins used concomi-tantly, the more challenging medication use optimiza-tion becomes. Therefore, the COVID-19 pandemic mayULJRI | https://ir.library.louisville.edu/jri/vol5/iss1/19 2ULJRI Post-Acute Sequelae of COVID-19 and PolypharmacyFigure 1. Scenario of an older adult with multiple chronic conditions, pre- and post-PASC. In addition to several new comorbidities, includingadded neurologic and psychiatric diagnoses, his added polypharmacy introduces an entire cascade of new problems.∗Self-prescribed.ULJRI | https://ir.library.louisville.edu/jri/vol5/iss1/19 3ULJRI Post-Acute Sequelae of COVID-19 and Polypharmacyin time raise the death toll and costs of non-optimizedmedication use well beyond the third leading cause ofdeath and $528 billion. Additionally, the added layersof complex psychoactive and chronic disease manage-ment medications will make adverse drug-drug anddrug-disease interactions, as well as toxidromes, morecommon, posing a difficult clinical management sce-nario for clinicians.ConclusionPASC patients are beginning to be characterized bybiomedical scholars. It would be of value to char-acterize, quantify, and study approaches to the ex-pected increase in rates of polypharmacy and poten-tial cascade of new medication-related problems. Froma public health and biomedical science perspective,polypharmacy has been as difficult a problem to tackleas the growing burden of chronic disease. Unman-aged polypharmacy is very costly in terms of morbid-ity and mortality, as well as monetarily. Tracking thecount of pre-COVID-19 infection and post-COVID-19-episode medication burden, as well as characterizationof medications used to treat post-COVID-19 symptoms,will help public health professionals, biomedical scien-tists, and stake holders address avoidable harm causedby complex medication use.Received: April 15, 2021Accepted: July 3, 2021Published: July 13, 2021Copyright: © 2021 The author(s). This original article isbrought to you for free and open access by ThinkIR: The Uni-versity of Louisville’s Institutional Repository. For more infor-mation, please contact thinkir@louisville.edu. This article isdistributed under the terms of the Creative Commons Attribu-tion 4.0 International License (CC BY 4.0), which permits un-restricted use, distribution, and reproduction in any medium,provided the original author and source are credited.Funding Source: The author(s) received no specific fundingfor this workConflict of Interest: All authors declared no conflict of inter-est in relation to the main objective of this work.References1. Institute for Health Metrics and Evaluation. The Lancet:Latest global disease estimates reveal perfect storm ofrising chronic diseases and public health failures fuellingCOVID-19 pandemic. Available at: http://www.healthdata.org/news-release/lancet-latest-global-disease-estimates-reveal-perfect-storm-rising-chronic-diseases-and. Accessed 17June 2021.2. Global burden of 369 diseases and injuries in 204 coun-tries and territories, 1990-2019: a systematic analysis forthe Global Burden of Disease Study 2019. Lancet 2020;396(10258):1204-22. doi: 10.1016/s0140-6736(20)30925-9.PMID: 33069326.3. Institute for Health Metrics and Evaluation. Global Bur-den of Disease (GBD). Available at: http://www.healthdata.org/gbd/2019. Accessed 10 April 2021.4. Jones DS, Podolsky SH, Greene JA. The burden of dis-ease and the changing task of medicine. N Engl J Med2012; 366(25):2333-8. doi: 10.1056/NEJMp1113569. PMID:22716973.5. Peach BC, Valenti M, Sole ML. A Call for the World HealthOrganization to Create International Classification of DiseaseDiagnostic Codes for Post-Intensive Care Syndrome in theAge of COVID-19. World Med Health Policy 2021. doi:10.1002/wmh3.401. PMID: 33821196.6. Ayoubkhani D, Khunti K, Nafilyan V, et al. Post-covidsyndrome in individuals admitted to hospital with covid-19:retrospective cohort study. BMJ 2021; 372:n693. doi:10.1136/bmj.n693. PMID: 33789877.7. Centers for Disease Control and Prevention. Late Se-quelae of COVID-19. 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Post-Acute Sequelae of COVID-19 and Polypharmacy: If You Think There’s Too Much Polypharmacy Now, Just Wait

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Post-Acute Sequelae of COVID-19 and Polypharmacy: If You Think There’s Too Much Polypharmacy Now, Just Wait

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