Evaluating Post-COVID-19 Conditions

Volume 26, Issue 6 — 11/01/2021

Garson M. Caruso, MD, MPH, CLCP

Les Kertay, PhD

Christopher R. Brigham, MD, MMS

Pages: 3–14

DOI: 10.1001/amaguidesnewsletters.2021.NovDec01

Publisher: American Medical Association

Keywords: COVID-19, Long COVID, Post-Acute COVID, Post-COVID-19, Post-COVID-19 Conditions, SARS-CoV-2

Abstract

Persistent symptoms, physical signs, and abnormal test results after acute coronavirus disease 2019 (COVID-19) illness have emerged as a significant problem in the current and ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus pandemic. Finding a rational balance between compelling subjective symptoms and limited objective findings in patients with post-COVID-19 conditions is challenging. We advise caution in adopting attributions, explanations, and management strategies, and especially in conferring formal disability status, for these disorders until we understand them more completely. The prevalent uncertainties threaten both overevaluation and overtreatment, with substantial personal and societal consequences, and all stakeholders need to be both intellectually open and cautious going forward. This article highlights several concerns in evaluating and treating patients with enduring COVID-19-related illness.

Introduction

Post-acute coronavirus 2019 (COVID-19) disease conditions (symptoms and signs persisting for more than 4 weeks after acute infection) can be a serious sequel to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus illness of any severity. Persistent pathologic e?ects attributed to many different mechanisms have been documented in multiple body systems. These disorders can cause substantial morbidity and should be investigated thoroughly but appropriately in affected individuals, with careful attention to multifactorial contributing factors and the quality and validity of evidence. The evaluating clinician should be particularly mindful of potential behavioral influences, medically unexplained physical symptoms, deconditioning, activity intolerance, and the potential for administrative or medical iatrogenicity. Unresolved questions include the association between post-COVID-19 conditions and myalgic encephalomyelitis, misinformation and disinformation in popular media, and the influence of rapidly proliferating post-COVID-19 care clinics and support groups.

Physicians will be asked to evaluate individuals with post-COVID-19 conditions. These evaluations will typically be performed by internal medicine, occupational medicine, physical medicine, or family medicine physicians. If a specific organ system is of concern, the evaluation may involve a medical subspecialist. The assessment of causation, maximum medical improvement (MMI), permanent impairment, and functional ability can be challenging.¹

It is essential to confirm that the examinee did have COVID-19, and in the settings of workers' compensation and liability, it is often necessary to determine whether the COVID-19 diagnosis was the result of work exposure or exposure in a setting associated with potential liability.² It may be necessary to assess permanent impairment within the respiratory, cardiac, vascular, neurologic, renal, gastrointestinal, and/or mental systems.³ After 6 to 12 months without outgoing improvement and with appropriate investigation, treatment, and rehabilitation, the examinee can be considered at MMI. However, because this disorder is new and appropriate treatment may be unclear, the time to achieve MMI is less certain.

The Centers for Disease Control and Prevention (CDC) have adopted the designation “post-COVID-19 conditions” as an “umbrella term for the wide range of health consequences that are present four or more weeks after infection with SARS-CoV-2.” ⁴

This problem is not new; knowledge of postinfectious symptoms dates back at least to the Russian flu pandemics of 1889 and 1892,⁵ and persisting post-viral symptoms have been documented more recently after both Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS),^6–8 and Ebola virus infection.⁹ Due to both frequency and severity, persisting e?ects of COVID-19 illness present a potential threat to the health and well-being of survivors of SARS-CoV-2 infection and a challenge to medical care and benefits systems.

Other labels used to describe prolonged symptoms following COVID-19 illness include:

long-term effects or late sequelae of COVID-19,
chronic COVID-19, long or long-haul COVID-19,
post-acute COVID-19,
post-acute COVID syndrome (PACS), and
post-acute sequelae of SARS-CoV-2 (PASC) infection.

Despite these labels, there are no widely accepted clinical diagnostic criteria for “long COVID.”¹⁰

As of October 1, 2021, a new International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code for unspecified post-COVID-19 conditions was approved by the CDC, ie, code U09.9, Post COVID-19 condition, unspecified.¹¹

Characteristics of Post-COVID-19 Conditions

Incidence and Prevalence

Post-COVID-19 conditions are generally considered to be symptoms, signs, and testing abnormalities that continue beyond 4 weeks from the onset of illness.^12,13 They may occur in initially asymptomatic persons (40% to 45% of those affected)¹⁴ or in those with mild COVID-19 illness and are generally more severe in those who require hospitalization and particularly intensive care (5% to 15% of those affected).¹⁵ Studies on persistent symptoms are often limited by lack of control groups, reporting, nonresponse, and selection bias; therefore, prevalence reports are broad.¹⁶ (See Figure 1 for some of the COVID-19 symptoms and the proportion of patients affected by these symptoms.)

Studies have revealed the following:

Approximately 27% to 32% of persons who initially had no complaints typical of SARS-CoV-2 infection but tested positive for the virus experience later symptoms, most commonly chest pain, dyspnea, anxiety, cough, abdominal and low back pain, and fatigue.¹⁷
Among patients with complaints who test positive for SARS-CoV-2 but were not hospitalized, two-thirds are symptom-free by 14 days after illness onset, and 90% have no complaints after 21 days.^18,19 Symptoms persist in 10% to 33% of affected individuals. The most frequent ongoing complaints are arthralgia, chest pain, cough, dyspnea, fatigue, and persistent alteration in smell and taste; other reported symptoms include cognitive impairment, depression, fever, headache, myalgia, and palpitations.
Huang et al²⁰ reported that 76% of hospitalized patients had at least one residual symptom 6 months after acute illness. The most common specific complaints included fatigue, muscle weakness, sleep difficulties, alopecia, anosmia (loss of smell), palpitations, and joint pain.
Huang et al²¹ undertook an ambidirectional cohort study of 1276 COVID-19 survivors who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between January 7 and May 29, 2020. Most COVID-19 survivors had a good physical and functional recovery at 1-year follow-up and had returned to their original work and life. The health status in the cohort of COVID-19 survivors at 12 months was still lower than that in the control population.
Becker et al²² found a relatively high frequency of cognitive impairment several months after patients contracted COVID-19. Impairments in executive functioning, processing speed, category fluency, memory encoding, and recall were predominant among hospitalized patients.
More serious complications are less common but may involve multiple body systems, including cardiovascular (myocarditis, pericarditis, and heart failure); dermatologic (alopecia and rash); hematologic (hypercoagulability with arterial and venous thrombosis and pulmonary embolism); neurologic (dysautonomia, altered cognition, memory impairment, and sleep disturbance); psychiatric (symptoms of anxiety and depression or other mood changes); renal (acute and chronic kidney injury); and respiratory (interstitial and reactive airway disease, decreased carbon dioxide [CO₂] di?using capacity [DLCO], and corresponding pulmonary function abnormalities) disorders.²³

Pathology

SARS-CoV-2 can infect many human cell types, often entering through the angiotensin-converting enzyme 2 receptor on the cell surface.²⁴ Many biological factors have been postulated or identified as contributing to post-COVID-19 conditions^25–28:

Direct injury to tissues and organs, including brain and central nervous system; respiratory tract, including small airways and lung parenchyma; esophagus and stomach; kidney; liver; spleen; and pancreatic beta cells
Neuroinflammation, with disruption of brainstem signaling and possible intra-axonal transport
Vascular effects, including endothelial and vascular smooth muscle damage, microvascular injury and dysfunction, and hypercoagulability with microthrombus deposition and macrothrombosis
Endocrine disruption, including the renin-angiotensin-aldosterone system
Immune dysregulation (including disrupted interferon and interleukin-6 metabolism) and production of a hyperinflammatory state (“cytokine storm”)²⁹; disturbance of both cellular and humoral immune function; reactivation of preexisting cardiomyopathic and neurotrophic pathogens; modified activity of other pathogens, including bacteria, fungi, and parasites, with functionally redundant pathologic effects (“multiple hit model”)³⁰; and autoantibody production³¹
Autonomic dysfunction^32,33
Dysregulation of host microbiome and virome balance (dysbiosis),³⁴ with reciprocal increase in pathogenicity and virulence
Viral persistence in tissues, possibly through immunosuppression³⁵

In critically ill patients who require intensive care, there may be a component of post-intensive care syndrome (PICS), which includes symmetrical muscle weakness, cognitive dysfunction, and behavioral health disorders, including anxiety, depressed mood, and posttraumatic stress disorder (PTSD).³⁶ Risk factors for PICS include preexisting cognitive deficits and/or brain dysfunction; alcoholism; stroke; sepsis-3 with hypotension; adult respiratory distress syndrome with hypoxemia and prolonged mechanical ventilation; neuroinflammation and disruption of the blood-brain barrier; hypoglycemia; and use of renal replacement therapy and analgesic and sedative medications.³⁷

The variety of tissues potentially affected by SARS-CoV-2 infection, and the range of its effects and severity, has led to the idea that post-COVID-19 illness may represent several subdisorders. Maxwell³⁸ suggested that the condition may represent at least four distinct clinical syndromes. These included continuing COVID-19 symptoms, PICS, postviral fatigue syndrome, and symptoms attributable to permanent heart and lung organ damage. Proal and VanElzakker²⁵ observed, “It is likely that individual patients with a PASC diagnosis have different underlying biological drivers of their symptoms, none of which are mutually exclusive,” suggesting that “[d]ifferences in PASC symptom clusters may shed light on biological contributors to individual PASC cases” and that “[t]he individualized nature of PASC symptoms also means that different therapeutic approaches may be required to best treat patients with the diagnosis.”

Evaluation and Treatment

Knowledge and practice in assessing and managing post-COVID-19 conditions is evolving. The American College of Occupational and Environmental Medicine³⁹ has published guidelines with serial updates since April 2020. Hyman et al⁴⁰ and Talmage et al¹ have written detailed guides for evaluation, particularly in the compensation setting. The National Institute for Health and Care Excellence,⁴¹ the World Health Organization,⁴² and the CDC⁴³ have all provided overviews and guidance. Crook et al⁴⁴ reviewed treatment options, and Wade⁴⁵ and Maxwell³⁸ presented excellent reviews of rehabilitation approaches and available resources. Several multidisciplinary post-COVID-19 care centers (PCCCs) have been established, usually in major academic centers.⁴⁶ Walter⁴⁷ supplied an “inside look at a COVID-19 clinic,” and Vanichkachorn et al⁴⁸ outlined the approach used by the Mayo Clinic (the COVID-19 Activity Rehabilitation Program [CARP]). (See Box 1 for a sample list of web resources for COVID-19 and post-COVID-19.)

Box 1.Web Resources

The following is a list of some of the web resources for COVID-19 and post-COVID-19.

American College of Occupational and Environmental Medicine: COVID-19 Resource Center (https://acoem.org/COVID-19-Resource-Center)
Centers for Disease Control and Prevention (CDC): COVID-19 Science Update (https://www.cdc.gov/library/covid19/scienceupdates.html)
CDC: Post-COVID Conditions: Information for Healthcare Providers (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html)
Impairment.com: Post–COVID-19 (https://www.impairment.com/covid/)
JAMA Network: Coronavirus Disease 2019 (COVID-19) (https://jamanetwork.com/journals/jama/pages/coronavirus-alert)
Lancet: COVID-19 Resource Center (https://www.thelancet.com/coronavirus)
Medscape: Novel Coronavirus (COVID-19) (https://www.medscape.com/resource/coronavirus)
National Academy of Medicine: Coronavirus Disease 2019 (COVID-19) News and Resources (https://www.who.int/emergencies/diseases/novel-coronavirus-2019)
National Institutes of Health: COVID-19 Portfolio (https://icite.od.nih.gov/covid19/search/)
UpToDate: Coronavirus disease 2019 https://www.uptodate.com/landing/covid19?search=long%20covid and (https://www.uptodate.com/contents/covid-19-evaluation-and-management-of-adults-following-acute-viral-illness)
World Health Organization: Coronavirus disease (COVID-19) Pandemic (https://www.who.int/emergencies/diseases/novel-coronavirus-2019)

Specific Issues in Managing Post-COVID-19 Conditions

The complexity of post-COVID-19 conditions poses particular difficulties for both administrators and clinicians in making decisions about treatment, stay-at-work and return-to-work, work activity restrictions, and short- and long-term disability determination.

Factors to Be Considered

Medical evaluation of a patient with suspected post-COVID-19 must be thorough but focused. Elements that should be considered in overall assessment include the following^1,40,49:

Pre-COVID-19 medical history
COVID-19 illness severity
Current and ongoing treatment, including medications
Residual symptoms, signs, and testing abnormalities
Vocational considerations, including the individual's job demands compared with current physical and mental capabilities, whether the job is safety-sensitive, and any risks to the individual or other employees if an individual returns to work too early

Hyman et al⁴⁰ provided a brief questionnaire to be used for evaluating COVID-19 disease and injury claims, and Talmage et al¹ addressed additional considerations in permanent impairment assessment.

Comprehensive and Accurate Information Is Needed

The examiner should obtain as much information as possible about the individual, and all available medical information should be critically considered for accuracy, validity, consistency, and relevance.

Required Information

The appropriate evaluation of post-COVID-19 conditions requires careful consideration of all available data. The assembled medical information should be as complete as possible and may be more extensive than usual, including:

Medical records of recent clinical encounters before the onset of COVID-19 to establish the individual's baseline health status and potential risk factors
Comprehensive medical, family, and social history, including an assessment of activities of daily living, both basic and instrumental
One or more sets of vital signs, including room air pulse oximetry, both at rest and with exertion
Detailed physical examination findings that address all affected organ systems
In-office clinical screening tools:
- Six-minute walk test with pulse oximetry to assess for desaturation or deconditioning⁵⁰
- Cognitive screens,⁵¹ such as the Montreal Cognitive Assessment (MoCA),⁵² Saint Louis University Mental Status Examination (SLUMS),⁵³ or Mini-Mental State Examination (MMSE)⁵⁴
- Screens for psychological symptoms, such as the Patient Health Questionnaire (PHQ-2/9/15),⁵⁵ the Generalized Anxiety Disorder Scale (GAD 2/7),⁵⁶ or the Kessler scales for assessing psychological distress (K-6/10)⁵⁷ (note that the MoCA, SLUMS, MMSE, PHQ, GAD, and Kessler screens are not diagnostic; positive results may suggest the need for more comprehensive neuropsychological or psychiatric evaluation but should not be used to assign cognitive or mental health diagnostic labels)
Laboratory test results, which may include complete blood cell count, comprehensive metabolic panel with kidney and liver functions, and polymerase chain reaction testing for SARS-CoV-2, as well as more specialized assays as indicated (eg, cardiac enzymes, coagulation and immunologic analysis)
Imaging studies, including chest X ray and/or computed tomography
Other testing results when clinically indicated, such as electrocardiography, pulmonary function (especially DLCO), echocardiogram or treadmill stress testing, and advanced imaging, such as brain magnetic resonance imaging
Consultation with the individual's primary care physician (PCP) or other caretaker in situations in which adequate information is not available from medical records

As always, evaluation should proceed from general to specific and be initiated with detailed history and physical examination, with screening measures, imaging or other studies, and/or advanced testing based on abnormalities suggested or uncovered by the basic assessment.^1,40,58

Evaluate the Degree to Which the Available Information Is Accurate and Reliable

The accuracy and reliability of the available information needs to be considered. The examiner needs to construct an overall picture of the individual's clinical status and should corroborate information from various sources when possible. Ultimately, the validity of the assessment may be limited by the quality and quantity of available information.^59,60 Potential sources of error in assessing COVID-19 claimants are considered herein.

Uncorroborated Self-report. People may not accurately remember common symptoms that they had before onset of the illness (such as everyday forgetting and sleep disturbance) and their previous functional capability (recall bias).^61,62 Self-report of past and present medical history, as well as current symptoms and functional capacity, may be inaccurate.⁶³ The claimant may have other conscious or unconscious influences, such as poor health literacy about COVID-19 issues (especially because of cyberchondria) or secondary gain (eg, missing work owing to illness).^64–68

Suboptimal Quality and Quantity of Available Medical Records. The examiner may encounter numerous difficulties when attempting to incorporate information from medical records. Office or hospital records may not be received in response to requests for information, and those supplied may be incomplete and not contain important elements like specialist consultations and testing outcomes. Clinical notes may be handwritten and poorly legible. Records obtained from an electronic medical record may contain considerable irrelevant information or “boilerplated” text (repeated more or less verbatim from patient to patient or visit to visit) without much relevance to the individual being examined.⁶⁹ There may be few recorded objective findings, which may not support clinically significant illness even when a valid condition is present; in these situations, clinicians often resort to the use of nonspecific symptoms as diagnoses (eg, “shortness of breath” instead of “post-acute sequelae of COVID”).

Face-to-Face Evaluation is Preferable

Whenever possible, assessment of post-COVID-19 conditions should be based on face-to-face encounters with the clinician.^40,70 The widespread use of telemedicine for patient visits has been reasonable during the COVID-19 pandemic. This venue is appropriate for screening and straightforward conversational encounters, such as eliciting medical history and even extensive consultation.⁷¹ However, telemedicine adds uncertainty and complexity to the decision-making process, as it is impossible to make even simple objective physical observations, such as vital signs and heart and lung examination without patient cooperation,⁷² specialized equipment,⁷³ or the assistance of a third party such as a nurse or paramedic. Other problems with widespread use of telehealth modalities include concerns about privacy and data security, ease of use, access to technology (eg, broadband internet), reimbursement, licensing, and other regulations.^74,75 The importance of “bedside” skills in COVID-19 illness has been emphasized.⁷⁶

Complaints Are Often Nonspecific and Subjective

Many persistent post-COVID-19 complaints (eg, dyspnea, fatigue, “brain fog”⁷⁷) pose significant challenges for caretakers and examiners. These symptoms may have valid COVID-related pathological causes as described earlier (eg, tissue damage, inflammation, autonomic or immune dysregulation) and cannot be presumed to be purely subjective; most individuals with persistent post-COVID-19 complaints will merit further evaluation to ensure that they do not have significant underlying conditions that could benefit from treatment.⁷⁸ However, there are several additional considerations for clinicians in this regard.

Psychosocial Influences

Multiple behavioral health influences may affect the occurrence and severity of post-COVID-19 conditions with or without any physiologic substrate, including:

Individual's health cognitions, ie, unconscious or conscious appraisals of their symptoms, and attitudes, beliefs, and expectations about their illness and the health care system's response to it⁷⁹
Individual motivation and reward (primary, secondary, and tertiary gain) and the possibility of malingering⁶⁸
Learning and memory, including the effects of classic and operant conditioning on symptom occurrence and maintenance⁸⁰
Perceived injustice, especially regarding compensation⁸¹
Pre-existing or potentially new-onset psycho-pathology, including anxiety disorders, mood disorders, symptoms of anxiety or depression, and personality disorders⁸²
Environmental and situational elements, such as personal, sociocultural, and workplace factors⁸³

Individuals experiencing post-COVID-19 conditions may demonstrate symptom escalation despite appropriate management and the passage of time, which may be due to psychoendocrine, psychoimmune, neuroplastic, or psychological mechanisms related to any or all of the above elements.⁸³

Medically Unexplained Physical Symptoms

Preexisting or incident medically unexplained physical symptoms (MUPS) may confound the accurate and appropriate evaluation of post-COVID-19. MUPS are defined as “physical symptoms persisting for more than several weeks and for which adequate medical examination has not revealed a condition that adequately explains the symptoms.”⁸⁴ Complaints may include atypical and/or poorly localized pain (eg, arthralgia and myalgia, chest and abdominal pain), nonspecific neurologic symptoms (eg, headache, insomnia, numbness and tingling, paresthesia), heart palpitations, malaise, and chronic fatigue. MUPS are common in both primary and specialty care (occurring in up to 50% of patients) and usually do not represent serious medical conditions, but they may cause considerable distress and suffering.⁸⁵ Causation of MUPS is extremely complex, involving both biomedical and biopsychological influences,^86,87 with contributions from both somatization and central sensitization.⁸⁸ There is a substantial degree of overlap between the presentation of MUPS and COVID-19 illness; in the COVID-19 patient, MUPS may be preexisting or of new onset. The relationship between COVID-19 and MUPS is just beginning to be explored.^89–91

Additional Concerns

Due to the overall systemic effects of their illness, people recovering from COVID-19 may be significantly deconditioned from their usual level of capability and function, even in the absence of objective evidence of physiological compromise (eg, desaturation in arterial blood oxygen content with exertion). The presence of substantial deconditioning (if supported by other credible information, and in the judgment of the examining clinician) may necessitate careful and prolonged rehabilitation, and in some cases, justifies extending work activity restriction beyond usual guidelines.⁹² Even without plausible causative factors or reasonably objective physical and mental health findings, persistent subjective complaints such as dyspnea, fatigue, and cognitive dysfunction may be experienced as significantly debilitating for some individuals. It may be difficult for treating and evaluating clinicians to identify a threshold between a person's discomfort and/or distress and significant threats to health and well-being, which will complicate the task of identifying realistic limitations and appropriate activity restrictions.

The capacity limitation risk restriction–tolerance paradigm initially described by Talmage et al⁹³ serves as a guiding construct for work capability and risk determination and may provide a useful framework in COVID-19 cases. This approach systematically considers three aspects of the individual's condition:

Functional capability and consequent limitations (what the person can and cannot do)
Risk of harm to self or others, and thus necessary restrictions on activity (what the person should and should not do)
The individual's tolerance for work activity (what the person is willing to do)

Administrative and Medical Iatrogenicity

Iatrogenicity refers to causation, facilitation, or exacerbation of a condition by a health care practitioner or process (such as an insurance claim), rather than a pathological condition.⁹⁴ It may occur due to the actions or inactions of clinicians or other stakeholders, such as employers, insurers, allied health personnel, attorneys, and others. There are five specific aspects of iatrogenicity in the context of COVID-19 illness.

Advocagenicity

Advocagenicity refers to a clinician's inappropriate support for their patient's health or administrative claims (eg, medical intervention in response to complaints rather than actual need, supporting workplace absence based on the patient's perceived difficulty with work tasks). Some clinicians may be rushed in their evaluations due to time pressures and may advance opinions to “help” patients obtain a benefit, rather than performing an objective medical assessment. Recorded observations and statements of physicians and other healthcare practitioners may be biased or otherwise inaccurate; in some extreme cases, this may rise to the level of collusion.⁹⁵

Medicalization

Medicalization refers to the assumption that an uncomfortable but normal bodily condition, mental state, or behavior represents a medical disorder that merits evaluation and/or treatment. This may occur when clinicians overinterpret common health problems, such as musculo-skeletal discomfort or fatigue, or normal human responses to illness, such as anxiety, as pathological conditions mandating intervention. Kilburn⁹⁶ has eloquently addressed the medicalization of “stress,” which is a common complaint in COVID-19 patients.

Disproportionate Fear of Missing Organic Disease

This concern is a danger in settings in which the clinical presentation may be vague (such as post-COVID-19 illness), and the clinician is overconcerned about missing an identifiable and/or treatable cause of a condition. This may lead to overordering and overinterpreting testing and sometimes leads to unnecessary treatment, resulting in negative effects on the patient (eg, discomfort, time expended, expense, adverse effects, subtle behavioral health effects such as encouragement of the “sick” role).⁹⁷ In general, testing should be obtained only when indicated by the history and physical examination findings or dictated by sound clinical judgment, and with clear goals for the testing outcomes.⁹⁸

Focus On Symptom Relief Rather Than Functional Restoration

Focusing on symptom relief rather than functional restoration is a particular hazard in clinical situations such as post-COVID-19 conditions, as it is in any setting characterized by persistent complaints without clear diagnosis. By patient report, capabilities may be substantially compromised, but rehabilitation is difficult without demonstrable underlying pathology. In these cases, a focus on symptoms may reinforce maladaptive health cognitions (eg, variations on catastrophizing and fear avoidance, and in some cases COVID-19 stress syndrome)^99,100 and contribute to excessive and/or ineffective medical care without significantly improving overall function.¹⁰¹ A particular problem in this situation is unnecessary and medically unjustified work activity restrictions based on complaints rather than objective impairment or risk, which can lead to needless workplace absence without regard for the negative consequences of improper work activity restriction.

Disregarding the Critical Nature of Time

Unnecessary delays in diagnosis and treatment of post-COVID-19 conditions may result in physical, psychological, and vocational deconditioning and impede recovery and overall functional restoration.¹⁰² Prolonged illness and absence from normal social relationships and work may result in neuroplastic changes in the central nervous system,¹⁰³ loss of normal identity, feelings of hopelessness, and a disability mindset. There is some early evidence that systemic inflammatory markers are increased in unemployed persons, suggesting an interactive effect of underlying post-COVID-19 physiology and work absence.¹⁰⁴

Unusual Stress on Clinicians

Patients with post-COVID-19 conditions may stress PCPs and other clinicians caring for them in several ways: (1) clinicians may be uncomfortable because they are not trained or experienced in this condition; (2) they may be uncertain because of the non-verifiable nature of complaints and symptoms; (3) they may be exposed to conflicting and constantly changing medical information from different sources; and (4) they may experience either subtle or overt expectations of evaluation, treatment, and work activity restriction from the patient in response to subjective complaints. This situation may place the physician or other clinician in a precarious position subject to competing demands by patients and other stakeholders, such as insurers and employers. This presents a strong potential for the iatrogenic practices discussed in the previous subsection, in part due to stress and uncertainty. For example, underappreciating the nature and severity of an individual's symptoms of shortness of breath or fatigue may result in inadequate evaluation and treatment, whereas overestimation of the degree of illness may result in excessive testing, treatment, and work activity restriction.

Additional Considerations Regarding Post-COVID-19 Conditions

There are at least three major trends in the perception and evaluation of post-COVID-19 conditions that may profoundly affect our understanding and management of the condition going forward:

Many medical practitioners and researchers maintain that post-COVID-19 conditions represent a chronic disorder similar to myalgic encephalomyelitis and chronic fatigue syndrome,¹⁰⁵ which are in turn linked to other conditions such as fibromyalgia syndrome.¹⁰⁶ These disorders are syndromic illnesses, ie, consisting of and defined by symptoms, and remain controversial within the scientific community.¹⁰⁷ For example, there is at present no clear unifying or generally accepted physiologic or behavioral health basis for these conditions, with theories including genetic influences, prior or ongoing environmental exposures (especially infection), endocrine and metabolic derangements, behavioral health disorders such as depressed mood and sleep disturbance, effects of physical or emotional stress, and changes in the body's immune system or energy metabolism.^108,109 In addition, there is no consistently effective treatment approach for these syndromes except for symptom amelioration.¹¹⁰ Our comprehension of these illnesses is growing rapidly but is still in its infancy, and associations and parallels with post-COVID-19 conditions should be drawn cautiously.
There has been a profound explosion of information in the popular media about post-COVID-19 conditions. In many cases, this material has been produced and promulgated by responsible and conscientious authors, both with and without medical backgrounds, and is accurate and constructive; however, both misinformation (errors not intended to mislead) and disinformation (false information fabricated and distributed to deceive) are widespread.^111–113 This misrepresentation may contribute to misunderstanding post-COVID-19 conditions and their optimal management, with negative consequences for all stakeholders.^114–116
As noted earlier, many academic institutions in the United States and other developed countries have established PCCCs dedicated to the evaluation and management of post-COVID-19 patients. In addition, the recognition of post-COVID-19 conditions has rapidly led to numerous support groups advocating for recognition, enhanced treatment, and disability benefits for persons who have the disorder.¹¹⁷ Both of these developments are likely to have a net positive influence, but to date, there is little or no medical research literature on their effects or outcomes.

These trends may facilitate research and understanding into the cause(s) of post-COVID-19 conditions and have an overall positive influence on clinical management and outcomes of patients with the condition. However, the rapidity and extent of these developments raises concern about the potential for excess and cost-ineffective resource utilization (eg, unnecessary or unproductive laboratory testing and imaging not based on clinical findings) and for both new-occurrence and exacerbation of preexisting medically unexplained symptoms (unrelated to SARS-CoV-2 infection) in at least some of these patients. (See Box 2 for a summary of the challenges to managing post-COVID-19 conditions.)

Box 2.Summary of Challenges to Managing Post-COVID-19 Conditions

The following is a summary of the challenges to managing post-COVID-19 conditions

A wide range of contributing factors that must be considered
Unknowns about the nature of the disease, including incidence and prevalence, and potential subtypes
Nonspecific and variable symptom presentation
Potential overlap with post-intensive care syndrome (PICS)
Potential overlap with medically unexplained physical symptoms (MUPS) and nonspecific health concerns
Potential overlap with behavioral health concerns
Need for comprehensive and accurate information to inform decision making, all of which is subject to evaluation for accuracy, validity, and reliability
Need for in-person evaluation (amidst an ongoing pandemic)
Lack of evidence-based evaluation and treatment guidelines
Potential for clinician iatrogenicity with possible overmanagement or under-management, including evaluation and treatment
Potential for systemic iatrogenicity, including widespread misinformation and lack of appropriate policies

Conclusions

Post-COVID-19 conditions are worrisome sequelae to acute SARS-CoV-2 infection of any severity, and when they can be reasonably identified, these illnesses should be investigated thoroughly and appropriately. Evaluating and treating clinicians must pay careful attention to the accuracy and validity of available information and exercise great care to avoid iatrogenic effects, including over-investigation and under-investigation and treatment, and the causation of unnecessary work disability.

It is intuitively obvious that prevention, both of the initial infection and sequelae, should be a primary concern on individual, healthcare system, and societal levels. Two fundamental guiding principles in these cases are the overarching desirability of return to work as soon as possible and systematic use of the capacity limitation risk restriction–tolerance framework in assessment and management.

We do not question the validity—and associated morbidity and mortality—of post-COVID-19 conditions in some survivors of SARS-CoV-2 infection. However, it is challenging to clinicians to find a rational balance between compelling subjective symptoms and a relative lack of objective pathological findings in persons afflicted with this illness. We advise caution in adopting attributions and explanations and management strategies, and especially conferring formal disability status—potentially permanent—for disorders like post-COVID-19 conditions until we understand these illnesses more completely. On one hand, Lubet and Tuller¹¹⁸ pointed out that “medical classifications are always subject to revision based on subsequent research, and we therefore call for more humility before declaring categorically that patients are experiencing ‘illness without disease’.” On the other hand, the uncertainties still prevalent in this field (including the vigorous medical and popular media response to perceived illness in persons who may or may not have post-COVID-19) threaten both overevaluation and overtreatment, with substantial personal and societal consequences, and all stakeholders need to exercise both intellectual openness and caution going forward.

References

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3.↑ Talmage JB, Hyman M, Snyder RB. Rating survivors of COVID-19 for permanent impairment. AMA Guides Newsletter. July/August 2020:3–7.
4.↑ Centers for Disease Control and Prevention. Post-COVID Conditions: Information for Healthcare Providers. Updated July 9, 2021. Accessed Nov 2, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html.
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