Post-acute sequelae of SARS-CoV-2 infection: Caring for the ‘long-haulers’

TRUE NUMBERS ARE HARD TO ASSESS

A marked variability in reported symptoms, duration, and definitions of COVID-19 sequelae in studies makes it difficult to estimate the true incidence of PASC. However, by some estimates, at least 10% of patients who test positive for COVID-19 experience symptoms for longer than 3 weeks.⁴

Although advanced age, obesity, comorbid psychiatric conditions, and other chronic medical conditions are risk factors for PASC, nearly 20% of suspected cases are in adults ages 18 to 34 with no chronic medical conditions.⁵ Studies that included hospitalized patients report an even higher prevalence of protracted symptoms, with data suggesting more than two-thirds of these patients have continued symptoms 6 months after recovery from acute COVID-19.^6,7 We have insufficient data to directly attribute the prolonged symptoms in this population to PASC rather than to other causes of protracted symptoms in hospitalized patients, such as PICS. The prolonged symptoms are likely multifactorial and may be difficult to attribute to a single cause.

MECHANISMS PROPOSED, BUT PATHOPHYSIOLOGY UNKNOWN

The pathophysiology of the PASC is not known. Clinicians and researchers are exploring the possibilities of a persistent hyperinflammatory state, inadequate antibody response, ongoing viral activity, and organ damage as a reflection of acute insult from the infectious phase.⁸ Furthermore, it is likely that this syndrome represents a multifactorial presentation attributable to symptoms of underlying medical conditions, features of the acute disease state, and symptoms associated with physical deconditioning from precautionary isolation measures and acute illness.⁸

Despite the chronicity of symptoms, the US Centers for Disease Control and Prevention reports that most immunocompetent patients with mild to moderate COVID-19 are unlikely to be contagious at 10 days after symptom onset, or at 20 days for most immunocompromised patients and patients with severe illness, which allows for discontinuation of isolation precautions at those time points.^9,10

A RANGE OF SYMPTOMS

Data on symptoms of PASC commonly include outpatients with mild to moderate disease severity, but many studies have included patients with severe COVID-19 who required hospitalization with or without ICU admission.^1,8 Most studies to date have recognized symptoms consistent with PASC as persisting after at least 14 to 21 days. Emerging reports are recognizing PASC as persisting symptoms at 28 days in COVID-19 survivors, although an official definition has not been clearly delineated.

The most commonly reported symptoms are fatigue, cough, shortness of breath, chest pain, difficulty concentrating, arthralgia, low-grade fever, and headache (Table 1).^6–8,11 Other reported symptoms include cognitive impairment (“brain fog”), olfactory and gustatory dysfunction, sleep difficulty, depression, anxiety, gastrointestinal upset, rashes, alopecia, and palpitations.^4,6 Persistent dermatologic manifestations have been described : in a multinational study of patients with dermatologic manifestations, pernio (“COVID toes”) was observed in 103 patients, and persisted at 60 days after diagnosis in 7% of them.¹²

Two studies noted symptoms at the 60-day follow-up in more than two-thirds of patients recovering from COVID-19.^6,7 In a study from Italy, Carfi et al⁶ found that at 60 days after onset of COVID-19 symptoms, only 18 (12.6%) of 143 patients were completely free of any COVID-19 -related symptom, 32% had 1 or 2 symptoms, and 55% had 3 or more symptoms. Other studies have shown at least 1 persistent symptom, most commonly fatigue or dyspnea, in more than half of patients at 110 days or 180 days, suggesting the longest duration has yet to be determined.^13,14

Huang et al,¹⁴ reporting on patients 6 months after their acute COVID-19 diagnosis, noted continued fatigue in 63%, sleep difficulties in 24%, and anxiety or depression in 23%. The level of persistent lung diffusion impairment and exercise intolerance at 6 months correlated with the severity of COVID-19 illness.

Of note, PASC affects patients across the spectrum of disease severity. Garrigues et al¹³ found no statistically significant difference in the symptoms reported in patients with COVID-19 requiring hospitalization compared with those requiring admission to an ICU. On the other hand, a study from the United Kingdom found nearly twice the rate of psychological distress in patients who required ICU admission compared with those admitted to a general ward.¹¹

In a study of outpatients with COVID-19,⁵ 35% had not returned to their baseline health 2 to 3 weeks following positive testing for SARS-CoV-2.⁵ This trend of protracted symptoms was consistent even in previously healthy patients: approximately 20% of those ages 18 to 34 without chronic medical conditions who were diagnosed with mild COVID-19 not requiring hospitalization reported that they had not returned to their baseline state of health 2 to 3 weeks after testing.⁵ Even patients with dermatologic-dominant and otherwise mild COVID-19 have been reported to manifest dermatologic signs of pernio or livedo reticularis for as long as 150 days from initial diagnosis, again demonstrating the range of initial disease severity that variably becomes PASC.¹²

PASC has also had significant global economic impact. A single-center study in France reported that more than 25% of previously active workers (n = 41) discharged from the hospital ward (without ICU stay) had not returned to work after 110 days (mean 110.9 days).¹³ An observational cohort study of patients discharged after recovery from COVID-19 in Michigan showed that 40% of previously employed individuals had not returned to work, and that another 15% returned with reduced hours or responsibilities at 60-day follow-up.¹⁵

EVALUATION OF LONG-HAULERS

Guidelines for evaluation of PASC are being developed. Several large centers have created post-COVID-19 clinics that offer a multidisciplinary approach to evaluation and management, including follow-up for noncritically ill patients and post-ICU care. Most clinics accept COVID-19 patients referred for persistent symptoms 1 month after symptom onset. Most use multiple screening measures, including the Montreal Cognitive Assessment, Hospital Anxiety and Depression Scale, and Impact of Event Scale-6, in addition to medication reconciliation, screening for rehabilitation needs, and pulmonary function testing.¹⁶ A Post-COVID-19 Functional Status Scale has been created to grade the severity of symptoms, but it has not been validated or widely implemented.¹⁷

Multidisciplinary care teams typically include primary care, pulmonology, cardiology, infectious disease, neuropsychiatry, behavioral health, social work, physical and occupational therapy, pharmacy, and case management, but their involvement will vary depending on the particular needs of the patient.

The British Thoracic Society¹⁸ published a guidance algorithm suggesting a follow-up chest radiograph at the 12-week follow-up. However, the timing of imaging tests must be tailored to the individual patient, with some algorithms suggesting chest radiography or computed tomography at 1 month. Our approach to follow-up evaluation and care is shown in Figure 1.

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Figure 1

Care pathway for patients with the post-acute sequelae of SARS-CoV-2 infection.

Evaluation of persistent or changing symptoms in patients recovering from COVID-19 should be done comprehensively but also judiciously. COVID-19 may unmask or exacerbate underlying disease processes such as chronic lung disease or cardiovascular disease, and may serve as motivation to seek medical care for patients who may not typically schedule routine visits. Basic management of chronic medical conditions is important.

SPECIFIC TREATMENT FOR SYMPTOMS AND COMORBID CONDITIONS

At present, there are no specific treatments for PASC. But recognizing this syndrome is a key step toward seeking targeted treatment.

Management focuses on specific treatment of the most bothersome symptoms, such as fatigue or cognitive impairment, although efficacy data are lacking. Given the complexity and chronicity of the associated symptoms and their impact on several major organ systems, frequent routine follow-up, establishing rapport, and involving a patient’s support system serve as the foundation of management in these patients. A comprehensive, multidisciplinary approach that incorporates detailed management of comorbid medical conditions is the cornerstone of care. Referral to a dedicated post-COVID-19 clinic is recommended, if available.

LIMITATIONS OF CURRENT DATA, AND LESSONS LEARNED

There are significant limitations in the research efforts to understand the natural history of a pandemic that is merely 1 year old. Limitations include the relatively short time frame of follow-up and a heavy reliance on survey-reporting due to infection-prevention measures that limit in-person follow-up visits.

Reflecting on lessons learned from the outbreaks of severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS), both caused by related coronaviruses, clinicians should anticipate at least a similar range of long-term effects. Survivors of SARS and MERS have been found to have persistent respiratory compromise with abnormal pulmonary function test results, abnormal chest imaging, increased prevalence of psychological conditions, and fatigue that lasted several months.¹⁹ Mainstays of their treatment included management of comorbid conditions, pulmonary rehabilitation, and ongoing multidisciplinary follow-up aimed at recognizing impairments and improving outcomes.

FUTURE DIRECTIONS

As part of the PASC initiative, the NIH committed more than $1 billion in grant funding toward several research initiatives to streamline efforts of the medical and scientific communities to improve our understanding and treatment of PASC. The SARS-CoV-2 Recovery Cohort will be established as a core resource to help investigate PASC as an important public health concern.