The estimated incidence of PASC among previously hospitalized patients is alarmingly high, potentially greater than 50% and highest in older patients and those with co-morbidities [1-3]. Despite the growing body of observational literature, estimating a precise incidence is limited by lack of a unified definition as well as limitations identifying PASC in patients who were never hospitalized. One group surveyed a cohort of patients in Southern California and found as many as one-third of patients reporting symptoms of PASC following COVID-19 diagnosis [16]. In this group, a wide array of symptoms were present in several organ systems including constitutional, neurological, sensory, respiratory, gastrointestinal, musculoskeletal, and dermatological. The most common symptoms at the two-month mark were fatigue, dyspnea, ageusia, anosmia, and myalgia/arthralgia. Another study of non-hospitalized patients aged 16-30 years with mild to moderate COVID-19, 52% had persistent symptoms after 6 months of illness, underscoring the high prevalence of PASC in both hospitalized patients at higher risk of severe illness and in younger, non-hospitalized patients [15].

Large studies describing the morbidity and mortality associated with PASC are accumulating. One such study, including 267,000 patients, found 57% of patients with SARS-CoV-2 had one or more symptoms after 6 months. Cognitive dysfunction occurred in 7.8% overall, with a higher incidence and severity in the elderly [2]. Two large studies evaluating PASC among patients in the US Department of Veterans Affairs medical system analyzed over 70,000 US veterans who survived acute COVID-19 and assessed for excess morbidity and mortality in a variety of organ systems [17, 18]. They found COVID-19 survivors had a 46-73% increased hazard for death as well as excess burden of disease in respiratory, cardiovascular, gastrointestinal, nervous, metabolic and mental health outcomes. They also demonstrated objective laboratory evidence of persistent disease and excess use of opioid analgesia, benzodiazepines, antidepressants, and antihypertensive medications in COVID-19 survivors. These findings remained significant when comparing COVID-19 survivors to influenza survivors. A subsequent study looked at cardiovascular outcomes following COVID-19 [18]. They found significant excess morbidity among survivors of COVID-19 in all measured categories of cardiovascular disease, including ischemic heart disease, inflammatory heart disease, arrhythmia, heart failure, venous thromboembolism, and cerebrovascular disease. Despite the heterogeneity in these studies, the trend is clear. On review of studies for the most severe manifestations of PASC we found an estimated incidence of severe PASC among previously hospitalized patients ranged from 5-18% [1-7] (Table 1).

PASC poses a significant threat to entire healthcare systems and populations recovering from spikes in acute COVID-19. A systematic review including 57 studies and more than 250,000 patients on 3 continents demonstrated the massive burden of disease caused by PASC [3]. They found at least one symptom was present in more than half of patients at all time points studied, 1 month, 2-5 months, and >6 months post SARS-CoV-2 infection. Symptoms were experienced in all organ systems studied, the most common in each group were oxygen requirement, functional impairment, fatigue, difficulty concentrating, and anxiety. Mitigating these widespread impacts of PASC requires increased recognition, allocation of resources, and support for patients, clinicians, and health professionals taking care or PASC patients.

PASC related debility also likely has significant and severe economic impacts. In one study from China with one year of follow-up, 12% of previously hospitalized patients with SARS-CoV-2 had not returned to work after 12 months [1]. More worrisome is a UK survey of over 3,000 patients with PASC that revealed that 64-80% of patients had decreased ability to work or perform usual duties, 37% lost income, and 17% reported complete inability to work due to lingering symptoms following COVID-19 infection [2, 4]. These serious consequences extend beyond medicine and could impact entire global economies.

Despite the striking morbidity and mortality associated with PASC, the underlying pathogenesis and pathophysiology of PASC remain elusive. Given the multisystem manifestations of acute COVID-19, PASC may also be a collection of pathophysiologically distinct syndromes that have yet to be distinguished. The complex nature of PASC has also made treatment strategies difficult to establish. Current treatment modalities are focused on evaluation for medical conditions with symptomatic overlap, supportive care, symptomatic management, and return to functional status [19]. COVID-19 vaccination appears to offer protection against PASC and may even be a treatment strategy for those suffering from PASC, underlying the urgent need to make vaccination available to all populations [20-22]. In addition to vaccination, other treatments for acute COVID-19 have been extensively studied, such as passive immunity, immunomodulation, and direct antivirals [23]. Despite this extensive study, PASC is rarely if ever, considered a study endpoint for the efficacy of these treatments. Significant research is still needed to identify the impact of established COVID-19 treatments on PASC as well as novel treatment strategies directed at PASC. Recognizing PASC as a severe manifestation of COVID-19 is central to understanding the underlying pathophysiology, identifying optimal treatments, supporting PASC patients, and allocating appropriate resources to this morbid diagnosis.