Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

Main

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally¹. Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems². Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life^3,4,5. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae^6,7,8. Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. ^{9,10,11,12,13,14,15}).

Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. ^16,17), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks¹⁸. For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses^17,19. Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensive care of these patients in COVID-19 clinics (Box 1 and Fig. 2).

Box 1 Summary of post-acute COVID-19 by organ system

Pulmonary

• Dyspnea, decreased exercise capacity and hypoxia are commonly persistent symptoms and signs
• Reduced diffusion capacity, restrictive pulmonary physiology, and ground-glass opacities and fibrotic changes on imaging have been noted at follow-up of COVID-19 survivors
• Assessment of progression or recovery of pulmonary disease and function may include home pulse oximetry, 6MWTs, PFTs, high-resolution computed tomography of the chest and computed tomography pulmonary angiogram as clinically appropriate

Hematologic

• Thromboembolic events have been noted to be <5% in post-acute COVID-19 in retrospective studies
• The duration of the hyperinflammatory state induced by infection with SARS-CoV-2 is unknown
• Direct oral anticoagulants and low-molecular-weight heparin may be considered for extended thromboprophylaxis after risk–benefit discussion in patients with predisposing risk factors for immobility, persistently elevated D-dimer levels (greater than twice the upper limit of normal) and other high-risk comorbidities such as cancer

Cardiovascular

• Persistent symptoms may include palpitations, dyspnea and chest pain
• Long-term sequelae may include increased cardiometabolic demand, myocardial fibrosis or scarring (detectable via cardiac MRI), arrhythmias, tachycardia and autonomic dysfunction
• Patients with cardiovascular complications during acute infection or those experiencing persistent cardiac symptoms may be monitored with serial clinical, echocardiogram and electrocardiogram follow-up

Neuropsychiatric

• Persistent abnormalities may include fatigue, myalgia, headache, dysautonomia and cognitive impairment (brain fog)
• Anxiety, depression, sleep disturbances and PTSD have been reported in 30–40% of COVID-19 survivors, similar to survivors of other pathogenic coronaviruses
• The pathophysiology of neuropsychiatric complications is mechanistically diverse and entails immune dysregulation, inflammation, microvascular thrombosis, iatrogenic effects of medications and psychosocial impacts of infection

Renal

• Resolution of AKI during acute COVID-19 occurs in the majority of patients; however, reduced eGFR has been reported at 6 months follow-up
• COVAN may be the predominant pattern of renal injury in individuals of African descent
• COVID-19 survivors with persistent impaired renal function may benefit from early and close follow-up in AKI survivor clinics

Endocrine

• Endocrine sequelae may include new or worsening control of existing diabetes mellitus, subacute thyroiditis and bone demineralization
• Patients with newly diagnosed diabetes in the absence of traditional risk factors for type 2 diabetes, suspected hypothalamic–pituitary–adrenal axis suppression or hyperthyroidism should undergo the appropriate laboratory testing and should be referred to endocrinology

Gastrointestinal and hepatobiliary

• Prolonged viral fecal shedding can occur in COVID-19 even after negative nasopharyngeal swab testing
• COVID-19 has the potential to alter the gut microbiome, including enrichment of opportunistic organisms and depletion of beneficial commensals

Dermatologic

• Hair loss is the predominant symptom and has been reported in approximately 20% of COVID-19 survivors

MIS-C

• Diagnostic criteria: <21 years old with fever, elevated inflammatory markers, multiple organ dysfunction, current or recent SARS-CoV-2 infection and exclusion of other plausible diagnoses
• Typically affects children >7 years and disproportionately of African, Afro-Caribbean or Hispanic origin
• Cardiovascular (coronary artery aneurysm) and neurologic (headache, encephalopathy, stroke and seizure) complications can occur

Show morefrom this box

Epidemiology

Early reports have now emerged on post-acute infectious consequences of COVID-19, with studies from the United States, Europe and China reporting outcomes for those who survived hospitalization for acute COVID-19. The findings from studies reporting outcomes in subacute/ongoing symptomatic COVID-19 and chronic/post-COVID-19 syndrome are summarized in Table 1.Table 1 Findings from clinical studies on the prevalence of post-acute COVID-19 syndromeFull size table

An observational cohort study from 38 hospitals in Michigan, United States evaluated the outcomes of 1,250 patients discharged alive at 60 d by utilizing medical record abstraction and telephone surveys (hereby referred to as the post-acute COVID-19 US study)²⁰. During the study period, 6.7% of patients died, while 15.1% of patients required re-admission. Of 488 patients who completed the telephone survey in this study, 32.6% of patients reported persistent symptoms, including 18.9% with new or worsened symptoms. Dyspnea while walking up the stairs (22.9%) was most commonly reported, while other symptoms included cough (15.4%) and persistent loss of taste and/or smell (13.1%).

Similar findings were reported from studies in Europe. A post-acute outpatient service established in Italy (hereby referred to as the post-acute COVID-19 Italian study)³ reported persistence of symptoms in 87.4% of 143 patients discharged from hospital who recovered from acute COVID-19 at a mean follow-up of 60 d from the onset of the first symptom. Fatigue (53.1%), dyspnea (43.4%), joint pain (27.3%) and chest pain (21.7%) were the most commonly reported symptoms, with 55% of patients continuing to experience three or more symptoms. A decline in quality of life, as measured by the EuroQol visual analog scale, was noted in 44.1% of patients in this study. A study focused on 150 survivors of non-critical COVID-19 from France similarly reported persistence of symptoms in two-thirds of individuals at 60 d follow-up, with one-third reporting feeling worse than at the onset of acute COVID-19 (ref. ²¹). Other studies, including in-person prospective follow-up studies of 110 survivors in the United Kingdom at 8–12 weeks after hospital admission²² and 277 survivors in Spain at 10–14 weeks after disease onset²³, as well as survey studies of 100 COVID-19 survivors in the United Kingdom at 4–8 weeks post-discharge²⁴, 183 individuals in the United States at 35 d post-discharge²⁵ and 120 patients discharged from hospital in France, at 100 d following admission²⁶, reported similar findings. Fatigue, dyspnea and psychological distress, such as post-traumatic stress disorder (PTSD), anxiety, depression and concentration and sleep abnormalities, were noted in approximately 30% or more study participants at the time of follow-up.

In a prospective cohort study from Wuhan, China, long-term consequences of acute COVID-19 were evaluated by comprehensive in-person evaluation of 1,733 patients at 6 months from symptom onset (hereby referred to as the post-acute COVID-19 Chinese study)⁵. The study utilized survey questionnaires, physical examination, 6-min walk tests (6MWT) and blood tests and, in selected cases, pulmonary function tests (PFTs), high-resolution computed tomography of the chest and ultrasonography to evaluate post-acute COVID-19 end organ injury. A majority of the patients (76%) reported at least one symptom. Similar to other studies, fatigue/muscular weakness was the most commonly reported symptom (63%), followed by sleep difficulties (26%) and anxiety/depression (23%).

These studies provide early evidence to aid the identification of people at high risk for post-acute COVID-19. The severity of illness during acute COVID-19 (measured, for example, by admission to an intensive care unit (ICU) and/or requirement for non-invasive and/or invasive mechanical ventilation) has been significantly associated with the presence or persistence of symptoms (such as dyspnea, fatigue/muscular weakness and PTSD), reduction in health-related quality of life scores, pulmonary function abnormalities and radiographic abnormalities in the post-acute COVID-19 setting^5,22,24. Furthermore, Halpin et al.²⁴ reported additional associations between pre-existing respiratory disease, higher body mass index, older age and Black, Asian and minority ethnic (BAME) and dyspnea at 4–8 weeks follow-up. The post-acute COVID-19 Chinese study also suggested sex differences, with women more likely to experience fatigue and anxiety/depression at 6 months follow-up⁵, similar to SARS survivors¹⁵. While other comorbidities, such as diabetes, obesity, chronic cardiovascular or kidney disease, cancer and organ transplantation, are well-recognized determinants of increased severity and mortality related to acute COVID-19 (refs. ^2,27), their association with post-acute COVID-19 outcomes in those who have recovered remains to be determined.

Pathophysiology

The predominant pathophysiologic mechanisms of acute COVID-19 include the following: direct viral toxicity; endothelial damage and microvascular injury; immune system dysregulation and stimulation of a hyperinflammatory state; hypercoagulability with resultant in situ thrombosis and macrothrombosis; and maladaptation of the angiotensin-converting enzyme 2 (ACE2) pathway². The overlap of sequelae of post-acute COVID-19 with those of SARS and MERS may be explained by phylogenetic similarities between the responsible pathogenic coronaviruses. The overlap of genomic sequence identity of SARS-CoV-2 is 79% with SARS-CoV-1 and 50% with MERS-CoV^28,29. Moreover, SARS-CoV-1 and SARS-CoV-2 share the same host cell receptor: ACE2. However, there are notable differences, such as the higher affinity of SARS-CoV-2 for ACE2 compared with SARS-CoV-1, which is probably due to differences in the receptor-binding domain of the spike protein that mediates contact with ACE2. In contrast with the other structural genes, the spike gene has diverged in SARS-CoV-2, with only 73% amino acid similarity with SARS-CoV-1 in the receptor-binding domain of the spike protein³⁰. Moreover, an additional S1–S2 cleavage site in SARS-CoV-2 enables more effective cleavage by host proteases and facilitates more effective binding^30,31. These mechanisms have probably contributed to the more effective and widespread transmission of SARS-CoV-2.

Potential mechanisms contributing to the pathophysiology of post-acute COVID-19 include: (1) virus-specific pathophysiologic changes; (2) immunologic aberrations and inflammatory damage in response to the acute infection; and (3) expected sequelae of post-critical illness. While the first two are discussed in more detail in the organ-specific sections below, post-intensive care syndrome is now well recognized and includes new or worsening abnormalities in physical, cognitive and psychiatric domains after critical illness^{32,33,34,35,36}. The pathophysiology of post-intensive care syndrome is multifactorial and has been proposed to involve microvascular ischemia and injury, immobility and metabolic alterations during critical illness³⁴. Additionally, similar to previous studies of SARS survivors, 25–30% of whom experienced secondary infections^37,38, survivors of acute COVID-19 may be at increased risk of infections with bacterial, fungal (pulmonary aspergillosis) or other pathogens^39,40,41. However, these secondary infections do not explain the persistent and prolonged sequelae of post-acute COVID-19.

Pulmonary sequelae

Epidemiology and clinical manifestations

A spectrum of pulmonary manifestations, ranging from dyspnea (with or without chronic oxygen dependence) to difficult ventilator weaning and fibrotic lung damage, has been reported among COVID-19 survivors. Similar to survivors of acute respiratory distress syndrome (ARDS) from other etiologies, dyspnea is the most common persistent symptom beyond acute COVID-19, ranging from 42–66% prevalence at 60–100 d follow-up^3,20,24,26. In the post-acute COVID-19 Chinese study, the median 6-min walking distance was lower than normal reference values in approximately one-quarter of patients at 6 months⁵—a prevalence similar to that in SARS and MERS survivors⁹. The need for supplemental oxygen due to persistent hypoxemia, or new requirement for continuous positive airway pressure or other breathing support while sleeping, was reported in 6.6 and 6.9% of patients, respectively, at 60 d follow-up in the post-acute COVID-19 US study²⁰. Among 1,800 patients requiring tracheostomies during acute COVID-19, only 52% were successfully weaned from mechanical ventilation 1 month later in a national cohort study from Spain⁴². A reduction in diffusion capacity is the most commonly reported physiologic impairment in post-acute COVID-19, with significant decrement directly related to the severity of acute illness^{5,43,44,45,46}, which is consistent with studies of SARS and MERS survivors⁹, mild H1N1 influenza survivors⁴⁷ and historical ARDS survivors⁴⁸. Although less common, hospitalized COVID-19 survivors have been found to have restrictive pulmonary physiology at 3 and 6 months^5,49, which has also been observed in historical ARDS survivor populations^48,50.

Approximately 50% of 349 patients who underwent high-resolution computed tomography of the chest at 6 months had at least one abnormal pattern in the post-acute COVID-19 Chinese study⁵. The majority of abnormalities observed by computed tomography were ground-glass opacities. This study did not investigate chronic pulmonary embolism as computed tomography pulmonary angiograms were not obtained. The long-term risks of chronic pulmonary embolism and consequent pulmonary hypertension are unknown at this time. Fibrotic changes on computed tomography scans of the chest, consisting primarily of reticulations or traction bronchiectasis, were observed 3 months after hospital discharge in approximately 25 and 65% of survivors in cohort studies of mild-to-moderate cases⁴⁵ and mostly severe cases⁴⁹, respectively, as distinguished by a requirement for supplemental oxygen. However, these prevalence estimates should be considered preliminary given the sample size of each of these cohorts. The prevalence estimates of post-acute COVID-19 sequelae from these studies suggest that patients with greater severity of acute COVID-19 (especially those requiring a high-flow nasal cannula and non-invasive or invasive mechanical ventilation) are at the highest risk for long-term pulmonary complications, including persistent diffusion impairment and radiographic pulmonary abnormalities (such as pulmonary fibrosis)^5,22.

Pathology and pathophysiology

Viral-dependent mechanisms (including invasion of alveolar epithelial and endothelial cells by SARS-CoV-2) and viral-independent mechanisms (such as immunological damage, including perivascular inflammation) contribute to the breakdown of the endothelial–epithelial barrier with invasion of monocytes and neutrophils and extravasation of a protein-rich exudate into the alveolar space, consistent with other forms of ARDS⁵¹. All phases of diffuse alveolar damage have been reported in COVID-19 autopsy series, with organizing and focal fibroproliferative diffuse alveolar damage seen later in the disease course^52,53, consistent with other etiologies of ARDS^54,55. Rare areas of myofibroblast proliferation, mural fibrosis and microcystic honeycombing have also been noted. This fibrotic state may be provoked by cytokines such as interleukin-6 (IL-6) and transforming growth factor-β, which have been implicated in the development of pulmonary fibrosis^6,56,57,58 and may predispose to bacterial colonization and subsequent infection^59,60,61. Analysis of lung tissue from five cases with severe COVID-19-associated pneumonia, including two autopsy specimens and three specimens from explanted lungs of recipients of lung transplantation, showed histopathologic and single-cell RNA expression patterns similar to end-stage pulmonary fibrosis without persistent SARS-CoV-2 infection, suggesting that some individuals develop accelerated lung fibrosis after resolution of the active infection⁶².

Pulmonary vascular microthrombosis and macrothrombosis have been observed in 20–30% of patients with COVID-19 (refs. ^{63,64,65,66,67}), which is higher than in other critically ill patient populations (1–10%)^68,69. In addition, the severity of endothelial injury and widespread thrombosis with microangiopathy seen on lung autopsy is greater than that seen in ARDS from influenza^70,71.

Management considerations

Post-hospital discharge care of COVID-19 survivors has been recognized as a major research priority by professional organizations⁷², and guidance for the management of these patients is still evolving¹⁹. Home pulse oximetry using Food and Drug Administration-approved devices has been suggested as a useful tool for monitoring patients with persistent symptoms; however, supporting evidence is currently lacking^73,74. Some experts have also proposed evaluation with serial PFTs and 6MWTs for those with persistent dyspnea, as well as high-resolution computed tomography of the chest at 6 and 12 months⁷⁵.

In a guidance document adopted by the British Thoracic Society, algorithms for evaluating COVID-19 survivors in the first 3 months after hospital discharge are based on the severity of acute COVID-19 and whether or not the patient received ICU-level care⁷⁶. Algorithms for both severe and mild-to-moderate COVID-19 groups recommend clinical assessment and chest X-ray in all patients at 12 weeks, along with consideration of PFTs, 6MWTs, sputum sampling and echocardiogram according to clinical judgment. Based on this 12-week assessment, patients are further recommended to be evaluated with high-resolution computed tomography of the chest, computed tomography pulmonary angiogram or echocardiogram, or discharged from follow-up. In addition to this 12-week assessment, an earlier clinical assessment for respiratory, psychiatric and thromboembolic sequelae, as well as rehabilitation needs, is also recommended at 4–6 weeks after discharge for those with severe acute COVID-19, defined as those who had severe pneumonia, required ICU care, are elderly or have multiple comorbidities.

Treatment with corticosteroids may be beneficial in a subset of patients with post-COVID inflammatory lung disease, as suggested by a preliminary observation of significant symptomatic and radiological improvement in a small UK cohort of COVID-19 survivors with organizing pneumonia at 6 weeks after hospital discharge⁷⁷. Steroid use during acute COVID-19 was not associated with diffusion impairment and radiographic abnormalities at 6 months follow-up in the post-acute COVID-19 Chinese study⁵. Lung transplantation has previously been performed for fibroproliferative lung disease after ARDS⁷⁸ due to influenza A (H1N1) infection⁷⁹ and COVID-19 (refs. ^62,80). Clinical trials of antifibrotic therapies to prevent pulmonary fibrosis after COVID-19 are underway (Table 2)⁸¹.

Cite this article

Nalbandian, A., Sehgal, K., Gupta, A. et al. Post-acute COVID-19 syndrome. Nat Med 27, 601–615 (2021). https://doi.org/10.1038/s41591-021-01283-z

• Received18 October 2020
• Accepted09 February 2021
• Published22 March 2021
• Issue DateApril 2021