key: cord-0744647-4enf2nl7
authors: Korompoki, Eleni; Gavriatopoulou, Maria; Hicklen, Rachel S; Ntanasis-Stathopoulos, Ioannis; Kastritis, Efstathios; Fotiou, Despina; Stamatelopoulos, Kimon; Terpos, Evangelos; Kotanidou, Anastasia; Hagberg, Carin A; Dimopoulos, Meletios A; Kontoyiannis, Dimitrios P
title: Epidemiology and organ specific sequelae of post-acute COVID19: A Narrative Review
date: 2021-05-14
journal: J Infect
DOI: 10.1016/j.jinf.2021.05.004
sha: 311014cdc5e97cfcfd6e5534c64a372a4e070c9b
doc_id: 744647
cord_uid: 4enf2nl7

OBJECTIVES: “Long COVID”, a term coined by COVID-19 survivors, describes persistent or new symptoms in a subset of patients who have recovered from acute illness. Globally, the population of people infected with SARS-CoV-2 continues to expand rapidly, necessitating the need for a more thorough understanding of the array of potential sequelae of COVID-19. The multisystemic aspects of acute COVID-19 have been the subject of intense investigation, but the long–term complications remain poorly understood. Emerging data from lay press, social media, commentaries, and emerging scientific reports suggest that some COVID-19 survivors experience organ impairment and/or debilitating chronic symptoms, at times protean in nature, which impact their quality of life. METHODS/RESULTS: In this review, by addressing separately each body system, we describe the pleiotropic manifestations reported post COVID-19, their putative pathophysiology and risk factors, and attempt to offer guidance regarding work-up, follow-up and management strategies. Long term sequelae involve all systems with a negative impact on mental health, well-being and quality of life, while a subset of patients, report debilitating chronic fatigue, with or without other fluctuating or persistent symptoms, such as pain or cognitive dysfunction. Although the pathogenesis is unclear, residual damage from acute infection, persistent immune activation, mental factors, or unmasking of underlying co-morbidities are considered as drivers. Comparing long COVID with other post viral chronic syndromes may help to contextualize the complex somatic and emotional sequalae of acute COVID-19. The pace of recovery of different aspects of the syndrome remains unclear as the pandemic began only a year ago. CONCLUSIONS: Early recognition of long-term effects and thorough follow-up through dedicated multidisciplinary outpatient clinics with a carefully integrated research agenda are essential for treating COVID-19 survivors holistically.

SARS-CoV-2 has spread rapidly with devastating consequences worldwide. Although mortality from acute COVID-19 rivals or exceeds that of influenza [1, 2] , 80% of hospitalized patients and 60% of those admitted to intensive care units survive [1] . A more subacute or chronic stage of disease is however increasingly being reported in a portion of COVID-19 survivors (named "COVID-19 long haulers") [3] (Table 1 ) and has been the subject of considerable interest in lay press, social media and academic centers (Appendix Table 1 ) catalyzing the creation of several post COVID units in US and overseas [3] [4] [5] . The term long COVID was conceived by COVID-19 survivors on social media [3] while in academic literature, terms such as post-acute COVID-19 (defined as presence of symptoms >3 weeks from onset of COVID-19 symptoms) and chronic COVID-19 (symptoms >12 weeks) have been used [6, 7] . A discussion on the most appropriate standardized nomenclature for this entity is ongoing.

Recently published cohort studies have reported symptoms from most body systems in following the acute disease phase reflecting its multi-systemic nature [8- 23] (Table1, Appendix Table 2 ).

The pathogenesis of late sequelae of COVID-19 is undefined [24] . Patients with long COVID comprise a heterogeneous group: those with frailty and organ damage following intensive care unit (ICU) admissions, those with moderate acute phase of COVID-19 but persistent organ damage or patients with a spectrum of lingering, occasionally remitting-relapsing chronic ailments such as fatigue, brain dysfunction (''brain fog"), weakness, or chronic pain, significantly impacting quality of life post-recovery (Table1, Appendix Table 2 ). This expanding population of patients, increasingly seek medical advice and stress an already overwhelmed medical system [25] . Currently, there is no evidence-based cost-effective approach and work-up for the care of these patients. Not uncommonly, they undergo expensive, exhaustive work-ups and at the same time are viewed with skepticism ("medical gaslighting") [3] .

Fifteen months following the recognition of the pandemic, there is a paucity of reviews on this rapidly evolving and important topic [26] . Herein, we seek to comprehensively review the long-term multisystemic complications that have been described post-acute COVID-19 recovery.

We conducted a comprehensive literature search (English only) in Ovid-Medline, Ovid-Embase, Pubmed, Scopus, and Google Scholar through April 2021 (see Appendix) .

Observational studies deriving from different populations (USA, Europe and Asia) revealed a variable proportion of persistent symptoms following SARS-CoV-2 infection ( Table 1, Appendix Table 2 ). Early studies provided evidence of persistent COVID sequelae reporting short term outcomes covering the post-acute phase (4-12 weeks) of COVID-19 [8, 13, 17, [19] [20] [21] [22] [23] 27 ]. Most recent publications present data from larger cohorts with longer follow-up periods (beyond 12 weeks) illustrating the multisystemic manifestations of the so called "long" or "chronic'' COVID [10, 12, 18] .

Eight retrospective and four prospective studies have investigated the post-acute and long COVID sequalae across different populations regarding ethnicity, inpatient/outpatient setting, disease severity (mild, moderate and severe COVID-19 patients). Of these nine studies focused on the post-acute phase with a median follow up ranging from 32 days post discharge up to 83 days (IQR 74-88) after hospital admission. Three studies provided data beyond 12 weeks with a median follow ranging between 97 days (median, IQR 95-102) post discharge and 186 (IQR after symptom onset.

The proportion of persistent symptoms varied considerably among studies. The highest proportion of post-acute COVID syndrome, 84 .7%, has been reported in an Italian study on 143 hospitalized patients, 20% of them required non-invasive or invasive ventilation [8] . The most common reported symptoms were fatigue (53.1%), dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%). A high proportion of persistent symptoms of 74% has been reported in a prospective study from the UK on 110 consecutive hospitalized patients [28] . The most common symptoms included breathlessness, excessive fatigue and limitations in reported physical ability. The largest study reporting on post-acute COVID syndrome included 1409 patients admitted to home health care [23] . The most common symptoms included 42% pain, daily or all the time, 84% dyspnea with any exertion, 50% symptoms of anxiety, 47% confusion. Fatigue was the most common reported symptom across different studies ranging from 30%-72%, followed by breathlessness/dyspnea cough, confusion/loss of memory, persistent pain, headache, joint pain/arthralgias, chest pain, anosmia/ageusia, palpitations, anxiety/depression, sleep difficulties, GI symptoms and hair loss.

Three studies, two from China and one from France, reported on chronic or long COVID syndrome [10, 12, 18] . The largest study on 1733 patients after a 6 month follow-up reported in 63% of patients fatigue or muscle weakness, 26% sleep difficulties, 23% anxiety or depression, up to 29% abnormal median 6-min walking distance and importantly, acute kidney injury (AKI) in 13% of patients without AKI at the acute phase [12] . Another study that included 538 patients, 39% of them with critical or severe disease, showed that 49.6% of patients presented at least one symptom during follow up, with 28.3% reporting physical decline or fatigue, 39% respiratory difficulties, 21.4% dyspnea, 14.1% chest distress, 12.3% chest pain, 7.1% cough, 13% cardiovascular complications, 23.6% excessive sweating and 18.6% alopecia [10] .

Obviously, the incidence of reporting symptoms should be considered under the prisma of selection bias, as most studies were retrospective in nature, with small sample sizes and included hospitalized patients with variable degree of COVID-19 severity. Future prospective population-based studies are need in order to provide more reliable estimation on the post-acute or long COVID syndrome on the general population.

The lungs are the organ most likely to sustain serious injury from COVID-19 [29, 30] . Even mildly symptomatic patients may have lung involvement on CT imaging

[31] and persistent alterations of pulmonary function tests (PFTs) [8, 18, 29, [32] [33] [34] [35] [36] [37] [38] . Abnormal lung function (restrictive abnormalities, reduced diffusion capacity, small airways obstruction) have been identified both early and later (2-12 weeks) after discharge [29, 35, [38] [39] [40] [41] [42] . However, the most severe complication is lung fibrosis (LF) and fibrotic changes have been detected as early as 3 weeks after symptoms onset, regardless of the severity of the acute illness (Appendix Table 2 (Table 2) , although persistent lung function abnormalities appear to be more common among patients who had severe acute COVID-19 and high levels of inflammatory markers [29, 35, 38, 40, 51] . Long term follow-up studies of SARS and MERS have shown that radiologic abnormalities, pulmonary function impairment and reduced exercise capacity were common, improved over time in most, but persisted for months or years in some patients [52] [53] [54] . Additionally, patients hospitalized with severe COVID-19 tend to be older than the ones with MERS or SARS; since age, in addition to COVID-19 severity, is also a risk factor for LF [37] , the burden of this complication after COVID-19 recovery could be substantial. Other potential late COVID-19 complications include pneumothorax, secondary infections, massive hemoptysis, airway strictures, and pulmonary hypertension with or without evidence of thrombosis (Table 2 ).

There are several mechanisms which may be implicated in acute and long-term damage after COVID-19 including hypoxia-related and mechanical ventilationrelated damage, tissue destruction due to uncontrolled cytokine release and immune system activation, direct pneumocyte apoptosis due to ACE2-mediated viral invasion, surfactant inactivation, micro-vascular/thrombotic disease and endothelial dysfunction. Isolated decreased diffusion capacity in several patients also points to the vascular damage induced by SARS-CoV-2; pulmonary hypertension, with or without evidence of thrombosis, has been reported.

Polymorphisms in ACE2, the entry receptor of SARS-COV-2, may also predispose to lung injury after COVID-19. Although virus persistence in lung tissues is not considered to be a cause, persistence of virally infected cells forming syncytia might play a role. SARS-CoV-2-induced proinflammatory and profibrotic cytokines

[55] are overproduced during acute and sub-acute COVID-19, whereas homeostatic mechanisms of lung repair are deregulated leading to the development of LF; the antiviral interferons attenuate lung repair, further increasing disease severity [56] .

It is unknown whether administration of antivirals (remdesivir), corticosteroids or other immunomodulators may affect the risk of long-term post-COVID-19 pulmonary abnormalities. Some guidance has been published for respiratory follow up [57] [58] [59] [60] but management of late pulmonary effects is not straightforward.

It is unknown if drugs used in idiopathic LF (e.g., pirfenidone, nintedanib) could have a positive effect on the natural history of LF post COVID-19 [51].

Accumulating evidence indicates that COVID-19 related cardiac complications ( Table 2 , Appendix Table 2 ) may arise or persist weeks or months after resolution of the infection [61] . Among COVID-19 survivors, 5%-29% complain of chest pain, dyspnea, or palpitations post-recovery ( Table 2, Appendix Table 2 ), even 6 months after the acute infection [12] . Late cardiac magnetic resonance (CMR) findings indicative of subacute myocarditis [62] [63] [64] [65] [66] have been also reported in COVID-19 patients. Although post-recovery persistence of SARS-CoV-2 in myocardial tissue or myocardial inflammation could explain these findings, histological data are lacking. After 24-71 days, CMR studies suggest myocardial inflammation or scarring in 15% to 60% of patients, even those who were asymptomatic or experienced only mild symptoms of acute disease (Appendix Table 2 ). These findings were correlated with troponin levels [64] and inflammatory markers such as C-reactive protein, white cell count and procalcitonin, indicating a role of inflammation in myocardial tissue abnormalities [67] . Alarmingly, CMR findings consistent with myocarditis were found in 4 out of 26 competitive athletes 11-53 days after recommended quarantine, while in another study CMR findings indicative of resolving pericardial inflammation were reported in 19 out of 48 student athletes, after a median of 27 days from diagnosis [65, 68] . In contrast, in a more recent case series of 145 competitive student athletes, only 2 (1.4%) presented CMR findings consistent with myocarditis, 15 (range 11 to 195) days after diagnosis, with one of them having increased troponin levels [69] . This finding suggests against routine CMR screening in recovering athletes [70] . Given the lack of histological adjudication, further research with careful follow-up is needed to explore the clinical relevance of persistent myocardial abnormalities by CMR [59] .

Another point of concern is that late cardiovascular complications were found in 80% of children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection [71] . SARS-CoV-2 infection has also been associated with persistently high inflammatory and procoagulant mediators [72, 73] and small vessel endothelitis [74] in heart specimens of COVID-19 patients. Given that other viral infections may increase atherosclerotic events through increased inflammatory and procoagulant burden [75] , these observations have led to the hypothesis that endothelial dysfunction may play a pivotal role in late COVID-19 cardiovascular complications which is currently under investigation (NCT04468412, NCT04525443, Appendix Table 3 ).

Despite the relative lack of studies examining the long-term impact of SARS-CoV-2 on cardiovascular system, existing evidence suggests an increased rate of major adverse cardiovascular events in recovered COVID-19 patients after a median follow-up of 140 days [76] . In another study, in accordance with previous data for subacute complications, myocardial injury was detected in 30% of patients at 3-month follow-up after COVID-19 infection [77] . Moreover, postural orthostatic tachycardia syndrome has been observed in recovered patients who still experience significant disability even 6-8 months after acute infection [78] .

There is cumulative evidence that COVID-19 affects brain function and could exacerbate neurodegenerative and neuroimmune disorders [79] [80] [81] . CNS and peripheral neural system (PNS) symptoms have been attributed to SARS-CoV-2 neurotropism, post-viral immune-mediated process, or neurological manifestations of systemic and non-specific inflammatory effects [82, 83] . The global CNS dysfunction due to microglial activation, persistent neuroinflammation, dysregulated neuro-immunity, and hippocampal atrophy is well recognized in critical illness (e.g., sepsis) [84] [85] [86] . Prolonged ICU stay, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, pre-existing cognitive dysfunction, neurological injury, and delirium increase the risk of cognitive decline and neurological complications post-ARDS [87] , [88] . The long-term sequelae in patients with early neurological complications, such as encephalitis or stroke, in the setting of acute COVID-19 may result in severe lifelong disability, requiring long term rehabilitation [82, 89, 90] Furthermore, immunomodulatory treatments such as corticosteroids used in the acute phase of COVID-19 frequently have CNS adverse effects , including cognitive and sleep disturbances, delirium, psychiatric manifestations, although symptoms resolve after drug withdrawal [85] . The most common self-reported neurologic symptoms post COVID-19 include headache, vertigo/dizziness, anosmia/ageusia/hypogeusia/dysgeusia, insomnia, memory impairment and inability to concentrate ("brain fog") ( Table 2, Appendix Table 2 ). Less common late manifestations include ischemic stroke, intracranial hemorrhage, encephalitis, encephalopathy, seizures, peripheral neuropathies and autoimmune acute demyelinating encephalomyelitis ( Table 2 ). The CNS damage is not specific to SARS-CoV-2, as several post-acute and long-term neurologic manifestations have been reported during pandemics with influenza and other coronaviruses (SARS, MERS) ( Table 3) . Direct neuro-invasion, neuronal injury secondary to tissue hypoxia or inflammation, local cytokine network dysregulation, and compromised blood brain barrier integrity with resulting transmigration of infected immune cells have been postulated as pathophysiological mechanisms underlying longterm neurological sequalae after coronavirus infections [81, 91] .

A retrospective cohort study among 236,379 patients in the USA showed that the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months post COVID-19 was approximately 33% with 12% of patients diagnosed for the first time with neurological or psychiatric disorders. The estimated incidence was even higher, roughly 46%, for severely ill patients admitted to ICU. Interestingly, most diagnostic categories were more common in COVID-19 patients as compared to patients with influenza [92] . Memory impairment with or without delirium during the acute phase is a common ailment, affecting up to 44% of COVID-19 survivors [93] , possibly attributed to microthrombi and cerebral structural changes in the hippocampus, insulas, and partial white matter [81, 89, 94] . Not surprisingly, elderly patients are more prone to long-term neurocognitive complications. Parkinsonism-like symptomatology has been reported as a late manifestation of influenza, SARS, and recently post-COVID-19 in elderly patients (probably due to a-synuclein accumulation and cross-autoimmunity reaction triggered by viral infections) [95] [96] [97] , raising concerns that COVID-19 might incite a new wave of neuro-degenerative diseases in susceptible patients [97] . Whether COVID-19 predisposes to worsening of preexisting chronic neurodegenerative brain conditions or if chronic COVID-19 sequalae are more common in these patients merits further investigation [81, 95, 97] .

Additionally, isolated chronic dysfunction of central nerve function (SARS-CoV-2 could invade CNS through the olfractory nerve) such as anosmia, dysgeusia or ageusia, common early symptoms of acute COVID-19, may persist for a long time post-acute infection [86, 94, 98, 99] and have been associated with higher bilateral gray matter volumes in olfactory cortices related to smell loss, as compared with non-COVID-19 volunteers [94] .

Finally, COVID-19 can cause dysautonomia by damaging the vagus nerve and postural orthostatic tachycardia syndrome (POTS) [100] characterized by intermittent tachycardia, fluctuating blood pressure and chronic cough or gastrointestinal complaints, as it has been described in other post viral syndromes (Table 3 ). The frequency of post COVID-19 POTS is unknown.

The cumulative incidence of thrombosis and hemorrhage at day 30 post discharge were reported to be 2.5% and 3.7% respectively in the USA (Appendix Table 2 ) [73] . Retrospective studies from the UK have shown a similar rate of venous thromboembolism of approximately 3%, whereas it has been estimated that the odds of such events following a hospital discharge are 60% higher in the post-acute COVID-19 setting compared to 2019 [101, 102] . However, even lower rates of deep vein thrombosis (<1%) assessed by venous ultrasound have been reported in other prospective, post-acute COVID-19 studies conducted in Belgium and China, including a low proportion of patients receiving thromboprophylaxis [103, 104] . Severe acute COVID-19 is characterized by lymphopenia, increased inflammatory indices and hypercoagulable state on the grounds of endothelitis, cytokine storm, and thrombotic microangiopathy [105, 106] . A prothrombotic state is sustained even at the early chronic COVID-19 setting, eg. at 4 months post discharge, as documented upon elevated plasma levels of factor VIII and plasminogen-activator inhibitor type 1 [107] . In addition, the incidence of lupus anticoagulant positivity was increased in patients with or without thrombosis [108] . Abnormalities in lymphocyte and platelet count tend to normalize over time [27] . However, persistent lymphocytopenia may be evident even at 6 weeks from the onset of initial symptoms, especially among patients with severe acute COVID-19 disease, as compared with healthy controls [109] . This finding is particularly relevant for CD3+, CD4+ and CD8+ lymphocyte subsets [109] . It is unknown whether COVID-19 results in acute or long term hypogammaglobulinemia in some patients. Furthermore, new onset late hematologic events were rarely reported. Lufti et al reported GSCF-responsive agranulocytosis combined with thrombocytosis occurring one week after resolution of COVID-19 symptoms [110] . Additionally, agents used in acute COVID-19 such is tocilizumab occasionally result in thrombosis and prolonged severe neutropenia, even after the resolution of the acute infection [111] . Regular monitoring of blood abnormalities and evaluating the individualized thrombotic risk based on comorbidities (cancer, immobility, prior thrombosis etc) and coagulation profile (elevated d-dimers) are considered essential both in the post-acute and chronic COVID-19 (Table 2) [73, 112] .

Viruses are known to trigger autoimmune/autoinflammatory diseases. In fact, in addition to aberrant activation of acquired and innate immune responses [113, 114] , production of autoantibodies again INF I has been associated with severe COVID-19 [115] . Molecular mimicry with induction of autoreactive humoral and/or cell mediated immunity have been postulated as drivers of the immunopathology of a variety of inflammatory/ autoantibody-related autoimmunedisease related conditions (such as scattered cases of Guillain-Barre [116] , neuromyelitis optica, systemic lupus erythematosus, psoriasis, arthritis, myasthenia gravis , and multiple sclerosis) post-acute COVID-19 (Table 2, Appendix Table 2 ). Delayed onset (3-4 weeks following initial symptoms) immune thrombocytopenic purpura (ITP) has also been reported in the context of COVID-19 [117] . Furthermore, a delayed-phase thrombocytopenia of putative immune origin has been reported in 11.8% among 271 patients with COVID-19 [118] . Aberrant release of neutrophil extracellular traps (NETs) consisting of myeloperoxidase-and neutrophil elastase-containing granules could be seen in COVID-19 [119] . The non-specific action of NETs along with the concomitant release of auto-antigens by apoptotic neutrophils could also stimulate auto-immunity and normal tissue damage [119] . It is not clear whether there is only postinfectious dysregulation of the immune system, as direct injury by the low-grade virus from a sanctuary site or multiorgan dysfunction from persisting systemic inflammation might coexist.

Whether COVID-19 predisposes to flares of preexisting rheumatologic (e.g. SLE) or inflammatory (e.g. multiple sclerosis) conditions or if chronic COVID-19 sequalae are more common in these patients awaits further study. Emerging evidence indicates that SARS-CoV-2 may also lead to autoimmune and autoinflammatory pediatric diseases such as Kawasaki disease, a manifestation of pediatric inflammatory multisystemic syndrome (PIMS) [120, 121] Finally, a link between COVID-19 and carcinogenesis has been postulated because of aberrant activation of signaling cascades promoting cell survival (JAK-STAT, MAPK) and deregulation of immune surveillance [122] . Large observational long-term cohorts to evaluate temporal patterns and calculate excess risk are required.

Acute kidney injury (AKI) is the most common renal complication in severe COVID-19 and kidney dysfunction after discharge may persist in a group of patients.

The rates of in-hospital AKI vary substantially among different series as well as rates of non-recovery of kidney function after convalescence [123, 124] ; however, given the numbers of patients surviving severe COVID-19, a surge of post-COVID-19 persistent kidney disease may occur. In a large study from Wuhan, 13% of patients without AKI and with normal estimated glomerular filtration rate (eGFR) at the acute phase had decreased eGFR at follow-up, necessitating postdischarge close monitoring of renal function [12] .

Development of AKI is multifactorial, caused by hemodynamic instability, systemic inflammatory response, coagulopathy, and microangiopathy in renal vasculature [125, 126] , all of which may lead to chronic renal insufficiency. Furthermore, SARS-CoV-2 directly invades tubular cells and podocytes [127] via binding with ACE2, which is highly expressed in these renal cells, leading to collapsing focal glomerulopathy [128] , tubulo-reticular injury [129] , manifesting as proteinuria, hematuria, renal failure and excess demand for dialysis. Obesity, older age, other comorbidities (including pre-existing renal dysfunction) and genetic factors (collapsing glomerulopathy FSGS in black patients with high risk APOL1 alleles [130] are additional risk factors (Table 2) .

Patients with acute COVID-19 often present with gastrointestinal symptoms and liver impairment (table 2), attributed to hypoxia-mediated injury, drug-induced hepatitis, veno-occlusive disease and direct invasion by SARS-CoV-2 via ACE2, which is richly expressed in hepatocytes/bile duct cells and enterocytes [131, 132] .

Pre-existing liver abnormalities, such as hepatic steatosis (seen in patients with obesity and metabolic syndrome) and cirrhosis can exacerbate the COVID-19

induced injury [133] [134] [135] . Superior mesenteric artery thrombosis is a rare and atypical manifestation of COVID-19 necessitating long-term recovery [136] . Cases of bowel perforation attributed to tocilizumab were reported [137] .

Acute pancreatitis in COVID-19 patients has been reported, but it is unclear if SARS-CoV-2 can induce chronic pancreatitis. Although long-term outcomes in patients with liver dysfunction in the setting of acute COVID-19 are sparse, liver MRI performed 2-3 months after disease onset revealed signs of fibroinflammation in 5 out of 52 of such patients [27] . Therefore, follow up for early-and late-onset gastrointestinal symptoms, along with monitoring of liver function tests and abdominal imaging in selected patients should be considered (Table 2 ). In fact, a SARS-CoV-2 can persist in the gut for weeks following initial COVID-19 diagnosis, even without prominent gastrointestinal symptoms, and this could explain some of the long-term symptoms of some patients, such as dyspepsia and post-infectious manifestations in the spectrum of irritable bowel syndrome [138, 139] .

Diabetes mellitus (DM) is a well-identified risk factor for severe acute COVID-19. SARS-CoV-2 induces a proinflammatory state [140] and the cytokine storm is more likely to develop in patients with DM [141] . In addition, direct invasion of SARS-CoV-2 to the pancreas, via ACE2 which is highly expressed in pancreatic tissue, contributes to pancreatic damage and hyperglycemia [141] , which can be further exacerbated by corticosteroids [142] . Long-term follow-up is needed to evaluate for late-onset DM in patients without such history who developed hyperglycemia in the acute phase of COVID-19. The occult effects of SARS-CoV-2 in adrenal, thyroid/parathyroid glands and hypophysis are not well studied. Cases of subacute thyroiditis and emergence of autoimmune disorders including Graves' disease and Hashimoto's thyroiditis have been reported in the post COVID-19 setting [143, 144] . Similarly, targeted endocrine work-up, especially in patients with unexplained fatigue and mental impairment post COVID-19 is advisable. Home-isolation during lockdowns might decrease vitamin D levels and impair immunity (Appendix Table 2 ) [145] . Several patients have presented with abnormally low vitamin D and increased parathormone levels 8 weeks post COVID-19 onset, which may also have a clinically relevant impact on bone health (Table 2 ) [146, 147] .

The long-term effects of SARS-CoV-2 on the reproductive system are largely unknown. Ovarian function could be affected by autoimmune disorders, whereas testes express ACE2 and can serve as a deposit for SARS-CoV-2 [148] . A testicular ultrasound, sperm analysis and FSH/LH/ testosterone measurements should be performed upon clinical indication ( Table 2) . Although pregnancy itself is not a clear risk factor for severe COVID-19, a meta-analysis indicated an increased risk of premature delivery as a long-term COVID-19 complication [149] .

Long term musculoskeletal complications are anticipated in patients with COVID-19 as reported previously in patients with SARS and in critically ill, especially post-ICU, patients [150] [151] [152] . Proinflammatory effects [150] and deconditioning have been postulated as mechanisms leading to deficits in both muscle strength and endurance. Myositis may also occur as a late complication and has been associated with cytokine storm, hypoxia, thromboembolic events or as a medication-related adverse event [152] . Myositis, muscle atrophy, and weakness can also be induced by long term use of corticosteroids and hydroxychloroquine, a treatment widely used during the first months of the pandemic [153] .

Systemic inflammation and cytokine storm induce osteoclastogenesis and impair osteoblast differentiation resulting to reduction of bone mineral density or even osteonecrosis, both of which can be further exacerbated by corticosteroids [154] . Hypercoagulability, leukocyte aggregation, and vessel inflammation may impair bone microvascular blood flow contributing to osteocytic ischemia and development of osteonecrosis [155] . These preliminary data support that COVID-19 may impair bone metabolism in the long term and invites further investigation.

Skin changes are multiform and among the most frequently patient-reported symptoms, whereas up to 64% emerge in the post-acute setting of the disease [156] [157] [158] [159] . However, it seems that COVID-19-related skin rashes do not usually persist in the long-term, as only 3% of the Chinese patients reported a skin rash at 6 months post COVID-19 [103] . Interestingly, up to one fifth of the long haulers report hair loss, which might be attributed to telogen effluvium due to direct SARS-CoV-2 infection or/and stress response during COVID-19 [103, 160] .

Long-lasting pain is emerging as a frequent and important complication of SARS-CoV-2, in patients with severe illness but also in non-hospitalized patients with mild-to moderate illness. The pain is often poorly characterized and constitutes an important element of the broader long COVID post-viral syndrome ( Table 2, Appendix Table 2 ). Reports place it either in the subacute setting or in the more chronic phase following SARS-CoV-2 infection. It remains unclear how such pain results from the complex and dynamic interactions of viral-associated long-term organ damage, therapeutic-agent induced side-effects, exacerbation of preexisting pain, and/or cognitive and psychosocial dysfunction [161] . Similarly, it is unknown if SARS-COV-2 infection exacerbates preexisting neuropathies (e.g., diabetic neuropathy) Long-lasting and disabling fatigue is another frequently reported symptom under the umbrella of long COVID ( Table 2, Appendix Table 2 ) [162, 163] . Based on recent cohort studies, the frequency of fatigue and/or muscular weakness at 6 months post-symptom onset can reach 60% [162, 164, 165] . Intensity can fluctuate, it is typically exacerbated by physical or mental effort, it seems to affect mostly young women although exact frequency is hard to ascertain due to reporting bias. Such chronic pain often results leads to a decline in quality of life and sedentary life-styles in previously active people [166, 167] . Its pathogenesis remains undefined. Proinflammatory cytokines [168] , low grade endothelitis [168] , and/or autoimmunity and the neurotropism of the SARS-CoV-2 causing dysautonomia may be relevant [169] . Emerging data also support a role for intracortical GABAergic dysfunction [170] . Typically, there is a mismatch between the severity of complaints and the unrevealing clinical and laboratory evaluation. Severe fatigue in combination with "brain fog" and other less defined chronic complaints resemble myalgic encephalomyelitis/chronic fatigue syndrome [168] , which has been described following other post viral syndromes (Table 3 ).

There are also substantial implications to health economics associated with chronic pain syndromes associated with long COVID, which are the results of frequent health-care visits and expensive investigations. Capturing the magnitude of the problem is paramount for post COVID-19 rehabilitation. Screening tools, early measured intervention with concrete "triggers" for targeted and expanded workups and specialist consultations are needed (Table 2) .

Beyond physical illness, the current pandemic has created and amplified psychosocial stressors including social isolation, future uncertainty, fear of stigmatization, poor healthcare access, racial and gender biases, lack of social support, and financial strain. Sleeping disorders, anxiety, post-traumatic stress disorder (PTSD), depression, drug and alcohol abuse [171] , impaired quality of life and inability to return to normal daily routine have all been reported among people recovering from an acute infection (Table 1, Appendix Table 2 ) [172, 173] . For example, the isolation and lack of ability of family to visit hospitalized patients with acute COVID-19, could amplify feelings of depression and PTSD post discharge. Eighteen to 50% of SARS-CoV-2 survivors screen positive in at least one of the neuropsychiatric domains evaluated in cross-sectional and cohort studies, both in the sub-acute and more long-term setting [173] [174] [175] .

Delineating which part of the array of problems are explained by "mechanistic" pathophysiological complications of SARS-CoV-2 and which are secondary to the deep anxiety of a new disease and the bidirectional association between SARS-CoV-2 infection and psychiatric disorders, is difficult [176, 177] . Those interactions between physical and psychological symptoms are complex and often referred to as "medically unexplained symptoms" [176] . Neuroinflammatory mechanisms implicated in other psychiatric diseases may play a role, triggered by cytokine dysregulation and the neurotropic potential of SARS-CoV-2, possibly inducing autoimmunity and immune dysregulation [27] . GABAergic dysfunction has also been implicated. [178] Determining which patients are at risk and which will require long-term follow-up is crucial ( Table 3 ). The potential emergence of a "wave" of late-onset neuropsychiatric manifestations remains to be elucidated. There is great need for strategies on screening processes, resource provision, validated care pathways, and multidisciplinary rehabilitation services [179] [180] [181] .

Our review included studies with significant heterogeneity. These studies had different definitions, follow-up, and investigations (e.g., to rule out concomitant illness); many had an organ-centric approach in measured outcomes (e.g., lungs); and the majority had no case control design or comorbidity adjustments (Table   1 , Appendix Table 2 ). Studies were conducted in different stages of the year during the pandemic (with confounders of different demographics, changing treatment modalities and different degrees of capacity in treating institutions); and had possible referral and reporting biases. Small numbers and a monocentric retrospective nature in most were additional limitations. Importantly, the association of some ill-defined chronic symptoms with prior acute COVID-19 might be problematic with current tests. For example, the presence or absence of a positive SARS-CoV-2 antibody (that can be false positive or false negative due to antibody decay) or the absence (lack of testing, false negative tests) of positivity of SARS-CoV-2 PCR test (that can persist in low titer chronically without reflecting active disease) might correlate poorly with downstream complaints or symptoms. In addition, COVID19 pandemic is being transformed to a series of different "waves" each of which is driven by mutations of the SARS-CoV-2 virus that carry different risks to affect different demographics and cause serious illness. It is unknown if the fluidity in COVID19 epidemiology and if SARS-COV-2 ultimately become endemic in long -term, would be translated to differences in incidence, clinical spectrum and severity of post-acute COVID19.

Given the pandemic spread of COVID-19, the long-term health of millions might be affected. COVID-19 is not always an acutely reversible disease but could have a second act in some patients. Long COVID-19 is a multisystem disease with far-reaching and lingering effects and a complex constellation of symptoms that even if uncommon, could result in significant chronic morbidity. The pace of recovery of the symptoms is non-linear, largely undefined and a complete picture of the natural history and burden of chronic COVID-19 disease might take many months or even years to emerge. At the population level, long COVID-19 rapidly challenges our health care systems and has the potential to aggravate fragmentation of care. Although rapid guidelines started emerging [182], several research questions exist (Table 4 ) and are subjects of intense investigation (Appendix Table 3 summarizes ongoing registries and trials regarding long COVID-19). A holistic and evidenced-based approach to medical care and support of the COVID-19 long haulers is needed.

All authors report no relevant conflicts of interests. Table 3 . Similarities and differences of post COVID-19 syndromes with other post viral syndromes (relevant references can be found in the Appendix Table 4 ) Table 4 . Clinical/translational research and care needs in patients with subacute and/or chronic COVID-19

Development of a uniform diagnostic code of the disease, for better access of patients to clinical care

Develop robust multi-institutional "holistic" registries and case control studies with appropriate comorbidity matched controls, especially in non-hospitalized COVID-19 patients How one uses existing databases and big data analysis for granular predictions of late COVID-19 complications?

How to use patient-driven reporting data (e.g., in social media or applications) along with traditional epidemiological studies to capture the spectrum and burden of long COVID-19?

Creation of "living" prediction models based on the evolution of clinical/laboratory imaging data) along with translational readouts (e.g., humoral and cellular immunity and cytokines, microbiome, metabolomics) of the progression from acute to subacute or chronic COVID-19

Do specific patient groups such as those with cancer patients, transplant rheumatologic or inflammatory or neurodegenerative diseases have heightened risk for late and specific complications?

Do patients with other pre-existing somatic or psychologic comorbidities have predilection towards specific organ dysfunction in late COVID-19?

Is the pattern and severity of clinical manifestations in acute COVID-19 as predictor of type and degree of organ dysfunction in late COVID-19?

How the type and sequence of antiviral and/or immunomodulating drugs used in acute COVID-19 affect risk for late onset sequelae

How reversible and when are each of the symptoms?

Is long COVID-19 a state of functional immunosuppression vs low grade infection (if so, what is the viral reservoir) vs inflammatory state? Is this organ specific?

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Management of post-acute covid-19 in primary care

Need for an appropriate medical terminology for Long-COVID and COVID Long-Haulers

Persistent Symptoms in Patients After Acute COVID-19

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Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered from Coronavirus Disease 2019 (COVID-19)

Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering From COVID-19 Infection

Myocarditis detected after COVID-19 recovery

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge

High Prevalence of Pericardial Involvement in College Student Athletes Recovering From COVID-19

Evaluation for Myocarditis in Competitive Student Athletes Recovering From Coronavirus Disease 2019 With Cardiac Magnetic Resonance Imaging

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PubMed Central PMCID: PMC8010267 www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; KK is chair of the ethnicity subgroup of the Independent Scientific Advisory Group for Emergencies (SAGE), a member of Independent SAGE, a trustee of the South Asian Health Foundation (SAHF), and director of the University of Leicester Centre for Black Minority Ethnic Health; and AB is a trustee of SAHF and has received a research grant unrelated to the current work from AstraZeneca. 79. Nath A. Long-Haul COVID

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Hematological findings and complications of COVID-19

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications

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Assessment of Lupus Anticoagulant Positivity in Patients With Coronavirus Disease 2019 (COVID-19)

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Autoantibodies against type I IFNs in patients with life-threatening COVID-19

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Clinical characteristics, management and outcome of COVID-19-associated immune thrombocytopenia: a French multicentre series

Delayed-phase thrombocytopenia in patients with coronavirus disease 2019 (COVID-19)

How NETosis could drive "Post-COVID-19 syndrome" among survivors

Autoimmune and inflammatory diseases following COVID-19

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Clinical sequelae of the novel coronavirus: does COVID-19 infection predispose patients to cancer?

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PubMed Central PMCID: PMCPMC7769434 disclose. MRO and MJC are both investigators for Remdesivir (sponsored by Gilead) and convalescent plasma (sponsored by Amazon). This does not alter our adherence to PLOS ONE policies on sharing data and materials

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High rates of 30-day mortality in patients with cirrhosis and COVID-19

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PubMed Central PMCID: PMCPMC7212817. Is there an immunogenetic component in long COVID-19? Do preexisting cross reactive antibodies play a role for late manifestations as in a pattern of antibody-mediated enhancement? Would an antigenic drift of the SARS-COV-2 (through mutations) influence risk for late complications as we move deeper in the pandemic? Can some patients with long COVID-19 have occult reactivation of another virus

Long COVID-19 in children Long COVID-19 in health care workers EBV: Epstein-Barr virus; CT: computed tomography; MRI: magnetic resonance imaging

Supported in part by the Robert C Hickey Chair in Clinical Care endowment to DPK and in part by the Cancer Center Support Grant (CCSG). We thank Ms. Salli Saxton for administrative support.

Eleni Korompoki: Design, analysis, interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content. 

What interventions are useful to prevent severe sequalae in patients with early organ damage in subacute or chronic COVID-19? (e.g., routine anticoagulation in patients with heart damage, antifibrotic agents in patients with early pulmonary fibrosis, metabolic therapeutics?)How can we do randomized control trials with adaptive design for therapeutic and/or rehabilitation interventions?Can prior immune therapies (e.g., IL-6 inhibitors, corticosteroids) ameliorate chronic symptoms?Can therapies for early COVID19 (e.g., monoclonal antibodies) prevent long COVID through decrease of hospitalizations and ICU admissions?How safe are vaccines in patients with long COVID-19?

How to organize a cost-effective and coordinated model of care delivery and avoid fragmentation of care?What is the best practice and business model (primary care driven vs specialist -driven vs co-managed model) in patients with long COVID-19?What is the role of telehealth and how to triage COVID-19 survivors based on pattern and severity of reported symptoms?How to establish quality criteria for services in long COVID-19?Best methods to measure the impact of long COVID-19 to social strains, emotional toll and stigmatization of victims