Recognizing the Clinical Sequelae of COVID-19 in Adults: COVID-19 Long-Haulers

      Highlights

      • Long-hauler is a term that refers to the long-term effects of COVID-19
      • Long-haul COVID-19 is a diagnosis of exclusion
      • Do not ignore the emotional dimension of long-haul COVID-19

      Abstract

      As the numbers of acute severe acute respiratory syndrome coronavirus 2 infections continue to rise, we are learning that symptoms do not resolve quickly in all patients. Although why some patients experience persistent symptoms is not clear, these individuals suffer. Long-hauler is the term that is associated with these persistent symptoms, and this review of the literature provides information to nurse practitioners working in primary care about symptoms, risk factors, and resources for disease management.

      Keywords

      Coronavirus disease 2019 (COVID-19) is caused by an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients infected with SARS-CoV-2 exhibit a wide spectrum of clinical manifestations, ranging from asymptomatic to severe, during the acute phase of illness. The focus of research and publications has been the acute illness; however, as we enter the second year of the COVID-19 pandemic, it is becoming more apparent that COVID-19 has lingering effects. This article provides the nurse practitioner (NP) with a general overview of these persistent symptoms and resources for the clinical management of these patients.

      Long-Haulers

      Not all patients who are diagnosed with COVID-19 completely recover; some experience persistent symptoms that wax and wane.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
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      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      Approximately 10% of people who experience mild COVID-19 symptoms will become long-haulers.
      • Greenhalgh T.
      • Knight M.
      • A’Court C.
      • Buxton M.
      • Husain L.
      Management of post-acute COVID-19 in primary care.
      There is a higher incidence of persistent symptoms in patients with comorbidities
      • Mendelson M.
      • Nel J.
      • Blumberg L.
      • et al.
      Long-COVID: an evolving problem with an extensive impact.
      ,
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      or more severe SARS-CoV-2 infection.
      • Greenhalgh T.
      • Knight M.
      • A’Court C.
      • Buxton M.
      • Husain L.
      Management of post-acute COVID-19 in primary care.
      • Mendelson M.
      • Nel J.
      • Blumberg L.
      • et al.
      Long-COVID: an evolving problem with an extensive impact.
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      • Petersen M.S.
      • Kristiansen M.F.
      • Hanusson K.D.
      • et al.
      Long COVID in the Faroe Islands–a longitudinal study among non-hospitalized patients.
      These persistent symptoms wax and wane.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      While no standard time frame has been established to identify when symptoms become persistent, it is generally agreed that symptoms lasting longer than 3 to 4 weeks after the initial diagnosis of mild, moderate, and severe illness and lasting longer than 6 weeks in critical illness are considered persistent.
      • Raveendrangh A.V.
      Long COVID-19: challenges in the diagnosis and proposed diagnostic criteria.
      The physical and psychologic symptoms experienced by COVID-19 long-haulers are similar to the symptoms survivors of sepsis or other critical illness experience when there is immune dysregulation.
      • Leviner S.
      Post-sepsis syndrome.
      At this time, why symptoms persist is unclear. It is possible that the symptoms are the result of chronic fatigue syndrome or myalgic encephalomyelitis, which has been associated with other viral infections.
      • Soriano V.
      • Ganado-Pinilla P.
      • Sanchez-Santos M.
      • Barreiro P.
      Unveiling long COVID-19 disease.
      It is also possible that the persistent symptoms are related to persistent inflammation or damage due to direct viral entry into tissues. Researchers have discovered evidence that patients with persistent symptoms have signs of vessel wall inflammation on imaging
      • Sollini M.
      • Ciccarelli M.
      • Cecconi M.
      • et al.
      Vasculitis changes in COVID-19 survivors with persistent symptoms: an [18F]FDG-PET/CT study.
      and elevated biomarkers consistent with inflammation.
      • Doykov I.
      • Hällqvist J.
      • Gilmour K.C.
      • Grandjean L.
      • Mills K.
      • Heywood W.E.
      ‘The long tail of Covid-19’ – the detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
      During the SARS-CoV-1 outbreak in 2003, the SARS-CoV-1 virus was detected in myocardial tissue during autopsy, providing evidence of direct viral entry into tissues.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.

      Clinical Sequelae of COVID-19

      The cellular entry point for SARS-CoV-2 is the angiotensin converting enzyme 2 (ACE2) receptor.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.
      Attachment of the virus to the ACE2 receptor is associated with increased levels of angiotensin leading to inflammation, vasoconstriction, and thrombosis.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.
      In addition to the ACE2 receptor, SARS-CoV-2 requires a protease to prime the spike protein before the virus can enter the cell.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.
      ,
      • Hoffmann M.
      • Hofmann-Winkler H.
      • Pöhlmann S.
      Priming time: how cellular proteases arm coronavirus spike proteins.
      The ACE2 receptor and the required protease are both expressed in lung, heart, gut smooth muscle, liver, kidney, neurons, and immune cells, which provide an explanation for the symptomatology of COVID-19.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.
      Long-haulers may experience sequelae from 1 or multiple systems. The sequelae are discussed below, and a summary is also provided in Table 1.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      ,
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      ,
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.
      Cognitive Assessment Group
      Brain Fog Evaluation. 2021.
      • LaHue S.C.
      • James T.C.
      • Newman J.C.
      • Esmaili A.M.
      • Ormseth C.H.
      • Ely E.W.
      Collaborative delirium prevention in the age of COVID-19.
      • Manca R.
      • De Marco M.
      • Venneri A.
      The impact of COVID-19 infection and enforced prolonged social isolation on neuropsychiatric symptoms in older adults with and without dementia: a review.
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.
      • Vechi H.T.
      • Maia L.R.
      • Alves M.D.M.
      Late acute pulmonary embolism after mild coronavirus disease 2019 (COVID-19): a case series.
      • Dani M.
      • Dirksen A.
      • Taraborrelli P.
      • et al.
      Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies.
      NIH VideoCast-Workshop on Post-Acute Sequelae of COVID-19 Breakout Session 4 (Renal/GI/Metabolic). Air date December 4, 2020. U.S. Department of Health and Human Services.
      National Institutes of Health
      Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
      • Feldman S.R.
      • Freeman E.E.
      Coronavirus disease 2019 (COVID-19): cutaneous manifestation and issues related to dermatological care. UptoDate; 2021.
      • Sachdeva M.
      • Gianotti R.
      • Shah M.
      • et al.
      Cutaneous manifestations of COVID-19: report of three cases and a review of literature.
      • Ladds E.
      • Rushforth A.
      • Wieringa S.
      • et al.
      Persistent symptoms after COVID-19: qualitative study of 114 “long Covid” patients and draft quality principles for services.
      Table 1Sequelae of COVID-2019
      SystemSequelaeSource
      Mental HealthAnxiety

      Depression

      Insomnia

      Posttraumatic stress disorder (PTSD)
      Mazza et al (2020)
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      PulmonaryDyspnea

      Cough

      Impaired exercise capacity

      Lung fibrosis

      Impaired diffusing capacity
      Carfi et al (2020)
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.


      Kingstone et al (2020)
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.


      Higgins et al (2020)
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.


      Tenforde et al (2020)
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.


      Mandal et al (2020)
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      Central nervous systemStroke

      Polyneuropathy

      Headaches

      Hyposomia

      Mental fatigue & confusion–“Brain fog”

      Delirium
      Higgins et al (2020)
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.


      Amenta et al (2020)
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.


      Cognitive Assessment Group (2021)
      Cognitive Assessment Group
      Brain Fog Evaluation. 2021.


      LaHue et al (2020)
      • LaHue S.C.
      • James T.C.
      • Newman J.C.
      • Esmaili A.M.
      • Ormseth C.H.
      • Ely E.W.
      Collaborative delirium prevention in the age of COVID-19.


      Manca et al (2020)
      • Manca R.
      • De Marco M.
      • Venneri A.
      The impact of COVID-19 infection and enforced prolonged social isolation on neuropsychiatric symptoms in older adults with and without dementia: a review.


      Tenforde et al (2020)
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.
      CardiovascularChest pain

      Myocardial infarction

      Cardiomyopathy

      Arrhythmias

      Heart failure

      LV dysfunction and myocardial inflammation

      Coagulopathies and thrombosis

      Orthostatic hypotension
      Carfi et al (2020)
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.


      Kingstone et al (2020)
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.


      Liu et al (2020)
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.


      Madjid et al (2020)
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.


      Amenta et al (2020)
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.


      Higgins et al (2020)
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.


      Vechi et al (2020)
      • Vechi H.T.
      • Maia L.R.
      • Alves M.D.M.
      Late acute pulmonary embolism after mild coronavirus disease 2019 (COVID-19): a case series.


      Dani et al (2021)
      • Dani M.
      • Dirksen A.
      • Taraborrelli P.
      • et al.
      Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies.
      GastrointestinalAbdominal pain

      Gastrointestinal bleeding

      Nausea, vomiting, diarrhea

      Hepatitis

      Pancreatitis
      Carfi et al (2020)
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.


      Tenforde et al (2020)
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.
      RenalGlomerular diseaseNIH VideoCast (2020)
      NIH VideoCast-Workshop on Post-Acute Sequelae of COVID-19 Breakout Session 4 (Renal/GI/Metabolic). Air date December 4, 2020. U.S. Department of Health and Human Services.
      MusculoskeletalMyalgias

      Arthralgias
      Carfi et al (2020)
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.


      Kingstone et al (2020)
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.


      NIH (2020)
      National Institutes of Health
      Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.


      Amenta et al (2020)
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.


      Mikkelsen et al (2021)

      Tenforde et al (2020)
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.
      CutaneousSkin lesions

      Chilblain-like acral lesions “COVID toes”
      Feldman et al (2021)
      • Feldman S.R.
      • Freeman E.E.
      Coronavirus disease 2019 (COVID-19): cutaneous manifestation and issues related to dermatological care. UptoDate; 2021.


      Sachdeva et al. (2020)
      • Sachdeva M.
      • Gianotti R.
      • Shah M.
      • et al.
      Cutaneous manifestations of COVID-19: report of three cases and a review of literature.
      Constitutional symptomsFatigue

      Fever
      Carfi et al (2020)
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.


      NIH (2020)
      National Institutes of Health
      Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.


      Amenta et al (2020)
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.


      Mikkelsen et al (2021)

      Tenforde et al (2020)
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.


      Mandal et al (2020)
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      COVID-19 = coronavirus disease 2019; LV = left ventricular.

       Mental Health Sequelae

      The uncertainty surrounding long-haul COVID-19 leaves patients feeling helpless and alone in managing their symptoms.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      In interviews, long-haulers report feeling frustrated by the lack of assistance and empathy they receive from family and health care providers.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      Previously healthy and independent functioning individuals now, as long-haulers, have difficulty completing basic daily activities and are unable to work due to limited endurance and other symptoms.,
      • Ladds E.
      • Rushforth A.
      • Wieringa S.
      • et al.
      Persistent symptoms after COVID-19: qualitative study of 114 “long Covid” patients and draft quality principles for services.
      The changes in mental health experienced by many long-haulers have many etiologies. Multiple psychologic stressors have emerged as a result of the COVID-19 pandemic, including financial, social isolation, and uncertainty and fear regarding the infection.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      Long-haulers experience additional psychologic stressors related to prolonged changes in physical functioning and the perception that family and health care providers are not supportive.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      The inflammatory response to the virus itself may also cause an increased amount of psychologic symptoms.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      Regardless of the cause, survivors of COVID-19 experience a significant impact on mental health to include anxiety, depression, insomnia, and posttraumatic stress disorder.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.

       Pulmonary Sequelae

      Cough and dyspnea are common complaints among long-haulers.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.
      ,
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      The pulmonary sequelae include impaired exercise capacity, fibrotic lung tissue, and impaired diffusing capacity.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      Pulmonary function can improve over time, but fibrosis is irreversible.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      At this time, the duration of pulmonary symptoms associated with long-haul COVID-19 is unknown. However, patients with SARS-CoV-1, which is similar to SARS-CoV-2, the infection that causes COVID-19, have experienced impaired pulmonary function up to 15 years after infection.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.

       Central Nervous System Sequelae

      Sequelae of the central nervous system include stroke, polyneuropathy, headaches, and hyposomia.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      New or worsened concentration problems are commonly seen among long-haulers.
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.
      The term brain fog has been used to describe the mental fatigue and confusion occurring after COVID-19.
      Cognitive Assessment Group
      Brain Fog Evaluation. 2021.
      Patients hospitalized with acute COVID-19 have additional risk factors for delirium due to physical isolation measures instituted to prevent the spread of disease. Physical isolation measures, such as facial coverings and personal protective equipment, create a physical and emotional barrier between providers and patients. Hospital staff cluster care to minimize exposure time, which has decreased the number of interactions staff have with patients. Visitation by friends and families has also been restricted for all patients to prevent disease transmission. These infection control measures have increased the social isolation for all patients, but older individuals, in particular, are at increased risk for mental health issues and cognitive decline as a result of social isolation.
      • LaHue S.C.
      • James T.C.
      • Newman J.C.
      • Esmaili A.M.
      • Ormseth C.H.
      • Ely E.W.
      Collaborative delirium prevention in the age of COVID-19.
      ,
      • Manca R.
      • De Marco M.
      • Venneri A.
      The impact of COVID-19 infection and enforced prolonged social isolation on neuropsychiatric symptoms in older adults with and without dementia: a review.

       Cardiovascular Sequelae

      Survivors of COVID-19 are also at increased risk for cardiovascular complications to include myocardial infarction, cardiomyopathy, arrhythmias, and heart failure.
      • Liu P.P.
      • Blet A.
      • Smyth D.
      • Li H.
      The science underlying COVID-19: implications for the cardiovascular system.
      ,
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      ,
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.
      Some long-haulers also have evidence of impaired lower left ventricular ejection fraction and myocardial inflammation on cardiac magnetic resonance imaging.
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.
      Long-haulers have an increased incidence of coagulopathies and thrombosis.
      • Higgins V.
      • Sohaei D.
      • Diamandis E.P.
      • Prassas I.
      COVID-19: from an acute to chronic disease? Potential long-term health consequences.
      Pulmonary embolus has been reported 3 to 4 weeks after the acute illness.
      • Vechi H.T.
      • Maia L.R.
      • Alves M.D.M.
      Late acute pulmonary embolism after mild coronavirus disease 2019 (COVID-19): a case series.
      Patients presenting with symptoms consistent with embolus need to have this condition ruled, out even in patients who had mild acute illness.
      Viral illnesses such as COVID-19 can also affect the autonomic nervous system. Affected individuals may display orthostatic hypotension along with tachycardia in response to position changes.
      • Dani M.
      • Dirksen A.
      • Taraborrelli P.
      • et al.
      Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies.
      Individuals with these findings are at risk for injury due to vasovagal syncope. These symptoms should be evaluated to rule out other causes for their symptoms, and patients should be educated on how to avoid injury and to manage symptoms.
      • Dani M.
      • Dirksen A.
      • Taraborrelli P.
      • et al.
      Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies.

       Gastrointestinal, Renal, and Musculoskeletal Sequelae

      The gastrointestinal system may also be affected. Complaints of abdominal pain, gastrointestinal bleeding, nausea and vomiting, diarrhea, hepatitis, and pancreatitis may be experienced by long-haulers. Long-haulers who experienced kidney dysfunction during the acute illness period are more likely to have continued kidney dysfunction after discharge.
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.
      The development of acute kidney injury is associated with worse long-term outcomes in other diseases, but we are uncertain how this will affect COVID-19 long-haulers.
      NIH VideoCast-Workshop on Post-Acute Sequelae of COVID-19 Breakout Session 4 (Renal/GI/Metabolic). Air date December 4, 2020. U.S. Department of Health and Human Services.
      The musculoskeletal symptoms of myalgias and arthralgias are also common complaints among long-haulers.
      • Amenta E.M.
      • Spallone A.
      • Rodriguez-Barradas M.C.
      • El Sahly H.M.
      • Atmar R.L.
      • Kulkarni P.A.
      Postacute COVID-19: an overview and approach to classification.
      ,
      National Institutes of Health
      Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
      ,

       Cutaneous Sequelae

      Skin lesions may develop up to 2 weeks after acute COVID-19 infection
      • Sachdeva M.
      • Gianotti R.
      • Shah M.
      • et al.
      Cutaneous manifestations of COVID-19: report of three cases and a review of literature.
      and normally resolve within 2 to 8 weeks.
      • Feldman S.R.
      • Freeman E.E.
      Coronavirus disease 2019 (COVID-19): cutaneous manifestation and issues related to dermatological care. UptoDate; 2021.
      Common cutaneous manifestations of COVID-19 include morbilliform rash and chilblain-like acral lesions, “COVID toes.”
      • Feldman S.R.
      • Freeman E.E.
      Coronavirus disease 2019 (COVID-19): cutaneous manifestation and issues related to dermatological care. UptoDate; 2021.
      Dermatologic findings may be the only symptom associated with COVID-19 infection. The etiology of dermatologic lesions associated with COVID-19 is uncertain, and iatrogenic causes cannot be ruled out.
      • Feldman S.R.
      • Freeman E.E.
      Coronavirus disease 2019 (COVID-19): cutaneous manifestation and issues related to dermatological care. UptoDate; 2021.

       Constitutional Symptoms

      Fatigue is one of the most common symptoms reported by COVID-19 survivors.
      • Mandal S.
      • Barnett J.
      • Brill S.E.
      • et al.
      ‘Long-COVID’: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19.
      ,
      • Carfì A.
      • Bernabe R.
      • Landi F.
      Persistent symptoms in patients after acute COVID-19.
      ,
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.
      This symptom can be debilitating for some individuals, particularly when other symptoms are present. Fever, while less commonly reported than fatigue, is another symptom that long-haulers experience but is not associated with acute infection.
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • et al.
      Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020.

      Implications for Primary Care NPs

      The diagnosis of long-haul COVID-19 is a diagnosis of exclusion, and there is uncertainty regarding symptom duration.
      National Institutes of Health
      Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
      Long-term data regarding COVID-19 survivors are not currently available; however, current reports indicate that symptoms may persist months after the acute illness.
      • Petersen M.S.
      • Kristiansen M.F.
      • Hanusson K.D.
      • et al.
      Long COVID in the Faroe Islands–a longitudinal study among non-hospitalized patients.
      The list of sequelae discussed above is not exclusive. As the pandemic continues, we learn more about long-haulers, and with that knowledge, we improve management.
      NPs are recommended to approach each patient as an individual and to perform a comprehensive history and physical examination to rule out serious complications and comorbidities as causes for symptoms.
      • Greenhalgh T.
      • Knight M.
      Long COVID: a primer for family physicians.
      Physical, cognitive, psychologic, psychiatric, and functional status needs to be evaluated in patients with persistent symptoms.,
      National Institute for Health and Care Excellence
      COVID-19 rapid guideline: managing the long-term effects of COVID-19. 2020.
      As explained earlier, long-haul COVID-19 is a diagnosis of exclusion, and alternative explanations for symptoms need to be ruled out before deciding that a patient is presenting with the sequelae of COVID-19. After serious complications and comorbidities have been ruled out as a cause for symptoms, most symptoms can be managed symptomatically.
      • Greenhalgh T.
      • Knight M.
      • A’Court C.
      • Buxton M.
      • Husain L.
      Management of post-acute COVID-19 in primary care.
      A list of resources and guidelines for managing persistent symptoms is presented in Table 2.
      Table 2Resources for Managing Persistent Symptoms of COVID-19
      ResourceSynopsis
      NIH COVID-19 Treatment Guidelines

      Available for download from https://www.covid19treatmentguidelines.nih.gov/
      Section on persistent symptoms or illnesses after recovery from acute COVID-19
      Management of post-acute COVID-19 in primary care

      Available for download from https://www.bmj.com/content/bmj/370/bmj.m3026.full.pdf
      Guidance on symptom evaluation and management
      NICE COVID-19 guideline

      Available for download from https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-66142028400325
      General guidance on the identification, assessment, investigation, and management of persistent symptoms
      COVID-19 = coronavirus disease 2019; NICE = National Institute of Health and Care Excellence; NIH = National Institutes of Health.
      Note: Scan the QR code with your mobile device.
      Long-haul COVID-19 is a relatively unknown syndrome and one that benefits from multidisciplinary management. Post-COVID-19 care centers are opening at many academic medical centers,
      Centers for Disease Control and Prevention
      Science Brief: Evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from COVID-19.
      and if available, long-haulers should be referred.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      If a post-COVID-19 care center is not available in your area, specialty consultation is another option.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      ,
      • Greenhalgh T.
      • Knight M.
      Long COVID: a primer for family physicians.
      When these patients are evaluated, it is important to remember that the disease has a high emotional impact and that the emotional dimension of COVID-19 should not be ignored in patients who present with persistent symptoms.
      • Mazza M.G.
      • De Lorenzo R.
      • Conte C.
      • et al.
      Anxiety and depression in COVID-19 survivors: role of inflammatory and clinical predictors.
      Most patients with persistent symptoms can be evaluated via telemedicine or in person. However, in interviews, people with persistent symptoms indicated a desire to be assessed face-to-face, when possible.
      • Kingstone T.
      • Taylor A.K.
      • O’Donnell C.A.
      • Atherton H.
      • Blane D.N.
      • Chew-Graham C.A.
      Finding the ‘right’ GP: a qualitative study of the experiences of people with long-COVID.

      Conclusion

      The persistent symptoms associated with COVID-19 are frustrating for patients who just want to be normal and to return to their previous level of function before COVID-19. Unfortunately there are no clear answers for them at this time, and NPs should share this with them. Alternative explanations for symptoms need to be ruled out before associating the symptoms with long-haul COVID-19. If a COVID-19 care center is available, patients should be referred. If a COVID-19 care center is not available, specialists need to be consulted. Given the impact on mental health, evaluating the mental health of long-haulers is a priority.
      More research is needed regarding the long-haulers of COVID-19. More than 27 million Americans have already been infected with COVID-19, and there have been more than 106 million cases globally.
      Johns Hopkins Coronavirus Center
      2021. Coronavirus 2019 Maps.
      Given that 10% of patients with acute COVID-19 are predicted to become long-haulers,
      • Greenhalgh T.
      • Knight M.
      • A’Court C.
      • Buxton M.
      • Husain L.
      Management of post-acute COVID-19 in primary care.
      the number of patients presenting to primary care with persistent symptoms will be the next wave of the pandemic. NPs who are knowledgeable about the long-term effects of COVID-19 will improve the quality of care that long-haulers receive while minimizing frustration for these individuals.

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      Biography

      Sherry Leviner, PhD, FNP-C, is an assistant professor at Fayetteville State University, Fayetteville, NC, and can be contacted at [email protected] .