Post‑COVID‑19 Syndrome Mechanisms, Prevention and Management

Majed B. Najaf, Shaghayegh H. Javanmard

Abstract


As the population of patients recovering from COVID‑19 grows, post COVID‑19 challenges are recognizing by ongoing evidences at once. Long COVID is defined as a syndrome with a range of persistent symptoms that remain long after (beyond 12 weeks) the acute SARS‑CoV‑2 infection. Studies have shown that long COVID can cause multi‑organ damages with a wide spectrum of manifestations. Many systems, but not limited to, including respiratory, cardiovascular, nervous, gastrointestinal, and musculoskeletal systems, are involved in long COVID. Fatigue and dyspnea are the most common symptoms of long COVID. Long COVID‑19 may be driven by tissue damage caused by virus‑specific pathophysiologic changes or secondary to pathological long‑lasting inflammatory response because of viral persistence, immune dysregulation, and autoimmune reactions. Some risk factors like sex and age, more than five early symptoms, and specific biomarkers have been revealed as a probable long COVID predicator discussed in this review. It seems that vaccination is the only way for prevention of long COVID and it can also help patients who had already long COVID. Managing long COVID survivors recommended being in a multidisciplinary approach, and a framework for identifying those at high risk for post‑acute COVID‑19 must be proposed. Possible therapeutic options and useful investigation tools for follow‑up are suggested in this review. In sum, as evidence and researches are regularly updated, we provide the current understanding of the epidemiology, clinical manifestation, suspected pathophysiology, associated risk factors, and treatment options of long COVID in this review.

Keywords


Chronic COVID syndrome; long COVID; long haul COVID; long hauler COVID; post‑acute COVID syndrome; post‑acute COVID‑19 syndrome

Full Text:

PDF

References


Baud D, Qi X, Nielsen‑Saines K, Musso D, Pomar L, Favre G.

Real estimates of mortality following COVID‑19 infection.

Lancet Infect Dis 2020;20:773.

Oronsky B, Larson C, Hammond TC, Oronsky A, Kesari S, Lybeck M, et al. A review of persistent post‑COVID

syndrome (PPCS). Clin Rev Allergy Immunol 2021:1‑9. doi:

1007/s12016‑021‑08848‑3.

Garg M, Maralakunte M, Garg S, Dhooria S, Sehgal I, Bhalla AS,

et al. The conundrum of ‘long‑COVID‑19ʹ: A narrative review.

Int J Gen Med 2021;14:2491‑506.

Carroll E, Neumann H, Aguero-Rosenfeld ME, Lighter J,

Czeisler BM, Melmed K, et al. Post–COVID-19 inflammatory

syndrome manifesting as refractory status epilepticus. Epilepsia

;61:e135‑e9.

Carfì A, Bernabei R, Landi F. Persistent symptoms in patients

after acute COVID‑19. JAMA 2020;324:603‑5.

Tenforde MW, Kim SS, Lindsell CJ, Rose EB, Shapiro NI,

Files DC, 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. MMWR Morb Mortal Wkly 2020;69:993‑8.

Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6‑month

consequences of COVID‑19 in patients discharged from hospital:

A cohort study. Lancet 2021;397:220‑32.

Greenhalgh T, Knight M, Buxton M, Husain L. Management of

post‑acute COVID‑19 in primary care. BMJ 2020;370:m3026.

doi: 10.1136/bmj.m3026.

Nabavi N. Long COVID: How to define it and how to manage it.

BMJ 2020;370:m3489. doi: 10.1136/bmj.m3489.

Garg P, Arora U, Kumar A, Wig N. The “post-COVID” syndrome:

How deep is the damage? J Med Virol 2021;93:673‑74.

Shah W, Hillman T, Playford ED, Hishmeh L. Managing the

long term effects of COVID‑19: Summary of NICE, SIGN, and

RCGP rapid guideline. BMJ 2021;372:n136. doi: 10.1136/bmj.

n136.

Lopez‑Leon S, Wegman‑Ostrosky T, Perelman C, Sepulveda R,

Rebolledo PA, Cuapio A, et al. More than 50 Long‑term effects

of COVID‑19: A systematic review and meta‑analysis. SSRN J

Available from: https://ssrn.com/abstract=3769978.

Lee SH, Shin H‑S, Park HY, Kim JL, Lee JJ, Lee H, et al.

Depression as a mediator of chronic fatigue and post‑traumatic

stress symptoms in Middle East respiratory syndrome survivors.

Psychiatry investig 2019;16:59‑64.

Lam MH‑B, Wing Y‑K, Yu MW‑M, Leung C‑M, Ma RC,

Kong AP, et al. Mental morbidities and chronic fatigue in severe

acute respiratory syndrome survivors: Long‑term follow‑up. Arch

Intern Med 2009;169:2142‑7.

Cellai M, O’Keefe JB, editors. Characterization of prolonged

COVID‑19 symptoms in an outpatient telemedicine clinic. Open

Forum Infectious Diseases: Oxford University Press US; 2020.

Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS,

Bowyer RC, et al. Attributes and predictors of long COVID. Nat

Med 2021;27:626‑31.

Cirulli E, Barrett KMS, Riffle S, Bolze A, Neveux I, Dabe S,

et al. Long‑term COVID‑19 symptoms in a large unselected

population. medrxiv 2020. doi: 10.1101/2020.10.07.20208702.

Bliddal S, Banasik K, Pedersen OB, Nissen J, Cantwell L,

Schwinn M, et al. Acute and persistent symptoms in

non‑hospitalized PCR‑confirmed COVID‑19 patients. Sci Rep

;11:1‑11. doi: 10.1038/s41598‑021‑92045‑x.

Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P,

Hober S, et al. Symptoms and functional impairment assessed

months after mild COVID‑19 among health care workers.

JAMA 2021;325:2015‑6.

Nehme M, Braillard O, Alcoba G, Aebischer Perone S,

Courvoisier D, Chappuis F, et al. COVID‑19 symptoms:

Longitudinal evolution and persistence in outpatient settings.

Ann Intern Med 2021;174:723‑5.

Moreno‑Pérez O, Merino E, Leon‑Ramirez J‑M, Andres M,

Ramos JM, Arenas‑Jiménez J, et al. Post‑acute COVID‑19

syndrome. Incidence and risk factors: A Mediterranean cohort

study. J Infect 2021;82:378‑83.

Venturelli S, Benatti SV, Casati M, Binda F, Zuglian G, Imeri G,

et al. Surviving COVID‑19 in Bergamo province: A post‑acute

outpatient re‑evaluation. Epidemiol Infect 2021;149:e32. doi:

1017/S0950268821000145.

Chiesa-Estomba CM, Lechien JR, Radulesco T, Michel J,

Sowerby LJ, Hopkins C, et al. Patterns of smell recovery in

patients affected by the COVID-19 outbreak. Eur J Neurol

;27:2318‑21.

Ayoubkhani D. Prevalence of ongoing symptoms following

coronavirus (COVID‑19) infection in the UK: 1 April 2021. Off

Natl Stat 2021:1‑16.

Morin L, Savale L, Pham T, Colle R, Figueiredo S, Harrois A,

et al. Four‑month clinical status of a cohort of patients after

hospitalization for COVID‑19. JAMA 2021;325:1525‑34.

Ghosn J, Piroth L, Epaulard O, Le Turnier P, Mentré F,

Bachelet D, et al. Persistent COVID‑19 symptoms are highly

prevalent 6 months after hospitalization: Results from a large

prospective cohort. Clin Microbiol Infect 2021:1041.e1‑1041.e4.

doi: 10.1016/j.cmi. 2021.03.012.

Augustin M, Schommers P, Stecher M, Dewald F, Gieselmann L,

Gruell H, et al. Post‑COVID syndrome in non‑hospitalised

patients with COVID‑19: A longitudinal prospective cohort

study. Lancet Reg Health Eur 2021;6:100122. doi: 10.1016/j.

lanepe. 2021.100122.

Whitaker M, Elliott J, Chadeau‑Hyam M, Riley S, Darzi A,

Cooke G, et al. Persistent symptoms following SARS‑CoV‑2

infection in a random community sample of 508,707 people.

medRxiv 2021. doi: 10.1101/2021.06.28.21259452.

Thompson EJ, Williams DM, Walker AJ, Mitchell RE,

Niedzwiedz CL, Yang TC, et al. Risk factors for long COVID:

Analyses of 10 longitudinal studies and electronic health records

in the UK. medRxiv 2021. doi: 10.1101/2021.06.24.21259277.

Inoue S, Hatakeyama J, Kondo Y, Hifumi T, Sakuramoto H,

Kawasaki T, et al. Post-intensive care syndrome: Its

pathophysiology, prevention, and future directions. Acute Med

Surg 2019;6:233‑46.

Ehrenfeld M, Tincani A, Andreoli L, Cattalini M, Greenbaum A,

Kanduc D, et al. COVID‑19 and autoimmunity. Autoimmun Rev

;19:102597. doi: 10.1016/j.autrev. 2020.102597.

Ye G, Pan Z, Pan Y, Deng Q, Chen L, Li J, et al. Clinical

characteristics of severe acute respiratory syndrome coronavirus

reactivation. J Infect 2020;80:e14‑e7.

Centers for Diseases Control and Prevention. Investigative criteria

for suspected cases of SARS‑CoV‑2 reinfection (ICR). 2020.

Available from: https://www.cdc.gov/coronavirus/2019‑ncov/php/

invest‑criteria.html.

Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C,

Stevens JS, et al. Post‑acute COVID‑19 syndrome. Nat Med

;27:601‑15.

Stratton CW, Tang YW, Lu H. Pathogenesis-directed therapy of

novel coronavirus disease. J Med Virol 2021;93:1320‑42.

Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of

angiotensin‑converting enzyme 2 (ACE2) in COVID‑19. Crit

Care 2020;24:1‑10. doi: 10.1186/s13054‑020‑03120‑0.

Afrin LB, Weinstock LB, Molderings GJ. COVID‑19

hyperinflammation and post‑COVID‑19 illness may be rooted in

mast cell activation syndrome. Int J Infect Dis 2020;100:327‑32.

Michelen M, Cheng V, Manoharan L, Elkheir N, Dagens D, Hastie C, et al. Characterising long term COVID‑19:

A living systematic review. MedRxiv 2021. doi:

1101/2020.12.08.20246025.

Aiyegbusi OL, Hughes SE, Turner G, Rivera SC, McMullan C,

Chandan JS, et al. Symptoms, complications and management of

long COVID: A review. J R Soc Med 2021;114:428‑42.

Lombardo MDM, Foppiani A, Peretti GM, Mangiavini L,

Battezzati A, Bertoli S, et al. Long‑term coronavirus disease

complications in inpatients and outpatients: A one‑year

follow‑up cohort study. Open Forum Infect Dis 2021;8:ofab384.

doi: 10.1093/ofid/ofab384.

Ngai JC, Ko FW, Ng SS, TO KW, Tong M, Hui DS. The

long-term impact of severe acute respiratory syndrome on

pulmonary function, exercise capacity and health status.

Respirology 2010;15:543‑50.

Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y,

et al. Characterizing long COVID in an international cohort:

months of symptoms and their impact. SSRN J 2021. Available

from: https://ssrn.com/abstract=3820561.

Simani L, Ramezani M, Darazam IA, Sagharichi M,

Aalipour MA, Ghorbani F, et al. Prevalence and correlates of

chronic fatigue syndrome and post‑traumatic stress disorder after

the outbreak of the COVID‑19. J Neurovirol 2021;27:154‑9.

Garg M, Prabhakar N, Bhalla AS, Irodi A, Sehgal I, Debi U,

et al. Computed tomography chest in COVID‑19: When & why?

Indian J Med Res 2021;153:86‑92.

Froidure A, Mahsouli A, Liistro G, De Greef J, Belkhir L,

Gerard L, et al. Integrative respiratory follow‑up of severe

COVID‑19 reveals common functional and lung imaging

sequelae. Respir Med 2021;181:106383. doi: 10.1016/j.rmed.

106383.

Garrigues E, Janvier P, Kherabi Y, Le Bot A, Hamon A,

Gouze H, et al. Post‑discharge persistent symptoms and

health‑related quality of life after hospitalization for COVID‑19.

J Infect 2020;81:e4‑e6.

Xiong Q, Xu M, Li J, Liu Y, Zhang J, Xu Y, et al. Clinical

sequelae of COVID‑19 survivors in Wuhan, China:

A single‑centre longitudinal study. Clin Microbiol Infect

;27:89‑95.

Frija‑Masson J, Debray MP, Gilbert M, Lescure FX, Travert F,

Borie R, et al. Functional characteristics of patients with

SARS‑CoV‑2 pneumonia at 30 days post‑infection. Eur Respir J

;56:2001754. doi: 10.1183/13993003.01754‑2020.

Chopra V, Flanders SA, O’Malley M, Malani AN, Prescott HC.

Sixty‑day outcomes among patients hospitalized with COVID‑19.

Ann Intern Med 2021;174:576‑8.

Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O,

McLean L, et al. Postdischarge symptoms and rehabilitation

needs in survivors of COVID‑19 infection: A cross‑sectional

evaluation. J Med Virol 2021;93:1013‑22.

Lund LC, Hallas J, Nielsen H, Koch A, Mogensen SH, Brun NC,

et al. Post‑acute effects of SARS‑CoV‑2 infection in individuals

not requiring hospital admission: A Danish population‑based

cohort study. Lancet Infect Dis 2021;21:1373‑82.

Darcis G, Bouquegneau A, Maes N, Thys M, Henket M,

Labye F, et al. Long‑term clinical follow‑up of patients suffering

from moderate‑to‑severe COVID‑19 infection: A monocentric

prospective observational cohort study. Int J Infect Dis

;109:209‑16.

Han X, Fan Y, Alwalid O, Li N, Jia X, Yuan M, et al. Six‑month

follow‑up chest CT findings after severe COVID‑19 pneumonia.

Radiology 2021;299:E177‑86.

Sonnweber T, Sahanic S, Pizzini A, Luger A, Schwabl C,

Sonnweber B, et al. Cardiopulmonary recovery after COVID‑19:

An observational prospective multicentre trial. Eur Respir J

;57:2003481. doi: 10.1183/13993003.03481‑2020.

Alharthy A, Abuhamdah M, Balhamar A, Faqihi F, Nasim N,

Ahmad S, et al. Residual lung injury in patients recovering

from COVID‑19 critical illness: A prospective longitudinal

point‑of‑care lung ultrasound study. J Ultrasound Med

;40:1823‑38.

Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF,

et al. Follow‑up study of the pulmonary function and related

physiological characteristics of COVID‑19 survivors three

months after recovery. EClinicalMedicine 2020;25:100463. doi:

1016/j.eclinm. 2020.100463.

Tabatabaei SMH, Rajebi H, Moghaddas F, Ghasemiadl M,

Talari H. Chest CT in COVID‑19 pneumonia: What are the

findings in mid‑term follow‑up? Emerg Radiol 2020;27:711‑9.

Mo X, Jian W, Su Z, Chen M, Peng H, Peng P, et al.

Abnormal pulmonary function in COVID‑19 patients at time

of hospital discharge. Eur Respir J 2020;55:2001217. doi:

1183/13993003.01217‑2020.

Huppert LA, Matthay MA, Ware LB, editors. Pathogenesis of

acute respiratory distress syndrome. Seminars in Respiratory and

Critical Ccare Medicine. Thieme Medical Publishers; 2019.

Sidarta‑Oliveira D, Jara CP, Ferruzzi AJ, Skaf MS, Velander WH,

Araujo EP, et al. SARS‑CoV‑2 receptor is co‑expressed

with elements of the kinin–kallikrein, renin–angiotensin and

coagulation systems in alveolar cells. Sci Rep 2020;10:1‑19. doi:

1038/s41598‑020‑76488‑2.

Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A,

Zerbi P, et al. Pulmonary post‑mortem findings in a series of

COVID‑19 cases from northern Italy: A two‑centre descriptive

study. Lancet Infect Dis 2020;20:1135‑40.

Schaller T, Hirschbühl K, Burkhardt K, Braun G, Trepel M,

Märkl B, et al. Postmortem examination of patients with

COVID‑19. JAMA 2020;323:2518‑20.

De Michele S, Sun Y, Yilmaz MM, Katsyv I, Salvatore M,

Dzierba AL, et al. Forty postmortem examinations in

COVID‑19 patients: Two distinct pathologic phenotypes and

correlation with clinical and radiologic findings. Am J Clin

Pathol 2020;154:748‑60.

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical

and immunological features of severe and moderate coronavirus

disease 2019. J Clin Invest 2020;130:2620‑9.

Bharat A, Querrey M, Markov NS, Kim S, Kurihara C,

Garza‑Castillon R, et al. Lung transplantation for patients with

severe COVID‑19. Sci Transl Med 2020;12.

Ramadan MS, Bertolino L, Zampino R, Durante‑Mangoni E,

Monaldi Hospital Cardiovascular Infection Study Group. Cardiac

sequelae after coronavirus disease 2019 recovery: A systematic

review. Clin Microbiol Infect 2021;27:1250‑61.

Moulson N, Petek BJ, Drezner JA, Harmon KG, Kliethermes SA,

Patel MR, et al. SARS‑CoV‑2 cardiac involvement in young

competitive athletes. Circulation 2021;144:256‑66.

Johansson M, Ståhlberg M, Runold M, Nygren‑Bonnier M,

Nilsson J, Olshansky B, et al. Long‑haul post–COVID‑19

symptoms presenting as a variant of postural orthostatic

tachycardia syndrome: The Swedish experience. JACC Case Rep

;3:573‑80.

Miglis MG, Prieto T, Shaik R, Muppidi S, Sinn D‑I, Jaradeh S.

A case report of postural tachycardia syndrome after COVID‑19.

Clin Auton Res 2020;30:449‑51.

Ståhlberg M, Reistam U, Fedorowski A, Villacorta H,

Horiuchi Y, Bax J, et al. Post‑COVID‑19 Tachycardia syndrome: A distinct phenotype of post‑acute COVID‑19 syndrome. Am J

Med 2021;134:1451‑6.

Martinez MW, Tucker AM, Bloom OJ, Green G, DiFiori JP,

Solomon G, et al. Prevalence of inflammatory heart disease

among professional athletes with prior COVID‑19 infection

who received systematic return‑to‑play cardiac screening. JAMA

Cardiol 2021;6:745‑52.

Kotecha T, Knight DS, Razvi Y, Kumar K, Vimalesvaran K,

Thornton G, et al. Patterns of myocardial injury in recovered

troponin‑positive COVID‑19 patients assessed by cardiovascular

magnetic resonance. Eur Heart J 2021;42:1866‑78.

Al‑Aly Z, Xie Y, Bowe B. High‑dimensional characterization of

post‑acute sequelae of COVID‑19. Nature 2021;594:259‑64.

Ayoubkhani D, Khunti K, Nafilyan V, Maddox T, Humberstone B,

Diamond I, et al. Post‑COVID syndrome in individuals admitted

to hospital with COVID‑19: Retrospective cohort study. BMJ

;372:n693. doi: 10.1136/bmj.n693.

Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C,

Meissner K, et al. Association of cardiac infection with

SARS‑CoV‑2 in confirmed COVID‑19 autopsy cases. JAMA

Cardiol 2020;5:1281‑5.

Siripanthong B, Nazarian S, Muser D, Deo R, Santangeli P,

Khanji MY, et al. Recognizing COVID‑19–related myocarditis:

The possible pathophysiology and proposed guideline for

diagnosis and management. Heart Rhythm 2020;17:1463‑71.

Wu Q, Zhou L, Sun X, Yan Z, Hu C, Wu J, et al. Altered

lipid metabolism in recovered SARS patients twelve

years after infection. Sci Rep 2017;7:1‑12. doi: 10.1038/

s41598‑017‑09536‑z.

Lazzerini PE, Laghi‑Pasini F, Boutjdir M, Capecchi PL.

Cardioimmunology of arrhythmias: The role of autoimmune

and inflammatory cardiac channelopathies. Nat Rev Immunol

;19:63‑4.

Roberts LN, Whyte MB, Georgiou L, Giron G, Czuprynska J,

Rea C, et al. Postdischarge venous thromboembolism following

hospital admission with COVID‑19. Blood 2020;136:1347‑50.

Patell R, Bogue T, Koshy A, Bindal P, Merrill M, Aird WC,

et al. Postdischarge thrombosis and hemorrhage in patients with

COVID‑19. Blood 2020;136:1342‑6.

Salisbury R, Iotchkova V, Jaafar S, Morton J, Sangha G, Shah A,

et al. Incidence of symptomatic, image‑confirmed venous

thromboembolism following hospitalization for COVID‑19 with

‑day follow‑up. Blood Adv 2020;4:6230‑9.

Giannis D, Allen SL, Tsang J, Flint S, Pinhasov T, Williams S,

et al. Postdischarge thromboembolic outcomes and mortality of

hospitalized patients with COVID‑19: The CORE‑19 registry.

Blood 2021;137:2838‑47.

Nicolai L, Leunig A, Brambs S, Kaiser R, Weinberger T,

Weigand M, et al. Immunothrombotic dysregulation in

COVID‑19 pneumonia is associated with respiratory failure and

coagulopathy. Circulation 2020;142:1176‑89.

Pons S, Fodil S, Azoulay E, Zafrani L. The vascular

endothelium: The cornerstone of organ dysfunction in severe

SARS‑CoV‑2 infection. Crit Care 2020;24:1‑8. doi: 10.1186/

s13054‑020‑03062‑7.

Ghebrehiwet B, Peerschke EI. Complement and coagulation:

Key triggers of COVID‑19–induced multiorgan pathology. J Clin

Invest 2020;130:5674‑6.

Hottz ED, Azevedo‑Quintanilha IG, Palhinha L, Teixeira L,

Barreto EA, Pão CR, et al. Platelet activation and

platelet‑monocyte aggregate formation trigger tissue factor

expression in patients with severe COVID‑19. Blood

;136:1330‑41.

Szturmowicz M, Demkow U. Neutrophil extracellular

traps (NETs) in severe SARS‑CoV‑2 lung disease. Int J Mol Sci

;22:8854. doi: 10.3390/ijms22168854.

Song W‑C, FitzGerald GA. COVID‑19, microangiopathy,

hemostatic activation, and complement. J Clin Invest

;130:3950‑3.

Bowe B, Xie Y, Xu E, Al‑Aly Z. Kidney outcomes in long

COVID. J Am Soc Nephrol 2021;32:2851‑62.

Robbins‑Juarez SY, Qian L, King KL, Stevens JS, Husain SA,

Radhakrishnan J, et al. Outcomes for patients with COVID‑19

and acute kidney injury: A systematic review and meta‑analysis.

Kidney Int Rep 2020;5:1149‑60.

Cummings MJ, Baldwin MR, Abrams D, Jacobson SD,

Meyer BJ, Balough EM, et al. Epidemiology, clinical

course, and outcomes of critically ill adults with COVID‑19

in New York City: A prospective cohort study. Lancet

;395:1763‑70.

Stevens JS, King KL, Robbins‑Juarez SY, Khairallah P, Toma K,

Alvarado Verduzco H, et al. High rate of renal recovery in

survivors of COVID‑19 associated acute renal failure requiring

renal replacement therapy. PLoS One 2020;15:e0244131. doi:

1371/journal.pone. 0244131.

Hirsch JS, Ng JH, Ross DW, Sharma P, Shah HH, Barnett RL,

et al. Acute kidney injury in patients hospitalized with

COVID‑19. Kidney Int 2020;98:209‑18.

Pei G, Zhang Z, Peng J, Liu L, Zhang C, Yu C, et al. Renal

involvement and early prognosis in patients with COVID‑19

pneumonia. J Am Soc Nephrol 2020;31:1157‑65.

Stockmann H, Hardenberg J‑HB, Aigner A, Hinze C, Gotthardt I,

Stier B, et al. High rates of long‑term renal recovery in

survivors of coronavirus disease 2019–associated acute kidney

injury requiring kidney replacement therapy. Kidney Int

;99:1021‑2.

Su H, Yang M, Wan C, Yi L‑X, Tang F, Zhu H‑Y, et al. Renal

histopathological analysis of 26 postmortem findings of patients

with COVID‑19 in China. Kidney Int 2020;98:219‑27.

Kudose S, Batal I, Santoriello D, Xu K, Barasch J, Peleg Y, et al.

Kidney biopsy findings in patients with COVID‑19. J Am Soc

Nephrol 2020;31:1959‑68.

Sharma P, Uppal NN, Wanchoo R, Shah HH, Yang Y, Parikh R,

et al. COVID‑19–associated kidney injury: A case series of

kidney biopsy findings. J Am Soc Nephrol 2020;31:1948‑58.

Golmai P, Larsen CP, DeVita MV, Wahl SJ, Weins A,

Rennke HG, et al. Histopathologic and ultrastructural findings in

postmortem kidney biopsy material in 12 patients with AKI and

COVID‑19. J Am Soc Nephrol 2020;31:1944‑7.

Santoriello D, Khairallah P, Bomback AS, Xu K, Kudose S,

Batal I, et al. Postmortem kidney pathology findings in patients

with COVID‑19. J Am Soc Nephrol 2020;31:2158‑67.

Velez JCQ, Caza T, Larsen CP. COVAN is the new HIVAN: The

re‑emergence of collapsing glomerulopathy with COVID‑19. Nat

Rev Nephrol 2020;16:565‑7.

Peleg Y, Kudose S, D’Agati V, Siddall E, Ahmad S, Nickolas T,

et al. Acute kidney injury due to collapsing glomerulopathy

following COVID‑19 infection. Kidney Int Rep 2020;5:940‑5.

Jhaveri KD, Meir LR, Chang BSF, Parikh R, Wanchoo R,

Barilla‑LaBarca ML, et al. Thrombotic microangiopathy in a

patient with COVID‑19. Kidney Int 2020;98:509‑12.

Sathish T, Cao Y, Kapoor N. Newly diagnosed diabetes in

COVID‑19 patients. Prim Care Diabetes 2020;15:194.

Akter F, Mannan A, Mehedi HH, Rob MA, Ahmed S,

Salauddin A, et al. Clinical characteristics and short term

outcomes after recovery from COVID‑19 in patients with and without diabetes in Bangladesh. Diabetes Metab Syndr

;14:2031‑8.

Kamal M, Abo Omirah M, Hussein A, Saeed H. Assessment and

characterisation of post-COVID-19 manifestations. Int J Clin

Pract 2021;75:e13746. doi: 10.1111/ijcp. 13746.

Ghosh A, Anjana RM, Rani CSS, Rani SJ, Gupta R, Jha A, et al.

Glycemic parameters in patients with new‑onset diabetes during

COVID‑19 pandemic are more severe than in patients with

new‑onset diabetes before the pandemic: NOD COVID India

Study. Diabetes Metab Syndr 2021;15:215‑20.

Yuan K, Gong Y‑M, Liu L, Sun Y‑K, Tian S‑S, Wang Y‑J, et al.

Prevalence of posttraumatic stress disorder after infectious

disease pandemics in the twenty‑first century, including

COVID‑19: A meta‑analysis and systematic review. Mol

Psychiatry 2021;26:4982‑4998.

Ruggeri RM, Campennì A, Siracusa M, Frazzetto G, Gullo D.

Subacute thyroiditis in a patient infected with SARS‑COV‑2:

An endocrine complication linked to the COVID‑19 pandemic.

Hormones 2021;20:219‑21.

Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F.

Subacute thyroiditis after Sars‑COV‑2 infection. J Clin

Endocrinol Metab 2020;105:2367‑70.

Moreno-Perez O, Merino E, Alfayate R, Torregrosa ME,

Andres M, Leon-Ramirez JM, et al. Male pituitary-gonadal axis

dysfunction in post-acute COVID-19 syndrome. Prevalence and

associated factors: A Mediterranean case series. Clin Endocrinol

doi: 10.1111/cen. 14537.

Mondal S, DasGupta R, Lodh M, Gorai R, Choudhury B,

Hazra AK, et al. Predictors of new‑onset diabetic ketoacidosis in

patients with moderate to severe COVID‑19 receiving parenteral

glucocorticoids: A prospective single‑centre study among Indian

type 2 diabetes patients. Diabetes Metab Syndr 2021;15:795‑801.

Gentile S, Strollo F, Mambro A, Ceriello A. COVID‑19,

ketoacidosis and new‑onset diabetes: Are there possible cause

and effect relationships among them? Diabetes Obes Metab

;22:2507‑8.

Yang J‑K, Lin S‑S, Ji X‑J, Guo L‑M. Binding of SARS

coronavirus to its receptor damages islets and causes acute

diabetes. Acta Diabetol 2010;47:193‑9.

Farag AA, Hassanin HM, Soliman HH, Sallam A, Sediq AM,

Elbanna K. Newly diagnosed diabetes in patients with

COVID‑19: Different types and short‑term outcomes. Trop Med

Infect Dis 2021;6:142. doi: 10.3390/tropicalmed6030142.

Baig AM. Deleterious outcomes in long‑hauler COVID‑19:

The effects of SARS‑CoV‑2 on the CNS in chronic COVID

syndrome. ACS Chem Neurosci 2020;11:4017‑20.

Wijeratne T, Crewther S. Post‑COVID 19 Neurological

Syndrome (PCNS); a novel syndrome with challenges for

the global neurology community. J Neurol Sci 2020;419. doi:

1016/j.jns. 2020.117179

Boscolo‑Rizzo P, Borsetto D, Fabbris C, Spinato G, Frezza D,

Menegaldo A, et al. Evolution of altered sense of smell or

taste in patients with mildly symptomatic COVID‑19. JAMA

Otolaryngol Head Neck Surg 2020;146:729‑32.

Lu Y, Li X, Geng D, Mei N, Wu P‑Y, Huang C‑C, et al. Cerebral

micro‑structural changes in COVID‑19 patients–an MRI‑based

‑month follow‑up study. EClinicalMedicine 2020;25:100484.

Siow I, Lee KS, Zhang JJ, Saffari SE, Ng A, Young B. Stroke

as a neurological complication of COVID‑19: A systematic

review and meta‑analysis of incidence, outcomes and predictors.

J Stroke Cerebrovasc Dis 2021;30:105549. doi: 10.1016/j.

jstrokecerebrovasdis. 2020.105549.

Hernández‑Fernández F, Sandoval Valencia H,

Barbella‑Aponte RA, Collado‑Jiménez R, Ayo‑Martín Ó,

Barrena C, et al. Cerebrovascular disease in patients with

COVID‑19: Neuroimaging, histological and clinical description.

Brain 2020;143:3089‑103.

Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional

associations between COVID‑19 and psychiatric disorder:

Retrospective cohort studies of 62 354 COVID‑19 cases in the

USA. Lancet Psychiatry 2021;8:130‑40.

Del Rio C, Collins LF, Malani P. Long‑term health consequences

of COVID‑19. JAMA 2020;324:1723‑4.

Mazza MG, De Lorenzo R, Conte C, Poletti S, Vai B, Bollettini I,

et al. Anxiety and depression in COVID‑19 survivors: Role

of inflammatory and clinical predictors. Brain Behav Immun

;89:594‑600.

Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE,

Spudich S. Neuropathogenesis and neurologic manifestations

of the coronaviruses in the age of coronavirus disease 2019:

A review. JAMA Neurol 2020;77:1018‑27.

Mendelson M, Nel J, Blumberg L, Madhi S, Dryden M,

Stevens W, et al. Long‑COVID: An evolving problem with an

extensive impact. S Afr Med J 2021;111:10‑2.

Guedj E, Campion J, Dudouet P, Kaphan E, Bregeon F,

Tissot‑Dupont H, et al. 18 F‑FDG brain PET hypometabolism

in patients with long COVID. Eur J Nucl Med Mol Imaging

;48:2823‑33.

Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ.

‑month neurological and psychiatric outcomes in 236 379

survivors of COVID‑19: A retrospective cohort study using

electronic health records. Lancet Psychiatry 2021;8:416‑27.

Heneka MT, Golenbock D, Latz E, Morgan D, Brown R.

Immediate and long‑term consequences of COVID‑19 infections

for the development of neurological disease. Alzheimer’s Res

Ther 2020;12:1‑3. doi: 10.1186/s13195‑020‑00640‑3.

Muccioli L, Pensato U, Cani I, Guarino M, Cortelli P, Bisulli F.

COVID‑19‑associated encephalopathy and cytokine‑mediated

neuroinflammation. Ann Neurol 2020;88:860‑1.

Pilotto A, Padovani A. Reply to the letter” COVID‑19‑associated

encephalopathy and cytokine‑mediated neuroinflammation”. Ann

Neurol 2020;88:861‑2.

South K, McCulloch L, McColl BW, Elkind MS, Allan SM,

Smith CJ. Preceding infection and risk of stroke: An old

concept revived by the COVID‑19 pandemic. Int J Stroke

;15:722‑32.

Reichard RR, Kashani KB, Boire NA, Constantopoulos E, Guo Y,

Lucchinetti CF. Neuropathology of COVID‑19: A spectrum of

vascular and acute disseminated encephalomyelitis (ADEM)‑like

pathology. Acta Neuropathol 2020;140:1‑6.

Ameres M, Brandstetter S, Toncheva AA, Kabesch M, Leppert D,

Kuhle J, et al. Association of neuronal injury blood marker

neurofilament light chain with mild‑to‑moderate COVID‑19.

J Neurol 2020;267:3476‑8.

Bortolato B, F Carvalho A, K Soczynska J, I Perini G,

S McIntyre R. The involvement of TNF‑α in cognitive

dysfunction associated with major depressive disorder: An

opportunity for domain specific treatments. Curr Neuropharmacol

;13:558‑76.

Perrin R, Riste L, Hann M, Walther A, Mukherjee A, Heald A.

Into the looking glass: Post‑viral syndrome post COVID‑19. Med

Hypotheses 2020;144:110055. doi: 10.1016/j.mehy. 2020.110055.

Kaseda ET, Levine AJ. Post‑traumatic stress disorder:

A differential diagnostic consideration for COVID‑19 survivors.

Clin Neuropsychol 2020;34:1498‑514.

Miglis MG, Goodman BP, Chemali KR, Stiles L. Re: ‘Post‑COVID‑19 chronic symptoms’ by Davido et al. Clin

Microbiol Infect 2021;27:494.

Tian Y, Rong L, Nian W, He Y. gastrointestinal features in

COVID-19 and the possibility of faecal transmission. Aliment

Pharmacol Ther 2020;51:843‑51.

Schmulson M, Dávalos M, Berumen J. Beware: Gastrointestinal

symptoms can be a manifestation of COVID‑19. Rev

Gastroenterol Méx (Engl Ed) 2020;85:282‑7.

Rizvi A, Patel Z, Liu Y, Satapathy SK, Sultan K, Trindade AJ,

et al. Gastrointestinal sequelae 3 and 6 months after

hospitalization for coronavirus disease 2019. Clin Gastroenterol

Hepatol 2021;271‑81.

Weng J, Li Y, Li J, Shen L, Zhu L, Liang Y, et al. Gastrointestinal

sequelae 90 days after discharge for COVID‑19. Lancet

Gastroenterol Hepatol 2021;6:344‑6.

Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged

presence of SARS‑CoV‑2 viral RNA in faecal samples. Lancet

Gastroenterol Hepatol 2020;5:434‑5.

Effenberger M, Grabherr F, Mayr L, Schwaerzler J, Nairz M,

Seifert M, et al. Faecal calprotectin indicates intestinal

inflammation in COVID‑19. Gut 2020;69:1543‑4.

Wang MK, Yue HY, Cai J, Zhai YJ, Peng JH, Hui JF, et al.

COVID‑19 and the digestive system: A comprehensive review.

World J Clin Cases 2021;9:3796‑813.

Cheung KS, Hung IFN, Chan PPY, Lung KC, Tso E, Liu R, et al.

Gastrointestinal manifestations of SARS‑CoV‑2 infection and

virus load in fecal samples from a Hong Kong cohort: Systematic

review and meta‑analysis. Gastroenterology 2020;159:81‑95.

Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for

Gastrointestinal Infection of SARS‑CoV‑2. Gastroenterology

;158:1831‑3.e3.

Donati Zeppa S, Agostini D, Piccoli G, Stocchi V, Sestili P.

Gut microbiota status in COVID‑19: An unrecognized player?

Front Cell Infect Microbiol 2020;10:576551. doi: 10.3389/fcimb.

576551.

Bradley KC, Finsterbusch K, Schnepf D, Crotta S, Llorian M,

Davidson S, et al. Microbiota‑driven tonic interferon signals in

lung stromal cells protect from influenza virus infection. Cell

Rep 2019;28:245‑56 e4.

McMahon DE, Gallman AE, Hruza GJ, Rosenbach M, Lipoff JB,

Desai SR, et al. Long COVID in the skin: A registry analysis

of COVID‑19 dermatological duration. Lancet Infect Dis

;21:313‑4.

Tammaro A, Parisella FR, Adebanjo GAR. Cutaneous long

COVID. J Cosmet Dermatol 2021;20:2378‑9.

Moreno-Arrones O, Lobato-Berezo A, Gomez-Zubiaur A,

Arias-Santiago S, Saceda-Corralo D, Bernardez-Guerra C, et al.

SARS-CoV-2-induced telogen effluvium: A multicentric study.

J Eur Acad Dermatol Venereol 2021;35:e181‑3.

Abrantes TF, Artounian KA, Falsey R, Simão JCL,

Vañó‑Galván S, Ferreira SB, et al. Time of onset and duration

of post‑COVID‑19 acute telogen effluvium. J Am Acad Dermatol

;85:975‑6.

Mehta P, Bunker CB, Ciurtin C, Porter JC, Chambers RC,

Papdopoulou C, et al. Chilblain‑like acral lesions in long

COVID‑19: Management and implications for understanding

microangiopathy. Lancet Infect Dis 2021;21:912. doi: 10.1016/

S1473‑3099(21)00133‑X.

Sykes DL, Holdsworth L, Jawad N, Gunasekera P,

Morice AH, Crooks MG. Post‑COVID‑19 symptom burden:

What is long‑COVID and how should we manage it? Lung

;199:113‑9.

Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F,

et al. Persistent fatigue following SARS‑CoV‑2 infection is

common and independent of severity of initial infection. Plos

One 2020;15:e0240784.

Office for National Statistics. UK Office for National

Statistics. Prevalence of long COVID symptoms and

COVID‑19 complications. Available from: https://www.ons.

gov.uk/peoplepopulationandcommunity/healthandsocialcare/

healthandlifeexpectancies/datasets/prevalenceoflongCOVID

symptomsandCOVID19complications.

Miyazato Y, Morioka S, Tsuzuki S, Akashi M, Osanai Y,

Tanaka K, et al., editors. Prolonged and late‑onset symptoms

of coronavirus disease 2019. Open Forum Infectious Diseases.

Oxford University Press US; 2020.

van den Borst B, Peters JB, Brink M, Schoon Y,

Bleeker‑Rovers CP, Schers H, et al. Comprehensive health

assessment 3 months after recovery from acute coronavirus

disease 2019 (COVID‑19). Clin Infect Dis 2021;73:e1089‑98.

Poyraz BÇ, Poyraz CA, Olgun Y, Gürel Ö, Alkan S,

Özdemir YE, et al. Psychiatric morbidity and protracted

symptoms after COVID‑19. Psychiatry Res 2021;295:113604.

doi: 10.1016/j.psychres. 2020.113604.

Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS,

Bowyer RC, et al. Attributes and predictors of Long‑COVID:

Analysis of COVID cases and their symptoms collected

by the COVID symptoms study app. medRxiv 2020. doi:

1101/2020.10.19.20214494.

Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Persistent

symptoms 1.5–6 months after COVID‑19 in non‑hospitalised

subjects: A population‑based cohort study. Thorax 2021;76:405‑7.

Taboada M, Cariñena A, Moreno E, Rodríguez N, Domínguez MJ,

Casal A, et al. Post‑COVID‑19 functional status six‑months after

hospitalization. J Infect 2021;82:e31‑3.

Raman B, Cassar MP, Tunnicliffe EM, Filippini N, Griffanti L,

Alfaro‑Almagro F, et al. Medium‑term effects of SARS‑CoV‑2

infection on multiple vital organs, exercise capacity, cognition,

quality of life and mental health, post‑hospital discharge.

EClinicalMedicine 2021;31:100683. doi: 10.1016/j.eclinm.

100683.

Hewitt J, Carter B, Vilches‑Moraga A, Quinn T, Braude P,

Verduri A. Th e effect of frailty on survival in patients with

COVID‑19 (COPE): A multicentre, European, observational

cohort study. Lancet Public Health 2020;5:e444‑51.

Mandal S, Barnett J, Brill SE, Brown JS, Denneny EK, Hare SS,

et al. ‘Long‑COVID’: A cross‑sectional study of persisting

symptoms, biomarker and imaging abnormalities following

hospitalisation for COVID‑19. Thorax 2021;76:396‑8.

Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E,

Berry S, et al. Risk factors and disease profile of post‑vaccination

SARS‑CoV‑2 infection in UK users of the COVID Symptom

Study app: A prospective, community‑based, nested, case‑control

study. Lancet Infect Dis 2021;22:43‑55.

Ledford H. Do vaccines protect against long COVID? What the

data say. Nature 2021;599:546‑8.

Office for National Statistics. Coronavirus (COVID‑19)

vaccination and self‑reported long COVID in the UK:

October 2021. 2021. Available from: https://www.ons.

gov.uk/peoplepopulationandcommunity/healthandsocialcare/

conditionsanddiseases/articles/coronavirus COVID19vaccinationa

ndselfreportedlongCOVIDintheuk/25october2021.

Akrami A, Assaf G, Davis H, Harris K, Iwasaki A, Krumholz H,

et al. Change in symptoms and immune response in people

with post‑acute sequelae of SARS‑Cov‑2 infection (PASC)

after SARS‑Cov‑2 vaccination. medRxiv 2021. doi:

1101/2021.07.21.21260391.

Guideline N. NICE Guideline; COVID‑19 rapid guideline:

Managing the long‑term effects of COVID‑19. Available from:

https://www.nice.org.uk/guidance/ng188.

George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A,

Forrest I, et al. Respiratory follow‑up of patients with COVID‑19

pneumonia. Thorax 2020;75:1009‑16.

Sivan M, Taylor S. NICE guideline on long COVID. BMJ

;371:m4938. doi: 10.1136/bmj.m4938.

Barker‑Davies RM, O’Sullivan O, Senaratne KPP, Baker P,

Cranley M, Dharm‑Datta S, et al. The Stanford Hall consensus

statement for post‑COVID‑19 rehabilitation. Br J Sports Med

;54:949‑59.

Wang TJ, Chau B, Lui M, Lam G‑T, Lin N, Humbert S. PM&R

and pulmonary rehabilitation for COVID‑19. Am J Phys Med

Rehabil 2020. doi: 10.1097/PHM.0000000000001505.

Grigoletto I, Cavalheri V, de Lima FF, Ramos EMC. Recovery

after COVID‑19: The potential role of pulmonary rehabilitation.

Braz J Phys Ther 2020;24:463‑4.

Liu K, Zhang W, Yang Y, Zhang J, Li Y, Chen Y. Respiratory

rehabilitation in elderly patients with COVID‑19: A randomized

controlled study. Complement Ther Clin Pract 2020;39:101166.

doi: 10.1016/j.ctcp. 2020.101166.

Demeco A, Marotta N, Barletta M, Pino I, Marinaro C, Petraroli A,

et al. Rehabilitation of patients post‑COVID‑19 infection:

A literature review. J Int Med Res 2020;48:0300060520948382.

doi: 10.1177/0300060520948382.

Fu Q, Levine BD. Exercise and non‑pharmacological treatment

of POTS. Auton Neurosci 2018;215:20‑7.

Larun L, Brurberg KG, Odgaard‑Jensen J, Price JR. Exercise

therapy for chronic fatigue syndrome. Cochrane Database Syst

Rev 2019;10:CD003200. doi: 10.1002/14651858.CD003200.

pub8.

Twisk F, Maes M. A review on cognitive behavorial

therapy (CBT) and graded exercise therapy (GET) in myalgic

encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/

GET is not only ineffective and not evidence‑based, but also

potentially harmful for many patients with ME/CFS. Neuro

Endocrinol Lett 2009;30:284‑99.

Torrisi SE, Kahn N, Vancheri C, Kreuter M. Evolution and

treatment of idiopathic pulmonary fibrosis. Presse Méd

;49:104025. doi: 10.1016/j.lpm. 2020.104025.

Raghu G, Wilson KC. COVID‑19 interstitial pneumonia:

Monitoring the clinical course in survivors. Lancet Respir Med

;8:839‑42.

Desai AD, Boursiquot BC, Melki L, Wan EY. Management

of arrhythmias associated with COVID‑19. Curr Cardiol Rep

;23:1‑9. doi: 10.1007/s11886‑020‑01434‑7.

Hendren NS, Drazner MH, Bozkurt B, Cooper Jr LT. Description

and proposed management of the acute COVID‑19 cardiovascular

syndrome. Circulation 2020;141:1903‑14.