Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers"

Edith L Graham, Jeffrey R Clark, Zachary S Orban, Patrick H Lim, April L Szymanski, Carolyn Taylor, Rebecca M DiBiase, Dan Tong Jia, Roumen Balabanov, Sam U Ho, Ayush Batra, Eric M Liotta, Igor J Koralnik, Edith L Graham, Jeffrey R Clark, Zachary S Orban, Patrick H Lim, April L Szymanski, Carolyn Taylor, Rebecca M DiBiase, Dan Tong Jia, Roumen Balabanov, Sam U Ho, Ayush Batra, Eric M Liotta, Igor J Koralnik

Abstract

Objective: Most SARS-CoV-2-infected individuals never require hospitalization. However, some develop prolonged symptoms. We sought to characterize the spectrum of neurologic manifestations in non-hospitalized Covid-19 "long haulers".

Methods: This is a prospective study of the first 100 consecutive patients (50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+ ) and 50 laboratory-negative (SARS-CoV-2- ) individuals) presenting to our Neuro-Covid-19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid-19, were never hospitalized for pneumonia or hypoxemia, and had neurologic symptoms lasting over 6 weeks. We recorded the frequency of neurologic symptoms and analyzed patient-reported quality of life measures and standardized cognitive assessments.

Results: Mean age was 43.2 ± 11.3 years, 70% were female, and 48% were evaluated in televisits. The most frequent comorbidities were depression/anxiety (42%) and autoimmune disease (16%). The main neurologic manifestations were: "brain fog" (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%), with only anosmia being more frequent in SARS-CoV-2+ than SARS-CoV-2- patients (37/50 [74%] vs. 18/50 [36%]; p < 0.001). Moreover, 85% also experienced fatigue. There was no correlation between time from disease onset and subjective impression of recovery. Both groups exhibited impaired quality of life in cognitive and fatigue domains. SARS-CoV-2+ patients performed worse in attention and working memory cognitive tasks compared to a demographic-matched US population (T-score 41.5 [37, 48.25] and 43 [37.5, 48.75], respectively; both p < 0.01).

Interpretation: Non-hospitalized Covid-19 "long haulers" experience prominent and persistent "brain fog" and fatigue that affect their cognition and quality of life.

Conflict of interest statement

The authors report no conflict of interest pertaining to this publication.

© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Patient‐reported outcomes measurement information system (PROMIS®) quality of life and NIH Toolbox cognitive assessments demographic‐matched T‐scores in SARS‐CoV‐2+ (circles) and SARS‐CoV‐2‐ (squares) individuals. A T‐score of 50 is the mean/median for the demographic‐matched United States normative population with a standard deviation of 10. (A) PROMIS® cognitive function (C, filled symbols) and fatigue (F, empty symbols) assessments. Lower cognition scores indicate worse cognition quality of life and higher fatigue scores correspond to worse fatigue quality of life. Patient group median values are represented by horizontal bars. (B) NIH Toolbox assessments for processing speed (PS), attention (A), executive function (EF), and working memory (WM). Median values are represented by horizontal bars. One‐sample Wilcoxon signed‐rank test p‐values between patient group T‐scores and the demographic‐matched normative US population median of 50 are provided in the figure table.
Figure 2
Figure 2
Subjective impression of recovery compared to pre‐Covid‐19 baseline for SARS‐CoV‐2+ (A) and SARS‐CoV‐2‐ individuals (B). The patients were asked to grade their recovery at the time of their visit, assuming a pre‐Covid‐19 baseline of 100%. Each person is represented by a single time point, and r values demonstrate no meaningful relationship between time from onset and percentage of recovery.

References

    1. COVID‐19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University and Medicine. : Johns Hopkins University & Medicine; 2021; Available from: .
    1. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID‐19. Lancet Neurol 2020;19(9):767–783.
    1. Koralnik IJ, Tyler KL. COVID‐19: A global threat to the nervous system. Ann Neurol 2020;88(1):1–11.
    1. Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID‐19. JAMA 2020;324(6):603–605.
    1. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol 2020;77(6):683–690.
    1. Romero‐Sánchez CM, Díaz‐Maroto I, Fernández‐Díaz E, et al. Neurologic manifestations in hospitalized patients with COVID‐19. Neurology 2020;95(8):e1060–e1070.
    1. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy‐associated morbidity in Covid‐19 patients. Ann Clin Transl Neurol 2020;7(11):2221–2230.
    1. 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. BMC Health Serv Res 2020;20(1):1144.
    1. Lancet T. Facing up to long COVID. Lancet 2020;396(10266):1861.
    1. NIH announces research opportunities to study “Long COVID”. National Institutes of Health; 2021; Available from: .
    1. Bergquist SH, Partin C, Roberts DL, et al. Non‐hospitalized adults with COVID‐19 differ noticeably from hospitalized adults in their demographic, clinical, and social characteristics. SN Compr Clin Med 2020;2(9):1349–1357.
    1. Wu Z, McGoogan JM. Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID‐19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323(13):1239–1242.
    1. Callard F, Perego E. How and why patients made Long Covid. Soc Sci Med. 2020;1–5.
    1. Goërtz YMJ, Van Herck M, Delbressine JM, et al. Persistent symptoms 3 months after a SARS‐CoV‐2 infection: the post‐COVID‐19 syndrome? ERJ Open Res 2020;6(4):00542. 10.1183/23120541.00542-2020
    1. Deeks JJ, Dinnes J, Takwoingi Y, et al. Antibody tests for identification of current and past infection with SARS‐CoV‐2. Cochrane Database Syst Rev 2020;6.
    1. Lisboa Bastos M, Tavaziva G, Abidi SK, et al. Diagnostic accuracy of serological tests for covid‐19: systematic review and meta‐analysis. BMJ 2020;370:m2516.
    1. Muecksch F, Wise H, Batchelor B, et al. Longitudinal analysis of serology and neutralizing antibody levels in COVID19 convalescents. J Infect Dis 2020.
    1. Zhou H, Lu S, Chen J, et al. The landscape of cognitive function in recovered COVID‐19 patients. J Psychiatr Res 2020;129:98–102.
    1. Belluck P. Beating Covid, only to be left with brain fog: [Foreign Desk]. New York Times; 2020.
    1. First travel‐related case of 2019 novel coronavirus detected in United States. Centers for Disease Control and Prevention Newsroom: Centers for Disease Control and Prevention; 2020. [updated January 21]; Available from: .
    1. Hanson KE, Caliendo AM, Arias CA, et al. Infectious Diseases Society of America guidelines on the diagnosis of COVID‐19. Clin Infect Dis 2020.
    1. Lai JS, Cella D, Choi S, et al. How item banks and their application can influence measurement practice in rehabilitation medicine: a PROMIS fatigue item bank example. Arch Phys Med Rehabil 2011;92(10 Suppl):S20–S27.
    1. Lai J‐S, Wagner LI, Jacobsen PB, Cella D. Self‐reported cognitive concerns and abilities: two sides of one coin? Psychooncology 2014;23(10):1133–1141.
    1. Gershon RC, Wagster MV, Hendrie HC, et al. NIH toolbox for assessment of neurological and behavioral function. Neurology 2013;80(11 Suppl 3):S2–S6.
    1. Heaton RK, Akshoomoff N, Tulsky D, et al. Reliability and validity of composite scores from the NIH Toolbox Cognition Battery in adults. J Int Neuropsychol Soc. 2014;20(6):588–598.
    1. Weintraub S, Dikmen SS, Heaton RK, et al. Cognition assessment using the NIH Toolbox. Neurology 2013;80(11 Suppl 3):S54–S64.
    1. Weintraub S, Dikmen SS, Heaton RK, et al. The cognition battery of the NIH toolbox for assessment of neurological and behavioral function: validation in an adult sample. J Int Neuropsychol Soc 2014;20(6):567–578.
    1. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of Long‐COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv 2020.
    1. Greenhalgh T, Knight M, A’Court C, et al. Management of post‐acute covid‐19 in primary care. BMJ 2020;370:m3026.
    1. COVID‐19 rapid guideline: managing the long‐term effects of COVID‐19. National Institute for Health and Care Excellence; 2020; Available from: .
    1. Cevik M, Tate M, Lloyd O, et al. SARS‐CoV‐2, SARS‐CoV, and MERS‐CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta‐analysis. Lancet Microbe 2020;1–9.
    1. Abbott Laboratories . SARS‐CoV‐2 IgG Architect ‐ Instructions for Use. Food and Drug Administration; 2020. Available from: .
    1. Graham NR, Whitaker AN, Strother CA, et al. Kinetics and isotype assessment of antibodies targeting the spike protein receptor‐binding domain of severe acute respiratory syndrome‐coronavirus‐2 in COVID‐19 patients as a function of age, biological sex and disease severity. Clin Transl Immunology 2020;9(10):e1189.
    1. Bruni M, Cecatiello V, Diaz‐Basabe A, et al. Persistence of anti‐SARS‐CoV‐2 antibodies in non‐hospitalized COVID‐19 convalescent health care workers. J Clin Med 2020;9(10).
    1. Ibarrondo FJ, Fulcher JA, Goodman‐Meza D, et al. Rapid decay of anti–SARS‐CoV‐2 antibodies in persons with mild Covid‐19. N Engl J Med 2020;383(11):1085–1087.
    1. Long Q‐X, Tang X‐J, Shi Q‐L, et al. Clinical and immunological assessment of asymptomatic SARS‐CoV‐2 infections. Nat Med 2020;26(8):1200–1204.
    1. Seow J, Graham C, Merrick B, et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS‐CoV‐2 infection in humans. Nat Microbiol 2020;5(12):1598–1607.
    1. Wang Y, Zhang L, Sang L, et al. Kinetics of viral load and antibody response in relation to COVID‐19 severity. J Clin Invest 2020;130(10):5235–5244.
    1. Ward H, Cooke G, Atchison C, et al. Declining prevalence of antibody positivity to SARS‐CoV‐2: a community study of 365,000 adults. medRxiv 2020.
    1. Schnurra C, Reiners N, Biemann R, et al. Comparison of the diagnostic sensitivity of SARS‐CoV‐2 nucleoprotein and glycoprotein‐based antibody tests. J Clin Virol 2020;129:104544.
    1. Chamie G, Bonacini M, Bangsberg DR, et al. Factors associated with seronegative chronic hepatitis C virus infection in HIV infection. Clin Infect Dis 2007;44(4):577–583.
    1. Berger JR, Houff SA, Gurwell J, et al. JC virus antibody status underestimates infection rates. Ann Neurol 2013;74(1):84–90.
    1. Research opportunity announcement OTA‐21‐015B post‐acute sequelae of SARS‐CoV‐2 infection initiative: SARS‐CoV‐2 recovery cohort studies; 2021; Available from: .
    1. Duquette P, Pleines J, Girard M, et al. The increased susceptibility of women to multiple sclerosis. Can J Neurol Sci 1992;19(4):466–471.
    1. Myasoedova E, Crowson CS, Kremers HM, et al. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum 2010;62(6):1576–1582.
    1. Chakravarty EF, Bush TM, Manzi S, et al. Prevalence of adult systemic lupus erythematosus in California and Pennsylvania in 2000: estimates obtained using hospitalization data. Arthritis Rheum 2007;56(6):2092–2094.
    1. The Autoimmune Diseases Coordinating Committee . Progress in Autoimmune Diseases Research. National Institutes of Health, U.S. Dept of Health and Human Services; 2005. Report No.: NIH Publication No. 05‐5140. Available from: .
    1. Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum 1997;40(9):1601–1611.
    1. Guan W‐j, Ni Z‐y, Hu Y, et al. Clinical characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020;382(18):1708–1720.
    1. Yamanaka H, Sugiyama N, Inoue E, et al. Estimates of the prevalence of and current treatment practices for rheumatoid arthritis in Japan using reimbursement data from health insurance societies and the IORRA cohort (I). Mod Rheumatol 2014;24(1):33–40.
    1. Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. Br Med J (Clin Res Ed) 2020;369:m1966.
    1. NCS‐R Lifetime prevalence estimates (Table 1. Lifetime prevalence of DSM‐IV/WMH‐CIDI disorders by sex and cohort). Harvard Medical School; 2005. [updated July 19, 2007]; Table 1. Lifetime prevalence of DSM‐IV/WMH‐CIDI disorders by sex and cohort.]. Available from: .
    1. Ettman CK, Abdalla SM, Cohen GH, et al. Prevalence of depression symptoms in US adults before and during the COVID‐19 pandemic. JAMA Netw Open 2020;3(9):e2019686.
    1. Nauen DW, Hooper JE, Stewart CM, Solomon IH. Assessing brain capillaries in Coronavirus Disease 2019. JAMA Neurol 2021.
    1. Batra A, Clark JR, LaHaye K, et al. Transcranial doppler ultrasound evidence of active cerebral embolization in COVID‐19. J Stroke Cerebrovasc Dis 2021;30(3).
    1. HealthMeasures . PROMIS® Score Cut Points. Northwestern University; 2020; Available from: .
    1. Islam MF, Cotler J, Jason LA. Post‐viral fatigue and COVID‐19: lessons from past epidemics. Fatigue 2020;8(2):61–69.
    1. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS‐CoV‐2 infection is common and independent of severity of initial infection. PLoS One 2020;15(11):e0240784.
    1. Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160(2):221–236.
    1. Norrie J, Heitger M, Leathem J, et al. Mild traumatic brain injury and fatigue: a prospective longitudinal study. Brain Inj 2010;24(13–14):1528–1538.
    1. Marshall M. The lasting misery of coronavirus long‐haulers. Nature 2020;585:339–341.
    1. Yong E. COVID‐19 can last for several months. The Atlantic 2020.
    1. Garner P. Paul Garner: For 7 weeks I have been through a roller coaster of ill health, extreme emotions, and utter exhaustion. BMJ Opinion: BMJ Publishing Group Limited, 2020.
    1. Rubin R. As their numbers grow, COVID‐19 “Long Haulers” stump experts. JAMA 2020;324(14):1381–1383.
    1. Asbring P, Närvänen AL. Women's experiences of stigma in relation to chronic fatigue syndrome and fibromyalgia. Qual Health Res 2002;12(2):148–160.
    1. Bleck TP, Nowinski CJ, Gershon R, Koroshetz WJ. What is the NIH Toolbox, and what will it mean to neurology? Neurology 2013;80(10):874–875.
    1. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in Adults at 6 Months After COVID‐19 Infection. JAMA Netw Open 2021;4(2):e210830.
    1. Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 1983;14(4):403–418.
    1. COVID Symptom Study . One in 20 people likely to suffer from ‘Long COVID’, but who are they?. London: Kings College London; 2020; Available from: .
    1. Petersen MS, Kristiansen MF, Hanusson KD, et al. Long COVID in the Faroe Islands ‐ a longitudinal study among non‐hospitalized patients. Clin Infect Dis 2020;1–19.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir