Journal of the Neurological Sciences 443 (2022) 120487

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Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Life stressors significantly impact long-term outcomes and post-acute

symptoms 12-months after COVID-19 hospitalization
Jennifer A. Frontera a, *, Sakinah Sabadia a, Dixon Yang f, Adam de Havenon g, Shadi Yaghi h,
Ariane Lewis a, Aaron S. Lord a, Kara Melmed a, Sujata Thawani a, Laura J. Balcer a, b, c,
Thomas Wisniewski a, d, e, Steven L. Galetta a, c, the NYU Neurology COVID-19 Study Team
a
Departments of Neurology, New York University Grossman School of Medicine, New York, NY, USA
b
Population Health, New York University Grossman School of Medicine, New York, NY, USA
c
Ophthalmology, New York University Grossman School of Medicine, New York, NY, USA
d
Pathology, New York University Grossman School of Medicine, New York, NY, USA
e
Psychiatry, New York University Grossman School of Medicine, New York, NY, USA
f
Department of Neurology, New York Presbyterian, Columbia Medical Center, New York, NY, USA
g
Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
h
Department of Neurology, Brown University School of Medicine, Providence, RI, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Limited data exists evaluating predictors of long-term outcomes after hospitalization for COVID-19.
Predictors Methods: We conducted a prospective, longitudinal cohort study of patients hospitalized for COVID-19. The
Outcomes following outcomes were collected at 6 and 12-months post-diagnosis: disability using the modified Rankin Scale
Disability
(mRS), activities of daily living assessed with the Barthel Index, cognition assessed with the telephone Montreal
Cognition
Quality of life
Cognitive Assessment (t-MoCA), Neuro-QoL batteries for anxiety, depression, fatigue and sleep, and post-acute
Anxiety symptoms of COVID-19. Predictors of these outcomes, including demographics, pre-COVID-19 comorbidities,
Depression index COVID-19 hospitalization metrics, and life stressors, were evaluated using multivariable logistic
Post-acute sequelae of COVID regression.
Post-COVID syndrome Results: Of 790 COVID-19 patients who survived hospitalization, 451(57%) completed 6-month (N = 383) and/or
Long-hauler 12-month (N = 242) follow-up, and 77/451 (17%) died between discharge and 12-month follow-up. Significant
Long-COVID life stressors were reported in 121/239 (51%) at 12-months. In multivariable analyses, life stressors including
COVID-19
financial insecurity, food insecurity, death of a close contact and new disability were the strongest independent
SARS-CoV-2
predictors of worse mRS, Barthel Index, depression, fatigue, and sleep scores, and prolonged symptoms, with
adjusted odds ratios ranging from 2.5 to 20.8. Other predictors of poor outcome included older age (associated
with worse mRS, Barthel, t-MoCA, depression scores), baseline disability (associated with worse mRS, fatigue,
Barthel scores), female sex (associated with worse Barthel, anxiety scores) and index COVID-19 severity (asso­
ciated with worse Barthel index, prolonged symptoms).
Conclusions: Life stressors contribute substantially to worse functional, cognitive and neuropsychiatric outcomes
12-months after COVID-19 hospitalization. Other predictors of poor outcome include older age, female sex,
baseline disability and severity of index COVID-19.

1. Introduction batteries at 12-months [1]. Others have reported post-acute symptoms

Long term sequelae of COVID-19 are increasingly recognized as
major public health issues. We have previously reported that 87% of
patients who survived COVID-19 hospitalization had abnormal scores on
functional, cognitive, quality of life and/or activities of daily living
of COVID-19 in 33–90% of hospitalized patients [2–6]. Among non-
hospitalized cohorts, post-acute sequelae have been estimated to occur
in 25–69% [3,7–9]. This variable prevalence can be explained by dif­
ferences in study design, ascertainment, symptoms assessed, timing of
assessment and whether objective metrics (in addition to subjective

* Correspondence author at: NYU Department of Neurology, 150 55th St., Brooklyn, NY 11220, USA.
E-mail address: jennifer.frontera@nyulangone.org (J.A. Frontera).

https://doi.org/10.1016/j.jns.2022.120487
Received 20 July 2022; Received in revised form 12 October 2022; Accepted 1 November 2022
Available online 5 November 2022
0022-510X/© 2022 Elsevier B.V. All rights reserved.
J.A. Frontera et al.
symptom reporting) were evaluated [10]. Despite a plethora of litera­
ture reporting prevalence rates of post-COVID-19 symptoms, there is a
paucity of data reporting predictors of long-term functional, cognitive
and quality of life quantitative outcomes.
In this prospective study, we evaluated the impact of four categories
of predictors on 6- and 12-month outcome metrics including: de­
mographics, pre-COVID-19 comorbidities, index COVID-19 hospitali­
zation metrics, and life stressors within the month prior to interview.
Outcome measures included not only long-term COVID-19 symptoms,
but functional outcomes (modified Ranking Score), activities of daily
living (Barthel Index), cognitive outcomes (telephone Montreal Cogni­
tive Assessment [t-MoCA]) and NIH/PROMIS Neurological Quality Of
Life (NeuroQoL) self-reported measures of anxiety, depression, fatigue
and sleep.
2. Methods
2.1. Study design and patient cohort
We conducted a prospective, observational study of consecutive
COVID-19 patients hospitalized at four New York City area hospitals
within the same hospital system between March 10, 2020 and May 20,
2020. Follow-up interviews were performed at 6 and 12 months after
initial SARS-CoV-2 diagnosis. Detailed enrollment, methodology and
outcome measures have been previously reported [1,11–13]. Inclusion
criteria were: RT-PCR positive SARS-CoV-2 infection, age ≥ 18 years,
hospital admission, and consent to participate in a follow-up interview.
Exclusion criteria were: evaluation in an outpatient or emergency
department setting only.
2.2. Standard protocol approvals and patient consents
This study was approved by the NYU Grossman School of Medicine
Institutional Review Board. All patients or their surrogates provided
informed consent for participation.
2.3. Predictor variables
Demographic data, past medical/neurological history, new neuro­
logical events or other complications during hospitalization, and
COVID-19 specific medications administered during the acute phase of
illness were recorded. Severity of illness during hospitalization was
graded based on the Sequential Organ Failure Assessment (SOFA) score
[14] and requirement for intubation. Pre-COVID baseline functional
status was assessed with modified Rankin Scale (mRS) [15] scores as
reported by patients and/or their surrogate. Subjects were also asked to
indicate if they had experienced any of 15 life stressors [7] within the
month prior to the 12-month interview (Supplemental Table 1).
2.4. Study outcomes
Longitudinal follow-up assessments were conducted by telephone
interview among patients or their surrogates who consented to partici­
pate. Contact was attempted at 6-months (±1 month) and 12-months
(±2 months) from the onset of COVID-19 symptoms. Three attempts
at contact were required before patients/surrogates were coded as
“unreachable”. Patients who were “unreachable” at 6-months, were also
contacted at 12-months for participation. Functional status and
disability were assessed using the modified Rankin Scale (mRS; 0 = no
symptoms, 6 = dead, dichotomized as 0–3 versus 4–6) [15], activities of
daily living were evaluated with the Barthel Index of activities of daily
living (0 = completely dependent, 100 = independent for all activities,
dichotomized as completely independent with a score of 100 versus
〈100) [16], cognition was assessed with the telephone-MoCA (t-MoCA;
22 = perfect score; ≤18 = abnormal cognition) [17], and Quality of Life
in Neurological Disorders [18] (NeuroQoL) short form self-reported
2
Journal of the Neurological Sciences 443 (2022) 120487
health measures of anxiety, depression, fatigue and sleep were
collected. NeuroQoL raw scores were converted into T-scores with a
mean of 50 and standard deviation of 10 in a reference population (U.S.
general population or clinical sample) [19]. Higher T-scores indicate
worse self-reported health for the anxiety, depression, fatigue and sleep
metrics. NeuroQoL scores were dichotomized at the mean + 1 standard
deviation (T-scores ≥60 versus <60). Patients with fewer than 13 years
of education received an additional point when scoring the t-MoCA [20].
With the exception of the t- MoCA, all of the above batteries have been
validated for surrogate completion, and surrogates were asked to com­
plete these metrics for patients who were unable to do so.
The outcome of post-acute symptoms of COVID-19 was defined ac­
cording to Centers for Disease Control and Prevention (CDC) criteria as
new or persistent symptoms occurring ≥4 weeks after SARS-CoV-2
infection [21]. Symptoms were categorized following the World
Health Organization (WHO) clinical case report form for post-acute
COVID-19 symptoms [22] (Supplemental Table 2). Post-acute symp­
tom data was only collected at the 12-month follow-up interview.
2.5. Statistical analyses
Demographic variables, past medical/neurological history, life
stressors, and hospital clinical variables were evaluated as predictors of
dichotomized 6- and 12-month outcomes using univariate logistic
regression analyses. Data on life stressors and post-COVID-19 symptoms
were only available from the 12-month interview. Multivariable back­
ward, stepwise logistic regression models were constructed utilizing
univariate variables with P values <0.05. Discharge metrics including
length of stay, and discharge disposition (home, skilled nursing facility,
acute rehabilitation facility) were not entered into multivariable models
due to collinearity. Receiver operating characteristic curves were used
to determine the area under the curve (AUC) for each multivariable
model.
For patients who died, a mRS score of 6 was assigned, but no other
outcome variables were scored or imputed. Incomplete or partial re­
sponses to a given metric were excluded from analysis. All analyses were
conducted using IBM SPSS Statistics for Mac version 25 (IBM Corp.,
Armonk, NY).
3. Results
Follow-up interviews were attempted in 790 and 590 patients at 6
and 12 months post COVID-19 hospitalization, respectively [1]. A total
of 451 patients completed follow-up either time point and were included
in analyses. Fewer patients were eligible for the 12-month call due to
language barrier, missing or defunct contact information or indication at
the 6-month call that the respondent did not wish to be re-contacted.
Interviews were completed in 382/790 (48%) patients at 6 months,
242/590 (41%) patients at 12-months and 174 patients completed
follow-up at both time points. There were no differences in sex, race,
education level, pre-COVID-19 history of psychiatric disease or de­
mentia, pre-COVID-19 mRS scores, index COVID-19 severity, or rates of
neurological events during index hospitalization between those who
completed the 6-month versus 12-month follow-up interview. However,
patients who completed only 6-month follow-up (and were then lost to
follow-up) were significantly older than those who completed 12-month
follow-up (median age 69 years versus 65 years, P < 0.001) and had
slightly higher body mass index (Table 1). Among those who completed
12-month follow-up, the most common neurological post-COVID-19
symptoms reported were headache (22%), cognitive abnormalities
(20%), anxiety (12%), depression (11%,), sleep disturbance (11%) and
fatigue (10%, Supplemental Table 2) [23].
The mean values for outcome metrics and percent of patients who
had poor or abnormal test results at 6- and 12-months post COVID-19
are shown in Table 2. As previously reported [1,12], 90% of patients
at 6 months and 87% of patients at 12 months had abnormalities on at
J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 1 and 12-months and higher anxiety scores at 12-months. Lower educa­
Demographics of the study population at 6 and 12 months post index SARS-CoV- tion levels were associated with worse cognitive scores at 6- and 12-
2 hospitalization. months [13], as well as worse depression and fatigue NeuroQoL scores
6 months 12 months at 12-months. Pre-COVID disability (as measured by baseline mRS) was
N = 382 N = 242 a strong predictor of worse mRS and Barthel scores at both time points,
Demographics and was associated with worse NeuroQoL fatigue scores at 12-months. A
Age (years), median (IQR) 69 (57–78)* 65 (53–73)* pre-COVID history of dementia/cognitive disorder or psychiatric disease
Sex (male), N (%) 248 (65%) 155 (64%) were associated with worse mRS and Barthel scores. A history of de­
Race (white), N (%) 213/309 128/189
mentia/cognitive disorder was also associated with worse t-MoCA scores
(69%) (68%)
Education level > 12 years, N (%) 227/303 164/214 and higher anxiety NeuroQoL scores. The presence of post-acute COVID-
(75%) (77%) 19 symptoms was not associated with any demographic or comorbidity
Comorbidities predictors.
Pre-COVID disability (mRS score), median (IQR) 0 (0–1) 0 (0–1) Tables 4a and 4b delineate index COVID-19 hospitalization metrics
BMI, median (IQR) 27 (24–32)* 28 (25–33)*
Hypertension, N (%) 164 (43%) 98 (41%)
and their association with 6- and 12-month outcomes. Neurological
Diabetes, N (%) 109 (29%) 60 (25%) complications including toxic metabolic encephalopathy and hypoxic
COPD/Asthma, N (%) 38 (10%) 24 (10%) ischemic brain injury were strong predictors of worse mRS and Barthel
Headache Disorder, N (%) 9 (2%) 9 (4%) Index at 6 and 12 months and worse depression and fatigue scores at 12
Dementia, N (%) 40 (10%) 20 (8%)
months, while mechanical ventilation and worse SOFA scores (markers
Psychiatric history, N (%) 47 (12%) 28 (12%)
Index COVID-19 Hospitalization of severe COVID) were only predictive of worse Barthel Index at 6-
Neuro complication, N (%) 193 (50%) 113 (47%) months, and with much lower odds ratios. There was no consistent ef­
Mechanically ventilated, N (%) 130 (34%) 81 (34%) fect of COVID-19 related pharmaceuticals on outcome metrics, however,
Worst Sequential Organ Failure Assessment (SOFA) 4 (3–7) 4 (3–7) nitazoxanide (used in N = 14 patients) was associated with worse fa­
score, median (IQR)
tigue, depression and anxiety scores at 6 months. There were signifi­
mRS = modified Rankin Score; IQR = interquartile range, * indicates P < 0.05. cantly worse Barthel Index scores in univariate analysis with
corticosteroid use, but this medication was preferentially utilized in the
most severely ill patients, suggesting a bias by indication. Post-acute
Table 2
COVID-19 symptoms at 12-months were more common in those with
Number, mean (standard deviation), and percent of patients with abnormal or
severe COVID-19 illness, as measured by the requirement for mechanical
poor outcome metrics at 6- and 12-months post COVID-19.
ventilation and worse SOFA scores. Worse mRS and Barthel scores were
Metric Mean, SD N (%) abnormal or poor associated with discharge to a nursing home, but cognitive and Neuro­
6 months 12 6 months 12 months QoL scores did not vary significantly with discharge disposition. We
months evaluated inflammatory markers collected during hospitalization
Modified Rankin Scale, N = 381 N = 236 189/381 79/236 including blood IL-6 (N = 300), D-dimer (N = 398), C-reactive peptide
(poor = 4–6) 3 (2) 2 (2) (50%) (34%) (N = 420) and ferritin levels (N = 414), but did not find any correlations
Barthel Index, N = 304 N = 236 134/304 86/236 with 6- or 12-month outcome metrics.
(abnormal <100) 85.7 (25) 87.2 (24) (44%) (36%)
T-MoCA, N = 215 N = 170 106/215 69/170
Next, we evaluated the impact of life stressors (Table 5 and Sup­
(abnormal ≤18) 17.0 17.5 (3.8) (49%) (41%) plemental Table 1) on 12- month outcomes. Over 50% (121/239) of
(3.5) subjects reported experiencing at least one life stressor within the month
NeuroQoL anxiety, N = 280 N = 225 21/280 (8%) 16/225 prior to the 12-month follow-up interview (median 1 stressor, range 0–7
(abnormal T-score ≥ 48.4 (9) 46.8 (9) (7%)
stressors). The most common stressors were: new personal illness within
60)
NeuroQoL depression, N = 279 N = 225 8/279 (3%) 9/225 (4%) the month prior to the 12-month interview (23%), financial insecurity
(abnormal T-score ≥ 44.6 (8) 44.3 (8) (17%), social isolation (13%) and death or illness of a close contact. The
60) presence and number of stressors were strongly related to worse anxiety,
NeuroQoL fatigue, N = 272 N = 223 14/272 (5%) 20/223 depression, fatigue and sleep NeuroQoL scores and PASC. Social isola­
(abnormal T-score ≥ 45.7 (10) 45.6 (11) (9%)
60)
tion, financial insecurity, unemployment, food insecurity, personal
NeuroQoL sleep, N = 278 N = 221 27/278 22/221 illness (within the month prior to 12-month interview), new disability
(abnormal T-score ≥ 46.3 (10) 46.1 (11) (10%) (10%) and death of a close contact were all significantly associated with worse
60) NeuroQoL measures, while personal illness, new disability and increased
t-MOCA = telephone Montreal Cognitive Assessment; NeuroQoL = neurological caregiver responsibilities were the only life stressors associated with
quality of life. mRS and Barthel scores. We did not identify associations with any of the
measured stressors and cognitive scores.
least one of the metrics assessed (e.g. mRS > 0, Barthel Index<100, t- Results of multivariable analyses for each outcome at 6 and 12
MoCa ≤18, or a NeuroQoL T score ≥ 60), with abnormalities in t-MoCA months, including variables entered into each model, are shown in
and mRS being most prevalent. There was a small but significant cor­ Table 6 and Fig. 1. Older age and baseline disability (pre-COVID-19 mRS
relation between abnormal 12-month NeuroQoL anxiety scores≥60 and scores) were significantly predictive of worse mRS and Barthel Index
post-acute symptoms of COVID-19 (Pearson correlation coefficient scores at both 6 and 12 months. Older age was also associated with
0.191, P = 0.005). There were no other significant correlations of post- worse cognitive scores and worse NeuroQoL depression scores at 12-
acute symptoms with other 6- or 12-months outcomes (mRS 4–6, Barthel months. Neurological events during index hospitalization, specifically
Index <100, t-MoCA scores<18, or depression, fatigue or sleep T- hypoxic ischemic encephalopathy, were independently associated with
scores≥60). worse mRS scores at both timepoints. Severity of index COVID-19 illness
Tables 3a and 3b demonstrate univariate demographic and pre- was only associated with 6-month Barthel Index (SOFA scores) and post-
COVID comorbidity predictors of 6- and 12-month outcomes. Older acute COVID-19 symptoms at 12 months (mechanical ventilation).
age was consistently associated with worse mRS, Barthel Index and t- COVID-19 severity was not associated with mRS, t-MoCA or NeuroQoL
MoCA scores at both time points, as well as NeuroQoL depression scores anxiety, depression, fatigue or sleep scores at any time point. The
at 12-months. Female sex was associated with worse Barthel scores at 6- presence of a variety of life stressors were independently associated with
a number of 12-month outcomes including worse mRS, Barthel,

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J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 3a
Association of demographic and comorbidity variables and 6- and 12-month mRS, Barthel Index, T-MoCA and post-acute COVID-19 symptoms. Univariate logistic
regression odds ratios, 95% confidence intervals (CI) and P values are shown.
mRS 4–6 mRS 4–6 Barthel <100 Barthel <100 T-MoCA (≤18) 6- T-MoCA (≤18) 12-month Post-acute
6 months 12 months 6 months 12 months months 12-months COVID-19 symptoms N
N = 381 N = 236 N = 304 N = 236 N = 215 N = 170 = 242

Demographics
Age 1.04 (1.02–1.05) 1.04 (1.02–1.06) 1.04 (1.02–1.05) 1.05 (1.03–1.08) 1.03 (1.01–1.05) 1.03 (1.01–1.06) 1.00 (0.98–1.02) P =
P < 0.001 P < 0.001 P < 0.001 P < 0.001 P ¼ 0.009 P ¼ 0.007 0.913
Sex (male) 0.74 (0.49–1.13) 0.59 (0.34–1.03) 0.53 (0.33–0.85) 0.43 (0.25–0.74) 0.88 (0.51–1.55) P 0.95 (0.50–1.81) 0.73 (0.43–1.27) P =
P = 0.162 P = 0.063 P ¼ 0.009 P ¼ 0.003 = 0.662 P = 0.880 0.265
Race (white) 0.94 (0.58–1.53) 0.92 (0.48–1.75) 0.91 (0.53–1.55) 0.87 (0.47–1.63) 0.44 (0.23–0.84) 0.63 (0.30–1.31) 0.54 (0.28–1.04) P =
P = 0.812 P = 0.790 P = 0.718 P = 0.671 P ¼ 0.013 P = 0.217 0.066
Education level > 0.57 (0.33–0.96) 0.68 (0.35–1.32) 0.76 (0.45–1.29) 0.72 (0.38–1.39) 0.39 (0.19–0.79) 0.45 (0.21–1.00) 1.80 (0.94–3.46) P =
12 years P ¼ 0.035 P = 0.253 P = 0.315 P = 0.331 P ¼ 0.009 P = 0.050 0.078
Comorbidities
Pre-COVID 2.06 (1.66–2.55) 2.07 (1.63–2.64) 1.95 (1.56–2.45) 2.36 (1.78–3.13) 1.27 (0.99–1.64) P 1.13 (0.84–1.53) 0.84 (0.69–1.03) P =
disability (mRS) P < 0.001 P < 0.001 P < 0.001 P < 0.001 = 0.063 P = 0.427 0.091
BMI 0.97 (0.94–1.00) 1.01 (0.97–1.05) 0.99 (0.96–1.02) 1.02 (0.98–1.07) 1.02 (0.98–1.06) P 1.00 (0.95–1.04) 1.04 (0.99–1.08) P =
P = 0.058 P = 0.770 P = 0.521 P = 0.299 = 0.443 P = 0.855 0.106
Hypertension 1.50 (1.00–2.25) 1.28 (0.74–2.22) 1.51 (0.95–2.41) 1.62 (0.95–2.78) 0.74 (0.43–1.28) P 0.89 (0.48–1.65) 0.73 (0.43–1.24) P =
P = 0.053 P = 0.377 P = 0.079 P = 0.079 = 0.276 P = 0.699 0.244
Diabetes 1.48 (0.95–2.32) 1.15 (0.62–2.14) 1.45 (0.88–2.41) 1.69 (0.93–3.08) 1.20 (0.65–2.22) P 1.24 (0.62–2.47) 1.12 (0.62–2.04) P =
P = 0.086 P = 0.651 P = 0.149 P = 0.087 = 0.556 P = 0.539 0.707
COPD/Asthma 1.23 (0.62–2.42) 1.01 (0.41–2.47) 1.54 (0.70–3.35) 1.55 (0.66–3.62) 1.03 (0.43–2.49) P 0.79 (0.41–3.26) 1.27 (0.54–2.99) P =
P = 0.558 P = 0.988 P = 0.282 P = 0.316 = 0.945 P = 0.787 0.584
Headache Disorder 1.28 (0.34–4.86) – 1.29 (0.32–5.24) 0.21 (0.03–1.70) 0.61 (0.14–2.60) P 0.87 (0.20–3.78) 1.81 (0.44–7.42) P =
P = 0.713 P = 0.725 P = 0.143 = 0.500 P = 0.856 0.410
Dementia 4.02 (1.86–8.69) 3.39 (1.32–8.67) 2.97 (1.24–7.11) 2.69 (0.98–7.34) 4.09 (1.11–15.11) 1.90 (0.49–7.32) 0.78 (0.31–2.00) P =
P < 0.001 P ¼ 0.011 P ¼ 0.015 P = 0.054 P ¼ 0.035 P = 0.354 0.606
Psychiatric history 1.94 (1.03–3.66) 2.22 (1.00–4.93) 2.23 (1.07–4.64) 1.72 (0.77–3.85) 0.91 (0.35–2.34) P 0.96 (0.33–2.84) 0.58 (0.25–1.30) P =
P ¼ 0.040 P = 0.050 P ¼ 0.032 P = 0.189 = 0.843 P = 0.945 0.184

Bold indicates P < 0.05; mRS = modified Rankin Scale, t-MOCA = telephone Montreal Cognitive Assessment; BMI = body mass index; COPD = chronic obstructive
pulmonary disease.

depression, fatigue, and sleep scores, as well as post-acute COVID-19
symptoms. The AUCs for each model ranged from 0.664 to 0.903.
Generally, 12-month models that included life stressors yielded more
robust AUCs, however, models predicting cognitive outcomes and post-
acute symptoms performed less well than models for other outcomes.
4. Discussion
In this prospective, longitudinal cohort study we identified inde­
pendent predictors of 6- and 12-month functional (mRS, Barthel Index),
cognitive (t-MoCA), quality of life (NeuroQoL depression, anxiety, fa­
tigue and sleep) outcomes and post-acute COVID-19 symptoms
following COVID-19 hospitalization. While predictors of disability
(mRS, Barthel) were similar and largely consisted of age, baseline
functional status, neurological complications during hospitalization and
markers of higher severity of COVID-19 illness, life stressors, which were
present in >50% of subjects, played a larger role in predicting NeuroQoL
measures of depression, fatigue, sleep and post-acute symptoms of
COVID-19. Indeed, the adjusted odds ratios for life stressors (including
financial insecurity, food insecurity, death of a loved one and new
disability) for predicting a variety of 12-month outcomes ranged from
2.5 to 20.8. While there are several reports of predictors of short term
outcomes during hospitalization or within the first months following
COVID-19 (e.g. mortality or discharge disposition) [24–26], as well as
reports describing qualitative subjective post-acute COVID symptoms
[2,8,9,27–39], this study is distinct in that it prospectively explores the
impact of life stressors along with demographic, comorbid, and neuro­
logical events as predictors of quantitative long-term cognitive, func­
tional, quality of life and post-acute symptoms outcomes in a large
population.
Life stressors were significantly associated with several 12-month
outcomes, including worse mRS scores, activities of daily living, Neu­
roQoL depression, fatigue and sleep measures, and post-acute COVID-19
symptoms. The incorporation of pandemic-related stressors and related
social determinants of health into predictive models is critical because
these may represent areas of potential intervention. In a prior study of
risk factors for post-acute COVID-19 symptoms among U.S. community
dwellers with and without mild COVID-19 (not requiring hospitaliza­
tion) conducted in February 2021, we identified multiple stressors
(present within the month prior to interview) that were associated with
the development of post-acute symptoms, most notably financial inse­
curity and unemployment [7]. In that study, multivariable models pre­
dicting NeuroQoL measures of cognition, anxiety, depression, fatigue
and sleep, demonstrated that several stressors were stronger predictors
of abnormalities on quality of life testing than was SARS-CoV-2 infection
itself. These data suggest an interplay of environmental and pandemic-
related factors that may impact functional and neuropsychiatric
outcomes.
We found that older age was a consistent and prominent predictor of
worse functional status (mRS and Barthel scores), cognitive abnormal­
ities and depression. While these findings may appear intuitive, some
have identified a paradoxical relationship, wherein older patients hos­
pitalized with COVID-19 were more likely to make greater improve­
ments in functional status and return to pre-hospitalization status at 18
weeks compared to patients <45 years old [33]. Female subjects and
those who considered themselves “very fit” pre-COVID-19 were also less
likely to recover to pre-hospitalization functional status33. These data
may reflect a ceiling effect in frailty assessments that have limited ability
to detect nuanced differences in functional status. Others have found
that post-acute COVID-19 symptoms were more prevalent in older in­
dividuals [27,34]. However, the types of post-acute COVID-19 symp­
toms may vary by age. For example, one study found that older
individuals were more likely to have “any” post-acute COVID-19 feature
(notably cognitive and respiratory symptoms), while younger patients
more often reported headaches, anxiety/depression and abdominal
symptoms [28]. We also found that poor baseline functional status (pre-
COVID mRS score) was a strong, independent predictor of 6- and 12-
month mRS and Barthel Index scores and fatigue. Indeed, some studies
have found that baseline frailty or disability scores are more closely
associated with poor outcomes than age [40].

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J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 3b
Association of Demographic and Comorbidity variables and 6- and 12-month patient-reported NeuroQoL outcomes. Univariate logistic regression odds ratios, 95%
confidence intervals (CI) and P values shown.
Anxiety T-score Anxiety T-score Depression T- Depression T- Fatigue T- Fatigue T-score Sleep T-score ≥ Sleep T-score
≥ 60 at 6- ≥ 60 at 12- score ≥ 60 at 6- score ≥ 60 at 12- score ≥ 60 at 6- ≥ 60 at 12- 60 at 6-months ≥ 60 at 12-
months months months months months months N = 278 months
N = 280 N = 225 N = 279 N = 225 N = 272 N = 223 N = 221

Demographics
Age 1.03 1.00 1.05 1.10 0.99 1.02 0.99 0.99
(1.00–1.06) P = (0.96–1.03) P = (0.99–1.11) P = (1.03–1.17) P ¼ (0.96–1.03) P (0.99–1.06) P (0.97–1.02) P = (0.96–1.02) P
0.093 0.818 0.112 0.006 = 0.651 = 0.176 0.468 = 0.367
Sex (male) 0.72 0.17 0.31 0.28 0.40 0.54 0.92 0.56
(0.29–1.78) P = (0.05–0.55) P ¼ (0.07–1.34) P = (0.07–1.14) P = (0.14–1.19) P (0.21–1.35) P (0.40–2.09) P = (0.23–1.34) P
0.479 0.003 0.118 0.075 = 0.101 = 0.188 0.838 = 0.192
Race (white) 1.09 0.67 2.78 4.37 1.23 1.38 0.51 0.93
(0.37–3.22) P = (0.22–2.02) P = (0.33–23.53) P (0.53–35.79) P (0.32–4.79) P (0.47–4.07) P (0.21–1.25) P = (0.32–2.64) P
0.875 0.473 = 0.348 = 0.169 = 0.765 = 0.563 0.140 = 0.885
Education level 0.50 0.59 0.96 0.22 0.78 0.36 0.59 0.51
> 12 years (0.20–1.25) P = (0.17–2.05) P = (0.19–4.85) P = (0.06–0.87) P ¼ (0.24–2.58) P (0.13–0.95) P (0.25–1.39) P = (0.19–1.36) P
0.137 0.406 0.957 0.031 = 0.687 ¼ 0.039 0.231 = 0.178
Comorbidities
Pre-COVID 1.31 0.99 1.33 1.01 1.40 1.44 1.23 1.11
disability (0.97–1.76) P = (0.63–1.55) P = (0.84–2.12) P = (0.61–1.67) P = (0.98–1.99) P (1.07–1.93) P (0.93–1.63) P = (0.80–1.53) P
(mRS) 0.078 0.959 0.221 0.983 = 0.064 ¼ 0.017 0.150 = 0.547
BMI 0.97 1.03 0.95 0.94 0.97 0.96 0.97 1.04
(0.90–1.04) P = (0.96–1.11) P = (0.85–1.07) P = (0.81–1.09) P = (0.89–1.06) P (0.88–1.05) P (0.91–1.04) P = (0.98–1.11) P
0.324 0.450 0.419 0.396 = 0.516 = 0.370 0.361 = 0.185
Hypertension 1.39 1.18 1.50 0.74 2.09 1.23 0.50 (0.20 = 1.52
(0.57–3.39) P = (0.42–3.29) P = (0.37–6.13) P = (0.18–3.04) P = (0.71–6.21) P (0.49–3.11) P 1.23) P = 0.129 (0.63–3.67) P
0.469 0.751 0.572 0.678 = 0.183 = 0.658 = 0.353
Diabetes 0.86 0.68 0.92 – 0.71 0.75 0.80 0.90
(0.30–2.43) P = (0.19–2.48) P = (0.18–4.65) P = (0.19–2.64) P (0.24–2.33) P (0.31–2.06) P = (0.32–2.57) P
0.770 0.558 0.916 = 0.614 = 0.613 0.639 = 0.844
COPD/Asthma 1.63 0.57 1.34 2.65 0.68 1.62 0.72 2.24
(0.45–5.92) P = (0.07–4.50) P = (0.16–11.33) P (0.52–13.60) P (0.09–5.44) P (0.44–5.99) P (0.16–3.22) P = (0.68–7.32) P
0.462 0.591 = 0.788 = 0.242 = 0.719 = 0.474 0.667 = 0.184
Headache 1.79 – – – – – 1.34 1.14
Disorder (0.21–15.30) P (0.16–11.28) P (0.14–9.54) P
= 0.594 = 0.791 = 0.906
Dementia 1.32 7.46 1.79 1.56 0.91 2.38 0.97 2.09
(0.29–6.12) P = (2.23–24.95) P (0.21–15.24) P (0.18–13.29) P (0.11–7.33) P (0.62–9.12) P (0.21–4.42) P = (0.55–7.92) P
0.719 ¼ 0.001 = 0.596 = 0.683 = 0.931 = 0.205 0.971 = 0.280
Psychiatric 2.01 2.68 1.14 2.17 0.63 1.31 1.44 1.15
history (0.63–6.42) P = (0.80–9.01) P = (0.14–9.61) P = (0.43–11.04) P (0.08–4.99) P (0.36–4.80) P (0.46–4.47) P = (0.32–4.16) P
0.237 0.111 0.902 = 0.350 = 0.661 = 0.685 0.532 = 0.837

Bold indicates P < 0.05; mRS = modified Rankin Scale; NeuroQoL = neurological quality of life; BMI = body mass index; COPD = chronic obstructive pulmonary
disease.

We identified female sex as an independent predictor of both anxiety
and limitations in activities of daily living. Others have identified that
female sex may be a predictor of post-acute COVID-19 symptoms
[8,9,27,28,31–39,41]. In a survey of 999 community dwellers across the
U.S, female sex, along with younger age, racial/ethnic minority status,
baseline disability, fewer years of formal education, and/or a history of
psychiatric disease were significant predictors of post-acute COVID-19
symptoms [12,32]. Mechanisms of injury more common in women, such
as autoimmune disease, might explain some of these differences. Indeed,
women have higher basal levels of immunoglobulins and respond more
robustly to both infections and vaccines, with increased cytokine pro­
duction and T-cell response, compared to men [42–44]. Additionally,
baseline pre-COVID-19 prevalence rates of anxiety and depression are
nearly two-fold higher in women than men [45,46]. It is possible that
subclinical or undiagnosed mood disorders may have been unmasked in
the context of pandemic- or illness-related stressors.
We found that severity of index COVID-19 illness (SOFA scores or
intubation) was a predictor of limited activities of daily living and post-
acute COVID-19 symptoms. Indeed, many others have identified index
COVID-19 severity as a predictor of protracted COVID symptoms
[28,36,37,47–50]. Some studies have suggested that the severity of
acute respiratory failure, rather than the pathogen involved, predicts
neuropsychiatric sequelae. One study compared electronic medical re­
cords of patients hospitalized for COVID-19 or a severe acute respiratory
infection, to a reference population of hospitalized and non-hospitalized
patients without these conditions [51], and found significantly higher
rates of new onset anxiety, depression, bipolar disorder or psychotic
disorder compared to the reference population. However, rates of
neuropsychiatric sequelae were similar in COVID-19 and non-COVID-19
acute respiratory infection patients, suggesting that the prime driver of
long-term events is disease severity, and not the specific pathogen.
Conversely, other cohorts have found higher rates of post-acute
symptoms among patients with COVID-19 compared to seasonal influ­
enza, even after adjusting for severity of illness, suggesting that these
long-term sequelae may be unique to SARS-CoV-2 [47,48]. We did not
identify index COVID-19 severity as a predictor of NeuroQoL metrics
such as anxiety, depression, fatigue or sleep outcomes. Others have also
failed to find an association of severity of index illness (defined by ox­
ygen requirement or intubation status) when evaluating certain out­
comes of hospitalized patients [34]. Differing relationships of COVID-19
severity with sequelae may be explained by differences in comparator
groups, e.g. some studies evaluated hospitalized versus non-hospitalized
COVID-19 patients, whereas we compared mechanically ventilated
hospital patients to non-intubated hospitalized patients. Additionally,
these incongruities may simply reflect the fact that the sickest patients
died or were too impaired to participate in long-term outcome batteries.
Because we did not have a non-COVID-19 comparator group, we cannot
make any assertions regarding whether outcomes were driven by

5
J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 4a
Association of index COVID-19 hospitalization variables and 6 and 12 month mRS, Barthel, T-MoCA and PASC outcomes. Univariate logistic regression odds ratios,
95% confidence intervals (CI) and P values shown.
mRS 4–6 mRS 4–6 Barthel <100 Barthel <100 T-MoCA (≤18) T-MoCA (≤18) 12-month Post-acute
6 months 12 months 6 months 12 months 6-months 12-months COVID-19 symptoms
N = 381 N = 236 N = 304 N = 236 N = 215 N = 170 N = 242

Index COVID-19
Hospitalization
Neuro complication 1.61 1.31 (0.76–2.25) 1.71 1.21 (0.71–2.05) 1.32 (0.77–2.26) 0.92 0.74 (0.44–1.24) P =
(1.07–2.41) P P = 0.333 (1.08–2.70) P P = 0.490 P = 0.312 (0.50–1.70) P 0.251
¼ 0.021 ¼ 0.021 = 0.790
Hypoxic/ischemic brain 2.70 3.52 3.51 3.00 1.16 (0.45–2.97) 1.51 0.88 (0.34–2.29) P =
injury (1.37–5.34) P (1.31–9.47) P (1.56–7.92) (1.12–8.05) P P = 0.761 (0.47–4.89) P 0.788
¼ 0.004 ¼ 0.013 P ¼ 0.002 ¼ 0.029 = 0.493
Toxic-Metabolic 2.02 2.73 2.03 2.39 1.70 (0.88–3.28) 1.72 1.01 (0.53–1.92) P =
Encephalopathy (1.28–3.19) P (1.41–5.27) P (1.20–3.43) P (1.25–4.56) P P = 0.113 (0.73–4.04) P 0.982
¼ 0.002 ¼ 0.003 ¼ 0.008 ¼ 0.009 = 0.212
Mechanically ventilated 1.24 (0.81–1.89) 1.10 (0.62–1.94) 1.62 1.10 (0.63–1.93) 0.75 (0.43–1.32) 0.90 3.63 (2.01–6.58) P <
P = 0.330 P = 0.745 (1.01–2.61) P P = 0.728 P = 0.318 (0.47–1.72) P 0.001
¼ 0.048 = 0.756
Worst Sequential Organ 1.03 (0.98–1.08) 1.03 (0.96–1.10) 1.07 1.02 (0.96–1.09) 0.98 (0.92–1.05) 1.03 1.10 (1.03–1.18) P ¼
Failure Assessment (SOFA) P = 0.188 P = 0.410 (1.01–1.13) P P = 0.518 P = 0.570 (0.96–1.11) P 0.006
score ¼ 0.030 = 0.373
Lowest % oxygen saturation 1.00 (0.99–1.01) 1.00 (0.98–1.02) 1.00 (0.99–1.01) 1.01 (0.99–1.02) 1.00 (0.98–1.01) 0.99 0.98 (0.96–1.00) P ¼
P = 0.940 P = 0.778 P = 0.983 P = 0.495 P = 0.585 (0.97–1.01) P 0.035
= 0.408
Lowest mean arterial blood 1.00 (0.99–1.01) 1.01 (0.99–1.02) 0.99 (0.97–1.00) 1.00 (0.98–1.02) 1.00 (0.98–1.02) 0.99 0.99 (0.97–1.01) P =
pressure (mmHg) P = 0.694 P = 0.580 P = 0.102 P = 0.976 P = 0.953 (0.97–1.01) P 0.150
= 0.225
Acute renal failure 1.60 (0.93–2.74) 1.50 (0.71–3.16) 1.48 (0.79–2.78) 1.55 (0.74–3.26) 1.11 (0.52–2.39) 1.28 1.83 (0.84–4.00) P =
P = 0.087 P = 0.287 P = 0.221 P = 0.248 P = 0.781 (0.54–3.06) P 0.128
= 0.573
Medications during Index
Hospitalization
Tocilizumab/ clazakizumab 0.70 (0.42–1.17) 0.78 (0.41–1.48) 0.84 (0.48–1.46) 0.68 (0.36–1.29) 0.47 1.42 2.81 (1.46–5.38) P ¼
P = 0.176 P = 0.440 P = 0.531 P = 0.235 (0.25–0.90) P (0.72–2.81) P 0.002
¼ 0.023 = 0.308
Corticosteroids 1.51 (0.95–2.39) 1.44 (0.74–2.84) 2.08 1.78 (0.91–3.47) 0.99 (0.55–1.80) 1.15 2.35 (1.17–4.72) P ¼
P = 0.080 P = 0.286 (1.25–3.48) P P = 0.091 P = 0.982 (0.54–2.44) P 0.016
¼ 0.005 = 0.721
Remdesivir – – – – – – –
Hydroxychloroquine 0.75 (0.48–1.17) 0.82 (0.41–1.67) 1.01 (0.61–1.68) 0.93 (0.46–1.89) 0.62 (0.33–1.15) 0.69 2.59 (1.27–5.28) P ¼
P = 0.207 P = 0.591 P = 0.970 P = 0.847 P = 0.128 (0.30–1.56) P 0.009
= 0.367
Nitazoxanide 1.81 (0.52–6.28) 0.80 (0.15–4.22) 1.28 (0.31–5.20) 0.69 (0.13–3.64) 0.20 (0.02–1.73) 0.98 0.43 (0.08–2.41) P =
P = 0.351 P = 0.793 P = 0.733 P = 0.662 P = 0.143 (0.16–5.99) P 0.340
= 0.978
Zinc 0.69 (0.46–1.05) 0.79 (0.42–1.49) 0.82 (0.52–1.31) 1.18 (0.64–2.20) 0.84 (0.49–1.44) 1.12 1.93 (1.04–3.58) P ¼
P = 0.083 P = 0.461 P = 0.407 P = 0.594 P = 0.523 (0.55–2.29) P 0.037
= 0.748
Ascorbic acid 0.94 (0.60–1.49) 1.10 (0.62–1.97) 1.13 (0.69–1.85) 1.36 (0.77–2.39) 1.30 (0.72–2.35) 1.13 1.03 (0.59–1.82) P =
P = 0.798 P = 0.742 P = 0.634 P = 0.287 P = 0.379 (0.59–2.17) P 0.908
= 0.717
Lopinavir/ritonavir 0.77 (0.37–1.60) 0.70 (0.24–2.02) 0.78 (0.34–1.77) 0.93 (0.36–2.44) 1.42 (0.57–3.52) 2.21 1.09 (0.43–2.74) P =
P = 0.490 P = 0.509 P = 0.547 P = 0.889 P = 0.451 (0.84–5.80) P 0.854
= 0.109
Azithromycin 0.61 0.56 (0.29–1.08) 0.65 (0.41–1.05) 0.73 (0.38–1.41) 0.68 (0.38–1.21) 0.64 2.27 (1.17–4.38) P ¼
(0.40–0.93) P P = 0.085 P = 0.078 P = 0.344 P = 0.188 (0.29–1.39) P 0.015
¼ 0.022 = 0.257
Therapeutic anticoagulation 1.29 (0.85–1.97) 1.26 (0.72–2.22) 1.53 (0.95–2.46) 1.02 (0.58–1.78) 1.00 (0.57–1.76) 0.80 2.78 (1.56–4.95) P ¼
P = 0.236 P = 0.419 P = 0.078 P = 0.952 P = 0.995 (0.42–1.51) P 0.001
= 0.483
Discharge metrics
Length of stay 1.01 (1.00–1.02) 1.01 (1.00–1.03) 1.02 1.01 (1.00–1.03) 1.00 (0.98–1.01) 1.00 1.03 (1.01–1.04)
P = 0.102 P = 0.189 (1.01–1.03) P = 0.203 P = 0.549 (0.98–1.02) P ¼ 0.002
P ¼ 0.004 P = 0.974
Discharge home 0.18 0.23 0.17 0.28 0.86 (0.48–1.57) 0.77 0.89 (0.51–1.55)
(0.12–0.29) P < (0.13–0.42) P < (0.10–0.29) (0.16–0.50) P = 0.629 (0.39–1.50) P = 0.683
0.001 0.001 P < 0.001 P < 0.001 P = 0.438
Discharge SNF 4.92 3.69 5.18 4.67 2.06 (0.93–4.54) 1.80 0.94 (0.50–1.77)
(2.88–8.42) (1.91–7.11) (2.76–9.73) (2.38–9.18) P = 0.074 (0.80–4.04) P = 0.842
P < 0.001 P < 0.001 P < 0.001 P < 0.001 P = 0.154
Discharge rehab 1.71 (0.83–3.56) 1.86 (0.82–4.26) 2.50 1.08 (0.45–2.60) 0.47 (0.19–1.15) 0.36 1.21 (0.51–2.89)
P = 0.148 P = 0.140 (1.14–5.45) P = 0.858 P = 0.097 (0.12–1.15) P P = 0.667
P ¼ 0.022 = 0.084

Bold indicates P < 0.05; mRS = modified Rankin Scale, t-MOCA = telephone Montreal Cognitive Assessment; SNF = skilled nursing facility.

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J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 4b
Association of index COVID-19 hospitalization variables and 6- and 12-month patient-reported NeuroQoL outcomes. Univariate logistic regression odds ratios, 95%
confidence intervals (CI) and P values shown.
Anxiety T- Anxiety T- Depression T- Depression T- Fatigue T-score Fatigue T-score Sleep T-score Sleep T-score
score ≥ 60 at 6- score ≥ 60 at score ≥ 60 at 6- score ≥ 60 at ≥ 60 at 6- ≥ 60 at 12- ≥ 60 at 6- ≥ 60 at 12-
months 12-months months 12-months months months months months
N = 280 N = 225 N = 279 N = 225 N = 272 N = 223 N = 278 N = 221

Index COVID-19
Hospitalization
Neuro complication 0.51 1.51 1.10 4.21 1.06 3.77 1.46 0.77
(0.20–1.31) P (0.54–4.22) P (0.27–4.49) P = (0.86–20.75) P (0.36–3.12) P (1.32–10.76) P (0.66–3.23) P (0.32–1.89) P
= 0.162 = 0.428 0.894 = 0.077 = 0.910 ¼ 0.013 = 0.358 = 0.573
Hypoxic/ischemic 1.03 – 3.43 1.46 0.75 1.30 0.35 1.14
brain injury (0.23–4.70) P (0.66–17.94) P (0.17–12.40) P (0.09–5.99) P (0.28–6.10) P (0.05–2.67) P (0.25–5.34) P
= 0.969 = 0.144 = 0.727 = 0.786 = 0.741 = 0.310 = 0.864
Toxic-Metabolic 0.97 1.81 1.94 5.18 0.23 2.19 0.89 1.13
Encephalopathy (0.34–2.76) P (0.60–5.48) P (0.45–8.34) P = (1.33–20.12) P (0.03–1.78) P (0.82–5.86) P (0.34–2.31) P (0.40–3.25) P
= 0.958 = 0.296 0.373 ¼ 0.018 = 0.159 = 0.117 = 0.810 = 0.816
Mechanically 0.60 0.92 0.65 – 1.11 0.83 0.66 1.43
ventilated (0.21–1.68) P (0.31–2.76) P (0.13–3.28) P = (0.36–3.42) P (0.31–2.26) P (0.27–1.62) P (0.58–3.51) P
= 0.329 = 0.885 0.600 = 0.854 = 0.719 = 0.365 = 0.439
Worst Sequential Organ 0.90 0.98 0.82 0.79 0.90 0.94 0.89 0.97
Failure Assessment (0.78–1.03) P (0.86–1.12) P (0.62–1.08) P = (0.59–1.05) P= (0.76–1.07) P (0.83–1.07) P (0.78–1.01) P (0.87–1.09) P
(SOFA) score = 0.135 = 0.757 0.160 0.107 = 0.229 = 0.354 = 0.064 = 0.624
Lowest % oxygen 1.01 1.01 1.07 1.05 1.07 1.02 1.03 1.01
saturation (0.98–1.05) P (0.97–1.05) P (0.97–1.19) P = (0.97–1.14) P= (0.99–1.16) P (0.98–1.06) P (0.99–1.07) P (0.98–1.05) P
= 0.428 = 0.606 0.184 0.220 = 0.084 = 0.359 = 0.105 = 0.511
Lowest mean arterial 1.03 1.00 1.05 1.02 1.02 1.01 1.04 1.00
blood pressure (1.00–1.07) P (0.96–1.03) P (1.00–1.11) P = (0.97–1.07) P= (0.98–1.07) P (0.98–1.05) P (1.01–1.08) P (0.97–1.03) P
(mmHg) = 0.061 = 0.915 0.068 0.499 = 0.244 = 0.454 ¼ 0.007 = 0.905
Acute renal failure 2.64 2.16 2.04 0.75 2.46 1.56 1.82 1.36
(0.96–7.26) P (0.65–7.15) P (0.40–10.46) P (0.09–6.17) P= (0.73–8.25) P (0.49–5.01) P (0.68–4.82) P (0.43–4.31) P
= 0.061 = 0.210 = 0.395 0.786 = 0.146 = 0.453 = 0.232 = 0.604
Medications during
Index
Hospitalization
Tocilizumab/ 0.89 1.62 0.53 – 0.28 0.33 0.62 1.05
clazakizumab (0.29–2.76) P (0.43–6.09) P (0.06–4.35) P = (0.04–2.22) P (0.04–2.56) P (0.21–1.87) P (0.29–3.80) P
= 0.845 = 0.472 0.550 = 0.230 = 0.288 = 0.395 = 0.940
Corticosteroids 0.64 0.27 0.90 0.74 0.72 0.31 0.44 1.53
(0.21–1.95) P (0.03–2.18) P (0.18–4.58) P = (0.14–3.78) P = (0.20–2.65) P (0.07–1.43) P (0.15–1.32) P (0.51–4.56) P
= 0.429 = 0.217 0.903 0.714 = 0.619 = 0.134 = 0.143 = 0.445
Remdesivir – – – – – – – –
Hydroxychloroquine 0.73 0.40 0.59 0.55 2.28 0.94 0.71 1.42
(0.28–1.88) P (0.10–1.56) P (0.14–2.54) P = (0.13–2.39) P = (0.50–10.43) P (0.28–3.14) P (0.31–1.67) P (0.38–5.31) P
= 0.509 = 0.187 0.480 0.422 = 0.289 = 0.923 = 0.435 = 0.602
Nitazoxanide 5.35 – 14.72 – 7.00 – 3.27 –
(0.97–29.41) P (2.45–88.46) P (1.28–38.39) (0.63–17.05)
= 0.054 ¼ 0.003 P ¼ 0.025 P = 0.160
Zinc 0.68 1.37 0.45 0.63 0.55 0.38 0.37 0.71
(0.27–1.73) P (0.35–5.30) P (0.09–2.28) P = (0.15–2.74) P = (0.17–1.79) P (0.12–1.25) P (0.15–0.95) P (0.24–2.11) P
= 0.417 = 0.648 0.336 0.540 = 0.318 = 0.110 ¼ 0.040 = 0.543
Ascorbic acid 1.23 0.66 0.78 0.57 0.96 0.21 0.50 0.94
(0.48–3.16) P (0.21–2.13) P (0.16–3.96) P = (0.12–2.82) P = (0.29–3.15) P (0.05–0.94) P (0.18–1.38) P (0.37–2.42) P
= 0.672 = 0.488 0.766 0.492 = 0.944 ¼ 0.041 = 0.183 = 0.899
Lopinavir/ritonavir 1.71 – – – 1.70 – 2.01 1.07
(0.47–6.24) P (0.36–8.08) P (0.63–6.38) P (0.23–4.98) P
= 0.417 = 0.503 = 0.237 = 0.931
Azithromycin 0.53 0.33 0.28 0.25 0.48 0.26 0.60 0.48
(0.22–1.29) P (0.09–1.30) P (0.07–1.21) P = (0.06–1.08) P = (0.16–1.42) P (0.09–0.79) P (0.27–1.33) P (0.16–1.41) P
= 0.162 = 0.113 0.089 0.063 = 0.186 ¼ 0.017 = 0.206 = 0.183
Therapeutic 1.22 1.22 1.19 0.56 0.54 0.47 0.53 1.13
anticoagulation (0.49–3.05) P (0.43–3.49) P (0.28–5.08) P = 0.11–2.76) P = (0.15–1.97) P (0.15–1.44) P (0.21–1.36) P (0.45–2.82) P
= 0.675 = 0.714 0.817 0.476 = 0.348 = 0.185 = 0.186 = 0.800
Discharge metrics
Length of stay 0.99 1.01 0.98 0.95 0.99 0.98 0.98 1.01
(0.96–1.02) (0.98–1.04) (0.94–1.03) (0.88–1.02) (0.95–1.02) (0.95–1.01) (0.95–1.01) (0.99–1.03)
P = 0.546 P = 0.531 P = 0.486 P = 0.137 P = 0.469 P = 0.233 P = 0.119 P = 0.449
Discharge home 0.77 1.05 0.80 1.05 0.47 0.62 0.99 0.41
(0.31–1.94) (0.35–3.20) (0.19–3.43) (0.26–4.33) (0.16–1.39) (0.25–1.57) (0.42–2.30) (0.17–0.99)
P = 0.585 P = 0.927 P = 0.764 P = 0.944 P = 0.171 P = 0.315 P = 0.977 P ¼ 0.048
Discharge SNF 1.39 0.28 1.53 0.47 2.59 2.35 1.29 1.13
(0.49–4.00) (0.04–2.22) (0.30–7.79) (0.06–3.89) (0.83–8.10) (0.88–6.31) (0.49–3.37) (0.39–3.26)
P = 0.538 P = 0.230 P = 0.612 P = 0.487 P = 0.102 P = 0.090 P = 0.609 P = 0.819
Discharge rehab 0.87 2.47 1.19 1.05 1.43 0.41 1.04 3.79
(0.19–3.96) (0.64–9.59) (0.14–10.06) (0.13–8.76) (0.30–6.74) (0.05–3.21) (0.29–3.69) (1.31–10.98)
P = 0.860 P = 0.192 P = 0.871 P = 0.967 P = 0.652 P = 0.395 P = 0.953 P ¼ 0.014

Bold indicates P < 0.05; NeuroQoL = neurological quality of life; SNF = skilled nursing facility.

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J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 5
Impact of Life Stressors on 12-month outcomes. Univariate logistic regression odds ratios, 95% confidence intervals (CI) and P values shown.
mRS 4–6 Barthel < 100 t-MoCA Anxiety T- Depression T- Fatigue T- Sleep T-score 12-month Post-
N ¼ 236 N ¼ 236 ≤ 18 score ≥ 60 score ≥ 60 score ≥ 60 ≥ 60 acute COVID-19
N ¼ 170 N ¼ 225 N ¼ 225 N ¼ 223 N ¼ 221 symptoms N ¼
242

Stressors
At least one 1.32 1.55 1.03 7.07 – 5.61 3.43 2.08
stressor (0.76–2.28) P (0.91–2.64) P (0.56–1.90) P (1.57–31.87) (1.60–19.74) (1.22–9.67) P (1.23–3.52) P ¼
= 0.327 = 0.111 = 0.930 P ¼ 0.011 P ¼ 0.007 ¼ 0.019 0.006
Number of 1.10 1.18 1.02 1.37 1.42 1.47 1.43 1.29
stressors (0.92–1.31) P (0.99–1.39) P (0.84–1.23) P (1.06–1.77) P (1.03–1.96) P (1.16–1.87) P (1.14–1.80) P (1.07–1.56) P ¼
= 0.295 = 0.062 = 0.861 ¼ 0.016 ¼ 0.032 ¼ 0.001 ¼ 0.002 0.007
Social Isolation 1.28 1.91 1.09 4.22 3.22 2.17 2.50 1.83
(0.59–2.79) P (0.90–4.06) P (0.47–2.54) P (1.42–12.59) (0.76–13.61) P (0.73–6.46) P (0.90–6.95) P (0.84–4.00) P =
= 0.527 = 0.090 = 0.846 P ¼ 0.010 = 0.111 = 0.163 = 0.080 0.128
Financial 0.90 1.01 1.06 4.15 1.34 2.13 2.98 1.31
Insecurity (0.43–1.90) P (0.50–2.03) P (0.50–2.23) P (1.44–11.92) (0.27–6.70) P (0.76–5.94) P (1.16–7.69) P (0.66–2.60) P =
= 0.787 = 0.983 = 0.882 P ¼ 0.008 = 0.723 = 0.148 ¼ 0.024 0.438
Unemployment 0.96 1.00 0.65 0.60 – 1.02 2.24 3.34
(0.37–2.46) P (0.40–2.48) P (0.23–1.79) P (0.08–4.75) P (0.22–4.71) P (0.68–7.32) P (1.19–9.38) P ¼
= 0.933 = 0.994 = 0.399 = 0.626 = 0.983 = 0.184 0.022
Food Insecurity 0.68 0.43 1.48 9.81 6.63 7.41 – 1.34
(0.07–6.69) P (0.05–3.91) P (0.20–10.75) (1.51–63.60) (0.66–66.23) P (1.16–47.25) (0.22–8.15) P =
= 0.744 = 0.453 P = 0.700 P ¼ 0.017 = 0.107 P ¼ 0.034 0.753
Homelessness – – – – – – – –
Domestic violence – – – – – – – –
Relationship 0.91 0.86 1.24 1.01 4.86 3.08 1.56 1.35
problems in (0.27–3.07) P (0.29–2.62) P (0.36–4.23) P (0.12–8.21) P (0.91–25.95) P (0.78–12.12) P (0.33–7.46) P (0.47–3.94) P =
household = 0.884 = 0.796 = 0.734 = 0.996 = 0.065 = 0.107 = 0.579 0.578
Education – – 0.48 4.58 – 3.51 – –
disruption (0.05–4.72) P (0.45–46.73) P (0.35–35.04) P
= 0.529 = 0.199 = 0.287
Increased 5.15 3.52 1.90 1.85 3.83 1.39 1.23 0.77
caregiver (1.72–15.40) (1.25–9.89) P (0.49–7.32) P (0.38–8.90) P (0.73–20.07) P (0.30–6.58) P (0.26–5.76) P (0.29–2.08) P =
responsibilities P ¼ 0.003 ¼ 0.017 = 0.354 = 0.444 = 0.112 = 0.676 = 0.796 0.608
New Disability 4.42 8.34 0.72 1.72 3.57 8.57 4.21 1.57
(1.69–11.60) (2.69–25.88) (0.21–2.48) P (0.36–8.26) P (0.69–18.63) P (2.89–24.45) (1.34–13.22) (0.60–4.15) P =
P ¼ 0.003 P < 0.001 = 0.597 = 0.496 = 0.131 P < 0.001 P ¼ 0.014 0.360
Death of close 0.71 1.28 1.74 1.21 12.96 2.29 1.99 1.89
contact (0.27–1.87) P (0.54–3.02) P (0.64–4.77) (0.26–5.70) P (3.21–52.38) P (0.70–7.51) P (0.61–6.46) P (0.77–4.60) P =
= 0.483 = 0.575 P = 0.279 = 0.806 < 0.001 = 0.173 = 0.253 0.163
Illness of close 0.58 0.74 1.07 – 1.10 0.43 1.41 1.43
contact (0.21–1.64) P (0.29–1.88) P (0.41–2.82) P (0.13–9.23) P (0.06–3.39) P (0.38–5.20) P (0.59–3.44) P =
= 0.303 = 0.530 = 0.886 = 0.928 = 0.433 = 0.603 0.430
Political conflict – 0.18 0.47 3.59 – 1.14 4.33 3.72
with close (0.02–1.48) P (0.09–2.41) P (0.70–18.53) P (0.14–9.44) P (1.03–18.14) (0.77–17.91) P =
contacts = 0.112 = 0.368 = 0.127 = 0.907 P ¼ 0.045 0.101

Bold indicates P < 0.05; mRS = modified Rankin Scale, t-MOCA = telephone Montreal Cognitive Assessment.

severity of illness or are specific to the SARS-CoV-2 pathogen.
Finally, most COVID-19 specific medications used during index
hospitalization did not independently predict 12-month outcomes, with
the exception of azithromycin, which was protective against severe fa­
tigue scores. Since this cohort represents the first SARS-CoV-2 wave in
the U.S., many subsequent studies that identified effective acute thera­
pies were not yet published [52–56]. Indeed, many critically ill patients
were treated with anticoagulation based on ferritin and D-Dimer levels
per hospital protocol, while decadron was sporadically, and inconsis­
tently used. There were too few patients who received remdesivir to
even perform statistical analyses. Because certain COVID-19 specific
medications may have variable beneficial or harmful impact depending
on the population treated, it is likely we were unable to detect any effect
due to both underpowering and poor patient selection. The relationship
of in-hospital azithromycin use and 12-month fatigue scores is
intriguing, since azithromycin has been reported to provide symptom­
atic relief to patients with chronic fatigue syndrome [57]. Azithromycin
has been shown to have immune modulating capacity and its utility in
chronic fatigue syndrome patients is thought to be linked to its effect on
chronically primed immune cells in the brain [57]. Additionally, azi­
thromycin has anti-inflammatory and anti-viral properties [58], which
may play a role in the pathophysiology of post-COVID-19 chronic fa­
tigue. While acute COVID-19 studies did not demonstrate a beneficial
effect of azithromycin on symptoms at 14–28 days [59,60] post-
infection, hospitalization rates [60], requirement for invasive mechan­
ical ventilation [61], discharge disposition [61], clinical recovery [62],
or mortality [61,63], further study of azithromycin for the treatment of
PASC fatigue may be warranted.
Strengths of this study include the prospective ascertainment of data
from hospitalization through 12-month follow-up, the robust charac­
terization of neurological events during index hospitalization, account­
ing of pre-COVID functional status, assessment of life stressors, and the
use of both quantitative and patient-reported long-term outcome met­
rics. There are also several limitations to this study that should be noted.
First, we did not a priori investigate certain factors that may be
important outcome predictors. For example, a multi-omic study of 309
patients (51% were hospitalized for index COVID-19) examined pre­
dictors of post-acute symptoms (most commonly fatigue, cough and
anosmia/dysgeusia) at 2–3 months post SARS-CoV-2 infection. In this
study, type 2 diabetes, Epstein-Barr virus (EBV) viremia, SARS-CoV-2
RNAemia and several autoantibodies were identified as risk factors for
post-acute symptoms [64]. Because index hospitalization occurred early
in the pandemic in our study, we did not have measures of SARS-CoV-2
viral load, nor did we assess autoantibodies or EBV levels. Though we
evaluated the impact of diabetes on our outcome measures, we did not
find any significant associations. Differences in study populations

8
J.A. Frontera et al. Journal of the Neurological Sciences 443 (2022) 120487

Table 6 performed due to <2 univariate predictors with P < 0.05 Variables (univariate
Multivariable predictors of 6- and 12-month outcomes calculated using multi­ predictors with P < 0.05) assessed in each backwards, stepwise logistic regres­
variable, backwards, stepwise logistic regression analyses. Adjusted odds ratios sion model by outcome of interest:
(OR), 95% confidence intervals (CI), p values, and area under the curve (AUC) 6-month mRS: age, education>12 years, pre-COVID disability, history of de­
for the entire model are shown. mentia, history of psychiatric disorder, any neurological complication during
hospitalization, hypoxic ischemic brain injury, toxic-metabolic encephalopathy,
Variable Adjusted OR P Model AUC
(95% CI) (95% CI)
azithromycin use during hospitalization.
12-month mRS: age, pre-COVID disability, history of dementia, hypoxic
6-month mRS 4–6 0.755 ischemic brain injury, toxic-metabolic encephalopathy, increased caregiver re­
(0.697–0.813)
sponsibility, personal illness, new disability stressor.
Age 1.02 (1.00–1.04) 0.021
6-month Barthel Index: age, sex, pre-COVID disability, history of dementia,
Baseline mRS 1.99 (1.60–2.48) <0.001
Neurological event during 1.74 (1.02–2.98) 0.043 history of psychiatric disorder, any neurological complication during hospital­
index hospitalization ization, hypoxic ischemic brain injury, toxic-metabolic encephalopathy, me­
12-month mRS 4–6 0.830 chanical ventilation, worst SOFA score, use of corticosteroids during
(0.769–0.892) hospitalization.
Age 1.04 (1.01–1.06) 0.002 12-month Barthel Index: age, sex, pre-COVID disability, hypoxic ischemic brain
Baseline mRS 2.05 (1.59–2.65) <0.001 injury, toxic-metabolic encephalopathy, increased caregiver responsibility,
Hypoxic ischemic 3.58 0.037 personal illness, new disability stressor.
encephalopathy during index (1.08–11.92)
6-month t-MoCA: age, race, education>12 years, history of dementia, tocilizu­
hospitalization
mab use during hospitalization.
Stressor: new disability 4.88 0.007
(1.53–15.56) 12-month t-MoCA: age.
6-month Barthel < 100 0.789 12-month Anxiety: sex, history of dementia, at least one life stressor, number of
(0.737–0.841) stressors, social isolation, financial insecurity, food insecurity.
Age 1.04 (1.02–1.06) <0.001 12-month Depression: age, education>12 years, toxic-metabolic encephalopa­
Baseline mRS 2.02 (1.58–2.59) <0.001 thy, number of stressors, death of a close contact,
Maximum SOFA score during 1.10 (1.01–1.19) 0.024 12-month Fatigue: education>12 years, pre-COVID disability, any neurological
index hospitalization
complication during hospitalization, ascorbic acid use during hospitalization,
12-month Barthel < 100 0.882
azithromycin use during hospitalization, at least one life stressor, number of
(0.837–0.929)
Age 1.06 (1.03–1.09) <0.001
stressors, food insecurity, personal illness, new disability.
Baseline mRS 2.62 (1.90–3.62) <0.001 12-month Sleep: at least one life stressor, number of stressors, financial inse­
Male sex 0.33 (0.15–0.72) 0.005 curity, personal illness, new disability, political conflict with close contacts.
Stressor: new disability 11.74 0.001 Post-acute COVID-19 symptoms: mechanical ventilation during index hospital­
(2.76–50.05) ization, worst Sequential Organ Failure Assessment (SOFA) score during hos­
6-month Telephone MoCA ≤ 18 0.688 pitalization, oxygen saturation during hospitalization, tocilizumab,
(0.608–0.769) corticosteroid, hydroxychloroquine, zinc, azithromycin or therapeutic anti­
White race 0.41 (0.21–0.83) 0.012
coagulation during hospitalization, at least one life stressor, number of stressors,
History of dementia 6.82 0.019
unemployment, personal illness.
(1.38–33.67)
Education>12 years 0.30 (0.12–0.77) 0.012
12-month Telephone MoCA ≤ 18 0.664 (hospitalized versus not) and time frame of outcome assessments, may in
(0.573–0.755)
part explain this discrepancy. While most of our models demonstrated
Age 1.04 (1.01–1.07) 0.003
Education>12 years 0.34 (0.15–0.80) 0.014
robust AUCs, models for cognition and post-acute COVID-19 symptoms
12-month NeuroQoL Anxiety T-score ≥ 60 0.731 yielded middling AUC values, suggesting there are important factors
(0.592–0.870) that we did not account for in these models. We did not have baseline
Male sex 0.21 (0.06–0.74) 0.015 pre-COVID cognitive testing to evaluate change over time. It is also
History of dementia 6.42 0.011
likely that sicker patients may not have been able to participate in
(1.54–26.69)
12-month NeuroQoL Depression T-score ≥ 60 0.903 cognitive testing or review of post-acute symptoms. Second, there were
(0.812–0.993) some differences in the number participants between the two time
Age 1.11 (1.02–1.20) 0.011 points, and the same individuals are not represented at each time point.
Education>12 years 0.14 (0.03–0.77) 0.024
However, aside from older age in those lost to follow-up at 12-months,
Stressor: death of a close 20.79 0.001
contact (3.57–121.14)
there were no other significant differences between those who
12-month NeuroQoL Fatigue T-score ≥ 60 0.840 completed only 6-month follow-up and those who completed 12-month
(0.732–0.948) follow-up. Third, we did not collect life stressor data at the 6-month
Stressor: food insecurity 21.32 0.013 visit, so we were unable to account for these variables in 6-month
(1.92–236.80)
outcome models. Fourth, some medications utilized to treat COVID-19
Stressor: new disability 6.5 1 0.015
(1.45–29.33) appeared to be associated with worse outcomes in univariate analyses.
Baseline mRS 1.53 (1.05–2.23) 0.027 This is likely related to bias by indication, since many of these medi­
Azithromycin use during index 0.25 (0.08–0.82) 0.022 cations were reserved for the sickest patients, and little data existed to
hospitalization guide standardized management during the first wave of the pandemic.
12-month NeuroQoL Sleep T-score ≥ 60 0.694
(0.574–0.814)
Last, we dichotomized NeuroQoL scores at ≥1 standard deviation above
Number of stressors 1.43 (1.12–1.82) 0.004 the mean. There is some data to suggest that a clinically meaningful
12-month Post-Acute COVID-19 Symptoms 0.685 threshold for dichotomization may be 0.5 standard deviations (SD)
(0.616–0.753) above the mean [65,66]. Utilization of a more liberal 0.5 SD threshold
At least 1 stressor 2.47 (1.39–4.40) 0.002
would increase the prevalence of worse NeuroQoL measures and could
Mechanical ventilation during 6.37 0.001
index hospitalization (2.16–18.78) lead to differences in multivariable models.

mRS = modified Rankin Scale, t-MOCA = telephone Montreal Cognitive

5. Conclusions
Assessment; NeuroQoL = neurological quality of life; SOFA = Worst Sequential
Organ Failure Assessment.
Multivariable logistic regression analyses of 6-month NeuroQoL metrics not In adults hospitalized with COVID-19, we found that traditional
predictors of poor outcome, including older age, poor pre-COVID

9
J.A. Frontera et al.
Fig. 1. Independent predictors of outcome 6- and 12-months after COVID-19 hospitalization. Life stressors, age, female sex, baseline disability, and index COVID-19
severity were the most common predictors of functional status (measured by the modified Rankin Scale [mRS]), activities of daily living (ADLs, measured by the
Barthel Index), cognition (measured by the telephone MoCA) and patient-reported anxiety, depression, fatigue and sleep (assessed using NeuroQoL metrics).
functional status and index severity of illness, were independently
associated with worse mRS, Barthel Index, t-MoCA scores and persistent
COVID-19 symptoms. We additionally found that life stressors signifi­
cantly impacted disability, depression, fatigue, sleep and post-acute
COVID-19 symptom metrics. Interventions targeted at ameliorating
modifiable life stressors merit further investigation.
Author contributions
JAF contributed to conception, study design, data analysis and
drafting of the manuscript.
SS, DY, AL, ASL, KM, ST contributed to data curation, investigation,
writing- review and editing of the manuscript.
AdH, SY, AL, ASL, KM, LB, TW and SLG contributed to study
conception and design, data interpretation and critical revision of the
manuscript.
Declaration of Competing Interest
Potential conflict of interest: JAF receives funding for the following
COVID-19-related grants: NIH/NIA R01AG077422, NIH/NINDS
3U24NS11384401S1, NIH/NHLBI 1OT2HL161847-01; LJB and ST
receive funding for the following COVID-19-related grant: NIH/NHLBI
1OT2HL161847-01. TW receives funding for the following COVID-19
related grant: NIH/NIA R01AG077422. JAF and TW have received
funding for the COVID-19 related grant: NIH/NIA 3P30AG066512-
01S1. AdH, SY, SS, DY, AL, ASL, KM, and SLG do not report any relevant
conflicts of interest.
Data availability
De-identified data will be made available to qualified investigators
upon written request to the corresponding author
Acknowledgements
We would like to thank the patients and clinicians who contributed
data to this project.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jns.2022.120487.
10
Journal of the Neurological Sciences 443 (2022) 120487
References
[1] J.A. Frontera, D. Yang, C. Medicherla, et al., Trajectories of neurologic recovery 12
months after hospitalization for COVID-19: a prospective longitudinal study,
Neurology Jul 5;99(1):e33-e45 (2022).
[2] C. Huang, L. Huang, Y. Wang, et al., 6-month consequences of COVID-19 in
patients discharged from hospital: a cohort study, Lancet 397 (2021) 220–232.
[3] M.L. Bell, C.J. Catalfamo, L.V. Farland, et al., Post-acute sequelae of COVID-19 in a
non-hospitalized cohort: results from the Arizona CoVHORT, PLoS One 16 (2021),
e0254347.
[4] S. Misra, K. Kolappa, M. Prasad, et al., Frequency of neurologic manifestations in
COVID-19: a systematic review and meta-analysis, Neurology 97 (2021)
e2269–e2281.
[5] D. Groff, A. Sun, A.E. Ssentongo, et al., Short-term and long-term rates of Postacute
sequelae of SARS-CoV-2 infection: a systematic review, JAMA Netw. Open 4
(2021), e2128568.
[6] M.M. Maestre-Muniz, A. Arias, E. Mata-Vazquez, et al., Long-term outcomes of
patients with coronavirus disease 2019 at one year after hospital discharge, J. Clin.
Med. (2021) 10.
[7] J.A. Frontera, A. Lewis, K. Melmed, et al., Prevalence and predictors of prolonged
cognitive and psychological symptoms following COVID-19 in the United States,
Front. Aging Neurosci. (2021) 13.
[8] A. Perez-Gonzalez, A. Araujo-Ameijeiras, A. Fernandez-Villar, M. Crespo,
E. Poveda, Cohort C-otGSHRI, Long COVID in hospitalized and non-hospitalized
patients in a large cohort in Northwest Spain, a prospective cohort study, Sci. Rep.
12 (2022) 3369.
[9] F. Desgranges, E. Tadini, A. Munting, et al., PostCOVID19 syndrome in outpatients:
a cohort study, J. Gen. Intern. Med. Jun;37(8):1943-1952 (2022).
[10] J.A. Frontera, N.M. Simon, Bridging knowledge gaps in the diagnosis and
management of neuropsychiatric sequelae of COVID-19, JAMA Psychiatry Aug 1;
79(8):811-817 (2022).
[11] J.A. Frontera, S. Sabadia, R. Lalchan, et al., A prospective study of neurologic
disorders in hospitalized patients with COVID-19 in new York City, Neurology 96
(2021) e575–e586.
[12] J.A. Frontera, D. Yang, A. Lewis, et al., A prospective study of long-term outcomes
among hospitalized COVID-19 patients with and without neurological
complications, J. Neurol. Sci. 426 (2021), 117486.
[13] E. Valdes, B. Fuchs, C. Morrison, et al., Demographic and social determinants of
cognitive dysfunction following hospitalization for COVID-19, J. Neurol. Sci.
120146 (2022).
[14] J.L. Vincent, R. Moreno, J. Takala, et al., The SOFA (Sepsis-related organ failure
assessment) score to describe organ dysfunction/failure. On behalf of the working
group on Sepsis-related problems of the European Society of Intensive Care
Medicine, Intensive Care Med. 22 (1996) 707–710.
[15] J.C. van Swieten, P.J. Koudstaal, M.C. Visser, H.J. Schouten, J. van Gijn,
Interobserver agreement for the assessment of handicap in stroke patients, Stroke
19 (1988) 604–607.
[16] F.I. Mahoney, D.W. Barthel, Functional evaluation: the Barthel index, Md State
Med. J. 14 (1965) 61–65.
[17] S.T. Pendlebury, S.J. Welch, F.C. Cuthbertson, J. Mariz, Z. Mehta, P.M. Rothwell,
Telephone assessment of cognition after transient ischemic attack and stroke:
modified telephone interview of cognitive status and telephone Montreal cognitive
assessment versus face-to-face Montreal cognitive assessment and
neuropsychological battery, Stroke 44 (2013) 227–229.
[18] D. Cella, J.S. Lai, C.J. Nowinski, et al., Neuro-QOL: brief measures of health-related
quality of life for clinical research in neurology, Neurology 78 (2012) 1860–1867.
[19] Neuro-QoL, Neuro-QoL Reference Populations. https://www.healthmeasures.net
/score-and-interpret/interpret-scores/neuro-qol/reference-populations, 2021.
J.A. Frontera et al.
[20] H.C. Rossetti, L.H. Lacritz, C.M. Cullum, M.F. Weiner, Normative data for the
Montreal cognitive assessment (MoCA) in a population-based sample, Neurology
77 (2011) 1272–1275.
[21] CDC, Post-COVID Conditions [online], Available at: https://www.cdc.gov
/coronavirus/2019-ncov/long-term-effects/index.html, 2022.
[22] WHO, Global COVID-19 Clinical Platform Caser Report Form (CRF) for Post COVID
Condition [online], Available at: https://www.who.int/publications/i/item/
global-covid-19-clinical-platform-case-report-form-(crf)-for-post-covid-conditions-
(post-covid-19-crf-), 2022.
[23] J.A. Frontera, L.E. Thorpe, N.M. Simon, et al., Post-acute sequelae of COVID-19
symptom phenotypes and therapeutic strategies: a prospective, observational
study, PLoS One 17 (2022), e0275274.
[24] A.E. Leigh, J. McCall, R.V. Burke, R. Rome, A.M. Raines, Predictors of functional
dependence after COVID-19: a retrospective examination among veterans, Am. J.
Phys. Med. Rehabil. 100 (2021) 34–38.
[25] G.E.M. Boari, G. Chiarini, S. Bonetti, et al., Prognostic factors and predictors of
outcome in patients with COVID-19 and related pneumonia: a retrospective cohort
study, Biosci. Rep. 40 (2020).
[26] P.N. Perez-Guzman, A. Daunt, S. Mukherjee, et al., Clinical characteristics and
predictors of outcomes of hospitalized patients with coronavirus disease 2019 in a
multiethnic London National Health Service Trust: a retrospective cohort study,
Clin. Infect. Dis. 73 (2021) e4047–e4057.
[27] C.H. Sudre, B. Murray, T. Varsavsky, et al., Attributes and predictors of long
COVID, Nat. Med. 27 (2021) 626–631.
[28] M. Taquet, Q. Dercon, S. Luciano, J.R. Geddes, M. Husain, P.J. Harrison, Incidence,
co-occurrence, and evolution of long-COVID features: a 6-month retrospective
cohort study of 273,618 survivors of COVID-19, PLoS Med. 18 (2021), e1003773.
[29] H. Akbarialiabad, M.H. Taghrir, A. Abdollahi, et al., Long COVID, a comprehensive
systematic scoping review, Infection Dec;49(6):1163-1186 (2021).
[30] M.S. Alkodaymi, O.A. Omrani, N.A. Fawzy, et al., Prevalence of post-acute COVID-
19 syndrome symptoms at different follow-up periods: a systematic review and
meta-analysis, Clin. Microbiol. Infect. 28 (2022) 657–666.
[31] D.R.T. Knight, B. Munipalli, I.I. Logvinov, et al., Perception, prevalence, and
prediction of severe infection and post-acute sequelae of COVID-19, Am J Med Sci
Apr;363(4):295-304 (2022).
[32] Q. Xiong, M. Xu, J. Li, et al., Clinical sequelae of COVID-19 survivors in Wuhan,
China: a single-Centre longitudinal study, Clin. Microbiol. Infect. 27 (2021) 89–95.
[33] J.J. Capin, M.P. Wilson, K. Hare, et al., Prospective telehealth analysis of functional
performance, frailty, quality of life, and mental health after COVID-19
hospitalization, BMC Geriatr. 22 (2022) 251.
[34] F. Bai, D. Tomasoni, C. Falcinella, et al., Female gender is associated with long
COVID syndrome: a prospective cohort study, Clin. Microbiol. Infect. 28 (2022),
611 e619–611 e616.
[35] N.T. Kambhampati, Pillai M.G. Chithira, D. Ts, M. Moni, Assessment of post-Covid
symptoms in Covid-19 recovered patients: a prospective cohort study in a tertiary
Care Centre of South India, J. Assoc. Physicians India 70 (2022) 11–12.
[36] N. Lorent, Y. Vande Weygaerde, E. Claeys, et al., Prospective longitudinal
evaluation of hospitalised COVID-19 survivors 3 and 12 months after discharge,
ERJ Open Res. (2022) 8.
[37] M. Peghin, A. Palese, M. Venturini, et al., Post-COVID-19 symptoms 6 months after
acute infection among hospitalized and non-hospitalized patients, Clin. Microbiol.
Infect. 27 (2021) 1507–1513.
[38] L. Townsend, A.H. Dyer, K. Jones, et al., Persistent fatigue following SARS-CoV-2
infection is common and independent of severity of initial infection, PLoS One 15
(2020), e0240784.
[39] M. Whitaker, J. Elliott, M. Chadeau-Hyam, et al., Persistent COVID-19 symptoms in
a community study of 606,434 people in England, Nat. Commun. 13 (2022) 1957.
[40] N.R. Simon, A.S. Jauslin, M. Rueegg, et al., Association of Frailty with adverse
outcomes in patients with suspected COVID-19 infection, J. Clin. Med. (2021) 10.
[41] M.C. Sneller, C.J. Liang, A.R. Marques, et al., A longitudinal study of COVID-19
sequelae and immunity: baseline findings, Ann. Intern. Med. Jul;175(7):969-979
(2022).
[42] J.R. Rainville, G.E. Hodes, Inflaming sex differences in mood disorders,
Neuropsychopharmacology 44 (2019) 184–199.
[43] G. Nalbandian, V. Paharkova-Vatchkova, A. Mao, S. Nale, S. Kovats, The selective
estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell
differentiation and activation, J. Immunol. 175 (2005) 2666–2675.
11
Journal of the Neurological Sciences 443 (2022) 120487
[44] A. Bouman, M.J. Heineman, M.M. Faas, Sex hormones and the immune response in
humans, Hum. Reprod. Update 11 (2005) 411–423.
[45] P.R. Albert, Why is depression more prevalent in women? J. Psychiatry Neurosci.
40 (2015) 219–221.
[46] C.P. McLean, A. Asnaani, B.T. Litz, S.G. Hofmann, Gender differences in anxiety
disorders: prevalence, course of illness, comorbidity and burden of illness,
J. Psychiatr. Res. 45 (2011) 1027–1035.
[47] Z. Al-Aly, Y. Xie, B. Bowe, High-dimensional characterization of post-acute
sequelae of COVID-19, Nature 594 (2021) 259–264.
[48] M. Taquet, J.R. Geddes, M. Husain, S. Luciano, P.J. Harrison, 6-month neurological
and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort
study using electronic health records, Lancet Psychiatry 8 (2021) 416–427.
[49] S.M. Yoo, T.C. Liu, Y. Motwani, et al., Factors associated with post-acute sequelae
of SARS-CoV-2 (PASC) after diagnosis of symptomatic COVID-19 in the inpatient
and outpatient setting in a diverse cohort, J. Gen. Intern. Med. Jun;37(8):1988-
1995 (2022).
[50] A.S. Abdelhafiz, A. Ali, A.M. Maaly, M.A. Mahgoub, H.H. Ziady, E.A. Sultan,
Predictors of post-COVID symptoms in Egyptian patients: drugs used in COVID-19
treatment are incriminated, PLoS One 17 (2022), e0266175.
[51] A.K. Clift, T.A. Ranger, M. Patone, et al., Neuropsychiatric ramifications of severe
COVID-19 and other severe acute respiratory infections, JAMA Psychiatry Jul 1;79
(7):690-698 (2022).
[52] A.B. Cavalcanti, F.G. Zampieri, R.G. Rosa, et al., Hydroxychloroquine with or
without azithromycin in mild-to-moderate Covid-19, N. Engl. J. Med. 383 (2020)
2041–2052.
[53] Group RC, P. Horby, W.S. Lim, et al., Dexamethasone in hospitalized patients with
Covid-19, N. Engl. J. Med. 384 (2021) 693–704.
[54] J.H. Beigel, K.M. Tomashek, L.E. Dodd, et al., Remdesivir for the treatment of
Covid-19 - final report, N. Engl. J. Med. 383 (2020) 1813–1826.
[55] R.-C. Investigators, Investigators AC-a, Investigators A, et al., Therapeutic
anticoagulation with heparin in critically ill patients with Covid-19, N. Engl. J.
Med. 385 (2021) 777–789.
[56] A. Investigators, Investigators AC-a, Investigators R-C, et al., Therapeutic
anticoagulation with heparin in noncritically ill patients with Covid-19, N. Engl. J.
Med. 385 (2021) 790–802.
[57] R.C. Vermeulen, H.R. Scholte, Azithromycin in chronic fatigue syndrome (CFS), an
analysis of clinical data, J. Transl. Med. 4 (2006) 34.
[58] V.J. Venditto, D. Haydar, A. Abdel-Latif, et al., Immunomodulatory effects of
azithromycin revisited: potential applications to COVID-19, Front. Immunol. 12
(2021), 574425.
[59] C.E. Oldenburg, B.A. Pinsky, J. Brogdon, et al., Effect of Oral azithromycin vs
placebo on COVID-19 symptoms in outpatients with SARS-CoV-2 infection: a
randomized clinical trial, JAMA 326 (2021) 490–498.
[60] Group PTC, Azithromycin for community treatment of suspected COVID-19 in
people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a
randomised, controlled, open-label, adaptive platform trial, Lancet 397 (2021)
1063–1074.
[61] Group RC, Azithromycin in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial, Lancet 397
(2021) 605–612.
[62] R.H.M. Furtado, O. Berwanger, H.A. Fonseca, et al., Azithromycin in addition to
standard of care versus standard of care alone in the treatment of patients admitted
to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised
clinical trial, Lancet 396 (2020) 959–967.
[63] T.S.C. Hinks, L. Cureton, R. Knight, et al., Azithromycin versus standard care in
patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised
trial, Lancet Respir. Med. 9 (2021) 1130–1140.
[64] Y. Su, D. Yuan, D.G. Chen, et al., Multiple early factors anticipate post-acute
COVID-19 sequelae, Cell 185 (881–895) (2022), e820.
[65] PROMIS, Meaningful Change for PROMIS [online], Available at: https://www.
healthmeasures.net/score-and-interpret/interpret-scores/promis/meaningful-chan
ge, 2022. Accessed May 17.
[66] C.B. Terwee, J.D. Peipert, R. Chapman, et al., Minimal important change (MIC): a
conceptual clarification and systematic review of MIC estimates of PROMIS
measures, Qual. Life Res. 30 (2021) 2729–2754.