key: cord-0884299-v5y80mrr
authors: Vannorsdall, Tracy D.; Brigham, Emily; Fawzy, Ashraf; Raju, Sarath; Gorgone, Alesandra; Pletnikova, Alexandra; Lyketsos, Constantine G.; Parker, Ann M.; Oh, Esther S.
title: Rates of cognitive dysfunction, psychiatric distress and functional decline following COVID-19
date: 2021-11-15
journal: J Acad Consult Liaison Psychiatry
DOI: 10.1016/j.jaclp.2021.10.006
sha: b267b4f06ce5b2646812d2a19a22cfde7e562561
doc_id: 884299
cord_uid: v5y80mrr

INTRODUCTION: There is a limited understanding of the cognitive and psychiatric sequelae of COVID-19 during the post-acute phase, particularly among racially and ethnically diverse patients. METHODS: Approximately four months after COVID-19 diagnosis, patients in the Johns Hopkins Post-Acute COVID-19 Team (JH PACT) Pulmonary Clinic underwent a clinical telephone-based assessment of cognition, depression, anxiety, trauma, and function. RESULTS: The majority of JH PACT patients assessed were women (59%) and members of racial/ethnic minority groups (65%). Of 82 patients, 67% demonstrated ≥1 abnormally low cognitive score. Patients requiring ICU stays displayed greater breadth and severity of impairment than those requiring less intensive treatment. Processing speed (35%), verbal fluency (26-32%), learning (27%), and memory (27%) were most commonly impaired. Among all patients, 35% had moderate symptoms of depression (23%), anxiety (15%), or functional decline (15%); and 25% of ICU patients reported trauma-related distress. Neuropsychiatric symptoms and functional decline did not differ by post-ICU versus non-ICU status and were unrelated to global cognitive composite scores. DISCUSSION: At approximately 4 months after acute illness, cognitive dysfunction, emotional distress, and functional decline were common among a diverse clinical sample of COVID-19 survivors varying in acute illness severity. Patients requiring ICU stays demonstrated greater breadth and severity of cognitive impairment than those requiring less intensive treatment. Findings help extend our understanding of the nature, severity, and potential duration of neuropsychiatric morbidity following COVID-19 and point to the need for longitudinal assessment of cognitive and mental health outcomes among COVID-19 survivors of different demographic backgrounds and illness characteristics.

The potential for neuropsychiatric complications of COVID-19 were appreciated early in the pandemic based on observations from prior coronavirus infections. Both the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics were characterized by delirium, cognitive impairment, mood disturbances, and anxiety that persisted beyond the acute phase of illness (1) . Against this background, early reports of neurologic symptoms and delirium coupled with an ever-growing infection rate raised concerns that cognitive and mental health sequelae of COVID-19 could have significant individual and population health implications (2, 3) .

While critical illness and hospitalization alone represent risk factors for impaired cognition and neuropsychiatric sequelae, combined hypoxemia, coagulopathy, need for greater sedation, social isolation and related limits in access to rehabilitation services implies a potential for compounded neuropsychiatric risk in both short and long-term outcomes (3) (4) (5) (6) (7) (8) . At present, most available data characterize psychiatric and cognitive symptoms during the acute phase of COVID-19 illness, including delirium/altered mentation at presentation or during hospitalization (9, 10) . Existing knowledge of post-acute neuropsychiatric symptoms associated with COVID-19 infection is limited, and primarily focused on psychiatric rather than cognitive outcomes. When assessed one month following hospital discharge, more than half of patients in one study produced scores in the clinically elevated range across measures of anxiety (42%), insomnia (40%), depression (31%), and post-traumatic stress (28%) (11) . Among COVID-19 patients who lack prior psychiatric histories, data suggest heightened risk of new-onset psychiatric diagnosis within 90 days of a positive COVID-19 test relative to that occurring following a range of other medical events (12) .

To date, most studies have relied on brief cognitive screening measures or small case series rather than detailed neuropsychological test batteries in samples of sufficient size to permit detection of patterns of impairment and associated disease and treatment J o u r n a l P r e -p r o o f characteristics (13) (14) (15) (16) (17) . Much remains to be learned about the nature and severity of cognitive and psychiatric functioning across patients of varying disease severity and at various time points over the course recovery from COVID-19 (18) . Further, it is appreciated that racial and ethnic minority groups are disproportionately impacted by the pandemic and may be at higher risk of poor clinical outcomes, yet little data exist on long-term cognitive and psychiatric functioning in these groups (19) (20) (21) .

In order to characterize post-acute neuropsychiatric functioning, we prospectively evaluated a broad range of cognitive abilities, mental health symptoms, and functioning at approximately four months following an initial diagnosis of COVID-19 in a racially and ethnically diverse group of patients. 1.4. Cognitive assessment. Patients underwent a telephone-based neuropsychological assessment battery; telephone assessment has been shown to be feasible and provides valid assessment of cognitive function relative to in-person exams (24) (25) (26) . This battery has been successfully implemented in diverse patient populations (27, 28) .

Assessments occurred between July 6, 2020 and January 22, 2021.

The cognitive battery consisted of eight scores. The Rey Auditory Verbal Learning Test (RAVLT; (29, 30) ) assessed acquisition of a 15-item word list that was presented over multiple exposure trials as well as memory as indexed by delayed recall for word list items. Oral Trail Making Test parts A and B assessed processing speed by having patients count aloud to 25 as quickly as possible (part A) and executive functioning (part B) by having them do so while switching between numbers and letters (31) . Attention and working memory were assessed with a number span task during which patients repeated increasingly lengthy digit strings in forward and backward sequences (28) . Letter-cued verbal fluency assessed speeded word retrieval in response to phonetic cues by asking patients to name as many words as possible beginning with a certain letter of the alphabet over two 60-second trials (cues F and L(28)). Category-cued verbal fluency assessed rapid access to semantic information by asking patients to name as many items of a given semantic category as possible over J o u r n a l P r e -p r o o f two 60-second trials (cues animals and vegetables (28) ). Standardized scores were derived from age-adjusted published normative data (28, 30, 31) . A global cognitive composite was computed as the mean of age-adjusted standardized scores across up to 8 available cognitive scores. 1.6. Missing data. One patient declined to report race and two declined to report ethnicity.

Four patients could not complete Oral Trail Making Test part B and one declined to attempt the task. An additional patient declined to complete the letter and category fluency tasks as well as the GAD-7. Those with missing cognitive data were similar to those with complete data with respect to age, sex, racial/ethnic minority status, education, estimated IQ, cognitive composite scores, and psychiatric and functional assessment scores (ps > 0.05). Because neurologically healthy individuals may produce one or more low test scores on a cognitive battery, reliance on a single low score may increase the likelihood of false positive findings of impairment (38) (39) (40) . The likelihood of obtaining one or more low scores increases along with the number of tests in the battery (39, 40) . Based on the binomial probability distribution, in a cognitive battery such as this yielding 8 primary scores, there is a 10% probability that 2 scores will exceed the ≥1.5 standard deviation cutoff for mild/moderate impairment and a 1% probability that 2 scores will exceed the ≥2 standard deviation cutoff for severe impairment (41) . Tests for the significance of proportions determined whether the observed proportion of individuals within each clinic producing at least 2 scores ≥1.5 and ≥2 standard deviations below demographic means exceeded expectation (i.e., 10% and 1% probabilities, respectively). (59%) required >48 hours of ICU care (i.e., post-ICU clinic). The majority were women (59%) and members of racial/ethnic minority groups. The mean (SD) age was 54.5 (14.6) years. The majority (95%) had at least a high school (12 year) education with mean (SD) 14.7 (3.1) years. The mean (SD) estimated IQ score was 98.2 (8.6). Post-ICU patients were older and had fewer years of education as well as lower estimated IQ scores than non-ICU patients but did not differ with respect to sex, race, ethnicity, or time since initial COVID-19 diagnosis. See Table 1 . Severe impairment was most common on a test of processing speed (29%).

2.3. Mental health and functioning. Scores on the PHQ-9, GAD-7, and QDRS did not differ based on ICU status (all p > 0.05). Overall, 78% of PACT patients produced ≥ 1 mildly elevated score across measures of psychiatric distress and functional decline (74% non-ICU, 81% post-ICU), with 35% producing ≥ 1 moderately elevated score across these measures (35% non-ICU, 35% post-ICU). Mildly elevated PHQ-9 or GAD-7 were reported by 70% of PACT patients, with 27% reporting moderate to severe elevations.

Additionally, 62% and 69% of patients reported mild functional declines on the QDRS across non-ICU and post-ICU clinics, with 18% and 13% reporting moderate functional declines, respectively. One quarter of post-ICU patients reported symptomatic levels of trauma-related distress on the IES-6. See Table 3 .

Global cognitive composite scores were not associated with scores on the PHQ-9, GAD-7, IES-6 or QDRS (all p > 0.08). infection on an inpatient rehabilitation unit showed mild to severe cognitive impairment on a battery assessing memory and executive functioning, with deficits occurring most frequently in working memory, set shifting, divided, attention, and processing speed (43) .

Two studies have examined cognition in relatively younger and seemingly less severely ill patients early in the post-acute phase. Among 35 previously cognitively healthy COVID-19 survivors in Spain (age 24 -60 years) who were tested 10 to 35 days after hospital discharge, severe impairments (T score ≤ 30) were most frequent on tests of letter-cued verbal fluency (11%), mental flexibility (9%), and working memory (9%), with less frequent deficits (6%) observed on tests of processing speed, category-cued verbal fluency, attention, learning, and memory (44) . Subjective cognitive complaints were associated with the severity of anxiety and depressive symptoms, but not objective cognitive performance. A group of 29 hospitalized adults in China (ages 30 -64 years) underwent tablet-based cognitive testing of select cognitive domains 2 to 3 weeks after COVID-19 infection. Patients performed more poorly than age-and sex-matched peers on aspects of sustained attention but did not differ from controls with respect to processing speed, executive functioning, attention, or working memory nor did they report elevated symptoms of anxiety or depression (45) .

Data on longer-term cognitive outcomes following COVID-19 is just starting to take shape and suggest that outcomes may vary based on markers of disease severity. Of 179 previously cognitively and psychiatrically healthy patients in Spain (age 22 -81) assessed roughly two months after hospital discharge, 58% demonstrated moderate deficits (T score ≤ 40) on at least one of four cognitive tests, most frequently learning and category-cued verbal fluency. Clinically elevated symptoms of depression, anxiety and/or trauma were reported by 39% of patients (46) . In contrast, in an Australian sample of 78 patients tested two to three months post-diagnosis and of whom only 12% required hospitalization, objective cognitive impairment was demonstrated by only 10% of patients, most frequently on a test of psychomotor speed, with most deficits (63%) being of mild severity (47) . Symptoms of depression were reported by 21%. More recently, a prospective US cohort of 100 nonhospitalized patients found high rates of relatively young individuals (mean age 43 ± 11), females (70%) and those with pre-existing anxiety/depression (42%) and autoimmune disease (16%) presented to a post-COVID clinic. When assessed five to six months post-illness there was no difference in subjective rates of "brain fog" or cognition-related quality of life between those who had tested positive versus negative for SARS-CoV-2. Among a smaller subset undergoing objective assessment (n = 34), the groups did not differ in their performance on a brief cognitive battery though the SARS-CoV-2 positive group did underperform relative to demographic controls on measures of attention and working memory (48) . patients is warranted (6) (7) (8) . While depression has been found to independently predict long-term cognitive impairment in survivors of critical illness(49), the current study did not find psychiatric symptoms to track with the intensity of treatment or severity of cognitive dysfunction. More work is needed in order to understand the mechanisms driving cognitive and psychiatric morbidity among individuals treated for COVID-19.

The current study reflects a detailed assessment of cognitive functioning, psychiatric distress, and functional decline in a sample of clinically-referred COVID-19 patients during the post-acute phase. Patients spanned a wide age range and were of diverse racial and ethnic backgrounds. They varied in disease severity and level of care required during the acute phase of illness. Patients were not excluded based on pre-existing medical or neurological conditions; rather, findings reflect the neuropsychiatric functioning of patients who are likely to receive treatment in a post-acute COVID-19 pulmonary clinic. We employed a comprehensive battery and methodologically rigorous definitions of cognitive impairment. Assessments also occurred later in the post-acute phase than has previously been explored and provide novel data on the potential duration of neuropsychiatric sequelae among COVID-19 survivors.

The study findings are limited by the selective nature of patients seen in the JH PACT clinic and are not generalizable to those who do not seek outpatient post-COVID-19 care. As these are clinically referred patients, we also lack baseline data that could help determine the extent to which observed cognitive and psychiatric dysfunction reflects sequelae of COVID-19

illness. Further, ours is one of the first dedicated COVID-19 survivorship clinics in the US, with data collection beginning relatively early in the pandemic (22) . As such, we were unable to recruit healthy controls and instead relied on published normative data to establish rates of poor cognitive performance. The normative data for some tests were derived from samples that were relatively older and less racially and ethnically diverse than our own (28) . The use of regressionbased norms allowed for standardization of obtained cognitive scores for younger individuals J o u r n a l P r e -p r o o f who were not well represented in the normative dataset. The finding that a substantial proportion of patients showed cognitive impairment even when applying norms for older adults suggests that the extent of cognitive dysfunction in younger COVID-19 survivors may be higher than appreciated in the current study. Additionally, our finding that within racial/ethnic minority patients, those treated in ICU for ≥48 hours tended to perform more poorly than those requiring less intensive treatment while not differing in age, education, or intelligence suggests that disease severity rather than systematic biases in clinic makeup underly the observation of poorer cognition outcomes in ICU survivors. Further work is needed to elucidate and combat systemic inequalities that are contributing to the disproportional impact of the COVID-19 pandemic among racial minority groups. We may have underestimated rates of executive functioning by excluding those who could not complete the tasks rather than classifying these individuals as impaired. Finally, study data were collected over seven months in which rapid advances were made in the treatment of COVID-19. It remains to be seen whether neuropsychiatric outcomes will improve in parallel with treatment advances.

The current study's findings of persistent cognitive deficits, psychiatric symptoms, and functional decline at approximately 4 months post-diagnosis help extend our understanding of the breadth, severity, and potential duration of neuropsychiatric morbidity among patients presenting to a post-COVID-19 clinic. Consistent with reports that racial and ethnic minority groups are disproportionately impacted by the pandemic, minority patients composed the majority of individuals receiving care in the JH PACT clinic (20, 21) . This underscores the need for greater representation of minority groups in COVID-19 research in order to further understand the full impact of COVID-19 in vulnerable and traditionally underrepresented groups.

Findings highlight the need for multidisciplinary integrated care teams aimed at providing comprehensive survivorship care for COVID-19 survivors throughout the recovery process. Abbreviations: IES-6, Impact of Events Scale-6; PHQ-9, Patient Health Questionaire-9; GAD-7, Generalized Anxiety Disorder-7; QDRS, Quick Dementia Rating Scale * n = 81 † n = 33 J o u r n a l P r e -p r o o f * Note, age-adjusted standard scores have a mean of 100 and standard deviation = 15, with higher scores reflecting better performance. The cognitive composite was computed as the mean of age-adjusted standard scores across the cognitive scores. Proportion of PACT patients producing scores at or below cutoffs for mild/moderate and severe cognitive impairment across cognitive tests

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Long-term neurological threats of COVID-19: a call to update the thinking about the outcomes of the coronavirus pandemic

Cognitive impact of COVID-19: looking beyond the short term

Neurological infection with SARS-CoV-2-the story so far

Survivorship after COVID-19 ICU stay

Longterm cognitive impairment after critical illness

Posttraumatic stress disorder in critical illness survivors: a metaanalysis

Depressive symptoms after critical illness: a systematic review and meta-analysis

Neurologic features in severe SARS-CoV-2 infection

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors

Bidirectional associations between COVID-19 and psychiatric disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA

Neuropsychological Features of Severe Hospitalized Coronavirus Disease 2019 Patients at Clinical Stability and Clues for Postacute Rehabilitation

Functional and cognitive outcomes after COVID-19 delirium

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

Frequent neurocognitive deficits after recovery from mild COVID-19

Prolonged Neuropsychological Deficits, Central Nervous System Involvement, and Brain Stem Affection After COVID-19-A Case Series

Post-acute cognitive and mental health outcomes among COVID-19 survivors: Early findings and a call for further investigation

Epub ahead of print

Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis

Characteristics associated with Racial/Ethnic disparities in COVID-19 outcomes in an academic health care system

SARS-CoV-2 positivity rate for Latinos in the

The Johns Hopkins Post-Acute COVID-19 Team (PACT): A Multidisciplinary, Collaborative, Ambulatory Framework Supporting COVID-19 Survivors

Comparison of models of premorbid IQ estimation using the TOPF, OPIE-3, and Barona equation, with corrections for the Flynn effect

Patient Satisfaction with Telephone Neuropsychological Assessment

Telephone-based screening tools for mild cognitive impairment and dementia in aging studies: a review of validated instruments

Cognitive Assessment via Telephone: A Scoping Review of Instruments

Latent Structure of a Brief Clinical Battery of Neuropsychological Tests Administered In-Home Via Telephone

Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS)

A compendium of neuropsychological tests: Administration, norms, and commentary

Auditory Verbal Learning Test : RAVLT : a handbook

The Oral Trail Making Test: Effects of age and concurrent validity

The PHQ-9

A Brief Measure for Assessing Generalized Anxiety Disorder

Brief measure of posttraumatic stress reactions: Impact of Event Scale-6

Screening for posttraumatic stress disorder in ARDS survivors: validation of the

Use of the Quick Dementia Rating System (QDRS) as an Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer's Disease

The Quick Dementia Rating System (Qdrs): a Rapid Dementia Staging Tool

Abnormal" neuropsychological scores and variability are common in healthy adults

Frequency and bases of abnormal performance by healthy adults on neuropsychological testing

The association between the number of neuropsychological measures and the base rate of low scores

An empirical approach to determining criteria for abnormality in test batteries with multiple measures

Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom

Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19

Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment

The landscape of cognitive function in recovered COVID-19 patients

Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors

Persistent symptoms up to four months after community and hospital-managed SARS-CoV-2 infection

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

Estimated IQ (mean (sd)

Number Span Forward (mean (sd)

Number Span Backward (mean (sd)

Letter-cued Verbal Fluency (mean (sd); range)

Category-cued Verbal Fluency (mean (sd)

GAD-7 (mean (sd)