Long-term outcomes of patients with Parkinson’s disease 3.5 years post SARS-CoV-2 infection in an inner-city population in the Bronx

doi:10.21203/rs.3.rs-4373059/v1

Download PDF

Article

Long-term outcomes of patients with Parkinson’s disease 3.5 years post SARS-CoV-2 infection in an inner-city population in the Bronx

https://doi.org/10.21203/rs.3.rs-4373059/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objectives.

Although patients with pre-existing Parkinson’s disease (PD) are at a higher risk of severe acute COVID-19 outcomes compared to matched controls, the long-term outcomes of PD patients post SARS-CoV2 infection are largely unknown. This study investigated the clinical outcomes of patients with pre-existing PD up to 3.5 years post-infection in an inner-city population in the Bronx, New York.

Methods.

This retrospective study evaluated 3,512 patients with PD in the Montefiore Health System in the Bronx (January 2016 to July 2023), which serves a large Black and Hispanic population and was an epicenter of the early COVID-19 pandemic and subsequent surges of infections. COVID-19 status was defined by a positive polymerase-chain-reaction test. Comparisons were made with patients without a positive COVID-19 test. Outcomes were post-index date all-cause mortality, major adverse cardiovascular events (MACE), altered mental status, fatigue, dyspnea, headache, psychosis, dementia, depression, anxiety, dysphagia, falls, and orthostatic hypotension. Changes in Levodopa, a PD medication, prescriptions were also tabulated. Adjusted hazard ratios (aHR) were computed accounting for competing risks.

Results.

About 14% of PD patients had a positive COVID-19 test. PD patients with COVID-19 had similar demographics but a higher prevalence of pre-existing comorbidities and neurological disorders compared to PD patients without COVID-19. PD patients with COVID-19 had greater risk of mortality (aHR = 1.58 [95% CI:1.03,2.41] P = 0.03), MACE (HR = 1.57[95% CI:1.19,2.07], P < 0.005), dyspnea (aHR = 1.44 [1.11,1.87], P < 0.01), fatigue (aHR = 1.49 [1.12,1.97] P < 0.01), headache (HR = 1.35 [1.01,1.80] P = 0.04), and fall (aHR = 1.39 [1.01, 1.92] P = 0.04) compared to PD patients without COVID-19 up to 3.5 years post index-date. Levodopa equivalent dose adjustment was higher post-infection in the COVID-19 cohort compared to non-COVID-19 cohort (P < 0.04).

Conclusions.

PD patients with COVID-19 were at a higher risk of worse long-term outcomes compared to PD patients without COVID-19. Patients with PD who survive COVID-19 may benefit from heightened clinical awareness and close follow-up.

Health sciences/Medical research

Health sciences/Risk factors

Biological sciences/Microbiology/Virology/Sars cov 2

Health sciences/Diseases/Neurological disorders/Parkinsons disease

long covid

post-acute sequela of COVID-19 (PASC)

Parkinson’s disease

Patients with pre-existing Parkinson’s disease (PD) have been documented to be at a higher risk of severe acute manifestations of SARS-CoV-2 infection compared to matched controls without PD [1]. Acute SARS-CoV2 infection often triggers acute pulmonary and cardiovascular stress, pathologic hyperinflammation, hypercoagulable state, and secondary infections, which could have long lasting effects in some individuals. Indeed, many COVID-19 survivors reported post-infection COVID-19 symptoms [2–9], developed new COVID-19-related disorders [10–12], and/or experienced worsening of pre-existing medical conditions [13] months after acute SARS-CoV2 infection has resolved [14, 15], commonly referred to as long COVID. In individuals with pre-existing neurological disorders, including PD, SARS-CoV-2 infection may provoke accelerated neurodegenerative disease progression resulting in overall worse long-term outcomes compared to COVID-19 unexposed individuals. While studies have reported that patients with MS [16–25] show worsening of disease and long-term outcomes post SARS-CoV-2 infection compared to non-COVID matched controls, the potential impact of COVID-19 on the long-term outcomes of patients with pre-existing PD is largely unknown.

The goal of this study was to evaluate the long-term outcomes of patients with pre-existing PD up to 3.5 years post SARS-CoV-2 infection. Outcomes included all-cause mortality, major adverse cardiovascular events (MACE), and new-onset dyspnea, fatigue, headache, sleep disturbances, altered mental status, depression, anxiety, dementia, psychosis, fall, orthostatic hypotension, and dysphagia. The study population included patients seen in the Montefiore Health System, which serves a large, low-income, diverse population in the Bronx, New York and its environs, an epicenter of the early COVID-19 pandemic and subsequent surges of infection.

Data Sources

This study was approved by the Einstein-Montefiore Institutional Review Board (#2021–13658) with an exemption for informed consent. All data extraction and analysis were performed in accordance with the relevant guidelines and regulations. This single-center, retrospective cohort study was conducted at the Montefiore Health System consisting of multiple hospitals and outpatient clinics in the Bronx, the lower Hudson Valley, and Westchester County. Deidentified health data were made available for research after standardization to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) version 6. OMOP CDM represents healthcare data from diverse sources, stored in standard vocabulary concepts. This approach allows for the systematic analysis of disparate observational databases, including data from the electronic medical record (EMR), administrative claims, and disease classification systems (e.g., International Classification of Diseases, Tenth Revision (ICD-10), SNOMED, and LOINC). ATLAS, a web-based tool developed by the Observational Health Data Sciences and Informatics community that enables navigation of patient-level, observational data in the CDM format, was used to search vocabulary concepts and facilitate cohort building. Data was subsequently exported and queried as SQLite database files using the DB Browser for SQLite (version 3.12.2). To ensure data accuracy, we performed extensive cross-validation of all major variables by manual chart review on subsets of patients. Data extraction queried records from Jan 1, 2016 to Jul 1, 2023 from the Montefiore Health System, which includes multiple hospitals and outpatient clinics in the Bronx. Data were extracted as described previously [26–29]. The index date was defined as the date of positive polymerase chain reaction (PCR) COVID-19 test for COVID-19 patients and March 1, 2020 for non-COVID patients. There were 3,512 individuals with pre-existing PD at index date. The inclusion criteria for the COVID-19 cohort were as follows: 1) diagnosis of PD, 2) positive PCR COVID-19 test, 3) PD diagnosis occurring prior to positive PCR COVID-19 test, and 4) one or more visits to the Montefiore Health System fourteen days or more after their index date. The inclusion criteria for the non-COVID cohort were as follows: 1) diagnosis with PD prior to March 1, 2020, 2) no positive PCR COVID-19 test, or clinical history of COVID-19 in the EMR, and 3) one or more visits to the Montefiore Health System fourteen days or more after March 1, 2020. A few patients (less than 20) who had a documented positive result from antibody or at home COVID-19 test were excluded from both cohorts to limit COVID patients as being erroneously classified as non-COVID. Additionally, patients with a documented history of atypical Parkinsonian disorders were excluded from the study (40 patients). Studies using an earlier version of this large database to address different questions have been reported [10–13, 28–37].

Variables

Demographic data included age at index date, sex, race, and ethnicity. Pre-existing comorbidities included hypertension (HTN), type-2 diabetes (T2D), chronic obstructive pulmonary disease (COPD), asthma, congestive heart failure (CHF), chronic kidney disease (CKD), coronary artery disease (CAD) and obesity (defined as a body mass index of > 30 or a diagnosis of obesity) that were diagnosed at or prior to the index date. Tobacco use status was defined as the patient self-reporting tobacco use at any point in their lifetime. Pre-existing sleep disturbance, headaches, depression, anxiety, dementia, psychosis, orthostatic hypotension, and dysphagia were also tabulated. Steroid and antiviral treatments for acute COVID-19 were also tabulated. Critical illness was defined as having been treated with invasive mechanical ventilation or in intensive care unit.

Data about corticosteroid (hydrocortisone, methylprednisolone, dexamethasone, and prednisone) and antiviral drug (ritonavir and remdesivir) prescriptions for the treatment of COVID-19, and critical illness status (requiring intensive care unit or invasive mechanical ventilation) were collected.

Outcomes

The outcomes included all-cause mortality fourteen days or later after index date and major adverse cardiovascular events (MACE), defined as the composite of stroke, myocardial infarction, new-onset heart failure, and cardiogenic shock 30 days or more after index date. The secondary outcomes included development of the following conditions or symptoms 30 days or more post-index date: i) dyspnea, ii) fatigue (patient-reported symptom), iii) sleep disturbances (idiopathic insomnia, irregular sleep-wake pattern, or central sleep apnea), iv) altered mental status (due to any cause), v) headache (idiopathic migraine or headache), vi) depression (major depressive disorder diagnosis, PHQ-9 score of 10 or higher), and vii) anxiety (organic or generalized anxiety disorder diagnosis, GAD-7 score of 10 or higher, GAD-2 score of 3 or higher). PD-related outcomes included: i) dementia (newly documented diagnosis or newly prescribed donepezil, galantamine, rivastigmine, or memantine), ii) psychosis (newly documented diagnosis or newly prescribed quetiapine, clozapine, or pimavanserin), iii) fall, iv) orthostatic hypotension, and v) dysphagia. Patients who at index date had a history of anxiety, depression, sleep disturbances, headaches (only migraines), dementia, psychosis, orthostatic hypotension, and dysphagia were excluded from the analysis of the respective outcome.

To assess the impact of SARS-CoV-2 infection on PD medications, a history of PD medication prescriptions and their daily dosages were collected. PD medications included carbidopa, levodopa, entacapone, opicapone, selegiline, rasagiline, apomorphine, pramipexole, ropinirole, rotigotine, and amantadine. Using the daily dose and the active agent, the levodopa-equivalent dose (LED) of each prescription was calculated [38].

Analysis and Statistics

Python version 3.10.12 and the lifelines package, the survival, survminer, and cmprsk packages in RStudio version 4.3.2 (RStudio, PBC, Boston, MA), and GraphPad Prism 9 version 10.1.1 (GraphPad Software, Boston, Massachusetts USA) were used for data processing and statistical analyses. Group comparison of categorical variables used, chi-square test, and group comparison of continuous variables used the independent t-test. Kaplan-Meier curves and log-rank analysis were performed for all-cause mortality. Cumulative incidence function and Fine-Gray sub-distribution hazards model analysis were performed for post-index date for all other secondary outcomes associated with SARS-CoV-2 infection. In the univariate analysis, hazard ratios (HR) were computed using the Fine-Gray model to account for mortality as a competing risk for developing the outcomes. In addition, to adjust for other covariates, the multivariate Cox proportional hazards model was used to calculate adjusted hazard ratios (aHR) and 95% confidence interval (CI) for outcomes. The covariates included COVID-19 infection status, all comorbidities, sex, race, and ethnicity.

To analyze the impact of SARS-CoV-2 infection on the dosage of levodopa equivalent dose PD medications the Generalized Estimating Equations (GEE) model was used. Levodopa equivalent dose change is that of exponentiated coefficient of GEE model. The analysis considered several predictors, including the elapsed time since index date. COVID-19 status was treated as a binary variable, where patient observations shifted from 0 (before infection) to 1 (after infection) to assess immediate changes in medication doses. Additionally, an interaction term between the time from the baseline and COVID-19 status was included to examine long-term trend. Outcomes were adjusted for age, race, and ethnicity. The analysis was performed for male and female patients separately. Given the skewed distribution of the medication dose data, a log transformation was applied to normalize the distribution, with a constant of 1 added to accommodate medications with zero LED, particularly for patients on entacapone and opicapone, which don't directly contribute to the LED when prescribed without levodopa. The analysis utilized a Gaussian distribution assumption within the GEE framework to model the continuous outcome of LED. The choice of an autoregressive order 1 correlation structure was made to account for the correlation of repeated measures within the same patient over time.

P-values less than 0.05 were considered statistically significant.

Demographics

Among the 3,512 patients with pre-existing PD in the Montefiore Health System from Jan 1, 2016 to July 1, 2023, 434 (14%) had a documented positive COVID-19 PCR test and 3,078 did not (Fig. 1). Sixty-seven patients with COVID-19 (15.43%) died within the first two weeks of COVID-19 positive test. Excluding those who died and those who did not return to our health system, the final cohort used to assess long-term outcomes included 293 COVID-19 (17.7%) and 1649 non-COVID-19 patients with pre-existing PD.

PD patients with and without COVID-19 did not differ in terms of age or sex. PD patients with COVID-19 were less likely to be White and more likely to be Hispanic. PD patients with COVID-19 had a higher prevalence of all major pre-existing comorbidities (P < 0.05 for all) except tobacco use (P = 0.2). PD patients with COVID-19 also had a higher prevalence of pre-existing headache, depression, anxiety, dementia, and psychosis (P < 0.05 for all) (Table 1). Of the PD patients with COVID-19, 28.67% were treated with steroids, 29.01% were treated with antiviral drugs, and 2.05% had critical illness.

Table 1

Demographics & Comorbidities of COVID-19 and non-COVID-19 patients with pre-existing Parkinson’s disease (n = 1,942).
	COVID+ (n = 293)	COVID- (n = 1,649)	P values
Age at Index Date, mean ± SD (y)	75.54 ± 11.41	74.64 ± 11.48	0.22
Female, n (%)	152(51.88)	819(49.67)	0.53
Race and Ethnicity, n (%)
White	60(20.48)	437(26.50)	0.035
Black	76 (25.94)	359 (21.77)	0.13
Asian	9 (3.07)	47 (2.85)	0.98
Other Races	148 (50.51)	806 (48.88)	0.65
Hispanic	130 (44.37)	596 (36.14)	0.0089
Pre-Existing Comorbidities, n (%)
Hypertension	247(84.30)	1194(72.41)	< 0.0001
Type-2 Diabetes	172(58.70)	762(46.21)	0.0001
COPD	51(17.41)	156(9.46)	< 0.0001
Asthma	69(23.55)	227(13.77)	< 0.0001
Congestive Heart Failure	82(27.99)	244(14.80)	< 0.0001
Chronic Kidney Disease	114(38.91)	426(25.83)	< 0.0001
Coronary Artery Disease	117(39.93)	362(21.95)	< 0.0001
Current or Past Tobacco Use	113(38.57)	569(34.51)	0.2022
Obesity	82(27.99)	342(20.74)	0.0071
Pre-Existing Symptoms and Disorders, n (%)
Sleep disturbances	48(16.38)	209(12.67)	0.10
Headache	26(8.87)	66(4.00)	0.00053
Depression	100(34.13)	306(18.56)	< 0.0001
Anxiety	82(27.99)	323(19.59)	0.0015
Dementia	143(48.81)	573(34.75)	< 0.0001
Psychosis	50(17.06)	194(11.76)	0.015
Orthostatic Hypotension	23(7.85)	94(5.70)	0.120
Dysphagia	4(1.37)	6(0.36)	0.078
Acute COVID-19 Treatments, n (%)
Steroids	84(28.67)	N/A	N/A
Antiviral Drugs	85(29.01)	N/A	N/A
Critical Illness	6(2.05)	N/A	N/A

Outcomes

COVID-19 patients with PD had significantly higher all-cause mortality compared to non-COVID patients with PD (unadjusted log-rank HR = 2.06 [CI:1.39, 3.04] P = 0.0002) (Fig. 2). Notably, there was a comparatively higher risk of mortality within the first three months in the COVID-19 cohort.

Figure 2. Kaplan-Meier curve of all-cause mortality fourteen days or more post-index date between COVID-19 and non-COVID patients with PD.

SARS-CoV-2 infection was significantly associated with increased long-term risk of mortality (aHR = 1.58 [95% CI:1.03, 2.41] P = 0.03), along with age (aHR = 1.02 [1.00, 1.04] P = 0.01), CHF (aHR = 1.58 [1.07, 2.37] P = 0.02), and COPD (aHR = 1.80 [1.17, 2.77] P = 0.01). Other race vs. White was associated with a lower risk of mortality (aHR = 0.60 [0.38,0.94] P = 0.03) (Table 2).

Table 2

Cox proportional hazard ratios for (HR) for all-cause mortality.
Covariates	Hazard Ratio	95% [CI]	P value
Age (age)	1.02	1.00–1.04	0.01
SARS-CoV-2 Infection	1.58	1.03–2.41	0.03
Female vs. Male	0.74	0.53–1.03	0.08
Black vs. White	0.84	0.55–1.28	0.41
Asian vs. White	1.25	0.58–2.70	0.57
Other Race vs. White	0.60	0.38–0.94	0.03
Hispanic vs. Non-Hispanic	0.84	0.53–1.33	0.47
Hypertension	1.09	0.69–1.72	0.72
Type-2 Diabetes	1.27	0.88–1.82	0.20
Congestive Heart Failure	1.58	1.07–2.31	0.02
Chronic Obstructive Pulmonary Disease	1.80	1.17–2.77	0.01
Asthma	1.00	0.64–1.55	0.99
Coronary Artery Disease	1.18	0.82–1.70	0.36
Chronic Kidney Disease	1.40	0.97–2.00	0.07
Current or Past Tobacco Use	0.94	0.67–1.32	0.74
Obesity	1.13	0.77–1.66	0.53

Figure 3 shows the cumulative incidences for MACE, dyspnea, fatigue, sleep disturbances, altered mental status, headache, depression, and anxiety, as well as dementia, psychosis, fall, orthostatic hypotension, and dysphagia. Table 3 shows the results of univariate Fine-Gray HR and multivariate Cox proportional HR for the outcomes associated with SARS-CoV-2 infection. With the univariate analysis, SARS-CoV-2 infection was significantly associated with an increased long-term risk of MACE, dyspnea, and fatigue. With the multivariate analysis, SARS-CoV-2 infection was significantly associated with an increased long-term risk of MACE (aHR = 1.57 [95% CI:1.19,2.07], P < 0.005), dyspnea (aHR = 1.44 [1.11, 1.87], P < 0.01), fatigue (aHR = 1.49 [1.12, 1.97] P < 0.01), headache (aHR = 1.35 [1.01, 1.80] P = 0.04), and fall (aHR = 1.39 [1.01, 1.92] P = 0.04). In the multivariate model, sleep disturbances (P = 0.06) and dysphagia (P = 0.07) trended towards significant worsening in the COVID-19-exposed PD cohort.

Table 3

Univariate Fine-Gray HR and multivariate Cox proportional HR of post-index date outcomes. Hazard ratios (HR) show the relative risk of having the respective outcome if infected with SARS-CoV-2. Multivariate analysis adjusted for other covariates: all major comorbidities, sex, race, and ethnicity.
	Univariate			Multivariate
Outcomes	HR	95% [CI]	P value	HR	95% [CI]	P value
MACE	2.22	1.61–3.05	< 0.0001	1.72	1.31–2.26	< 0.005
Dyspnea	1.90	1.42–2.53	< 0.0001	1.44	1.11–1.87	0.01
Fatigue	1.65	1.17–2.33	0.004	1.49	1.12–1.97	0.01
Sleep disturbances	1.44	0.96–2.17	0.081	1.36	0.99–1.87	0.06
Altered Mental Status	1.29	0.82–2.03	0.27	1.29	0.90–1.77	0.17
Headache	1.43	0.98–2.07	0.061	1.35	1.01–1.80	0.04
Depression	1.08	0.82–1.43	0.57	1.35	0.89–2.04	0.16
Anxiety	1.11	0.82–151	0.49	1.28	0.85–1.93	0.24
Dementia	0.82	0.48–1.41	0.47	1.03	0.65–1.63	0.89
Psychosis	0.68	0.31–1.47	0.33	0.93	0.59–1.45	0.75
Fall	1.37	0.85–2.21	0.19	1.39	1.01–1.92	0.04
Orthostatic Hypotension	0.39	0.09–1.65	0.20	1.25	0.83–1.87	0.28
Dysphagia	1.37	0.94–1.98	0.10	1.47	0.97–2.23	0.07

Table 4 shows that the GEE analysis on the impact of COVID-19 infection on levodopa equivalent dose adjustments revealed a notable increase in levodopa equivalent dose for both genders post-infection. COVID-19 status was significantly associated with levodopa equivalent dose adjustments in both male and female. Males exhibited a slight but statistically significant decrease in medication dosage over time post-infection (0.22% per month since the index date, P = 0.018), whereas females showed a consistent medication dosage level over the observed period but not statistically significant (P = 0.842). Levodopa equivalent dose was not associated with race, ethnicity, or age.

Table 4

Associated changes in on levodopa equivalent dose after SARS-CoV-2 infection.
Variable	Males (n = 629)			Females (n = 633)
Variable	LED change	[95% CI]	P-value	LED change	[95% CI]	P-value
SARS-CoV-2 Infection	1.230	1.0100–1.4978	0.03	1.2473	1.0013–1.5537	0.04
Time Since Index Date (Months)	1.000	1.0000–1.0001	0.28	1.0001	1.0000–1.0002	0.01
Time Since Index Date × SARS-CoV-2 Infection	0.9978	0.9961–0.9996	0.01	1.0000	0.9995–1.0004	0.84
Asian vs. White	0.8566	0.5187–1.4146	0.54	0.9044	0.519–1.5762	0.72
Back vs. White	0.9721	0.7961–1.1870	0.78	0.9965	0.8223–1.2075	0.97
Hispanic vs. Non-Hispanic	0.9308	0.7854–1.1033	0.40	0.9990	0.8466–1.1788	0.99
Other Race vs. White	1.0369	0.8745–1.2295	0.67	1.2080	0.9866–1.4792	0.06
Age	0.9962	0.9901–1.0022	0.21	0.9995	0.9931–1.0059	0.87

This study investigated the clinical outcomes of patients with pre-existing PD up to 3.5 years post-SARS-CoV-2 infection in a large, low-income, racially and ethnically diverse population in the Bronx, New York. The major findings are that SARS-CoV-2 infection was significantly associated with higher risk for mortality, MACE, dyspnea, fatigue, headache, and fall in PD patients. Levodopa equivalent dose adjustment was higher post-infection in the COVID-19 patients PD compared to non-COVID-19 patients with PD.

About 14% of PD patients had a positive COVID-19 test. A meta-analysis in 2021 estimated the average SARS-CoV-2 infection rate to be approximately 4%. SARS-CoV-2 infection rates are highly dependent on region, COVID-19 testing rate, duration over which the study included, and the populations being studied [39]. The Bronx was hit hard by the initial pandemic and subsequent waves and minority populations have been reported to be at a high risk of infection [27]. PD patients infected with SARS-CoV-2 had a higher prevalence of major comorbidities compared to their non-COVID counterparts. In addition, we also found that PD patients infected with SARS-CoV-2 also had a higher prevalence of pre-existing neuropsychiatric conditions such as depression and anxiety compared to those without SARS-CoV-2 infection. The high prevalence of major comorbidities and neuropsychiatric conditions among PD patient cohort could further contribution to the comparatively high infection rate.

PD patients with COVID-19 showed increased mortality risk, most prominent in the first three months post infection, suggesting such risk was COVID-19 related. The adjusted hazard ratio for long-term risk for mortality of PD patients with SARS-CoV-2 infection over the study period was 1.58 times higher than PD patients without COVID-19. This risk was comparable to risk posed by pre-existing COPD (aHR = 1.80) and CHF (aHR = 1.58), underscoring the contribution of SARS-CoV-2 infection to long-term mortality. Age was also a significant risk factor as expected with a 2% increased risk for every year of age.

PD patients who survived acute SARS-CoV-2 infection also had a higher adjusted long-term risk of developing MACE compared to controls COVID-19 patients without PD have previously been shown to have increased incidence of long-term MACE [40, 41], presumably secondary to the impact of infection on acute pulmonary and cardiovascular stress. SARS-CoV-2 infection was significantly associated with higher adjusted risk for dyspnea, fatigue, headache, and fall in PD patients up to 3.5 years post infection. Sleep disturbance and dysphagia trended towards significant worsening in the COVID-19-exposed PD cohort. Although many of these symptoms occur in PD patients, most are non-specific to PD. Our cohort consisted of a large proportion of minorities. We found Other Races (non-White, non-Black, and non-Asian) to be at a lower risk of long-term mortality than White. These health disparity data need to be interpreted with caution because our cohort consisted of a relatively small proportion of White.

Similar studies of longer-term outcomes of PD patients with COVID-19 are sparse. None thus far have directly compared the long-term outcomes of PD patients, with and without a history of SARS-CoV-2 infection. Bougea et al. [42] studied PD patients with COVID-19 at baseline and at six months post-infection using clinicodemographic questionnaire. They found that among those with who reported post-COVID-19 syndrome, levodopa equivalent daily dose and Unified Parkinson’s Disease Rating Scale Part III increased after infection, indicating possibly elevated disease activity. Weiss et al. [43] analyzed data from over 2000 individuals with PD six months to two years post COVID-19 in Germany. Their analysis revealed that at follow-up, depression and fatigue were associated with difficulties with daily activities, perceived health-related quality of life, chronic exhaustion, unrestful sleep, and impaired concentration. Brown et al. [44] demonstrated that during the first two months of the pandemic, PD patients with COVID-19 experienced higher incidence of worsening and new occurrence of a variety of PD symptoms compared to non-COVID PD patients. Our outcome measures and findings are novel.

Mechanisms

Elevated long-term adverse outcomes among COVID-19 patients could be the result of an acute systemic inflammatory response [45]. SARS-CoV-2 could trigger cytokine storm, interleukin, and tumor necrosis factor (TNF) release [46]. SARS-CoV-2 may induce neuroinflammation and dopaminergic degeneration by triggering proinflammatory cytokines in microglia [45]. Persistent chronic inflammation and neuronal damage post SARS-CoV-2 infection could contribute to worse long-term outcomes. Biomarkers for central nervous system injury in cerebrospinal fluid have been found to be elevated in patients with COVID-19 and associated with neurological symptoms and disease severity [47]. These markers included neurofilament light chain protein, tau, and glial fibrillary acidic protein [47]. Notably, Wang et al. [48] report that the spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. They found that the S1 domain interacts with α-synuclein and promotes α-synuclein aggregation, which may contribute to PD pathogenesis. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-synuclein fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-synuclein in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.

Social Impact of Pandemic on PD Outcomes:

In addition to direct or indirect effects of SARS-CoV-2 infection on outcomes, the social impact of the pandemic, such as the effects of isolation, psychological stress, reduced physical activity, unhealthy diet, and reduced access to care, could also increase stress and exacerbate PD symptoms, resulting in overall worse long-term outcomes [49, 50]. Patients with PD exhibit cognitive and motor inflexibility, are more likely to have anxiety and depression, and are more susceptible to the effects of psychological stress [51, 52]. Increased stress levels during the COVID-19 pandemic could worsen various motor symptoms and reduce the efficacy of dopaminergic medication [50, 53]. Rezayi et al. [54] found negative effects of the COVID-19 pandemic on health-related quality of life and its determinants in patients with PD and their caregivers. Kataoka et al. [55] found that during the early COVID-19 pandemic, there was an increase in the severity of depression in patients with PD. Kinger et al. [56] conducted a survey study of PD patients before and during the COVID-19 pandemic and found a significant increase in apathy, but not in depression or anxiety, during the pandemic. Anxiety and depression, but not apathy, were correlated with the impact of COVID-19. The COVID-19 pandemic also resulted in worsening of sleep, cognitive disturbances, autonomic dysfunction, anxiety, depression, appetite disorders, repeated falls, and pain in PD patients [44]. We found psychiatric symptoms (depression, anxiety, psychosis) were not significantly different between COVID-19 and non-COVID-19 patients with PD 3.5 years post-infection, and these findings of suggest that these symptoms might be in part a result of social impact of COVID-19, more than the virus itself.

Outcomes of patients with other neurological conditions

Worse post-infection disease activity and other outcomes are not unique to individuals with PD. COVID-19 has been associated with an elevated post infection long-term risk of mortality, optic neuritis, all-cause re-hospitalization [57], increasing disability scores [23], neurological worsening [25], new Gd-enhancing MRI lesions [23] and other adverse outcomes [16–22] in patients with multiple sclerosis.

Strengths and Limitations

The strength of this study included a long follow-up time of 3.5 years post infection, a large sample size, and diverse and underserved population. This study has several limitations. Some PD patients may have been erroneously mischaracterized as COVID-19 negative. Some variables (i.e., diagnosis of new onset conditions) might not documented in our health system if patients were seen elsewhere for follow-up care and treatment. However, we expect such errors or misclassification occurred similarly in both groups and should not alter our overall conclusions. Our findings were limited to patients who returned to our health system. Although patient records included those who returned for any medical reason, including but not limited to routine office visits, patients who came to our health system could likely have had more severe COVID-19 and thus might not be representative of the general population at large. Outcomes might be affected by other factors including the COVID-19 vaccinations, strain of SARS-CoV-2, and disease severity. Vaccine status was not reliably recorded if patients received vaccines outside of the Montefiore Health System, and thus was not included in our analysis. Disease features such as PD stage and age of PD onset, which have been shown to predict post-COVID-19 recovery [58], were not consistently available, and therefore not included. Future studies should correlate PD disease activity with COVID-19-related hyperinflammatory markers, track PD symptoms and progression prospectively post-SARS-CoV-2 infection and identify risk factors for worse outcomes post-SARS-CoV2 infection. Given the retrospective nature of the study, there could be other unintended patient selection biases and latent confounding.

This was the first study to assess the long-term outcomes of patients with PD up to 3.5 years post SARS-CoV-2 infection in an inner-city underserved population. PD patients with COVID-19 had a greater adjusted risk of long-term mortality, greater adjusted risk of developing a major adverse cardiovascular event, dyspnea, fatigue, headache, and fall compared to PD patients without COVID-19. Patients with PD who survive COVID-19 may benefit from additional clinical follow-up.

Author Contribution

R.H.: conceptualization, formal analysis, investigation, methodology, validation, visualization, writing—original draft, writing—review & editing. Y.A.: conceptualization, formal analysis, investigation, methodology, validation, visualization, writing—review & editing. H.P.: methodology, writing—original draft, writing—review & editing. R.P.: formal analysis, investigation, methodology, validation, visualization.K.D.: investigation, methodology, validation, writing—original draft, writing—review & editing.H.J.: conceptualization, formal analysis, investigation, methodology, writing—original draft.S.W.: conceptualization, methodology, validation, writing—review & editing.S.H.: data curation, methodology, validation, writing—review & editing.C.M.: conceptualization, methodology, supervision, writing—review & editing.T.D.: conceptualization, data curation, investigation, methodology, project administration, supervision, writing—original draft, writing—review & editing.

Data Availability

The data used in this study are available upon request to the corresponding author.

El-Qushayri AE, Ghozy S, Reda A, Kamel AMA, Abbas AS, Dmytriw AA. The impact of Parkinson's disease on manifestations and outcomes of Covid-19 patients: A systematic review and meta-analysis. Rev Med Virol. 2022; 32(2):e2278. 10.1002/rmv.2278 PMID: 34260773
Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020; 324(6):603-5. 10.1001/jama.2020.12603 PMID: 32644129
Carvalho-Schneider C, Laurent E, Lemaignen A, Beaufils E, Bourbao-Tournois C, Laribi S, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021; 27(2):258 – 63. 10.1016/j.cmi.2020.09.052 PMID: 33031948
Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re'em Y, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021; 38:101019. 10.1016/j.eclinm.2021.101019 PMID: 34308300
Iosifescu AL, Hoogenboom WS, Buczek AJ, Fleysher R, Duong TQ. New-onset and persistent neurological and psychiatric sequelae of COVID-19 compared to influenza: A retrospective cohort study in a large New York City healthcare network. Int J Methods Psychiatr Res. 2022; 31(3):e1914. 10.1002/mpr.1914 PMID: 35706352
Rubin R. As Their Numbers Grow, COVID-19 "Long Haulers" Stump Experts. JAMA. 2020; 324(14):1381-3. 10.1001/jama.2020.17709 PMID: 32965460
Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021; 8(5):1073-85. 10.1002/acn3.51350 PMID: 33755344
Moghimi N, Di Napoli M, Biller J, Siegler JE, Shekhar R, McCullough LD, et al. The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection. Curr Neurol Neurosci Rep. 2021; 21(9):44. 10.1007/s11910-021-01130-1 PMID: 34181102
Wang F, Kream RM, Stefano GB. Long-Term Respiratory and Neurological Sequelae of COVID-19. Med Sci Monit. 2020; 26:e928996. 10.12659/MSM.928996 PMID: 33177481
Lu JQ, Lu JY, Wang W, Liu Y, Buczek A, Fleysher R, et al. Clinical predictors of acute cardiac injury and normalization of troponin after hospital discharge from COVID-19. EBioMedicine. 2022:103821. 10.1016/j.ebiom.2022.103821 PMID: 35144887
Lu JY, Wilson J, Hou W, Fleysher R, Herold BC, Herold KC, et al. Incidence of new-onset in-hospital and persistent diabetes in COVID-19 patients: comparison with influenza. EBioMedicine. 2023; 90:104487. 10.1016/j.ebiom.2023.104487 PMID: 36857969
Zhang V, Fisher M, Hou W, Zhang L, Duong TQ. Incidence of New-Onset Hypertension Post-COVID-19: Comparison With Influenza. Hypertension. 2023; 80(10):2135-48. 10.1161/HYPERTENSIONAHA.123.21174 PMID: 37602375
Xu AY, Wang SH, Duong TQ. Patients with prediabetes are at greater risk of developing diabetes 5 months postacute SARS-CoV-2 infection: a retrospective cohort study. BMJ Open Diabetes Res Care. 2023; 11(3):e003257. 10.1136/bmjdrc-2022-003257 PMID: 37295808
Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022; 101:93–135. 10.1016/j.bbi.2021.12.020 PMID: 34973396
Ballering AV, van Zon SKR, Olde Hartman TC, Rosmalen JGM, Lifelines Corona Research I. Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. Lancet. 2022; 400(10350):452 – 61. 10.1016/S0140-6736(22)01214-4 PMID: 35934007
Etemadifar M, Abhari AP, Nouri H, Salari M, Maleki S, Amin A, et al. Does COVID-19 increase the long-term relapsing-remitting multiple sclerosis clinical activity? A cohort study. BMC Neurol. 2022; 22(1):64. 10.1186/s12883-022-02590-9 PMID: 35193507
Babtain F, Bajafar A, Nazmi O, Badawi M, Basndwah A, Bushnag A, et al. The disease course of multiple sclerosis before and during COVID-19 pandemic: A retrospective five-year study. Mult Scler Relat Disord. 2022; 65:103985. 10.1016/j.msard.2022.103985 PMID: 35759904
Etemadifar M, Sedaghat N, Aghababaee A, Kargaran PK, Maracy MR, Ganjalikhani-Hakemi M, et al. COVID-19 and the Risk of Relapse in Multiple Sclerosis Patients: A Fight with No Bystander Effect? Mult Scler Relat Disord. 2021; 51:102915. 10.1016/j.msard.2021.102915 PMID: 33799284
Vercellino M, Bosa C, Alteno A, Muccio F, Marasciulo S, Garelli P, et al. SARS-CoV-2 pandemic as a model to assess the relationship between intercurrent viral infections and disease activity in Multiple Sclerosis: A propensity score matched case-control study. Mult Scler Relat Disord. 2023; 74:104715. 10.1016/j.msard.2023.104715 PMID: 37058763
Montini F, Nozzolillo A, Tedone N, Mistri D, Rancoita PM, Zanetta C, et al. COVID-19 has no impact on disease activity, progression and cognitive performance in people with multiple sclerosis: a 2-year study. J Neurol Neurosurg Psychiatry. 2023. 10.1136/jnnp-2023-332073 PMID: 37857497
Bsteh G, Assar H, Gradl C, Heschl B, Hiller MS, Krajnc N, et al. Long-term outcome after COVID-19 infection in multiple sclerosis: a nation-wide multicenter matched-control study. Eur J Neurol. 2022. 10.1111/ene.15477 PMID: 35751475
Andersen ML, Zegers FD, Jolving LR, Knudsen T, Stenager E, Norgard BM. Patients with multiple sclerosis: COVID-19 related disease activity and hospitalisations based on a nationwide cohort study. Mult Scler Relat Disord. 2023; 79:105031. 10.1016/j.msard.2023.105031 PMID: 37778157
Rahmani M, Moghadasi AN, Shahi S, Eskandarieh S, Azizi H, Hasanzadeh A, et al. COVID-19 and its implications on the clinico-radiological course of multiple sclerosis: A case-control study. Med Clin (Barc). 2023; 160(5):187 – 92. 10.1016/j.medcli.2022.06.020 PMID: 36089420
Peeters G, Van Remoortel A, Nagels G, Van Schependom J, D'Haeseleer M. Occurrence and Severity of Coronavirus Disease 2019 Are Associated With Clinical Disability Worsening in Patients With Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023; 10(3). 10.1212/NXI.0000000000200089 PMID: 36807080
Conway SE, Healy BC, Zurawski J, Severson C, Kaplan T, Stazzone L, et al. COVID-19 severity is associated with worsened neurological outcomes in multiple sclerosis and related disorders. Mult Scler Relat Disord. 2022; 63:103946. 10.1016/j.msard.2022.103946 PMID: 35709663
Hoogenboom WS, Fleysher R, Soby S, Mirhaji P, Mitchell WB, Morrone KA, et al. Individuals with sickle cell disease and sickle cell trait demonstrate no increase in mortality or critical illness from COVID-19 - A fifteen hospital observational study in the Bronx, New York. Haematologica. 2021; 106(11):3014-6. 10.3324/haematol.2021.279222 PMID: 34348452
Hoogenboom WS, Pham A, Anand H, Fleysher R, Buczek A, Soby S, et al. Clinical characteristics of the first and second COVID-19 waves in the Bronx, New York: A retrospective cohort study. Lancet Reg Health Am. 2021; 3:100041. 10.1016/j.lana.2021.100041 PMID: 34423331
Lu JY, Ho SL, Buczek A, Fleysher R, Hou W, Chacko K, et al. Clinical predictors of recovery of COVID-19 associated-abnormal liver function test 2 months after hospital discharge. Sci Rep. 2022; 12(1):17972. 10.1038/s41598-022-22741-9 PMID: 36289394
Lu JY, Hou W, Duong TQ. Longitudinal prediction of hospital-acquired acute kidney injury in COVID-19: a two-center study. Infection. 2022; 50(1):109 – 19. 10.1007/s15010-021-01646-1 PMID: 34176087
Lu JY, Boparai MS, Shi C, Henninger EM, Rangareddy M, Veeraraghavan S, et al. Long-term outcomes of COVID-19 survivors with hospital AKI: association with time to recovery from AKI. Nephrol Dial Transplant. 2023. 10.1093/ndt/gfad020 PMID: 36702551
Dell'Aquila K, Lee J, Wang SH, Alamuri TT, Jennings R, Tang H, et al. Incidence, characteristics, risk factors and outcomes of diabetic ketoacidosis in COVID-19 patients: Comparison with influenza and pre-pandemic data. Diabetes Obes Metab. 2023. 10.1111/dom.15120 PMID: 37254311
Feit A, Gordon M, Alamuri TT, Hou W, Mitchell WB, Manwani D, et al. Long-term clinical outcomes and healthcare utilization of sickle cell disease patients with COVID-19: A 2.5-year follow-up study. Eur J Haematol. 2023; 111(4):636 – 43. 10.1111/ejh.14058 PMID: 37492929
Eligulashvili A, Darrell M, Miller C, Lee J, Congdon S, Lee JS, et al. COVID-19 Patients in the COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx. Diagnostics (Basel). 2022; 13(1):119. 10.3390/diagnostics13010119 PMID: 36611411
Lu JY, Buczek A, Fleysher R, Musheyev B, Henninger EM, Jabbery K, et al. Characteristics of COVID-19 patients with multiorgan injury across the pandemic in a large academic health system in the Bronx, New York. Heliyon. 2023; 9(4):e15277. 10.1016/j.heliyon.2023.e15277 PMID: 37051049
Lu JY, Buczek A, Fleysher R, Hoogenboom WS, Hou W, Rodriguez CJ, et al. Outcomes of Hospitalized Patients With COVID-19 With Acute Kidney Injury and Acute Cardiac Injury. Front Cardiovasc Med. 2021; 8:798897. 10.3389/fcvm.2021.798897 PMID: 35242818
Eligulashvili A, Gordon M, Lee JS, Lee J, Mehrotra-Varma S, Mehrotra-Varma J, et al. Long-term outcomes of hospitalized patients with SARS-CoV-2/COVID-19 with and without neurological involvement: 3-year follow-up assessment. PLoS Med. 2024; 21(4):e1004263. 10.1371/journal.pmed.1004263 PMID: 38573873
Eligulashvili A, Darrell M, Gordon M, Jerome W, Fiori KP, Congdon S, et al. Patients with unmet social needs are at higher risks of developing severe long COVID-19 symptoms and neuropsychiatric sequela. Sci Rep. 2024; 14(1):7743. 10.1038/s41598-024-58430-y PMID: 38565574
Schade S, Mollenhauer B, Trenkwalder C. Levodopa Equivalent Dose Conversion Factors: An Updated Proposal Including Opicapone and Safinamide. Mov Disord Clin Pract. 2020; 7(3):343-5. 10.1002/mdc3.12921 PMID: 32258239
Moghadasi AN, Mirmosayyeb O, Barzegar M, Sahraian MA, Ghajarzadeh M. The prevalence of COVID-19 infection in patients with multiple sclerosis (MS): a systematic review and meta-analysis. Neurol Sci. 2021; 42(8):3093-9. 10.1007/s10072-021-05373-1 PMID: 34100130
Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. 2020; 5(7):802 – 10. 10.1001/jamacardio.2020.0950 PMID: 32211816
Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020; 17(5):259 – 60. 10.1038/s41569-020-0360-5 PMID: 32139904
Bougea A, Georgakopoulou VE, Palkopoulou M, Efthymiopoulou E, Angelopoulou E, Spandidos DA, et al. New–onset non–motor symptoms in patients with Parkinson's disease and post–COVID–19 syndrome: A prospective cross–sectional study. Med Int (Lond). 2023; 3(3):23. 10.3892/mi.2023.83 PMID: 37214229
Weiss M, Gutzeit J, Appel KS, Bahmer T, Beutel M, Deckert J, et al. Depression and fatigue six months post-COVID-19 disease are associated with overlapping symptom constellations: A prospective, multi-center, population-based cohort study. J Affect Disord. 2024; 352:296–305. 10.1016/j.jad.2024.02.041 PMID: 38360365
Brown EG, Chahine LM, Goldman SM, Korell M, Mann E, Kinel DR, et al. The Effect of the COVID-19 Pandemic on People with Parkinson's Disease. J Parkinsons Dis. 2020; 10(4):1365-77. 10.3233/JPD-202249 PMID: 32925107
Brugger F, Erro R, Balint B, Kagi G, Barone P, Bhatia KP. Why is there motor deterioration in Parkinson's disease during systemic infections-a hypothetical view. NPJ Parkinsons Dis. 2015; 1:15014. 10.1038/npjparkd.2015.14 PMID: 28725683
Fu YW, Xu HS, Liu SJ. COVID-19 and neurodegenerative diseases. Eur Rev Med Pharmacol Sci. 2022; 26(12):4535-44. 10.26355/eurrev_202206_29093 PMID: 35776055
Virhammar J, Naas A, Fallmar D, Cunningham JL, Klang A, Ashton NJ, et al. Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity. Eur J Neurol. 2021; 28(10):3324-31. 10.1111/ene.14703 PMID: 33369818
Wang J, Dai L, Deng M, Xiao T, Zhang Z, Zhang Z. SARS-CoV-2 Spike Protein S1 Domain Accelerates alpha-Synuclein Phosphorylation and Aggregation in Cellular Models of Synucleinopathy. Mol Neurobiol. 2024; 61(4):2446–58. 10.1007/s12035-023-03726-9 PMID: 37897633
Chambergo-Michilot D, Barros-Sevillano S, Rivera-Torrejon O, De la Cruz-Ku GA, Custodio N. Factors associated with COVID-19 in people with Parkinson's disease: a systematic review and meta-analysis. Eur J Neurol. 2021; 28(10):3467-77. 10.1111/ene.14912 PMID: 33983673
Helmich RC, Bloem BR. The Impact of the COVID-19 Pandemic on Parkinson's Disease: Hidden Sorrows and Emerging Opportunities. J Parkinsons Dis. 2020; 10(2):351-4. 10.3233/JPD-202038 PMID: 32250324
Helmich RC, Aarts E, de Lange FP, Bloem BR, Toni I. Increased dependence of action selection on recent motor history in Parkinson's disease. J Neurosci. 2009; 29(19):6105-13. 10.1523/JNEUROSCI.0704-09.2009 PMID: 19439588
Timmer MHM, van Beek M, Bloem BR, Esselink RAJ. What a neurologist should know about depression in Parkinson's disease. Pract Neurol. 2017; 17(5):359 – 68. 10.1136/practneurol-2017-001650 PMID: 28739866
Zach H, Dirkx MF, Pasman JW, Bloem BR, Helmich RC. Cognitive Stress Reduces the Effect of Levodopa on Parkinson's Resting Tremor. CNS Neurosci Ther. 2017; 23(3):209 – 15. 10.1111/cns.12670 PMID: 28071873
Rezayi S, Rahmani Katigari M, Shahmoradi L, Nilashi M. Vulnerability of Parkinson's Patients to COVID-19 and Its Consequences and Effects on Them: A Systematic Review. Parkinsons Dis. 2023; 2023:6272982. 10.1155/2023/6272982 PMID: 37144210
Kataoka H, Obayashi K, Tai Y, Sugie K, Saeki K. Increased depressive symptoms in Parkinson's disease during the COVID-19 pandemic: Preliminary findings from longitudinal analysis of the PHASE study. Clin Park Relat Disord. 2023; 8:100194. 10.1016/j.prdoa.2023.100194 PMID: 36974118
Kinger SB, Juneau T, Kaplan RI, Pluim CF, Fox-Fuller JT, Wang T, et al. Changes in Apathy, Depression, and Anxiety in Parkinson's Disease from before to during the COVID-19 Era. Brain Sci. 2023; 13(2). 10.3390/brainsci13020199 PMID: 36831742
Hadidchi R, Wang SH, Rezko D, Henry S, Coyle PK, Duong TQ. SARS-CoV-2 infection increases long-term multiple sclerosis disease activity and all-cause mortality in an underserved inner-city population. Mult Scler Relat Disord. 2024; 86:105613. 10.1016/j.msard.2024.105613 PMID: 38608516
Antonini A, Leta V, Teo J, Chaudhuri KR. Outcome of Parkinson's Disease Patients Affected by COVID-19. Mov Disord. 2020; 35(6):905-8. 10.1002/mds.28104 PMID: 32347572

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Long-term outcomes of patients with Parkinson’s disease 3.5 years post SARS-CoV-2 infection in an inner-city population in the Bronx

Status:

Version 1

Abstract

Objectives.

Methods.

Results.

Conclusions.

Figures

INTRODUCTION

METHODS

Data Sources

Variables

Outcomes

Analysis and Statistics

RESULTS

Demographics

DISCUSSION

Mechanisms

Social Impact of Pandemic on PD Outcomes:

Outcomes of patients with other neurological conditions

Strengths and Limitations

CONCLUSION

Declarations

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1