key: cord-0791133-4pij0x9q
authors: Fasano, Alfonso; Cereda, Emanuele; Barichella, Michela; Cassani, Erica; Ferri, Valentina; Zecchinelli, Anna Lena; Pezzoli, Gianni
title: COVID‐19 in Parkinson's Disease Patients Living in Lombardy, Italy
date: 2020-06-02
journal: Mov Disord
DOI: 10.1002/mds.28176
sha: e0b224fe2d730d330103dc9ceee26580f44bec75
doc_id: 791133
cord_uid: 4pij0x9q

BACKGROUND: It is unknown whether patients with Parkinson's disease (PD) are at greater risk of COVID‐19, what their risk factors are and whether their clinical manifestations differ from the general population. METHODS: In a case‐controlled survey, we interviewed 1486 PD patients attending a single tertiary centre in Lombardy, Italy and 1207 family members (controls). RESULTS: 105 (7.1%) and 92 controls (7.6%) were identified as COVID‐19 cases. COVID‐19 patients were younger, more likely to suffer from chronic obstructive pulmonary disease, to be obese and vitamin D non‐supplemented than unaffected patients. Six patients (5.7%) and seven family members (7.6%) died from COVID‐19. Patients were less likely to report shortness of breath and require hospitalization. CONCLUSIONS: In an unselected large cohort of non‐advanced PD patients, COVID‐19 risk and mortality did not differ from the general population but symptoms appeared to be milder. The possible protective role of vitamin D supplementation warrants future studies. This article is protected by copyright. All rights reserved.

Severe acute respiratory syndrome coronavirus 2 (SARS Co-V2) emerged in the region of Wuhan in China around December last year and spread so rapidly that the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. 1 Specific preexisting medical conditions and advanced age appear to be linked to more severe manifestations of the infection, 1, 2 thus raising the question of whether Parkinson's disease (PD) poses an increased risk of morbidity and mortality in COVID-19 patients. 3 The first reported case of COVID-19 in a 74-year-old PD patient complicated by encephalopathy has recently been described. 4 A series of 10 PD patients collected in Padua, Italy and London, UK reported a high mortality rate (40%), and worsening of anxiety and other non-motor features, 5 in keeping with a recent survey among patients and caregivers. 6 We recently gathered clinical information on 117 community-dwelling PD patients with COVID-19 followed in 21 tertiary centres in Italy, Iran, Spain, and the UK. 7 We found an overall mortality of 19.7%, with a significant effect of concomitant dementia, hypertension, and PD duration. 7

Many questions remain unanswered: 1. Are PD patients more at risk of being infected by SARS Co-V2 and developing COVID-19? What are the risk factors for COVID-19 infection in PD patients? 3. How is the clinical expression of COVID-19 in PD patients? What is the COVID-19 outcome in an unselected cohort of PD patients?

In order to answer these questions, we conducted a phone survey of all PD patients and family members included in the database of one of the largest tertiary centres for PD in Italy, located in Milan -Lombardy, the region with the highest incidence of COVID-19 in the country. 8, 9

We contacted (using all available phone numbers, up to three attempts on three different days) a total of 1926 patients fulfilling the following inclusion criteria: 1) clinical diagnosis of PD; 10 2) at least one evaluation at the Parkinson Institute (Pini-CTO, Milan, Italy) in 2019; and 3) living in Lombardy . Patients were asked about COVID-19-related symptoms during the previous 3 months, the execution of nasopharyngeal swabs, chest radiograph or computed tomography, and hospitalization. Interviews were standardized using an electronic case report form and conducted in the presence of one family member for support and in the event of patient hospitalization or death at the moment of the survey. In order to gather data from a control population with a similar environmental exposure, the survey also involved 1207 family members willing to participate.

A positive nasopharyngeal swab was needed for a 'confirmed' diagnosis of COVID-19, while a 'probable' diagnosis was formulated using the following criteria: presence of persistent COVID-19-related symptoms (≥3 including fever or ≥5 without fever) or ≥1 symptom in presence of suggestive chest radiologic signs and/or living with a family member with a confirmed diagnosis of COVID-19. If needed, the regional register of healthcare data was also accessed to obtain laboratory and radiologic findings as well as hospitalization data, and to confirm the date and cause of death.

Finally, relevant demographic and clinical data were extracted from the institutional electronic chart of the patient and confirmed during the interview.

Between-group comparisons (COVID-19 PD cases vs. unaffected PD patients and PD with COVID-19 vs. controls with COVID-19) were initially performed using Fisher's exact test for categorical variables and Student's t-test or Mann-Whitney (depending on data distribution) for continuous variables. Then, given the significant difference in age among these groups, dichotomous variables and outcomes were compared using age-adjusted logistic regression analysis (an independent model for each variable/outcome) to calculate odds ratio (OR) with 95 % Confidence Interval (95%CI). All analyses were conducted using STATA 15.1 statistical software (Stata Corporation, College Station, TX).

Data on 1486 patients were collected (response rate: 77.2%). Reasons of exclusion from the analysis were: patient unreachable (N=302), refusal (N=98), patient died before the pandemic or during it for causes other than COVID-19 (N=40). Among unreachable patients, 139, 129 and 54 had one, two and three available phone numbers, respectively; in 15% the number appeared to be wrong. No differences were detected when comparing responders vs. non-responders except for longer disease duration in the latter group (Suppl Table 1 ). We identified 32 confirmed and 73 probable cases of COVID-19 among the PD patients (total: 105, 7.1%). Compared to unaffected PD patients, COVID-19 PD cases were younger, more likely to suffer from chronic obstructive pulmonary disease, to be obese and vitamin D nonsupplemented (Table 1) . Fever, cough and nasal congestion were the most frequent symptoms (Table 2) . Eighteen patients (17.1%) were hospitalized and 6 died (5.7%).

Ninety-two family members were diagnosed with COVID-19 (7.6%, p=0.60 vs. PD patients). Their demographic and clinical characteristics were similar to PD patients with the exception of younger age and higher number of weekly outings (Table 2 and Suppl Table 2 ). When analyzing COVID-19 cases among PD patients and family members, the former were less likely to report shortness of breath (SOB) and require hospitalization after adjusting for age.

This single-centre case-controlled survey described the clinical features and predictors of COVID-19 infection and outcome in a relatively unselected and homogeneous large cohort of PD patients and controls (their family members). Our study sought to answer important questions.

All interviewees live in Lombardy, the region where the first Italian patient was diagnosed with COVID-19 on February 20, 2020. Since then, the increasing number of cases recorded in Lombardy, and subsequently throughout the country, led Italy to be the third most affected country worldwide. 9 More than 36% of Italian COVID cases are to this date (May 3 rd ) in Lombardy, where roughly 0.8% of the population has been diagnosed with COVID- 19. 9 However, the accuracy of prevalence data is hampered by the existence of asymptomatic cases and the lack of population screening campaigns. In this survey COVID-19 prevalence was similar in PD patients and study controls (7.1% vs 7.6%).

Older age, longer disease duration and use of advanced therapies in one study 5 and dementia, hypertension, and -again -disease duration in another study 7 have been found to predict poor COVID-19 outcome in PD patients. Our study expands these notions focusing on the risk of getting infected. The most interesting result is the seemingly protective effect of Vitamin D intake, as hypothesized by several authors during the past weeks. 11-17 Vitamin D can reduce the risk of infections through several mechanisms, e.g. by reducing concentrations of proinflammatory cytokines. Evidence supporting this role of vitamin D has been confirmed by two recent studies. One study found significant negative correlations (r=-0.44) between the average vitamin D levels of different European countries and the national prevalence of COVID-19 cases and associated mortality. 18 Another age-stratified study in Swiss patients has found significantly lower vitamin D levels in SARS-CoV-2 PCR-positive vs. negative cases (median of 11.1 ng/mL vs. 24.6 ng/mL, respectively, P=0.004). 19 When comparing COVID-19 affected with non-affected PD patients, the former were younger, more frequently obese and suffering from chronic obstructive pulmonary disease. While obesity and comorbid respiratory disorders are well-known COVID-19 risk factors, 20 the younger age of affected patients might rely on the more aggressive preventive measures adopted for older patients. No role for hypertension was detected, in contrast with reports in non-PD 20 and other PD cohorts. 7 Hypertension in PD is rare and related to the occurrence of dysautonomia. Likewise, smoking is not common in PD, thus explaining why it did not increase COVID-19 risks in spite of what has been seen in the general population. 20 In keeping with another PD series, 7 we did not find any significant effect of anti-PD drugs in spite of the hypothesized protective role of levodopa, 21 entacapone, 22 and amantadine. 23, 24 The same was true for angiotensin-receptor blockers and angiotensin-converting-enzyme inhibitors 25 . Finally, although the role of nonsteroidal anti-inflammatory drugs is still unclear, 26 we did not find any significant effect.

No study has so far evaluated the clinical manifestation of COVID-19 in PD patients. Worsening of PD-related symptoms has been hypothesized, 27, 28 as later confirmed by a small series. 5 In our study we found that the clinical expression of COVID-19 largely overlaps with that of non-PD patients with few exceptions. The reason for the reduced occurrence of SOB is only speculative at the moment and probably related to the poorly understood pathophysiology of respiratory function in PD. 29 Uncontrolled studies have focused on the occurrence of dyspnea, reaching the overall conclusion that it is a common PD symptom, although patient selfreporting seems reduced. 30, 31 Alternatively, since SOB has been associated to anxiety or complications of levodopa therapy, 32 it is conceivable that surveyed PD patients found it difficult to attribute their respiratory symptoms to COVID-19 alone. In this survey we also found that hospitalization was required in PD patients less often, possibly due to the aforementioned reduced occurrence of SOB and the tendency for frail patients to be treated at home. 33

COVID-19 mortality in PD patients is still far from being elucidated. So far two studies have reported figures of 19.7% 7 and 40%. 5 Although PD patients might be at risk in light of their frailty and advanced age, we believe that the available data are misled by the ascertainment methods. Our survey found a much lower figure (5.7%) that did not differ importantly from the rate in the non-PD control population. Italian data suggest an overall mortality of 9.5% for all patients over 50 and of 12.8% for all patients aged 70 years of age and over . 2 Our mortality rate is probably underrepresented for the reasons detailed below.

Besides the well-known limitation of a telephone survey, our study has two other major limitations: 1. We directed our attention towards community-dwelling PD patients as we could not reach patients living in nursing homes or other long-term care facilities, where outbreaks with high mortality rates have been reported; 34 2. Some patients could not be reached for unknown reasons, thus raising the possibility of patient death due to COVID-19. Furthermore, COVID-19 diagnosis could not be confirmed in many cases, which is in line with the challenge of population screening during this unprecedented crisis. Other limitations include the younger age of non-PD COVID-19 cases, which we mitigated statistically and the small size for some comparisons.

In conclusion, this is the first case-controlled study on a relatively unselected and homogeneous large cohort of PD patients. Overall, we confirmed that COVID-19 risk, morbidity and mortality in patients with mild to moderate PD do not differ from the general population. Interestingly, we found a possible protective role of vitamin D intake, which should be confirmed by appropriate randomized controlled trials. Values are mean ± SD or n (%), significant data are bold-typed. Between-group comparisons of continuous variables were initially performed using the unpaired Student's t-test (normal distribution) or the Mann-Whitney test (non-normal distribution), while categorical variables were analyzed by the Fisher's exact test ( a ). Then, given the significant between-group age difference, ageadjusted ORs were calculated ( b ) to fully investigate differences in comorbidities and drugs/supplements (an independent model for each variable). Values are mean ± SD or n (%), significant data are bold-typed. Between-group comparisons of clinical features, pattern of symptoms and outcomes were performed using the unpaired Student's t-test while categorical variables were analyzed by the Fisher's exact test ( a ). Given the significant between-group age difference (Suppl Table 2 ), age-adjusted ORs ( b ) were used to further explore these comparisons (an independent model for each variable/outcome). Abbreviations: PD = Parkinson's disease, OR [95%CI]: odds ratio and 95% confidence intervals.

(N=105) 

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