Outcome of Parkinson's Disease Patients Affected by COVID-19.

There is extensive debate on the neurological consequences of corona virus disease 2019 (COVID‐19) and the impact this might have for patients with neurodegenerative conditions, including Parkinson's disease (PD). Older advanced PD patients may represent a particularly vulnerable population, as respiratory muscle rigidity as well as impairment of cough reflex alongside preexisting dyspnoea may lead to increased severity of COVID‐19. In addition, there are indirect possible effects, such as the impact of stress, self‐isolation, and anxiety, as well as the consequences of prolonged immobility because of the lockdown. ,

Several observations make the link between COVID‐19 and PD particularly intriguing. Antibodies against coronavirus were found in the cerebrospinal fluid of PD patients more than 2 decades ago, suggesting a possible role for viral infections in neurodegeneration. Angiotensin‐converting enzyme 2 (ACE2) receptors are highly expressed in dopamine neurons, and they are reduced in PD because of the degenerative process; therefore, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)–related brain penetration may cause additional harm and worsen symptoms and may increase the requirement of dopamine replacement therapy, as evident in 5 of our cases. , Interestingly, the ability of coronaviruses to enter the brain through the nasal cavity determines anosmia/hyposmia and ageusia in many infected subjects, a symptomatology that closely resembles one of the most prominent premotor symptom of PD. Finally, the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID‐19, as ACE2 and dopamine decarboxylase coexpress and coregulate in nonneuronal cell types, which may indicate dopamine depletion and the need for considering levodopa as treatment.

Outcomes of PD patients infected by SARS‐CoV‐2 are unknown. We present here the outcome of 10 clinical cases (Table 1) collected from the experience at the Parkinson and Movement Disorders Unit in Padua, Italy, and the Parkinson's Foundation Centre of Excellence at King's College Hospital in London, UK, from the beginning of March to the current period. The PD center in Padua has a catchment of 1022 patients, mainly in the province of Padua, which had 3407 cases of COVID‐19, 2 of whom were advanced PD patients. Both were women residing in nursing homes with severe motor manifestations, and both were treated with levodopa therapy (Table 1). One remained asymptomatic, whereas the other, who in the last months had been suffering from deteriorating cognition and hallucinations, developed respiratory problems and died. The King's center has 4000 PD patients in the catchment and is currently following more than 600 patients. In all, thus far, 8 cases have been identified with COVID‐19, and clinical details are presented here. The Kings' COVID‐19 PD group consists of 6 men and 2 women, all older than 60 years of age with severe motor dysfunction, comorbidities, and most requiring additional levodopa dosing following infection (Table 1). Anxiety and other nonmotor features, such as fatigue, orthostatic hypotension, cognitive impairment, and psychosis, also worsened during the infection. Fatigue was a dominant symptom during the SARS‐CoV‐2 infection in all cases on advanced therapies. Three patients died from COVID‐19 pneumonia.

Table 1

Clinical features and outcomes of Parkinson's disease patients with corona virus disease 2019.

Patients	Age	Sex	PD duration (years)	PD therapy	Comorbidities	Clinical picture requiring SARS‐CoV‐2 testing	Therapeutic interventions(antibiotics and intensive care)	Outcome
1	76	F	28	Carbidopa‐levodopa 25/100 mg 1 table t 3 times daily and ½ tablet once daily Rotigotine 4 mg 1 patch once daily Safinamide 50 mg 1 tablet once daily	Dementia Dysphagia Severe joint deformities	Fever	No intensive care required	Spontaneous recovery
2	79	F	12	Carbidopa‐levodopa 25/100 mg 1½ tablets 4 times daily	Dementia Hallucinations	Fever Cough Shortness of breath Confusion	CPAP required (no resuscitation was advised)	Died 14 days after onset of respiratory symptoms
3	81	M	10	Carbidopa‐Levodopa CR 25/100 mg 1 tablet once daily Carbidopa‐Levodopa 25/100 mg 2 tab 3 times daily	Hypertension Ischemic heart disease Chronic kidney disease Dementia	Fever Dry cough Shortness of breath	Antibiotics (piperacillin/tazobactam + clarithromycin) No intensive care or CPAP required Required increased levodopa dosing	Transferred to rehabilitation ward after 11 days of hospitalization
4	94	M	2	Carbidopa‐Levodopa 25/100 mg 1 tablet 3 times daily	Angina pectoris Osteoporosis	Multiple falls and head injury Cough Delirium Arrhythmia	Antibiotics (amoxicillin/clavulanic acid + clarithromycin) No intensive care or CPAP required	Transferred to rehabilitation ward for respite care; 10 days of hospitalisation
5	87	M	6	Carbidopa‐Levodopa 25/100 mg 1 tablet twice daily Carbidopa‐Levodopa 25/100 mg 1½ tablets twice daily	Congestive Cardiac failure Chronic obstructive pulmonary disease Atrial fibrillation Orthostatic hypotension Asthma	Syncopal episodes Hallucinations Fall with facial trauma Cough	Antibiotics (amoxicillin/clavulanic acid) No intensive care, CPAP not possible because of facial trauma (no resuscitation was advised) Required increased levodopa dosing	Died after 10 days of hospitalization
6	83	F	3	Carbidopa‐Levodopa 25/100 mg 2 tablets twice daily and 1½ tablets twice daily	Anxiety disorder	Worsening of mobility with fall and hyperCKemia Dry cough Fatigue Worsening of anxiety	No intensive care or CPAP required Required increase in levodopa dosing	Transferred to neurorehabilitation after 25 days of hospitalization
7	61	M	17	IJLI 1684 mg daily Carbidopa‐levodopa 25/100 mg 1 tablet once daily Rotigotine 4 mg 1 patch once daily Opicapone 50 mg 1 tablet once daily	Traumatic fractures secondary to falls Orthostatic hypotension	Fever Cough Fatigue	Antibiotics CPAP required	Died during hospitalization
8	75	M	10	IJLI 1262 mg daily Opicapone 50 mg 1 tablet once daily Carbidopa‐Levodopa CR 50/200 mg 1 tablet once daily Carbidopa‐Levodopa CR 25/100 mg 1 tablet once daily Levodopa‐ Benserazide 100/50 mg 1 tablet 3 times daily	Orthostatic hypotension Osteoporosis Benign prostatic hyperplasia Depression Neuropathic pain	Fever Cough Fatigue	Antibiotics CPAP required	Died during hospitalization
9	72	M	15	DBS bilateral STN Subcutaneous Apomorphine infusion 46 mg daily Rasagiline 1 mg 1 tablet once daily Ropirinole CR 2 mg 1 tablet once daily Levodopa‐benserazide 50/12.5 mg 1 tablet 4 times daily Carbidopa‐Levodopa CR 25/100 mg 1 tablet 3 times daily	Asthma Diabetes mellitus type II	Fever Fatigue Worsening of motor symptoms	Required increase in levodopa dosing No intensive care or CPAP required	Spontaneous recovery, waiting for transfer for rehabilitation
10	75	F	24	IJLI stopped due to recent PEG‐J tube malfunctioning Levodopa‐Benserazide 100/25 mg six times daily Carbidopa‐Levodopa CR 25/100 mg once daily	Atrial fibrillation Cognitive impairment	Fatigue Cough	Required increase in levodopa dosing No intensive care or CPAP required	Recovering

CPAP, continuous positive airway pressure; CR, controlled release; DBS, deep brain stimulation; IJLI, intrajejunal levodopa infusion; F, female; M, male; PD, Parkinson's disease; PEG‐J, percutaneous endoscopic transgastric jejunostomy; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; STN, subthalamic nucleus.

These findings suggest that PD patients of older age (mean, 78.3 years) with longer disease duration (mean, 12.7 years) are particularly susceptible to COVID‐19 with a substantially high mortality rate (40%). Those on advanced therapies, such as deep brain stimulation or levodopa infusion therapy, seem especially vulnerable, and a mortality rate of 50% among our 4 such cases is of concern. Although 2 recent articles have addressed the issue of COVID‐19 in PD, none specifically showed cases directly affected by COVID‐19, and we believe ours is the first report of this nature. , The report of Prasad et al focuses on the perceptions of SARS‐CoV‐2 infection in 100 PD patients and some symptoms listed tally with our observations in a real‐life population with COVID‐19. Many national and charity guidelines do not list PD or specifically older subjects on advanced therapies as a susceptible group, and this information needs to be amended in light of these new data.

Author Roles

Angelo Antonini: conception, data collection, manuscript, review and critique.

Valentina Leta: data collection, review and critique.

James Teo: data collection, review and critique.

K Ray Chaudhuri: conception, data collection, manuscript, review and critique.

Financial Disclosures of all authors (for the preceding 12 months)

Angelo Antonini has received compensation for consultancy and speaker‐related activities from UCB, Boehringer Ingelheim, AbbVie, Zambon, and Lundbeck; he receives research support from Chiesi Pharmaceuticals, Lundbeck, Horizon 2020 ‐ PD_Pal grant 825785, and Ministry of Education University and Research (MIUR) grant ARS01_01081. He serves as consultant for Boehringer–Ingelheim for legal cases on pathological gambling. Valentina Leta reports grants from BRC, Parkinson's UK, speaker‐related activities fees from Britannia Pharmaceuticals, and consultancy fees from Invisio Pharmaceuticals, outside the submitted work. James Teo has received research support and funding from InnovateUK, Bristol‐Myers‐Squibb, and iRhythm Technologies and holds shares < £5000 in Glaxo Smithkline and Biogen. K. Ray Chaudhuri has received honoraria for advisory board from AbbVie, UCB, Pfizer, Jazz Pharma, GKC, Bial, Cynapsus, Novartis, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Theravance, and Scion; hnoraria for lectures from AbbVie, Britannia Pharmaceuticals, UCB, Mundipharma, Zambon, Novartis, Boehringer Ingelheim, Neuroderm, and Sunovion; grants (investigator‐Initiated) from Britannia Pharmaceuticals, AbbVie, UCB, GKC, and Bial; academic grants from IMI EU, Parkinson's UK, NIHR, PDNMG, EU (Horizon 2020), Kirby Laing Foundation, NPF (USA), and MRC.