Abstract
Background
After more than 2 years of the pandemic, effective treatment for COVID-19 is still under research. In recent months, publications hypothesized amantadine's potential beneficial effect on SARS-CoV-2 infection.
Objective
To compare the groups of Parkinson's Disease (PD) patients who were administered amantadine chronically and those who did not take this medication in the context of the incidence and severity of COVID-19 infection.
Methods
An observational, retrospective, multicenter cohort study was conducted among consecutive patients with idiopathic PD. The structured questionnaires were completed during the patient's follow-up visits at the Outpatient Clinic or during hospitalization. The questionnaire included the following informations: patient's age, duration of PD, Hoehn-Yahr (H–Y) stage, comorbidities, medications, COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2 with specified symptoms and their severity (home or hospital treatment). The vaccination status was verified as well.
Results
Five hundred fifty-two (n = 552) patients participated in the study - 329 men (60%). The mean H–Y stage was 2.44 (range: 1–4) and the mean duration of PD was 9.6 years (range: 1–34). One hundred four subjects (19%) had confirmed COVID-19 infection. Subjects over 50 years of age had a significantly lower incidence of COVID-19 (17% vs 38%, p = 0.0001) with difference also in mean H–Y stage (2.27 vs 2.49; p = 0.011) and disease duration (8.4 vs 9.9 years, p = 0.007). There were no differences between patients with and without co-morbidities. In the whole analyzed group 219 (40%) subjects were treated with amantadine. Comparing COVID-19 positive and negative patients, amantadine was used by 48/104 (46%) and 171/448 (38%) respectively. 22% of patients on amantadine vs. 17% of patients without amantadine developed COVID-19. These differences were not significant. There were no differences in morbidity and severity of COVID-19 between amantadine users and non-users as well.
Conclusions
COVID-19 was less common in older (>50) with longer duration and more advanced patients. Amantadine did not affect the risk of developing COVID-19 or the severity of infection.
Keywords: Parkinson's disease, COVID-19, Amantadine, SARS-CoV-2, Morbidity
1. Introduction
The global scale of the Coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the high number of deaths and complications that affect the quality of life of patients, oblige to search for effective medication. Vaccination is currently an effective method of preventing and mitigating COVID-19, but the duration of the protection and efficacy against new variants of SARS-CoV-2 are still uncertain. Several medications were tested and included into treatment protocols [1], however till now there are no highly effective therapies available. In recent months, publications hypothesized the potential beneficial therapeutic effect of amantadine in COVID-19 treatment [[2], [3], [4], [5], [6], [7], [8], [9], [10]]. Currently, three clinical trials are ongoing to assess the effect of amantadine on COVID-19 compared to placebo [[11], [12], [13]]. Furthermore several observational studies have been published suggesting that amantadine may have a beneficial effect in the treatment of SARS-CoV-2 infection [[14], [15], [16], [17]]. However, these studies have significant limitations including: small number of patients (mostly case series reports), concurrent treatment with other therapies; no information on other medications, no endpoints predefined in the study methodology for the efficacy and safety of amantadine. Wszołek and Tipton pointed out the need to analyze the population of patients with neurodegenerative diseases with regard to SARS-CoV-2 infection, especially patients taking amantadine and memantine chronically due to their potential antiviral effect [18]. Even though amantadine is considered as a relatively safe drug, it should be used with caution. Amantadine has a potency to cause side effects, sometimes life-threatening [19,20]. Amantadine is frequently self-administered in belief of antiviral effect. The time of administration differs among patients and may be crucial for its effectiveness. Therefore, we hypothesized that PD patients (older population at risk of fatal outcome) taking amantadine chronically as a part of anti-parkinsonian treatment may be protected against infection or fatal outcomes.
2. Study aim
The aim of the study was to compare the group of PD patients who were on amantadine treatment chronically and those who did not take amantadine in the context of the incidence and severity of COVID-19. The secondary goal was to assess the impact of the COVID-19 pandemic on the population of patients with PD and comorbidities.
2.1. Study design
Between November 30, 2020 and October 18, 2021 a survey was conducted among patients with PD. Consecutive patients treated in 4 centers specializing in movement disorders were included and analyzed. The treating physicians filled in the questionnaires, during the patient's follow-up visit at the Outpatient Clinic or during hospitalization. The structured questionnaire included questions on patient's age, duration of PD, Hoehn-Yahr (H-Y) stage, comorbidities, medications used for both PD and comorbidities, advanced PD treatments (deep brain stimulation - DBS, continuous subcutaneous apomorphine infusions- CSAI, levodopa/carbidopa intestinal gel - LCIG). Patients were asked whether they had COVID-19 confirmed by a reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2. Patients were also questioned if they had been vaccinated against COVID-19 (partially or completed the full vaccination). The data on the severity of COVID-19 symptoms (dyspnoea, cough, fever, anosmia/ageusia, other infection symptoms), and the need of hospitalization (oxygen therapy, mechanical ventilation and hospitalization at the Intensive Care Unit) was collected as well. Patients were asked if they were taking amantadine before and during infection.
As the collected data are a part of routine history taking and there were no any interventions or additional scales, the Bioethical Committee approval was not necessary.
2.2. Statistical analysis
We calculated and presented the data as frequencies, percentages or mean. Qualitative comparisons were made using Chi-square and Yates corrected Chi-square test. Quantitative comparisons were made using Mann-Whitney U tests as all data in compared groups were not normally distributed. A p-value less than 0.05 was considered statistically significant for all comparisons. Statistical analyses were performed using Statistica 14 and SPSS 28.
3. Results
3.1. Basic demographics
Five hundred fifty two (n = 552) patients including 329 men (60%) and 223 women (40%), mean age of 64.8 years (SD ± 10.7, range: 27–89) participated in the study. The mean H–Y stage of PD was 2.44 (SD ± 1.15, range: 1–4). The mean duration of PD was 9.6 years (SD ± 6.06, range: 1–34) and the average levodopa equivalent daily dose (LEDD) was 1065 mg (SD ± 614, range). Three hundred nine subjects (n = 309, 56%) had at least one comorbidity.
3.2. Vaccination status
Four hundred eighteen patients (n = 418) were not vaccinated against SARS-CoV-2 at the time of completing the questionnaire. One hundred thirty-four (n = 134) were already fully vaccinated against COVID-19 before completing the survey, however, the study was performed mostly before SARS-CoV-2 vaccination availability. The first vaccination of the patient among the respondents was performed on January 23, 2021. Of the 134 subjects fully vaccinated before completing the survey, 25 developed SARS-CoV-2 infection in the time period between the onset of the pandemic and vaccination. Proportion of patients fully vaccinated prior to the study was the same in the COVID-19 positive and negative groups (both 24%) (Table 1 ).
Table 1.
The mean age, gender distribution, disease severity (H–Y: Hoehn-Yahr), disease duration and vaccination status at the time of completing the survey.
| COVID-19 (+) | COVID-19 (−) | p-value | |
|---|---|---|---|
| Number of patients | 104 | 448 | – |
| Amantadine users | 48 (46%) | 171 (38%) | 0.1338 |
| Mean daily amantadine intake | 237 mg | 257 mg | 0.1010 |
| Mean age (years) | 60.8 | 65.8 | 0.0001 |
| Gender | M: 67 (64%) | M: 262 (59%) | 0.2660 |
| F: 37 (36%) | F: 186 (41%) | ||
| Mean H–Y stage | 2.27 | 2.49 | 0.0110 |
| Mean PD duration (years) | 8.4 | 9.9 | 0.0078 |
| Mean LEDD | 994 mg | 1082 mg | 0.1140 |
| Vaccination status | 25 vaccinated (24%) | 109 vaccinated (24%) | 0.9501 |
| 79 non-vaccinated (76%) | 339 non-vaccinated (76%) |
3.3. COVID-19 infection
Out of all 552 patients, 104 patients (19%) had confirmed COVID-19 infection with the RT-PCR test, 447 patients (81%) were negative, in 1 patient the result of the RT-PCR test was inconclusive twice. This subject was included in the study and listed as negative in the statistical analysis. The mean age of subjects in COVID-19 positive and negative groups differed significantly (60.8 vs 65.8 years respectively; p = 0.0001). Among the respondents, SARS-CoV-2 infection was more frequent in younger patients with shorter duration (8.4 vs 9.9 years, p = 0.007) and with less advanced stage of PD (mean H–Y stage 2.27 vs 2.49; p = 0.011) (Table 1). Subjects over 50 years of age had a significantly lower incidence of COVID-19 as compared to those under 50 (17% vs 38%, p = 0.0001).
Among all subjects, 309 patients (56%) had at least one comorbidity, of which 261 were COVID-19 negative and 48 positive. There was no statistically significant increase in the SARS-CoV-2 infection in patients with any comorbidities (Supplementary material). Forty four (n = 44) subjects were diagnosed dementia, of which only 5 had COVID-19 (11%). Of the dementia patients, 8 were taking memantine, none of which developed COVID-19.
Among patients taking other medications (levodopa, dopamine receptor agonists, MAO-B inhibitors, COMT-inhibitors, anticholinergics), no one significantly reduced the incidence of COVID-19 (Table 2 ). Ninety-five patients who were treated with DBS had the lowest COVID-19 morbidity (12%, p = 0.040), however the number of patients in this group was small and requires further investigation.
Table 2.
(A) Anti-parkinsonian treatment and COVID-19 (+) percentage for each treatment. (B) COVID-19 symptoms in amantadine users and non-users. DBS- Deep Brain Stimulation LCIG – Levodopa/carbidopa intenstinal gel.
| A | ||||
|---|---|---|---|---|
| Medication | Number of patients | COVID-19 (+) | COVID-19 (−) | p-value |
| Levodopa | 514 | 96 | 418 | 0.7178 |
| Rasagiline | 223 | 40 | 183 | 0.2730 |
| Amantadine | 219 | 48 | 171 | 0.1338 |
| Ropinirole | 198 | 36 | 162 | 0.7672 |
| Pramipexole | 111 | 21 | 90 | 0.9812 |
| Selegiline | 4 | 1 | 3 | 0.7448 |
| LCIG | 12 | 2 | 10 | 0.8583 |
| Apomorphine | 5 | 2 | 3 | 0.8234 |
| Rotigotine | 3 | 0 | 3 | 0.9231 |
| Biperiden | 2 | 0 | 2 | 0.8234 |
| Pridinole | 2 | 0 | 2 | 0.8234 |
| Entacapone | 8 | 0 | 8 | 0.3590 |
| DBS | 95 | 11 | 84 | 0.0476 |
| B | |||
|---|---|---|---|
| COVID-19 symptoms | Amantadine users number | Amantadine non-users number | p-value |
| No symptoms | 12 | 15 | 0,8360 |
| Musculoskeletal pain | 3 | 2 | 0,8597 |
| Fatigue | 8 | 7 | 0,7467 |
| Gastrointestinal symptoms | 0 | 3 | 0,2985 |
| Dyspnoea | 18 | 12 | 0,0713 |
| Cough | 24 | 20 | 0,1416 |
| Fever (>38 °C) | 22 | 26 | 0,9516 |
| Anosmia/Ageusia | 20 | 16 | 0,1617 |
| PD symptoms deterioration | 4 | 0 | 0,0907 |
| Respiratory failure (oxygen therapy) | 10 | 6 | 0,2488 |
| Mechanical ventilation | 3 | 0 | 0,1899 |
3.4. Amantadine
Among all patients, amantadine was taken by 219 (40%) with daily doses ranged between 100 and 400 mg (Table 3 ). Of COVID-19 negative subgroup amantadine was taken by 171/448 (38%) versus 48/104 (46%) in patients who were infected. The difference was not statistically significant (Table 1). Mean daily dose was similar (237 mg vs 257 mg) between COVID-19 positive and negative groups and the difference was statistically non-significant (p = 0.101).
Table 2.
Amantadine usage and dosages among COVID-19 positive and negative patients.
| Number of patients | |
|---|---|
| COVID-19 (+): | 104 |
| Amantadine users | 48 (46%) |
| 1 × 100 mg | 3 |
| 2 × 100 mg | 25 |
| 3 × 100 mg | 19 |
| 4 × 100 mg | 1 |
| Mean daily amantadine intake | 237 mg |
| Amantadine non-users | 56 (54%) |
| COVID-19 (−): | 448 |
| Amantadine users | 171 (38%) |
| 2 × 50 mg | 2 |
| 3 × 50 mg | 1 |
| 1 × 100 mg, 2 × 50 mg | 1 |
| 1 × 100 mg | 14 |
| 2 × 100 mg | 58 |
| 3 × 100 mg | 76 |
| 4 × 100 mg | 19 |
| Mean daily amantadine intake | 257 mg |
| Amantadine non-users | 277 (62%) |
The number of COVID-19 positive subjects was greater in patients taking amantadine (22% vs 17% without amantadine) however, this difference was not statistically significant (p = 0.133) (Fig. 1 ).
Fig. 1.
(A) Percentage of COVID-19 positive and negative patients, treated and not treated with amantadine. (B) COVID-19 positive patients treated and not treated with amantadine and COVID-19 negative patients with relation to age.
Majority (88/104) of COVID-19 positive patients underwent mild infection only. Fifteen (n = 15) patients were hospital admitted (9 of them were taking amantadine. Oxygen therapy was required in 16 (10 were taking amantadine), while 3 patients required respiratory therapy, all were on amantadine treatment (at the age of 53, 68, 81). Severity of symptoms of SARS-CoV-2 infection was similar between patients taking and not taking amantadine (Table 2).
4. Discussion
Amantadine's antiviral effect is to inhibit the M2 proton channel of influenza A virus. The M2 proton channel is necessary to release the viral genetic material into the cytoplasm by acidifying the inside of the virus, dissociating RNA from its bound matrix proteins which allows for the release of genetic material and further replication [21,22]. Amantadine has been widely used since 1966 in the prevention and treatment of influenza A; however, due to the numerous and rapidly spreading influenza virus mutations, the effectiveness of amantadine has become low and its use is currently not recommended [23].
SARS-CoV-2 enters the host cell by the reaction of spike protein (S-protein) with the angiotensin-converting enzyme type 2 (ACE-2) receptor, which is a membrane receptor widely present in many tissues of the body mainly in the epithelium of the respiratory tract, small intestine, endothelium as well as in the heart muscle and kidneys [24]. It is now also known that the ACE-2 receptor is found in many structures of the central nervous system - both in neurons and in glial cells. The invasion of host cells by SARS-CoV-2 involves binding the viral S protein to the ACE-2 receptor using Cathepsin L (CTSL) - an endosomal cysteine protease. These reactions cause the virus fusion with the host cell membrane, releasing the viral genetic material into the cytoplasm [25]. Several hypotheses have been described regarding the possible mechanisms of action of amantadine on COVID-19 [26]. SARS-CoV-2 in its genome has sequences encoding membrane proteins with ion channel activity (Protein E, Protein 3a, ORF7b and ORF10); amantadine can inhibit the activity of protein E and ORF10, reducing viral replication and virus-dependent inflammation [7]. It was hypothesized that amantadine has the ability to bind to the E-protein of the coronavirus ion channel, inhibiting the proton channel and thus preventing the release of viral genetic material into the cytoplasm [6]. In other publications, it is hypothesized that amantadine causes a change in the lysosomal microenvironment and their dysfunction, inhibiting the key reactions needed for SARS-CoV-2 infection [4]. Amantadine use may result in an increase in the pH of endosomes and down-regulation of cathepsin-L - a protease necessary for the connection of the S protein of the coronavirus with the ACE-2 receptor and impaired viral entry and replication [3]. In-vitro studies on the Vero 6 cell line showed that amantadine might potentially inhibit SARS-CoV-2 replication by inhibiting viroporins [27]. Amantadine has a beneficial immunomodulatory effect by reaction with dopaminergic receptors on T lymphocytes, activating resting T effector lymphocytes and inhibiting regulatory T cells [28].
In recent months, studies hypothesized the potential beneficial effect of amantadine on COVID-19 severity. In one of them, a survey was conducted among people with neurological diseases (10 with multiple sclerosis -MS, 5 with PD, 7 with dementia) taking amantadine or memantine who obtained positive COVID-19 RT-PCR swab results. None of the 22 patients developed infection [8]. Another study performed was a retrospective survey of 256 patients with MS and PD, 87 of whom were taking amantadine. Out of the group of patients taking amantadine, 5.7% developed COVID-19, while in the non-amantadine group it was 11.8% [15]. The largest observational-retrospective study of 136 855 patients with confirmed COVID-19 infection, including 319 patients taking amantadine (151 in monotherapy, 168 with antibiotics), indicated that amantadine was ineffective [14]. The use of amantadine monotherapy in COVID-19 treatment was associated with an increased risk of death in the general population. The authors pointed out that the use of amantadine is not justified. Several studies are currently being conducted worldwide to assess the potential effect of amantadine on COVID-19 infection [[11], [12], [13]].
The group of PD patients taking amantadine due to normal prescriptions (symptomatic treatment of parkinsonian symptoms or treating of choreatic peak – of - dose dyskinesias) is specifically interesting as they are already treated at the onset of infection and do not require dose titration. In other studies regarding the general population, amantadine is usually prescribed at the onset of symptoms or after PCR confirmation. It may result in substantial delay and potential decrease of effectiveness.
The results of our study conducted among PD patients indicate that there are no statistically significant differences in the incidence of COVID-19 and the severity of infection between the groups of patients taking and not taking amantadine. However, the results of the study showed that the incidence of COVID-19 is inversely proportional to the age of the respondents, H–Y stage and duration. Patients over 50 years old had a lower incidence of COVID-19 compared to younger subjects. Elderly patients in general population are at particular risk of the severe course of COVID-19 and the highest risk of death. This observation may be associated with less mobility and avoiding of social contacts during the pandemic in older PD patients, and therefore lower exposure to infection. Nevertheless, other factors have to be considered as well. Among the data collected during the study, no other significant factors were found among the PD patients that could affect the course and incidence of COVID-19 (other medications and co-morbidities) (Table 2). However, the subgroup of patients (n = 95) treated with DBS had the lowest percentage of SARS-CoV-2 infection (12%, p = 0.04), but the group was too small to make any firm conclusions and require further investigations.
The limitation of our study was the introduction of SARS-CoV-2 vaccinations during the course of the study. A part of respondents (n = 134, 24%) were vaccinated before taking part in the study. Twenty five vaccinated patients were COVID-19 positive, but this was in the pre-vaccination period. We collected data on vaccination and also did not find any significant differences. The next, but important limitation is the lack of information on mortality in this group of PD patients. It definitely would be of great value to compare this the most unfavourable disease outcome in amantadine users and not users.
5. Conclusions
Our study shows that chronic pre-treatment with amantadine does not reduce the incidence of COVID-19 and its severity among all respondents. However, patients over 50 years old, slightly more advanced and with longer duration PD had a lower incidence of SARS-CoV-2. Further studies on the effects of amantadine on COVID-19 should be continued, specially in terms of mortality.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We would like to thank Paweł Przytuła from Appsilon Sp. z o.o. for his for his contribution and support in the analysis and cleaning the source data.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.parkreldis.2022.105238.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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