코로나 감염으로 발생한 파킨슨 병 - 10일만에 와상환자가 앉기 가능해짐.

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8월 6일 70세 남, 와상 파킨슨 병 환자. 

병력 : 2022년 5월 코로나 감염후 체온 40도 발열 2일 지속 후 인지장애(보호자 표현으로 저 무서운 아줌마, 저 여자가 누구야?), 파킨슨 병 양상의 질병으로 진행.

2022년 7월 20일  서울 중앙대 병원에서 brain MRI 촬영, 기타 근전도, 혈액검사 후 파킨슨 진단.

이후 파킨슨 질병 악화일로에 들어감

2023년 5월 목포 00병원 입원. MMSE 2점, ADL 3점(혼자서는 아무것도 가능하지 않음) 수준으로 하락

2023년 8월 4일 아름다운 요양병원 입원

10일만에 일어나 앉음.... 영상으로 대체

치료 Process

다시 정리해야.....

논문을 찾아보니 코로나 감염으로 드물지만 파킨슨 병으로 진행하는 사례가 있음. 

관련 논문 탐구!!

SARS-CoV-2, COVID-19 and Parkinson’s Disease—Many Issues Need to Be Clarified—A Critical Review

by 

Tsepo Goerttler

 1,

Eun-Hae Kwon

 2,

Michael Fleischer

 1,

Mark Stettner

 1,

Lars Tönges

 2

 and

Stephan Klebe

 1,*

1

Department of Neurology, Essen University Hospital, 45147 Essen, Germany

2

Department of Neurology, Ruhr University Bochum, 44801 Bochum, Germany

*

Author to whom correspondence should be addressed.

Brain Sci. 2022, 12(4), 456; https://doi.org/10.3390/brainsci12040456

Received: 25 February 2022 / Revised: 20 March 2022 / Accepted: 22 March 2022 / Published: 28 March 2022

(This article belongs to the Special Issue COVID-19, Parkinson’s Disease and Other Neurodegenerative Disorders)

Abstract

Neurological manifestations during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are of interest, regarding acute treatment and the so-called post-COVID-19 syndrome. Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders worldwide. Hence, the influence of SARS-CoV-2 and the COVID-19 syndrome on PD patients has raised many questions and produced various publications with conflicting results. We reviewed the literature, with respect to symptoms, treatment, and whether the virus itself might cause PD during the SARS-CoV-2 pandemic in SARS-CoV-2-affected symptomatic PD patients (COVID-19 syndrome). In addition, we comment on the consequences in non-symptomatic and non-affected PD patients, as well as post-COVID syndrome and its potential linkage to PD, presenting our own data from our out-patient clinic.

중증 급성 호흡기 증후군 코로나바이러스 2(SARS-CoV-2) 팬데믹 기간 동안의 신경학적 증상은 급성 치료 및 소위 코로나19 이후 증후군과 관련하여 관심을 끌고 있습니다. 파킨슨병(PD)은 전 세계적으로 가장 흔한 신경 퇴행성 운동 장애 중 하나입니다. 따라서 SARS-CoV-2와 COVID-19 증후군이 PD 환자에게 미치는 영향에 대해 많은 의문이 제기되었고 상반된 결과를 담은 다양한 논문이 발표되었습니다. 저희는 증상, 치료, 그리고 SARS-CoV-2 팬데믹 기간 동안 SARS-CoV-2에 감염된 증상성 PD 환자(COVID-19 증후군)에서 바이러스 자체가 PD를 유발할 수 있는지 여부와 관련하여 문헌을 검토했습니다. 또한 무증상 및 비증상 PD 환자의 결과와 코로나19 증후군 및 PD와의 잠재적 연관성에 대해 논평하며 외래 환자 클리닉에서 얻은 자체 데이터를 제시합니다.

Translated with www.DeepL.com/Translator (free version)

Keywords: 

COVID-19; SARS-CoV2; Parkinson’s disease; viral parkinsonism; post-encephalitic parkinsonism

1. Introduction

Over the last two years, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has swept across the globe, infecting millions of people in every country and causing a global pandemic that was last observed over one hundred years ago. SARS-CoV-2 causes a syndrome called COVID-19, which comprises many major and minor, mostly unspecific, symptoms. Systemic symptoms, such as fever, fatigue, cough, and dyspnea, are the most apparent symptoms at onset, affecting the cardiopulmonary system, and leading to interstitial pneumonia and acute respiratory distress syndrome [1]–life-threatening conditions that overwhelm the capacity of intensive care units (ICU). Therefore, treating this disorder and preventing severe manifestations is the major challenge in the fight against the pandemic. Besides these disease manifestations, other acute and subacute symptoms also arise during SARS-CoV-2 infections, including neurological symptoms and syndromes [2], such as encephalopathy [3], meningoencephalitis [4], ischemic stroke [5], acute necrotizing encephalopathy [6], and Guillain–Barré syndrome [7].

지난 2년 동안 신종 코로나바이러스 중증 급성 호흡기 증후군 코로나바이러스 2(SARS-CoV-2)가 전 세계를 휩쓸며 모든 국가에서 수백만 명의 사람들을 감염시키고 100년 전에 마지막으로 관찰된 전 세계적인 팬데믹을 일으켰습니다. SARS-CoV-2는 COVID-19라는 증후군을 유발하며, 대부분 비특이적인 여러 가지 크고 작은 증상으로 구성됩니다. 발열, 피로, 기침, 호흡곤란과 같은 전신 증상은 발병 시 가장 명백한 증상으로 심폐계에 영향을 미치고 간질성 폐렴과 급성 호흡곤란 증후군[1]으로 이어져 중환자실(ICU)의 수용력을 압도하는 생명을 위협하는 질환입니다. 따라서 이 질환을 치료하고 심각한 증상을 예방하는 것이 팬데믹과의 싸움에서 가장 중요한 과제입니다. 이러한 질병 증상 외에도 뇌병증[3], 수막뇌염[4], 허혈성 뇌졸중[5], 급성 괴사성 뇌병증[6], 길랑-바레 증후군[7]과 같은 신경학적 증상 및 증후군[2]을 포함한 다른 급성 및 아급성 증상도 SARS-CoV-2 감염 중에 발생합니다.

Parkinson’s disease (PD) is one of the most common neurodegenerative movement disorders worldwide, which particularly affects older people. Patients at a more advanced age or stage of PD are at an increased risk of SARS-CoV-2 infections, due to their impaired motor functions, comorbidities, frailty, and, hence, increased risk of pneumonia. The impact of the SARS-CoV-2 pandemic has raised many questions, regarding symptoms, treatment, and outcomes in PD patients. In addition, pathophysiological considerations have raised the question of whether the virus itself can cause PD.

파킨슨병(PD)은 전 세계적으로 가장 흔한 신경 퇴행성 운동 장애 중 하나로, 특히 고령자에게 영향을 미칩니다. 파킨슨병이 더 진행된 연령이나 단계에 있는 환자는 운동 기능 장애, 동반 질환, 허약, 폐렴 위험 증가로 인해 SARS-CoV-2 감염 위험이 더 높습니다. SARS-CoV-2 팬데믹의 영향으로 PD 환자의 증상, 치료 및 결과와 관련하여 많은 의문이 제기되었습니다. 또한 병리 생리학적 고려 사항으로 인해 바이러스 자체가 PD를 유발할 수 있는지에 대한 의문이 제기되었습니다.

2. Association between PD and SARS-CoV-2: Pathophysiological Considerations

One of the most specific symptoms that occurs after SARS-CoV-2 infection is altered smell (hyposmia or dysosmia) and taste (dysgeusia), affecting about 65% of all infected people [8]. Hyposmia is also the most common symptom in presymptomatic PD patients, affecting numerous patients long before they develop motor symptoms [9,10]. This has led to the assumption that there may be a linkage between these two diseases, particularly because neurodegeneration in PD is thought to occur after a pathogenic encounter, e.g., a neurotropic virus, via a nasal or gastric pathway [11]. An overlap can be drawn with the recently published case–control PET study, with the differentiation of PD into the body-first and brain-first subtypes [12]. The authors stated that in the body-first subtype, the pathogen enters the brain via the gut, and the alpha-synuclein pathology spreads from there into the brain. In the brain-first subtype, the pathogen most likely enters the brain via the olfactory bulb, and the alpha-synuclein pathology spreads from there downwards into the body. Entering the brain via non-myelinated nerves, the pathogen most likely triggers chronic neuroinflammation and cytokine production, thus activating microglia [13] (Figure 1).

SARS-CoV-2 감염 후 발생하는 가장 구체적인 증상 중 하나는 후각(후각 저하 또는 후각 이상)과 미각(미각 장애)의 변화로, 전체 감염자의 약 65%에 영향을 미칩니다[8]. 저후각은 또한 전증상 PD 환자에서 가장 흔한 증상으로, 운동 증상이 나타나기 훨씬 전에 수많은 환자에게 영향을 미칩니다[9,10]. 특히 파킨슨병의 신경 퇴행은 비강 또는 위 경로를 통해 병원성 바이러스와 같은 병원체를 접한 후 발생하는 것으로 생각되기 때문에 이 두 질환 사이에 연관성이 있을 수 있다는 가정이 제기되었습니다[11]. 최근 발표된 사례 대조군 PET 연구와 PD가 신체 우선형과 뇌 우선형 아형으로 분화되는 것과 겹치는 부분이 있습니다[12]. 저자들은 신체 우선 아형에서 병원체가 장을 통해 뇌로 들어가고 알파-시누클레인 병리가 거기에서 뇌로 퍼진다고 말했습니다. 뇌 우선 하위 유형에서는 병원체가 후각을 통해 뇌로 들어가고 알파-시누클레인 병리가 거기에서 몸 아래로 퍼질 가능성이 높습니다. 비수초 신경을 통해 뇌에 침입한 병원체는 만성 신경 염증과 사이토카인 생성을 유발하여 미세아교세포를 활성화할 가능성이 높습니다[13](그림 1).

Neuroinflammation can be observed in autopsy studies in PD animal models [14] and, functionally, in positron emission tomography (PET) imaging in PD patients [15]. A study from 1992 demonstrated that coronavirus was present in the cerebrospinal fluid (CSF) of 18 PD patients compared to normal controls and patients with other neurological disorders [16]. SARS-CoV-2 enters and infects cells using the angiotensin-converting enzyme 2 (ACE2) receptor [17]. ACE2 receptors are expressed in neurons and glial cells in many brain regions, as well as in the substantia nigra and the olfactory bulb [18]. A preprint study showed that SARS-CoV-2 RNA could be found in brain tissue in 10 out of 11 performed autopsies, which provides evidence of substantial viral burden [19]. The invading neurons in the olfactory bulb might explain the occurrence of hyposmia, which, unlike in PD, is reversible in COVID-19. Studies showed recurrence of smelling in all patients (n = 46) who reported hyposmia 17 days after the onset of symptoms [20].

신경 염증은 다발성 경화증 동물 모델의 부검 연구[14]와 기능적으로 다발성 경화증 환자의 양전자 방출 단층 촬영(PET) 영상에서 관찰될 수 있습니다[15]. 1992년에 발표된 한 연구에서는 정상 대조군 및 다른 신경 장애가 있는 환자와 비교하여 18명의 PD 환자의 뇌척수액(CSF)에 코로나바이러스가 존재한다는 사실이 입증되었습니다[16]. SARS-CoV-2는 안지오텐신 전환 효소 2(ACE2) 수용체를 사용하여 세포에 침입하여 감염시킵니다[17]. ACE2 수용체는 많은 뇌 영역의 뉴런과 신경교 세포뿐만 아니라 흑질과 후각 전구에서도 발현됩니다[18]. 사전 인쇄 연구에 따르면 부검을 실시한 11명 중 10명에서 뇌 조직에서 SARS-CoV-2 RNA가 발견되었으며, 이는 상당한 바이러스 부담의 증거를 제공합니다[19]. 후각 구근에 침입한 뉴런은 PD와 달리 COVID-19에서는 가역적인 저산소증의 발생을 설명할 수 있습니다. 연구에 따르면 증상 발생 17일 후 저스모니아를 보고한 모든 환자(n = 46)에서 후각이 재발한 것으로 나타났습니다[20].

Figure 1. Schematic diagram of the potentially harmful pathway in COVID-19 and Parkinson’s disease (PD): (a) the SARS-CoV-2 virus enters the brain via the olfactory bulb, binding to the ACE receptors. From there, it spreads via non-myelinated nerves into the brain. (b) In PD, there are two hypothetical, not yet fully understood, routes that the viral pathogen can use to enter the brain, either via the olfactory bulb (“brain-first” theory) or via the gastrointestinal mucosa (“body-first” theory), spreading into the brain via the vagal nerve.

In 1917, von Economo described a syndrome called encephalitis lethargica [21,22], which was followed by the so-called ‘Spanish flu’ pandemic in 1918/1919 (caused by the H1N1 influenza virus and occurred in a significantly higher proportion of younger people than older people) [13,23]. Encephalitis lethargica included lethargy, cognitive decline, headache, and sickness; during disease progression, PD-like symptoms, such as bradykinesia, rigor, and the inability to move, also occurred [22,24].

1917년 폰 이코노모는 무기력성 뇌염[21,22]이라는 증후군을 설명했으며, 그 후 1918/1919년 소위 '스페인 독감'이 대유행했습니다(H1N1 인플루엔자 바이러스에 의해 발생하며 노인보다 젊은 층에서 훨씬 더 많이 발생)[13,23]. 무기력성 뇌염에는 무기력, 인지력 저하, 두통, 질병이 진행되는 동안 서동증, 경직, 거동 불능과 같은 PD 유사 증상도 발생했습니다[22,24]. 

In the 1920s, parkinsonism, due to encephalitis lethargica, was responsible for over 50% of all cases, affecting mostly young people in their third decade. Compared to idiopathic PD, this syndrome showed a coarse tremor, instead of a fine and rhythmic tremor, and more often presented with ocular movement disorders as oculogyric crises [24]. Encephalitis lethargica occurred less frequently during the following decades. Post-encephalitic parkinsonism (PEP) has been described in a few case series for several viruses, including the herpes simplex virus, cytomegalovirus, varicella zoster virus, influenza virus type A, coxsackie virus, poliovirus, human immunodeficiency virus, West Nile virus, and the Japanese encephalitis B virus [25,26]. In patients who developed PEP, an improvement in motor symptoms was observed after levodopa treatment, in the few cases administered this treatment [25,27,28,29]. Although the improvement in motor symptoms was good at the beginning, these patients also developed dyskinesia after prolonged treatment [30,31]. In contrast to PD, the symptoms associated with acute post-encephalic parkinsonism may also disappear in several cases [27,32,33]; in autopsy studies, no Lewy body formations have been found [34].

1920년대에는 무기력성 뇌염으로 인한 파킨슨병이 전체 사례의 50% 이상을 차지했으며, 대부분 30대의 젊은 층에 영향을 미쳤습니다. 특발성 PD에 비해 이 증후군은 미세하고 리드미컬한 떨림 대신 거친 떨림을 보였으며, 안구 운동 장애가 안과적 위기로 더 자주 나타났습니다[24]. 이후 수십 년 동안 무기력성 뇌염은 덜 자주 발생했습니다. 단순 포진 바이러스, 거대 세포 바이러스, 수두 대상 포진 바이러스, A형 인플루엔자 바이러스, 콕사키 바이러스, 소아마비 바이러스, 인간 면역 결핍 바이러스, 웨스트 나일 바이러스, 일본 뇌염 바이러스 등 여러 바이러스에 대한 몇 가지 사례 시리즈에서 뇌염 후 파킨슨증(PEP)이 설명되었습니다[25,26]. PEP가 발생한 환자에서 레보도파 치료 후 운동 증상의 개선이 관찰되었는데, 이 치료를 시행한 소수의 사례에서 운동 증상이 개선되었습니다[25,27,28,29]. 처음에는 운동 증상의 개선이 좋았지 만이 환자들은 장기간 치료 후 운동 이상증도 발생했습니다 [30,31]. PD와 달리 급성 뇌전증 후 파킨슨병과 관련된 증상도 몇몇 경우에서 사라질 수 있으며[27,32,33], 부검 연구에서 루이체 형성이 발견되지 않았습니다[34].

The pathogenesis of PD has been extensively discussed; in addition to genetics, neuroinflammation seems to play a likely role, whether idiopathic or triggered by a pathogen. The interactions between different causes have formed the ‘multiple hit’ theory, which assumes that many incidences, such as genetic disposition and several infections (gastric or respiratory), during a lifetime accumulate in the development of PD [11,35].

We have elaborated on these points in the following sections, and discussed important aspects of the SARS-CoV-2 pandemic and PD.

PD의 발병 기전은 광범위하게 논의되어 왔으며, 유전학 외에도 특발성이든 병원체에 의해 유발되든 신경 염증이 중요한 역할을 하는 것으로 보입니다. 다양한 원인 간의 상호 작용으로 인해 '다중 타격' 이론이 형성되었는데, 이는 일생 동안 유전적 성향과 여러 감염(위 또는 호흡기)과 같은 많은 발병 사례가 PD 발병에 누적된다고 가정합니다[11,35].

다음 섹션에서는 이러한 점에 대해 자세히 설명하고 SARS-CoV-2 팬데믹과 PD의 중요한 측면에 대해 논의했습니다.

3. PD Patients Infected with SARS-CoV-2 and Suffering from COVID-19

Many COVID-19 studies published to date are from regions in Italy that were severely affected during the first wave of the pandemic. A higher preval‎ence of COVID-19 in PD patients was confirmed in a case–control survey of 740 PD patients in Tuscany [36]. Overall, 7% of the entire PD population and up to 11% of those aged 65–85 years were affected by COVID-19, compared to <1% of the Italian population in general [36]. However, a case–control study in 1486 PD patients and 1207 family members from the Lombardy region demonstrated no difference in COVID-19 rates (7.1% vs. 7.6%, respectively) [37]. In terms of severe disease after SARS-CoV-2 infection, cardiovascular comorbidities appear to be a risk factor, rather than PD itself [36,38,39]. Data from 696 PD patients, 184 with parkinsonism symptoms and 8590 age-matched controls, from Northern Italy indicated that hospitalization rates due to SARS-CoV-2 infections were similar between the PD patients (0.7%) and the controls (0.6%) [40].

현재까지 발표된 많은 COVID-19 연구는 팬데믹 초기에 심각한 영향을 받은 이탈리아 지역에서 수행되었습니다. 토스카나에서 740명의 PD 환자를 대상으로 한 사례 관리 조사에서 PD 환자에서 COVID-19의 높은 유병률이 확인되었습니다[36]. 전체적으로 전체 PD 인구의 7%, 65~85세 인구의 최대 11%가 COVID-19에 감염된 것으로 나타났는데, 이는 이탈리아 전체 인구의 1% 미만인 것과 비교됩니다[36]. 그러나 롬바르디아 지역의 1486명의 PD 환자와 1207명의 가족 구성원을 대상으로 한 사례 대조 연구에서는 COVID-19 발병률에 차이가 없는 것으로 나타났습니다(각각 7.1% 대 7.6%)[37]. SARS-CoV-2 감염 후 중증 질환의 경우, PD 자체보다는 심혈관 동반 질환이 위험 요인인 것으로 보입니다[36,38,39]. 이탈리아 북부의 PD 환자 696명, 파킨슨병 증상이 있는 184명, 연령이 일치하는 대조군 8590명의 데이터에 따르면 SARS-CoV-2 감염으로 인한 입원율은 PD 환자(0.7%)와 대조군(0.6%) 간에 비슷했습니다[40]. 

However, there was a higher hospitalization rate (3.3%) in parkinsonism patients (e.g., those with progressive supranuclear palsy, multiple system atrophy or vascular parkinsonism), due to a more severe health status, greater frailty, and a higher need for care in nursing homes with higher infection rates [40]. Similarly, a small study from Spain showed that institutionalized PD patients were at a higher risk of SARS-CoV-2 infection, development of COVID-19, and suffered more often from dementia as a comorbidity [41].

그러나 파킨슨병 환자(예: 진행성 핵상 마비, 다계통 위축증 또는 혈관성 파킨슨병 환자)는 더 심각한 건강 상태, 더 허약하고 감염률이 높은 요양원에서 치료가 더 필요하기 때문에 입원율(3.3%)이 더 높았습니다[40]. 마찬가지로 스페인에서 실시한 소규모 연구에 따르면 시설에 입소된 파킨슨병 환자는 SARS-CoV-2 감염과 COVID-19 발병 위험이 더 높으며 동반 질환으로 치매를 더 자주 앓는 것으로 나타났습니다[41].

In a cross-sectional study of 102 SARS-CoV-2 PCR-positive patients, we investigated the frequency, type, severity, and risk of neurological involvement in COVID-19 patients [42]. Across the cohort, 59.8% of the patients had neurological involvement. We found that 25 (24.5%) patients suffered from unspecific neurological involvement, such as worsening of a pre-existing neurological condition (8.5%, n = 5), including one patient with exacerbation of pre-existing PD. We additionally investigated the relationship between pre-existing neurological comorbidities and the presence or severity of neurological involvement, and found increasing frequency and severity among those patients with pre-existing neurological comorbidities, including PD. This is not surprising, as PD patients with infections show an increase in severity of the disease symptoms—an observation that is also true for PD patients suffering from COVID-19 [39,43]. Several different hypotheses, directly or indirectly associated with PD, have been proposed for this phenomenon [44].

102명의 SARS-CoV-2 PCR 양성 환자를 대상으로 한 횡단면 연구에서 COVID-19 환자의 신경학적 침범 빈도, 유형, 중증도, 위험도를 조사했습니다[42]. 코호트 전체에서 59.8%의 환자가 신경학적 침범을 경험했습니다. 25명(24.5%)의 환자가 기존 신경 질환 악화(8.5%, n = 5)와 같은 비특이적 신경학적 침범을 겪은 것으로 나타났으며, 여기에는 기존 다발성 경화증이 악화된 환자 1명이 포함되었습니다. 또한 기존 신경학적 동반 질환과 신경학적 침범의 유무 또는 중증도 사이의 관계를 추가로 조사한 결과, PD를 포함한 기존 신경학적 동반 질환이 있는 환자에서 그 빈도와 중증도가 증가하는 것으로 나타났습니다. 감염된 PD 환자는 질병 증상의 중증도가 증가하기 때문에 이는 놀라운 일이 아니며, 이는 COVID-19로 고통받는 PD 환자에게도 해당되는 관찰 결과입니다[39,43]. 이 현상에 대해 PD와 직간접적으로 관련된 여러 가지 가설이 제안되었습니다 [44].

Increasing OFF times and motor fluctuations have been reported in a community-based study with 141 PD patients in the Lombardy region of Italy, of which 12 (8.5%) patients also had COVID-19 [39]. It was assumed that the deterioration of PD symptoms observed among the COVID-19 PD patients was due either to a direct influence of the infection or impaired pharmacokinetics of the dopaminergic treatment (e.g., diarrhea) [39]. As a direct consequence, it has been suggested that dopaminergic medication should be increased or adjusted during infection [39,45]. This study only observed patients for a period of three months, so data on long-term effects, worsening, or remission were not collected. Deterioration of PD motor symptoms may also precede a diagnosis of COVID-19, as described in two PD patients with poor outcomes after subthalamic nucleus deep brain stimulation [46]. On the other hand, common symptoms of COVID-19, such as anosmia or fatigue, belong to the spectrum of non-motor PD signs. In most published studies, the mortality rate due to COVID-19 does not differ between PD patients and the general population [36,37]. However, mortality is much higher (up to 40%) in the advanced stages of PD, with advanced age and comorbidities [45,47].

이탈리아 롬바르디아 지역의 141명의 PD 환자를 대상으로 한 지역사회 기반 연구에서 오프 시간 증가와 운동 변동이 보고되었으며, 이 중 12명(8.5%)의 환자도 COVID-19에 감염된 것으로 나타났습니다[39]. COVID-19 PD 환자에서 관찰된 PD 증상의 악화는 감염의 직접적인 영향 또는 도파민성 치료제의 약동학 장애(예: 설사) 때문인 것으로 추정되었습니다[39]. 직접적인 결과로, 감염 중에는 도파민성 약물의 용량을 늘리거나 조정해야 한다고 제안되었습니다 [39,45]. 이 연구는 3개월 동안만 환자를 관찰했기 때문에 장기적인 영향, 악화 또는 완화에 대한 데이터는 수집되지 않았습니다. 시상하핵 심부 뇌자극술 후 결과가 좋지 않은 두 명의 PD 환자에서 설명한 것처럼, PD 운동 증상의 악화는 COVID-19 진단에 앞서 나타날 수도 있습니다 [46]. 반면에 무감각이나 피로와 같은 COVID-19의 일반적인 증상은 비운동성 PD 징후에 속합니다. 발표된 대부분의 연구에서 COVID-19로 인한 사망률은 PD 환자와 일반 인구 사이에 차이가 없습니다[36,37]. 그러나 고령 및 동반 질환이 있는 PD 진행 단계에서는 사망률이 훨씬 더 높습니다(최대 40%)[45,47].

4. Newly Diagnosed PD Patients Linked to COVID-19

Parkinsonian symptoms due to the development of COVID-19 are rare, and evidence linking COVID-19 to developing PD is currently hypothetical. We screened the literature for cases describing the new onset of PD associated with COVID-19 and identified six cases of patients with new parkinsonism motor symptoms; in five of these cases, there was evidence of impaired dopaminergic uptake in the basal ganglia after nuclear imaging (Table 1) [48,49,50,51,52,53].

COVID-19 발병으로 인한 파킨슨병 증상은 드물며, COVID-19와 파킨슨병 발병을 연관시키는 증거는 현재로서는 가설에 불과합니다. COVID-19와 관련된 새로운 파킨슨병 발병 사례를 설명하는 문헌을 검색한 결과, 새로운 파킨슨병 운동 증상이 나타난 환자 6건을 확인했으며, 이 중 5건에서 핵의학 영상 촬영 후 기저핵에서 도파민 흡수 장애가 나타났다는 증거가 있었습니다(표 1)[48,49,50,51,52,53].

Table 1. Published cases of COVID-19 cases related to parkinsonism.

These six cases described the acute onset of parkinsonian symptoms with rigidity, bradykinesia, and tremor after SARS-CoV-2 infection. The ages ranged from 35 to 72 years. In three cases [48,50,51], COVID-19 symptoms were mild to moderate; one patient had a short hospitalization of three days, while the other two patients did not need hospital treatment. In the other three cases [49,52,53], treatment in an ICU, with mechanical ventilation or oxygen therapy, was required. PD symptoms began from 5 days up to 10 weeks after the positive SARS-CoV-2 test. Four cases were treated with dopaminergic medication, which improved the symptoms in two cases [48,50]. In one case, constipation for ten years was stated as a putative prodromal symptom [51]. Follow-up data were available in three cases; one patient had no symptoms after two months of follow-up [52], another had minor symptoms that were still present after 4 months of treatment with pramipexole [48], while the third patient was still impaired and unable to walk without aid [53].

이 6건의 사례는 SARS-CoV-2 감염 후 경직, 서동증, 떨림을 동반한 파킨슨 증상이 급성 발병한 사례입니다. 연령은 35세에서 72세까지 다양했습니다. 세 사례[48,50,51]에서 COVID-19 증상은 경증에서 중등도였으며, 한 환자는 3일의 짧은 입원을 했고 나머지 두 환자는 병원 치료가 필요하지 않았습니다. 나머지 세 사례[49,52,53]에서는 기계 환기 또는 산소 요법과 함께 중환자실에서 치료가 필요했습니다. PD 증상은 SARS-CoV-2 검사 양성 판정 후 5일에서 최대 10주 사이에 시작되었습니다. 4건은 도파민성 약물로 치료했으며, 2건에서 증상이 개선되었습니다[48,50]. 한 사례에서는 10년간 변비가 전구 증상으로 추정되는 것으로 나타났습니다[51]. 한 환자는 2개월 추적 관찰 후 증상이 없었고[52], 다른 환자는 프라미펙솔 치료 4개월 후에도 경미한 증상이 남아 있었으며[48], 세 번째 환자는 여전히 장애가 있어 도움 없이는 걸을 수 없었습니다[53].

Unfortunately, there are no follow-up data for evidence of a parainfectious or chronic impairment. In two cases, impairment was reported after nine months. The latter case [53] was still unable to walk without aid after nine months. This might be due to general weakness after COVID-19 and encephalopathy, rather than to parkinsonian symptoms. In the other case, their parkinsonian symptoms improved after treatment with pramipexole, with the addition of biperiden to manage the residual resting tremor [48].

안타깝게도 비감염성 또는 만성 장애의 증거에 대한 후속 데이터는 없습니다. 두 사례에서 9개월 후에 장애가 보고되었습니다. 후자의 경우[53]는 9개월이 지난 후에도 여전히 도움 없이는 걸을 수 없었습니다. 이는 파킨슨병 증상보다는 코로나19 이후 전반적인 쇠약과 뇌병증 때문일 수 있습니다. 다른 사례에서는 프라미펙솔 치료 후 파킨슨 증상이 개선되었으며, 잔류 안정 시 떨림을 관리하기 위해 비페리덴을 추가했습니다[48].

Nuclear imaging in five of these cases (using FP-CIT-SPECT and F-DOPA-PET) revealed evidence that the basal ganglia were affected, where chronic impairment of dopaminergic transmission, resulting from nigrostriatal degeneration, contributed to motor symptoms [54,55]. In one case [53], FDG-PET imaging showed diffuse cortical hypometabolism, with significant hypometabolism in the precuneus, most likely associated with dementia due to Alzheimer’s disease [56]. Congruently, this patient demonstrated cognitive decline during the progression of COVID-19, but also showed relative hypermetabolism in the basal ganglia, as often observed in PD patients [56]. Patients with acute encephalitis also show hypermetabolism in the affected brain regions and hypometabolism after remission [57,58]. Therefore, in this case [53], hypermetabolism in the basal ganglia was most likely due to the encephalopathic process. In two cases, good responses to dopaminergic medication indicated that the impairment was responsive to dopaminergic substitution, which is congruent with the nuclear imaging.

이 중 5건의 핵의학 영상(FP-CIT-SPECT 및 F-DOPA-PET 사용)에서 기저핵이 영향을 받았으며, 흑질 변성으로 인한 도파민 전달의 만성적 장애가 운동 증상에 기여한다는 증거가 밝혀졌습니다[54,55]. 한 사례[53]에서 FDG-PET 영상은 알츠하이머병으로 인한 치매와 관련이 있을 가능성이 높은 소뇌에서 상당한 대사율 저하와 함께 확산성 피질 대사율 저하를 보여주었습니다[56]. 이 환자는 코로나19가 진행되는 동안 인지 기능 저하를 보였지만, PD 환자에서 흔히 관찰되는 기저핵의 상대적 대사 과잉도 함께 나타났습니다[56]. 급성 뇌염 환자는 또한 감염된 뇌 부위에서 과대 대사를 보이고 관해 후 저 대사를 보입니다 [57,58]. 따라서이 경우 [53]에서 기저핵의 과대 대사는 뇌병증 과정 때문일 가능성이 큽니다. 두 사례에서 도파민 약물에 대한 좋은 반응은 장애가 도파민 대체에 반응한다는 것을 나타내며, 이는 핵 영상과 일치합니다.

It remains unclear whether COVID-19 induced PD, whether the disease revealed undiagnosed PD, or whether the disease induced encephalitis of the basal ganglia (post-encephalitic parkinsonism). Long-term data for evidence that SARS-CoV-2 induces PD do not yet exist. PD is defined by its motor symptoms of rigidity, bradykinesia, and tremor, and its loss of dopaminergic cells in the substantia nigra (because of the accumulation of alpha-synuclein, which leads to neurodegeneration). In addition, PD progressively worsens over time, which has not been observed in these cases so far.

COVID-19가 PD를 유발했는지, 이 질병으로 인해 진단되지 않은 PD가 드러났는지, 또는 이 질병이 기저핵 뇌염(뇌염 후 파킨슨병)을 유발했는지는 아직 불분명합니다. SARS-CoV-2가 PD를 유발한다는 증거에 대한 장기 데이터는 아직 존재하지 않습니다. PD는 경직, 서동증, 진전 등의 운동 증상과 흑질 내 도파민 세포 소실(알파-시누클레인 축적에 의한 신경 퇴화)로 정의됩니다. 또한 PD는 시간이 지남에 따라 점진적으로 악화되는데, 지금까지 이러한 사례에서는 관찰되지 않았습니다.

Clinical follow-up data to implicate a progressive neurodegenerative disease are missing in all six cases. However, at least one case had complete remission of PD symptoms [52], suggesting that an acute reversible parkinsonian condition is possible. On the other hand, nuclear imaging showed impaired dopaminergic transmission in all the examined patients, providing strong evidence for a neurodegenerative disease. Furthermore, in one case, a prodromal symptom (constipation) was present [51], indicating that undiagnosed PD must be considered, although constipation is a non-specific prodromal symptom that can have other causes.

진행성 신경 퇴행성 질환을 암시하는 임상 추적 데이터는 6건의 사례 모두에서 누락되었습니다. 그러나 적어도 한 사례는 PD 증상이 완전히 완화되어[52] 급성 가역성 파킨슨병이 발생할 수 있음을 시사합니다. 반면에 핵의학 영상은 모든 검사 대상 환자에서 도파민 전달 장애를 보여 신경 퇴행성 질환에 대한 강력한 증거를 제공했습니다. 또한 한 사례에서는 전구 증상(변비)이 있었는데[51], 이는 변비가 다른 원인이 있을 수 있는 비특이적 전구 증상이지만 진단되지 않은 PD를 고려해야 함을 나타냅니다.

Given the small number of reported cases and the large number of infected people worldwide, parkinsonian symptoms linked to a SARS-CoV-2 infection or COVID-19 are likely to be a very rare condition. In addition, compared to the small number of cases of viral parkinsonism caused by other viruses, post-encephalitic parkinsonism may be a neuroinflammatory reaction to the infection, rather than a virus-specific disease. However, coronaviruses have been found in the CSF; thus, infection with a virus such as SARS-CoV-2 might be linked to the onset of PD. Furthermore, only a relatively short period of time has passed since the start of the pandemic; it is possible that, in the long term, symptoms of PD may occur months after infection with SARS-CoV-2.

보고된 사례 수가 적고 전 세계 감염자 수가 많다는 점을 고려할 때, SARS-CoV-2 감염 또는 COVID-19와 관련된 파킨슨병 증상은 매우 드문 질환일 가능성이 높습니다. 또한, 다른 바이러스로 인한 바이러스성 파킨슨병 사례의 수가 적은 것과 비교할 때, 뇌염 후 파킨슨병은 바이러스 특정 질환이라기보다는 감염에 대한 신경염증 반응일 수 있습니다. 그러나 코로나바이러스가 CSF에서 발견되었으므로 SARS-CoV-2와 같은 바이러스 감염이 PD 발병과 관련이 있을 수 있습니다. 또한 팬데믹이 시작된 지 비교적 짧은 기간밖에 지나지 않았기 때문에 장기적으로는 SARS-CoV-2 감염 후 수개월이 지나서야 PD 증상이 나타날 수 있습니다.

5. Impact of SARS-CoV-2 Pandemic on PD Patients with Asymptomatic SARS-CoV-2 Infection or Unaffected PD Patients

The pandemic is not only a burden for PD patients with COVID-19. PD patients infected with SARS-CoV-2, but without COVID-19, and non-infected PD patients also suffer from the current situation. PD patients are vulnerable to new life events and changes, especially negative ones. In particular, negative emotional stress can lead to an increase in symptoms, effects that can be partially explained by the impaired dopaminergic function in PD patients [59,60]. Additionally, social isolation during lockdown periods has reduced the access of PD patients to their physicians and co-therapists (physiotherapists, occupational therapists, and speech therapists). For example, during the lockdown period in Italy, many PD patients reported worsening of their motor, non-motor, and neuropsychiatric symptoms [61]. A French study analyzed the consequences of a sudden lockdown in 2653 PD patients [62]. In 88% of all the patients, physiotherapy was interrupted, and many motor symptoms and pain worsened during the observation period of four weeks between March and April 2020. Around 45% of the patients also reported that their psychiatric state (i.e., depression and anxiety) had been exacerbated by the situation.

팬데믹은 COVID-19에 감염된 PD 환자에게만 부담이 되는 것이 아닙니다. 코로나19에 감염되지는 않았지만 SARS-CoV-2에 감염된 PD 환자와 감염되지 않은 PD 환자도 현재 상황으로 인해 어려움을 겪고 있습니다. PD 환자는 새로운 삶의 사건과 변화, 특히 부정적인 변화에 취약합니다. 특히 부정적인 정서적 스트레스는 PD 환자의 도파민 기능 장애로 부분적으로 설명될 수 있는 증상의 증가로 이어질 수 있습니다[59,60]. 또한, 봉쇄 기간 동안 사회적 고립으로 인해 PD 환자는 의사 및 보조 치료사(물리치료사, 작업치료사, 언어치료사)와의 접촉이 줄어들었습니다. 예를 들어, 이탈리아의 봉쇄 기간 동안 많은 파킨슨병 환자들이 운동, 비운동, 신경정신과적 증상이 악화되었다고 보고했습니다[61]. 프랑스의 한 연구에서는 2653명의 PD 환자를 대상으로 갑작스러운 봉쇄의 결과를 분석했습니다[62]. 전체 환자의 88%에서 물리 치료가 중단되었고, 2020년 3월과 4월 사이 4주 동안 관찰 기간 동안 많은 운동 증상과 통증이 악화되었습니다. 또한 환자의 약 45%는 이러한 상황으로 인해 정신과적 상태(예: 우울증 및 불안)가 악화되었다고 보고했습니다.

Adaptive digital (i.e., remote) treatment strategies during the pandemic are, therefore, important, including telemedicine treatment from physicians and services provided by co-therapists. Head-to-head studies must also eval‎uate whether this is a long-term alternative to personal contact. The pandemic provides an opportunity to assess these treatments and the potential of wearable sensors, for example, to monitor treatment or disease progression.

따라서 팬데믹 기간 동안 의사의 원격 진료와 공동 치료사가 제공하는 서비스 등 적응형 디지털(즉, 원격) 치료 전략이 중요합니다. 또한 일대일 연구가 대면 접촉을 대체할 수 있는 장기적인 대안인지도 평가해야 합니다. 팬데믹은 이러한 치료법과 웨어러블 센서의 잠재력(예: 치료 또는 질병 진행 모니터링)을 평가할 수 있는 기회를 제공합니다.

6. Post-COVID-19 Syndrome in PD Patients

The post-COVID-19 syndrome has been defined as the “signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks and are not explained by an alternative diagnosis” [63]. In a small series of 23 PD patients, 85% developed post-COVID-19 symptoms, including worsening of motor functions, fatigue, and cognitive disturbances [64]. This has been the only published study addressing this condition so far. However, these results must be interpreted with caution, due to the study’s small sample size and the diagnostic criteria that are yet to be defined for post-COVID-19 syndrome in PD patients. In addition, other effects, such as isolation due to lockdown periods and reduced access to physiotherapists, must be considered.

코로나19 후 증후군은 "COVID-19와 일치하는 감염 중 또는 감염 후에 발생하고 12주 이상 지속되며 다른 진단으로 설명되지 않는 징후와 증상"으로 정의되었습니다[63]. 23명의 PD 환자를 대상으로 한 소규모 연구에서 85%가 운동 기능 악화, 피로, 인지 장애 등 코로나19 이후 증상을 나타냈습니다[64]. 이 연구는 지금까지 이 질환을 다룬 유일한 연구입니다. 그러나 이 연구의 표본 규모가 작고 PD 환자의 코로나19 후 증후군에 대한 진단 기준이 아직 정의되지 않았기 때문에 이러한 결과는 신중하게 해석해야 합니다. 또한 봉쇄 기간으로 인한 고립, 물리치료사 접근성 감소와 같은 다른 영향도 고려해야 합니다.

In another unpublished study, we included 171 (mean age 43.2 ± 12.7 years (range 18–71 years)) patients who fulfilled the WHO case definition of the post-COVID-19 condition, as defined by the Delphi consensus [65]. In a subanalysis we performed on this dataset, we discovered that none of the patients described motor symptoms, such as bradykinesia, impaired posture, or tremor, after infection with SARS-CoV-2. These findings were underlined by the fact that, after diagnostic workup, PD was not diagnosed among these patients. In addition, none of the 171 post-COVID-19 patients presented previously diagnosed PD (own data).

또 다른 미공개 연구에서는 델파이 합의에 따라 정의된 코로나19 이후 상태에 대한 WHO 사례 정의를 충족하는 171명(평균 연령 43.2±12.7세(범위 18-71세))의 환자를 포함했습니다[65]. 이 데이터 세트에 대해 수행한 하위 분석에서 SARS-CoV-2 감염 후 서동증, 자세 장애, 떨림과 같은 운동 증상을 설명한 환자가 없다는 사실을 발견했습니다. 이러한 결과는 진단 검사 후 이들 환자 중 파킨슨병이 진단되지 않았다는 사실에서 더욱 강조되었습니다. 또한, 코로나19 이후 171명의 환자 중 이전에 진단된 PD(자체 데이터)를 보인 환자는 없었습니다.

On the one hand, this finding could be due to the younger age of the patients who presented with post-COVID-19 syndrome in our out-patient clinic, where neurodegenerative diseases do not have a high preval‎ence. However, we suppose that PD patients might not explicitly attribute the worsening of non-motor PD symptoms to COVID-19. Hence, we speculate that post-COVID syndrome does not play a major role in PD patients.

한편으로는 신경 퇴행성 질환의 유병률이 높지 않은 외래 진료소에서 코로나19 후 증후군을 보인 환자들의 연령이 젊었기 때문일 수 있습니다. 그러나 파킨슨병 환자들이 비운동성 파킨슨병 증상의 악화를 코로나19 때문이라고 명시적으로 밝히지 않을 수도 있다고 생각합니다. 따라서 코로나19 후 증후군은 파킨슨병 환자에서 중요한 역할을 하지 않는 것으로 추측됩니다.

Taking together the differentiation between post-COVID-19 syndrome in PD and the general worsening of PD symptoms due to COVID-19 bears difficulties. Most of the post-COVID-19 syndrome-associated symptoms, such as fatigue and cognitive disturbances, overlap with the non-motor symptoms of PD. Worsening of PD symptoms in PD patients often occurs during systemic inflammation, due to a viral or bacterial infection [66,67]. Patients do not always fully recover, and may remain in a worse condition than before. In a case study with 80 PD patients with systemic inflammation, 26 patients suffered from motor deterioration, 19 of whom still suffered a persistent decline in motor functions six months after infection [66]. The following pathophysiological considerations address this issue [44]: (1) Altered dopaminergic medication, due to swallowing difficulties, reduced intestinal uptake, e.g., diarrhea, or altered the permeability of the blood–brain barrier. (2) Altered cerebral dopamine metabolism, due to altered levels of cytokines. (3) Enhanced neurodegeneration, due to enhanced neuroinflammation. Chronic neuroinflammation is a driving factor in neurodegenerative diseases [15,68], so this aspect best explains the persistent decline in PD symptoms after infection.

PD에서 코로나19 후 증후군과 코로나19로 인한 PD 증상의 일반적인 악화를 구분하는 것은 어려운 일입니다. 피로 및 인지 장애와 같은 코로나19 후 증후군 관련 증상의 대부분은 PD의 비운동성 증상과 겹칩니다. PD 환자의 PD 증상 악화는 바이러스 또는 박테리아 감염으로 인한 전신 염증 중에 종종 발생합니다[66,67]. 환자가 항상 완전히 회복되는 것은 아니며 이전보다 더 나쁜 상태로 남아있을 수 있습니다. 전신 염증을 동반한 80명의 PD 환자를 대상으로 한 사례 연구에서 26명의 환자가 운동 기능 저하를 겪었으며, 이 중 19명은 감염 6개월 후에도 여전히 운동 기능이 지속적으로 저하되었습니다[66]. 다음과 같은 병태생리학적 고려사항이 이 문제를 해결합니다[44]: (1) 삼킴 곤란, 설사 등 장 흡수 감소, 혈액-뇌 장벽의 투과성 변화로 인한 도파민성 약물의 변경. (2) 사이토카인 수치의 변화로 인한 대뇌 도파민 대사 변화. (3) 신경염증 강화로 인한 신경 퇴화 촉진. 만성 신경염증은 신경 퇴행성 질환의 원동력이므로[15,68], 이러한 측면은 감염 후 PD 증상이 지속적으로 감소하는 것을 가장 잘 설명합니다.

Similarly, the mechanism of chronic neuroinflammation is discussed in post-COVID-19 syndrome [69,70], yet studies investigating this issue are still missing. Cases of patients who have developed parkinsonism after COVID-19, as a post-acute sequelae of COVID-19 (PASC), similar to encephalitis lethargica in the last century, have not been described yet, except in one case, who developed parkinsonism 10 weeks after SARS-CoV2-infection and had motor symptoms months later [53]. Since PD is a neurodegenerative disease, with a long latency until the onset of the first motor symptoms, it is important to ask patients with post-COVID-19 syndrome about motor symptoms. At this stage of the pandemic, predictions are difficult to make.

마찬가지로, 만성 신경염증의 메커니즘은 코로나19 후 증후군에서 논의되고 있지만[69,70], 이 문제를 조사한 연구는 아직 없습니다. 지난 세기의 무기력성 뇌염과 유사한 COVID-19 급성 후유증(PASC)으로 COVID-19 이후 파킨슨병이 발병한 환자 사례는 아직 보고된 바 없으며, SARS-CoV2 감염 10주 후 파킨슨병이 발병하고 수개월 후 운동 증상이 나타난 한 사례를 제외하고는 [53] 아직 보고된 바가 없습니다. 파킨슨병은 신경 퇴행성 질환으로 첫 번째 운동 증상이 나타날 때까지 잠복기가 길기 때문에 코로나19 이후 증후군 환자에게 운동 증상에 대해 물어보는 것이 중요합니다. 팬데믹의 현 단계에서는 예측이 어렵습니다.

7. Conclusions

The SARS-CoV-2 pandemic has a significant impact on PD patients, regardless of whether they have been infected by the virus. PD per se does not represent a risk factor for increased mortality associated with COVID-19, but advanced age and disease progression in a PD patient do have a negative impact. Isolation and limited access to medical care services can lead to aggravation of the symptoms in PD patients. Parkinsonian symptoms occurring in response to COVID-19 is a rare condition, and evidence linking it to the development of PD is currently hypothetical.

SARS-CoV-2 팬데믹은 바이러스 감염 여부와 관계없이 PD 환자에게 중대한 영향을 미칩니다. PD 자체는 COVID-19와 관련된 사망률 증가의 위험 요인이 아니지만, PD 환자의 고령과 질병 진행은 부정적인 영향을 미칩니다. 고립과 의료 서비스 이용 제한은 파킨슨병 환자의 증상 악화로 이어질 수 있습니다. 코로나19에 반응하여 발생하는 파킨슨병 증상은 드문 질환이며, 코로나19가 파킨슨병 발병과 관련이 있다는 증거는 현재로서는 가설에 불과합니다.

As a limitation, we have to state that many studies have been performed and data have been collected about PD patients and COVID-19 in the first six months of the pandemic, with cohorts of up to 2500 patients, but only a few were conducted in the following months and years. In the meantime, with millions of infected people worldwide, the number of infected PD patients is also expected to be higher. This gap must be filled, in order to understand the possible link between PD and COVID-19.

A second limitation is that most studies on PD and SARS-CoV-2 generally examined patients with idiopathic Parkinson’s disease, but no reliable data about atypical Parkinson’s disease were found.

According to our own data, Parkinson symptoms do not frequently occur in patients with post-COVID syndrome. The already broadly discussed threat of a post-pandemic Parkinson pandemic, as was the case almost a hundred years ago, cannot be confirmed at the current stage, but must be re-eval‎uated in the future.

팬데믹 초기 6개월 동안 최대 2,500명의 환자 코호트를 대상으로 PD 환자와 COVID-19에 대한 많은 연구가 수행되고 데이터가 수집되었지만, 그 이후 몇 달과 몇 년 동안 수행된 연구는 극히 일부에 불과하다는 점을 한계로 지적하지 않을 수 없습니다. 한편, 전 세계적으로 수백만 명의 감염자가 발생함에 따라 감염된 PD 환자 수도 더 많을 것으로 예상됩니다. PD와 COVID-19 사이의 가능한 연관성을 이해하려면 이 격차를 메워야 합니다.

두 번째 한계는 PD와 SARS-CoV-2에 대한 대부분의 연구가 특발성 파킨슨병 환자를 대상으로 진행되었지만 비정형 파킨슨병에 대한 신뢰할 수 있는 데이터는 발견되지 않았다는 점입니다.



자체 데이터에 따르면, 코로나19 이후 증후군 환자에게는 파킨슨 증상이 자주 발생하지 않습니다. 거의 100년 전에 그랬던 것처럼 이미 광범위하게 논의된 팬데믹 이후 파킨슨병 대유행의 위협은 현재 단계에서는 확인할 수 없지만 향후 재평가되어야 합니다.

Author Contributions

Conceptualization, T.G., L.T. and S.K.; data curation, M.F. and M.S.; writing—original draft preparation, T.G.; writing—review and editing, T.G., M.F., M.S., E.-H.K., L.T. and S.K.; visualization, T.G. Please turn to the CRediT taxonomy for the term explanation. Authorship must be limited to those who have contributed substantially to the work reported. All authors have read and agreed to the published version of the manuscript.

Funding

This work was further supported by the Bundesministerium für Forschung und Bildung (BMBF) through funding for the TreatHSP network (No01GM1905 to SK).

Institutional Review Board Statement

The study was performed in accordance with the principles of the Declaration of Helsinki and the local Ethics Committees approved the study plan (Ethics Committee University of Duisburg-Essen, approval number: 20-9284-BO).

Informed Consent Statement

Signed informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The study is registered in the German register for clinical trials (DRKS) under the registration number: DRKS00023312.

Acknowledgments

We acknowledge support from the Open Access Publication Fund of the University of Duisburg-Essen.

Conflicts of Interest

The authors declare no conflict of interest.

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