Journal Reading

* Kepaniteraan Klinik Senior/ G1A218104

* Pembimbing

Manifestasi Neurologis Pasien Rawat Inap dengan COVID-19 di Wuhan, China:

Studi Seri Kasus Retrospektif

Meika Amsi Munte, S.Ked* dr. Nidia Suriani, Sp.S, M. Biomed**

KEPANITERAAN KLINIK SENIOR

BAGIAN ILMU PENYAKIT SARAF RSUD RADEN MATTAHER
FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN
UNIVERSITAS JAMBI
2020
 Manifestasi Neurologis Pasien Rawat Inap dengan COVID-19 di Wuhan,
China: studi seri kasus retrospektif

Ling Mao*, Mengdie Wang*, Shengcai Chen*, Quanwei He*, Jiang Chang*, Can-dong Hong,
† † †
Yifan Zhou, David Wang, Yanan Li , Huijuan Jin , Bo Hu

Departemen neurologi (Prof. LM, MW Ph.D., SC Ph.D., Prof. QH, Prof. YL, Prof. HJ, Prof.
BH), Rumah Sakit Union, perguruan tinggi kedokteran Tongji, Universitas Sains dan Teknologi
Huazhong , Wuhan, 430022, Cina; Departemen Epidemiologi dan Biostatistik, Laboratorium
Kunci untuk Lingkungan dan Kesehatan, Sekolah Kesehatan Masyarakat (Prof. JC), perguruan
tinggi kedokteran Tongji, universitas ilmu pengetahuan dan teknologi Huazhong, Wuhan,
430022, China; Divisi Neurovaskular, Departemen Neurologi, Institusi Medis Neurologis
Barrow / Pusat Medis Rumah Sakit Saint Joseph Phoenix, AZ 85013 AS (Prof. DW)

* Berkontribusi sama

† Penulis korespondensi

Korespondensi dengan:

Prof. Bo Hu, Departemen neurologi, Rumah Sakit Union, perguruan tinggi kedokteran Tongji,
Universitas Huazhong sains dan teknologi, Wuhan, 430022, China hubo@mail.hust.edu.cn

Atau Prof. Huijuan Jin, Departemen Neurologi, Rumah Sakit Union, Universitas Tongji,
Universitas Sains dan Teknologi Huazhong, Wuhan, 430022, China jinhuijuan1983@163.com

Atau Prof. Yanan Li, Departemen Neurologi, Rumah Sakit Union, perguruan tinggi kedokteran
Tongji,Universitas sains dan teknologi Huazhong, Wuhan, 430022, Cina liyn@mail.hust.edu.cn
ABSTRAK

OBJEKTIF

Untuk mempelajari manifestasi neurologis pasien dengan penyakit coronavirus 2019 (COVID-
19).

DESAIN

Seri kasus retrospektif

SETTING

Tiga rumah sakit perawatan COVID-19 yang ditunjuk dari Rumah Sakit Persatuan Huazhong
Uni-versity Sains dan Teknologi di Wuhan, China.

PESERTA

Dua ratus empat belas pasien rawat inap dengan diagnosis yang dikonfirmasi laboratorium dari
sindrom pernafasan akut yang parah dari infeksi coronavirus 2 (SARS-CoV-2). Data
dikumpulkan dari 16 Januari 2020 hingga 19 Februari 2020.

PENGUKURAN HASIL UTAMA

Data klinis diekstraksi dari catatan medis elektronik dan ditinjau oleh tim dokter yang terlatih.
Gejala neurologis terbagi dalam tiga kategori: gejala sistem saraf pusat (SSP) atau penyakit
(sakit kepala, pusing, gangguan kesadaran, ataksia, penyakit serebrovaskular akut, dan epilepsi),
gejala sistem saraf perifer (PNS) (hipogeusia, hiposmia, hipopsia, dan neuralgia), dan gejala otot
skeletal. Data semua gejala neurologis diperiksa oleh dua ahli saraf terlatih.

HASIL

Dari 214 pasien yang diteliti, 88 (41,1%) adalah parah dan 126 (58,9%) adalah pasien tidak
parah. Dibandingkan dengan pasien yang tidak parah, pasien yang parah lebih tua (58,7 ± 15,0
tahun vs 48,9 ± 14,7 tahun), memiliki gangguan yang lebih mendasar (42 [47,7%] vs 41
[32,5%]), terutama hipertensi (32 [36,4%] vs 19 [15,1%]), dan menunjukkan lebih sedikit gejala
tipikal/khas seperti demam (40 [45,5%] vs 92 [73%]) dan batuk (30 [34,1%] vs 77 [61,1%]).
Tujuh puluh delapan (36,4%) pasien memiliki manifestasi neurologis. Pasien yang lebih parah
kemungkinan memiliki gejala neurologis (40 [45,5%] vs 38 [30,2%]), seperti penyakit
serebrovaskular akut (5 [5,7%] vs 1 [0,8%]), gangguan kesadaran (13 [14,8%] vs 3 [2,4%]) dan
cedera otot rangka (17 [19,3%] vs 6 [4,8%]).

KESIMPULAN

Dibandingkan dengan pasien yang tidak parah dengan COVID-19, pasien yang parah biasanya
memiliki gejala neurologis yang bermanifestasi sebagai penyakit serebrovaskular akut, gangguan
kesadaran dan gejala otot rangka.

Pendahuluan

Pada bulan Desember 2019, banyak kasus pneumonia yang tidak dapat dijelaskan terjadi di
Wuhan, China, dan telah dengan cepat menyebar ke bagian lain China, kemudian ke Eropa,
Amerika Utara dan Asia. Wabah ini dikonfirmasi disebabkan oleh virus corona baru (2019 novel
coronavirus, 2019-nCoV) [1]. 2019-nCov dilaporkan memiliki gejala yang mirip dengan
coronavirus syndrome pernapasan akut (SARS-CoV) pada tahun 2003 [2]. Keduanya berbagi
reseptor yang sama, angiotensin-converting enzyme 2 (ACE2) [3]. Oleh karena itu, virus ini
bernama SARS-CoV-2, dan baru-baru ini WHO menamainya penyakit coronavirus 2019
(COVID-19). Hingga 21 Februari 2020, ada 75569 kasus COVID-19 dan 2239 kematian di
China [4].

Virus corona dapat menyebabkan berbagai infeksi sistemik atau cedera pada berbagai hewan [5].
Namun, beberapa dari mereka dapat beradaptasi dengan cepat dan melewati barier spesies,
seperti dalam kasus SARS-CoV dan sindrom pernapasan Timur Tengah-CoV (MERS-CoV),
menyebabkan epidemi atau pandemi. Infeksi pada manusia sering menyebabkan gejala klinis
yang parah dan mortalitas yang tinggi [6]. Adapun COVID-19, beberapa penelitian telah
menggambarkan manifestasi klinis termasuk gejala pernapasan, mialgia dan kelelahan. COVID-
19 juga memiliki temuan laboratorium yang khas dan kelainan CT paru [7]. Namun, belum
dilaporkan bahwa pasien dengan COVID-19 memiliki manifestasi neurologis. Di sini, kami ingin
melaporkan manifestasi neurologis khas infeksi SARS-CoV-2 pada 78 dari 214 pasien dengan
diagnosis COVID-19 yang dikonfirmasi laboratorium dan dirawat di rumah sakit kami, yang
berlokasi di pusat gempa Wuhan.

Metode

Desain Studi dan Peserta

Ini adalah penelitian retrospektif. Data ditinjau pada semua pasien dengan COVID-19 dari 16
Januari hingga 19 Februari 2020 di tiga rumah sakit perawatan COVID-19 yang ditunjuk di
Rumah Sakit Union di Universitas Sains dan Teknologi Huazhong. Semua pasien dengan
COVID-19 yang terdaftar dalam penelitian ini didiagnosis berdasarkan pedoman sementara
WHO [8]. Hanya kasus-kasus yang dikonfirmasi oleh hasil positif terhadap uji reaksi balik-
transkriptase polimerase-rantai (RT-PCR) real-time dari spesimen swab/usap tenggorokan yang
dimasukkan dalam analisis [9]. Rumah Sakit Union, yang terletak di daerah endemik COVID-19
di Wuhan, Provinsi Hubei, adalah salah satu sistem perawatan kesehatan tersier utama dan
rumah sakit pendidikan yang bertanggung jawab untuk perawatan infeksi SARS-CoV-2 yang
ditunjuk oleh pemerintah. Studi ini dilakukan sesuai dengan prinsip-prinsip Deklarasi Helsinki
dan disetujui oleh Komite Etika Penelitian dari Tongji Medical College, Universitas Sains dan
Teknologi Huazhong, Wuhan, China. Persetujuan verbal diperoleh dari pasien sebelum
pendaftaran.

Pengumpulan data

Karakteristik demografi, riwayat medis, gejala, tanda-tanda klinis, temuan laboratorium, temuan
CT scan dada diekstraksi dari catatan medis elektronik. Data ditinjau oleh tim dokter yang
terlatih. Gejala neurologis dikategorikan menjadi tiga area utama: gejala atau penyakit sistem
saraf pusat (CNS), gejala sistem saraf perifer (PNS) dan gejala otot. Penyakit serebrovaskular
akut termasuk stroke iskemik dan perdarahan serebral yang didiagnosis dengan CT kepala.
Cidera otot didefinisikan ketika pasien mengalami mialgia dan peningkatan kadar kreatin kinase
serum di atas 200 U / L [7]. Semua gejala neurologis ditinjau dan dikonfirmasi oleh dua ahli
saraf terlatih. Tanggal timbulnya penyakit didefinisikan sebagai hari ketika gejala diketahui.
Tingkat keparahan COVID-19 didefinisikan oleh pedoman internasional untuk pneumonia yang
didapat masyarakat [10]. Sampel swab tenggorokan dikumpulkan dan ditempatkan ke dalam
tabung koleksi yang berisi larutan pengawet untuk virus [9]. SARS-CoV-2 dikonfirmasi oleh uji
RT-PCR real-time menggunakan kit deteksi asam nukleat SARS-CoV-2 sesuai dengan protokol
pabrik (Shanghai bio-germ Medical Technology Co Ltd).

Analisis statistik

Variabel kontinu digambarkan sebagai mean dan standar deviasi, atau nilai median dan rentang
interkuartil (IQR). Variabel kategorikal dinyatakan sebagai jumlah dan persentase. Variabel
kontinu dibandingkan dengan menggunakan uji peringkat-jumlah Wilcox tidak berpasangan.
Proporsi untuk variabel kategori dibandingkan menggunakan uji χ2. Semua analisis statistik
dilakukan dengan menggunakan perangkat lunak R (versi 3.3.0). Ambang signifikansi ditetapkan
pada P <0,05.

Hasil

Karakteristik demografis dan klinis

Sebanyak 214 pasien rawat inap dengan infeksi SARS-CoV-2 yang dikonfirmasi dimasukkan
dalam analisis ini. Karakteristik demografis dan klinis mereka ditunjukkan pada Tabel 1. Usia
rata-rata mereka adalah 52,7 ± 15,5 tahun, dan 127 (59,3%) adalah perempuan. Di antara pasien
ini, 83 (38,8%) memiliki setidaknya satu dari penyakit yang mendasari berikut: hipertensi (51
[23,8%]), diabetes (30 [14,0%]), penyakit kardiovaskular (15 [7,0%]), dan keganasan (13
[6,1%]). Gejala yang paling umum pada awal penyakit adalah demam (132 [61,7%]), batuk
kering (107 [50,0%]) dan anoreksia (68 [31,8%]). Tujuh puluh delapan (36,4%) pasien memiliki
gejala sistem saraf: SSP (53 [24,8%]), PNS (19 [8,9%]) dan otot rangka (23 [10,7%]). Pada
pasien dengan gejala SSP, keluhan yang paling umum adalah pusing (36 [16,8%] dan sakit
kepala (28 [13,1%]). Pada pasien dengan gejala PNS, keluhan yang paling umum adalah
hypogeusia (12 [5,6%]) dan hiposmia ( 11 [5.1%]).

Menurut kriteria diagnostik, masing-masing 88 (41,1%) pasien adalah parah dan 126 (58,9%)
pasien adalah tidak parah. Pasien dengan infeksi parah secara signifikan lebih tua (58,2 ± 15,0
tahun vs 48,9 ± 14,7 tahun; P <0,001) dan lebih cenderung memiliki gangguan mendasar lainnya
(42 [47,7%] vs 41 [32,5%], P <0,05), terutama -Di hipertensi (32 [36,4%] vs 19 [15,1%], P
<0,001), dan memiliki gejala yang kurang khas seperti demam (40 [45,5%] vs 92 [73%], P
<0,001) dan kering batuk (30 [34,1%] vs 77 [61,1%], P <0,001). Selain itu, gejala sistem saraf
secara signifikan lebih umum pada kasus yang parah dibandingkan dengan kasus yang tidak
parah (40 [45,5%] vs 38 [30,2%], P <0,05). Mereka termasuk penyakit serebrovaskular akut (5
[5,7%] (4 pasien dengan stroke iskemik dan 1 dengan pendarahan otak yang meninggal
kemudian karena gagal napas) vs 1 [0,8%] (1 pasien dengan stroke iskemik), P <0,05),
mengalami gangguan kesadaran (13 [14,8%] vs 3 [2,4%], P <0,001) dan cedera otot (17 [19,3%]
vs 6 [4,8%], P <0,001).

Temuan laboratorium pada pasien yang parah dan pasien yang tidak parah

Tabel 2 menunjukkan temuan laboratorium dalam subkelompok yang parah dan tidak parah.
Pasien yang parah memiliki respon inflamasi yang lebih meningkat, termasuk sel darah putih
yang lebih tinggi, jumlah neutrofil, jumlah limfosit yang lebih rendah dan lebih banyak
peningkatan kadar protein C-reaksi dibandingkan dengan pasien non-parah (sel darah putih:
median, 5,4 [IQR, 0,1 -20,4] vs 4,5 [IQR, 1,8-14,0], P <0,01; neutrofil: median, 3,8 [IQR, 0,0-
18,7] vs 2,6 [IQR, 0,7-11,8], P <0,001; limfosit: median, 0,9 [IQR , 0,1-2,6] vs 1,3 [IQR, 0,4-
2,6], P <0,001; protein reaksi-C: median, 37,1 [IQR, 0,1-212,0] vs 9,4 [IQR, 0,2-126,0], P
<0,001). Pasien yang parah memiliki tingkat D-dimer yang lebih tinggi daripada pasien yang
tidak parah (median, 0,9 [IQR, 0,1-20,0] vs 0,4 [IQR, 0,2-8,7], P <0,001), yang merupakan
indikasi sistem koagulasi konsumtif. Selain itu, pasien yang parah memiliki keterlibatan banyak
organ, seperti organ hati yang lebih serius (peningkatan laktat dehidrogenase, alanin
aminotransferase dan kadar aspartat aminotransferase), ginjal (peningkatan kadar nitrogen urea
darah dan kreatinin) dan kerusakan otot (peningkatan kadar kreatinin kinase).

Temuan laboratorium pada pasien dengan dan tanpa gejala SSP

Tabel 3 menunjukkan temuan laboratorium pasien dengan dan tanpa gejala SSP. Kami
menemukan bahwa pasien dengan gejala SSP memiliki limfosit yang lebih rendah, jumlah
trombosit dan kadar nitrogen urea darah yang lebih tinggi dibandingkan dengan mereka yang
tidak memiliki gejala SSP (limfosit: median, 1,0 [IQR, 0,1-2,3] vs 1,2 [IQR, 0,2-2,6], P < 0,05;
platelet: median, 180,0 [IQR, 18,0-564,0] vs 227,0 [IQR, 42,0-583,0], P <0,01; urea nitro-gen
darah: median, 4,5 [IQR, 1,6-48,1] vs 4,1 [IQR , 1,5-19.1], P <0,05). Untuk sub-kelompok yang
parah, pasien dengan gejala SSP juga memiliki limfosit yang lebih rendah, jumlah trombosit dan
kadar nitrogen urea darah yang lebih tinggi dibandingkan dengan mereka yang tidak memiliki
gejala SSP (limfosit: median, 0,7 [IQR, 0,1-1,6] vs 0,9 [IQR, 0,2-2,6], P <0,01; platelet: median,
169.0 [IQR, 18.0-564.0] vs 220.0 [IQR, 109.0-576.0], P <0,05; nitrogen urea darah: median, 5,0
[IQR, 2,3-48,1] vs 4,4 [IQR, 1,5-19,1], P <0,05). Untuk subkelompok yang tidak parah, tidak ada
perbedaan signifikan dalam temuan laboratorium pasien dengan dan tanpa gejala SSP.

Temuan laboratorium pada pasien dengan dan tanpa gejala PNS

Tabel 4 menunjukkan temuan laboratorium pasien dengan dan tanpa gejala PNS. Kami
menemukan bahwa tidak ada perbedaan signifikan dalam temuan laboratorium pasien dengan
PNS dan mereka yang tanpa PNS. Hasil serupa juga ditemukan pada subkelompok yang parah
dan subkelompok yang tidak parah.

Temuan laboratorium pada pasien dengan dan tanpa cedera otot

Tabel 5 menunjukkan temuan laboratorium pasien dengan dan tanpa cedera otot. Dibandingkan
dengan pasien tanpa cedera otot, pasien dengan cedera otot memiliki jumlah neutrofil yang lebih
tinggi, jumlah limfosit yang lebih rendah dan level protein C-reaktif yang lebih tinggi, kadar D-
dimer (neutrofil: median, 4,3 [IQR, 0,9-18,7] vs 2,9 [ IQR, 0,0-13.0], P <0,05; limfosit: median,
0,9 [IQR, 0,1-2,6] vs 1,2 [IQR, 0,1-2,6], P <0,01; protein aksi-ulang C: median, 56,0 [IQR, 0,1-
212,0] vs 11,1 [IQR, 0,1-204,5], P <0,001; D-dimer: median, 1,3 [IQR, 0,2-20,0] vs 0,5 [IQR,
0,1-20,0]). Kelainan tersebut merupakan manifestasi dari peningkatan respons inflamasi dan
fungsi pembekuan darah. Selain itu, kami menemukan bahwa pasien dengan cedera otot
mengalami kerusakan multi-organ termasuk hati yang lebih serius (peningkatan laktat
dehidrogenase, alanin aminotransferase dan kadar aspartat aminotransferase), dan kelainan ginjal
(peningkatan urea nitrogen dalam darah dan kadar kreatinin dalam darah).

Untuk subkelompok yang parah, pasien dengan cedera otot mengalami peningkatan respon
inflamasi (penurunan jumlah limfosit dan peningkatan kadar protein C-reaktif), dan hati yang
lebih serius (peningkatan laktat dehidrogenase, alanin aminotransferase dan kadar aspartate
aminotransferase), ginjal (kadar kreatinin yang meningkat) dan usia otot (peningkatan kadar
kreatinin kinase). Untuk subkelompok yang tidak parah, pasien dengan cedera otot hanya
memiliki kadar protein C-reaktif dan kreatinin kinase yang lebih tinggi dibandingkan dengan
mereka yang tidak mengalami cedera otot.
Diskusi

Ini adalah laporan pertama pada manifestasi neurologis terperinci dari pasien yang dirawat di
rumah sakit dengan COVID-19. Pada 19 Februari 2020, dari 214 pasien yang dilibatkan dalam
penelitian ini, 88 (41,1%) adalah parah dan 126 (58,9%) adalah tidak parah. Dari jumlah
tersebut, 78 (36,4%) memiliki berbagai manifestasi neurologis yang melibatkan SSP, PNS, dan
otot rangka. Dibandingkan dengan pasien yang tidak parah, pasien yang parah lebih tua dan
memiliki lebih banyak hipertensi tetapi lebih sedikit dengan gejala khas seperti demam dan
batuk. Pasien yang parah lebih cenderung mengembangkan gejala neurologis, terutama penyakit
serebrovaskular akut, gangguan sadar dan cedera otot. Oleh karena itu, untuk pasien dengan
COVID-19, kita perlu memperhatikan manifestasi neurologis mereka, terutama bagi mereka
yang memiliki infeksi berat, yang mungkin berkontribusi pada penurunan mereka. Selain itu,
selama periode epidemi COVID-19, ketika melihat pasien dengan manifestasi neurologis ini,
dokter harus mempertimbangkan infeksi SARS-CoV-2 sebagai diagnosis diferensial sehingga
untuk menghindari diagnosis yang tertunda atau kesalahan diagnosis dan pencegahan penularan.

Baru-baru ini, ACE2 diidentifikasi sebagai reseptor fungsional untuk SARS-CoV-2 [3], yang
hadir di banyak organ manusia, termasuk sistem saraf dan otot rangka.[11] Ekspresi dan
distribusi ACE2 mengingatkan kita bahwa SARS-CoV-2 dapat menyebabkan beberapa gejala
neurologis melalui mekanisme langsung atau tidak langsung. Cedera neurologis telah
dikonfirmasi dalam infeksi coronavirus lain seperti di SARS-CoV dan MERS-CoV. Para peneliti
mendeteksi asam nukleat SARS-CoV dalam cairan serebrospinal pasien tersebut dan juga di
jaringan otak mereka pada otopsi [12-13].

Gejala SSP adalah bentuk utama cedera neurologis pada pasien dengan COVID-19 dalam
penelitian ini. Mekanisme patologis mungkin dari invasi SSP dari SARS-CoV-2, mirip dengan
virus SARS dan MERS. Seperti virus pernapasan lainnya, SARS-COV-2 dapat memasuki SSP
melalui rute neuronal hematogen atau retrograde. Yang terakhir dapat didukung oleh fakta
bahwa beberapa pasien dalam penelitian ini memiliki hiposmia. Kami juga menemukan bahwa
jumlah limfosit lebih rendah untuk pasien dengan gejala SSP daripada tanpa gejala SSP.
Fenomena ini dapat menjadi indikasi imunosupresi pada pasien COVID-19 dengan gejala SSP,
terutama pada subkelompok yang parah. Selain itu, kami menemukan pasien yang parah
memiliki tingkat D-dimer yang lebih tinggi daripada pasien yang tidak parah. Ini mungkin
menjadi alasan mengapa pasien yang parah lebih mungkin untuk mengembangkan penyakit
serebrovaskular.

Konsisten dengan penelitian sebelumnya [7] gejala otot juga umum dalam penelitian kami. Kami
berspekulasi bahwa gejalanya disebabkan oleh cedera otot rangka, sebagaimana dikonfirmasi
oleh peningkatan kadar kreatin kinase. Kami menemukan bahwa pasien dengan gejala otot
memiliki kreatin kinase dan tingkat dehidrogenase laktat yang lebih tinggi dibandingkan pasien
tanpa gejala otot. Selain itu, kreatin kinase dan tingkat dehidrogenase laktat pada pasien yang
parah jauh lebih tinggi daripada pasien yang tidak parah. Cidera ini bisa berhubungan dengan
ACE2 pada otot rangka [14]. Namun, SARS-CoV, menggunakan reseptor yang sama, tidak
terdeteksi pada otot rangka dengan pemeriksaan post-mortem [15]. Karena itu, apakah SARS-
CoV-2 menginfeksi sel otot rangka dengan mengikat dengan ACE2 perlu dipelajari lebih lanjut.
Salah satu alasan lainnya adalah respon imun berbahaya yang dimediasi infeksi yang
menyebabkan kelainan sistem saraf. Sitokin pro-inflamasi yang meningkat secara signifikan
dalam serum dapat menyebabkan kerusakan otot.

Penelitian ini memiliki beberapa keterbatasan. Pertama, hanya 214 pasien yang diteliti, yang
dapat menyebabkan bias dalam pengamatan klinis. Akan lebih baik untuk memasukkan lebih
banyak pasien dari Wuhan, kota-kota lain di China, dan bahkan negara lain. Kedua, semua data
disarikan dari catatan medis elektronik, pasien tertentu dengan masalah neurologis mungkin
tidak dapat ditangkap jika gejala neurologis mereka terlalu ringan, seperti dengan hypogeusia
dan hyposmia. Ketiga, karena sebagian besar pasien masih dirawat di rumah sakit dan informasi
mengenai hasil klinis tidak tersedia pada saat analisis, sulit untuk menilai efek dari manifestasi
neurologis ini pada hasil mereka, dan pengamatan lanjutan dari sejarah alami penyakit
diperlukan.

Kesimpulannya, SARS-CoV-2 dapat menginfeksi sistem saraf, otot rangka serta saluran
pernapasan. Pada mereka dengan infeksi berat, keterlibatan neurologis lebih mungkin, yang
meliputi penyakit serebrovaskular akut, gangguan sadar dan cedera otot rangka. Keterlibatan
sistem saraf membawa prognosis yang buruk. Kondisi klinis mereka dapat memburuk dan pasien
dapat segera mati. Oleh karena itu, untuk pasien dengan COVID19, dokter harus memperhatikan
manifestasi neurologis selain gejala sistem pernapasan.
Pendanaan

Pekerjaan ini didukung oleh Program National Key Research and Development China (No.
2018YFC1312200 untuk BH), Yayasan Ilmu Pengetahuan Alam Nasional China (No.
81820108010 untuk BH, No.81974182 untuk LM, No.81671147 untuk JHJ dan Mayor proyek
percontohan penyakit refraktori kolaborasi klinis dengan Pengobatan China & Barat (SATCM-
20180339).

Referensi

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in
China. N Engl J Med 2020; 20:382-8. doi:10.1056/NEJMoa2001017

2. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new
coronavirus of probable bat origin. Nature 2020; published online 3 February.
doi:10.1038/s41586-020-2012-7

3. Zhao Y, Zhao Z, Wang Y, et al. Single-cell RNA expression profiling of ACE2, the
putative receptor of Wuhan 2019-nCov. bioRxiv 2020, published online 26 January. doi:
10.1101/2020.01.26.919985.

4. WHO. Coronavirus disease 2019 (COVID-19) Situation Report-32. January, 2020.

https://www.who.int/docs/default-source/coronaviruse/situation-re-ports/20200221-sitrep-32-
covid-19.pdf?sfvrsn=4802d089_2 (accessed Feb 21, 2020).

5. Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogen-esis of

coronaviruses. Trends Microbiol 2016; 24:490-502. doi:10.1016/j.tim.2016.03.003

6. WHO. Middle East respiratory syndrome coronavirus (MERS-CoV). November, 2019.

https://www.who.int/emergencies/mers-cov/en/ (accessed Jan 19, 2020).

7. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection
in China. medRxiv 2020, published online 9 February. doi:10.1101/2020.02.06.20020974.

8. WHO. Clinical management of severe acute respiratory infection when Novel

coronavirus (nCoV) infection is suspected: interim guidance. January, 2020.
https://www.who.int/internal-publications-detail/clinical-management-of-severe-acute
respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected (accessed February
5, 2020)

9. Huang C, Wang Y, Li X, et al. Clinical features of patients with 2019 novel coro-navirus
in Wuhan, China. Lancet 2020; 10223:497-506. doi: 10.1016/S0140-6736(20)30183-5

10. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with
community-acquired pneumonia: An official clinical practice guideline of the American
Thoracic Society and Infectious Disease Society of America. Am J Respir Crit Care Med 2019;
200:e45-e67. doi:10.1164/rccm.201908-1581ST

11. Hamming, W Timens, MLC Bulthuis, et al. Tissue distribution of ACE2 protein, the
functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J
Pathol 2004; 203:631–637. doi:10.1002/path.1570

12. Marc D, Dominique JF, Eleodie B, et al. Human coronavirus: respiratory pathogens revisited
as infectious neuroinvasive, neurotropic, and neurovirulent agents. In: Sunit KS, Daniel R.
Neuroviral Infections: RNA Viruses and Retroviruses. Florida Boca Raton: CRC press 2013: 93-
122.

13. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East Respiratory Syndrome. N Engl J Med
2017, 376: 584-594. doi: 10.1056 / NEJMsr1408795

14. Cabello-Verrugio C, Morales MG, Rivera JC, et al. Renin-Angiotensin System: An Old
Player with Novel Functions in Skeletal Muscle. Med Res Rev 2015, 35: 437–63. doi: 10.1002 /
med.21343

15. Ding Y, He L, Zhang Q, et al. Distribution of severe acute respiratory syndromes (SARS)
associated coronaviruses (SARS-CoV) in SARS patients: implications for pathogenesis and virus
transmission pathways. J Pathol 2004; 203: 622-30. doi: 10.1002 / path.1560
 Table 1 Karakteristik klinis pasien dengan COVID-19

Berat= Tidak berat =

Total Parah tidak Parah
P
(n=214) (n=88) (n=126)

Usia (tahun), berarti memiliki ±

52.7±15.5 58.2±15.0 48.9±14.7
sandar deviasi

Usia, n (%) <0.001

<50 tahun 90 (42.1) 24 (27.3) 66 (52.4)

≥50 tahun 124 (57.9) 64 (72.7) 60 (47.6)

Jenis Kelamin, n (%) <0.05

Perempuan 127 (59.3) 44 (50.0) 83 (65.9)

Laki-Laki 87 (40.7) 44 (50.0) 43 (34.1)

Komorbiditas, n (%)

Setidknya satu 83 (38.8) 42 (47.7) 41 (32.5) <0.05

Hipertensi 51 (23.8) 32 (36.4) 19 (15.1) <0.001

Diabetes 30 (14.0) 15 (17.0) 15 (11.9) 0.287

Penyakit kardio serebrovaskular 15 (7.0) 7 (8.0) 8 (6.3) 0.651

Keganasan 13 (6.1) 5 (5.7) 8 (6.3) 0.841

Penyakit Ginjal Kronik 6 (2.8) 2 (2.3) 4 (3.2) 0.694

Gejala tipikal/khas, n (%)

Demam 132 (61.7) 40 (45.5) 92 (73.0) <0.001

Batuk kering 107 (50.0) 30 (34.1) 77 (61.1) <0.001

 Anoreksia 68 (31.8) 21 (23.9) 47 (37.3) <0.05

Diare 41 (19.2) 13 (14.8) 28 (22.2) 0.1730

Pharyngalgia 31 (14.5) 10 (11.4) 21 (16.7) 0.278

Nyeri perut 10 (4.7) 6 (6.8) 4 (3.2) 0.214

Gejala Sistem saraf,n (%)

Setidaknya satu 78 (36.4) 40 (45.5) 38 (30.2) <0.05

Sistem Sarf Pusat (SSP) 53 (24.8) 27 (30.7) 26 (20.6) 0.094

Pusing (16.8) 17 (19.3) 19 (15.1) 0.415

Nyeri kepala 28 (13.1) 15 (17.0) 13 (10.3) 0.151

16 (7.5) 13 (14.8) 3 (2.4) <0.001

Kesadaran terganggu

6 (2.8) 5 (5.7) 1 (0.8) <0.05

Penyakit serebrovascular akut

Ataxia 1 (0.5) 1 (1.1) 0 (0.0) NA

Epilepsi 1 (0.5) 1 (1.1) 0 (0.0) NA

Sistem Saraf Tepi (PNS) 19 (8.9) 7 (8.0) 12 (9.5) 0.691

Hypogeusia 12 (5.6) 3 (3.4) 9 (7.1) 0.243

Hiposmia 11 (5.1) 3 (3.4) 8 (6.3) 0.338

Hipopsia 3 (1.4) 2 (2.3) 1 (0.8) 0.365

Neuralgia 5 (2.3) 4 (4.5) 1 (0.8) 0.074

Cedera otot 23 (10.7) 17 (19.3) 6 (4.8) <0.001

Data disajikan sebagai rata-rata ± standar deviasi dan n / N (%).
Singkatan: SSP, gejala saraf pusat; PNS, gejala saraf tepi. Nilai P menunjukkan perbedaan antara
pasien yang parah dan yang tidak parah. P <0,05 dianggap signifikan secara statistik.
 Table 2 Temuan laboratorium pasien dengan COVID-19

Median (range) Total Parah Tidak-parah

P
(n=214) (n=88) (n=126)
Jumlah sel darah putih,
4.9 (0.1-20.4) 5.4 (0.1-20.4) 4.5 (1.8-14.0) <0.01
9
×10 /L

9
Neutrofil, ×10 /L 3.0 (0.0-18.7) 3.8 (0.0-18.7) 2.6 (0.7-11.8) <0.001

9
Limfosit, ×10 /L 1.1 (0.1-2.6) 0.9 (0.1-2.6) 1.3 (0.4-2.6) <0.001

209.0 (18.0- 204.5 (18.0- 219.0 (42.0-

9
Trombosit, ×10 /L 0.251
583.0) 576.0) 583.0)

Protein C-reaktif, mg/L 12.2 (0.1-212.0) 37.1 (0.1-212.0) 9.4 (0.4-126.0) <0.001

D-dimer, mg/L 0.5 (0.1-20.0) 0.9 (0.1-20.0) 0.4 (0.2-8.7) <0.001

64.0 (8.8- 83.0 (8.8- 59.0 (19.0-

Creatine kinase, U/L <0.01
12216.0) 12216.0) 1260.0)

Dehidrogenase laktat, 241.5 (2.2- 302.0 (2.2- 215.0 (2.5-

<0001
U/L 908.0) 880.0) 908.0)

Alanin aminotransferase, 26.0 (5.0- 32.5 (5.0- 23.0 (6.0-

<0.05
U/L 1933.0) 1933.0) 261.0)

Aspartat aminotransfer- 26.0 (8.0- 34.0 (8.0- 23.0 (9.0-

<0.001
ase, U/L 8191.0) 8191.0) 244.0)

Nitrogen urea darah,

4.1 (1.5-48.1) 4.6 (1.5-48.1) 3.8 (1.6-13.7) <0.001
mmol/L
 68.2 (35.9- 71.6 (35.9- 65.6 (39.4-
Kreatinin, µmol/L <0.05
9435.0) 9435.0) 229.1)

Nilai P menunjukkan perbedaan antara pasien yang parah dan yang tidak. P <0,05 dianggap
signifikan secara statistik.
 Table 3 Temuan laboratorium pasien COVID-19 dengan gejala SSP

Total Berat Tidak-berat

Dengan Tanpa gejala Dengan Tanpa gejala Dengan Tanpa gejala

gejala SSP SSP P gejala SSP SSP P gejala SSP SSP P
(n=53) (n=161) (n=27) (n=61) (n=26) (n=100)

Median (range)

9
Jumlah sel darah putih, ×10 /L 4.6 (0.1-12.5) 4.9 (1.8-20.4) 0.582 5.3 (0.1-12.5) 5.5 (1.9-20.4) 0.769 4.1 (2.4-11.0) 4.6 (1.8-14.0) 0.397

9
Neutrofil, ×10 /L 2.6 (0.0-10.9) 3.1 (0.7-18.7) 0.413 3.8 (0.0-10.9) 3.6 (0.7-18.7) 1.000 2.2 (0.9-7.4) 2.8 (0.7-11.8) 0.106

9
Limfosit, ×10 /L 1.0 (0.1-2.3) 1.2 (0.2-2.6) <0.05 0.7 (0.1-1.6) 0.9 (0.2-2.6) <0.01 1.3 (0.7-2.3) 1.3 (0.4-2.6) 0.492

9
Trombosit, ×10 /L 180.0 (18.0-564.0) 227.0 (42.0-583.0) <0.01 169.0 (18.0-564.0) 220.0 (109.0-576.0) <0.05 188.5 (110.0-548.0) 232.0 (42.0-583.0) 0.093

Protein C-reaktif, mg/L 14.1 (0.1-212.0) 11.4 (0.1-204.5) 0.307 48.6 (0.1-212.0) 26.1 (0.1-204.5) 0.677 7.4 (3.1-111.0) 9.8 (0.4-126.0) 0.817

D-dimer, mg/L 0.5 (0.2-9.7) 0.5 (0.1-20.0) 0.750 1.2 (0.2-9.7) 0.9 (0.1-20.0) 0.424 0.4 (0.2-6.4) 0.4 (0.2-8.7) 0.455

Creatine kinase, U/L 79.0 (8.8-12216.0) 60.5 (19.0-1260.0) 0.167 104.0 (8.8-12216.0) 64.0 (19.0-1214.0) 0.081 52.5 (28.0-206.0) 59.0 (19.0-1260.0) 0.561

Dehydrogenase Laktat, U/L 243.0 (2.2-880.0) 241.0 (3.5-908.0) 0.766 334.0 (2.2-880.0) 299.0 (3.5-743.0) 0.324 198.0 (2.5-417.0) 226.0 (121.0-908.0) 0.142
Alanin aminotransferase, U/L 27.0 (5.0-261.0) 26.0 (6.0-1933.0) 0.214 35.0 (5.0-259.0) 31.0 (7.0-1933.0) 0.320 25.5 (13.0-261.0) 23.0 (6.0-135.0) 0.682

Aspartat aminotransferase, U/L 29.5 (13.0-213.0) 26.0 (8.0-8191.0) 0.1031 35.5 (14.0-213.0) 34.0 (8.0-8191.0) 0.319 23.0 (13.0-198.0) 23.5 (9.0-244.0) 0.575

Nitrogen urea darah, mmol/L 4.5 (1.6-48.1) 4.1 (1.5-19.1) <0.05 5.0 (2.3-48.1) 4.4 (1.5-19.1) 0.041 3.9 (1.6-9.4) 3.8 (1.7-13.7) 0.568

Kreatinin, µmol/L 71.7 (37.1-1299.2) 66.3 (35.9-9435.0) 0.062 71.7 (37.1-1299.2) 68.4 (35.9-9435.0) 0.245 72.0 (40.3-133.6) 63.4 (39.4-229.1) 0.265

Singkatan: CNS (Central Nervous System): Sistem Saraf Pusat (SSP)

Nilai P menunjukkan perbedaan antara pasien dengan dan tanpa SSP. P <0,05 dianggap signifikan secara statistik
 Table 4 Temuan laboratorium pasien COVID-19 dengan gejala PNS

Total Berat Tidak-berat

Dengan Tanpa gejala Dengan Tanpa gejala Dengan Tanpa

gejala PNS PNS P gejala PNS PNS P gejala PNS gejala PNS P
(n=19) (n=195) (n=7) (n=81) (n=12) (n=114)
Median (range)

9
Jumlah sel darah putih, ×10 /L 4.8 (2.8-7.5) 4.9 (0.1-20.4) 0.744 4.5 (3.1-6.8) 5.6 (0.1-20.4) 0.105 4.9 (2.8-7.5) 4.4 (1.8-14.0) 0.273

9
Neutrofil, ×10 /L 2.8 (1.5-5.4) 3.0 (0.0-18.7) 0.740 2.6 (1.5-5.3) 4.1 (0.0-18.7) 0.099 2.9 (1.9-5.4) 2.5 (0.7-11.8) 0.214

9
Limfosit, ×10 /L 1.2 (0.6-2.6) 1.1 (0.1-2.6) 0.433 1.2 (0.6-1.6) 0.9 (0.1-2.6) 0.257 1.2 (0.7-2.6) 1.3 (0.4-2.4) 0.917

9
Trombosit, ×10 /L 204.0 (111.0-305.0) 213.0 (18.0-583.0) 0.564 204.0 (111.0-245.0) 205.0 (18.0-576.0) 0.558 214.5 (155.0-305.0) 219.0 (42.0-583.0) 0.806

Protein C-reactif, mg/L 12.0 (3.1-81.0) 12.3 (0.1-212.0) 0.446 7.5 (3.1-76.4) 43.7 (0.1-212.0) 0.134 13.0 (3.1-81.0) 8.8 (0.4-126.0) 0.598

D-dimer, mg/L 0.4 (0.2-9.5) 0.5 (0.1-20.0) 0.399 0.5 (0.2-9.5) 1.3 (0.1-20.0) 0.272 0.4 (0.2-4.5) 0.4 (0.2-8.7) 0.989

Creatine kinase, U/L 67.0 (32.0-1214.0) 64.0 (8.8-12216.0) 0.413 105.0 (32.0-1214.0) 83.0 (8.8-12216.0) 0.761 66.0 (42.0-171.0) 57.5 (19.0-1260.0) 0.291
Dehidrogenase Laktat, U/L 205.0 (2.5-517.0) 242.0 (2.2-908.0) 0.284 170.0 (46.0-517.0) 309.0 (2.2-880.0) 0.050 254.0 (2.5-481.0) 215.0 (2.9-908.0) 0.669

Alanin aminotransferase, U/L 26.0 (5.0-116.0) 27.0 (6.0-1933.0) 0.695 19.0 (5.0-80.0) 35.0 (8.0-1933.0) 0.232 26.0 (8.0-116.0) 23.0 (6.0-261.0) 0.555

Aspartat aminotransferase,
22.0 (8.0-115.0) 27.0 (9.0-8191.0) 0.288 22.0 (8.0-53.0) 35.5 (12.0-8191.0) 0.126 22.0 (14.0-115.0) 23.5 (9.0-244.0) 1.000
U/L

Nitrogen urea darah, mmol/L 4.1 (1.6-8.8) 4.1 (1.5-48.1) 0.764 4.2 (3.5-8.8) 4.7 (1.5-48.1) 0.963 3.7 (1.6-5.3) 3.9 (1.7-13.7) 0.660

Kreatinin, µmol/L 62.5 (48.1-121.4) 68.3 (35.9-9435.0) 0.455 71.4 (58.3-121.4) 71.7 (35.9-9435.0) 0.717 59.9 (48.1-77.3) 66.6 (39.4-229.1) 0.235

Singkatan: PNS (Peripheral Nervous System): Sistem Saraf Tepi

Nilai P menunjukkan perbedaan antara pasien dengan dan tanpa PNS. P <0,05 dianggap signifikan secara statistik.
 Table 5 Temuan laboratorium pasien COVID-19 dengan cedera otot

Total Berat Tidak-berat

Dengan cedera Tanpa cedera Dengan cedera Tanpa cedera Tanpa cedera otot
Dengan cedera otot
otot otot P otot otot P otot P
(n=6)
(n=23) (n=191) (n=17) (n=71) (n=120)

Median (range)

9
Jumlah sel darah putih, ×10 /L 6.0 (2.3-20.4) 4.8 (0.1-15.6) 0.248 6.7 (2.3-20.4) 5.2 (0.1-15.6) 0.269 4.3 (2.4-6.1) 4.5 (1.8-14.0) 0.618

9
Neutrofil, ×10 /L 4.3 (0.9-18.7) 2.9 (0.0-13.0) 0.031 5.5 (0.9-18.7) 3.5 (0.0-13.0) 0.076 2.6 (1.1-4.5) 2.6 (0.7-11.8) 0.945

9
Limfosit, ×10 /L 0.9 (0.1-2.6) 1.2 (0.1-2.6) 0.002 0.8 (0.1-2.6) 0.9 (0.1-2.5) <0.05 1.2 (1.0-2.1) 1.3 (0.4-2.6) 0.846

9
Trombosit, ×10 /L 185.0 (82.0-436.0) 215.0 (18.0-583.0) 0.224 182.0 (82.0-436.0) 209.0 (18.0-576.0) 0.407 223.0 (122.0-304.0) 219.0 (42.0-583.0) 0.688

Protein C-reaktif, mg/L 56.0 (0.1-212.0) 11.1 (0.1-204.5) <0.001 70.8 (0.1-212.0) 21.0 (0.1-204.5) 0.078 18.1 (9.7-126.0) 8.1 (0.4-123.0) <0.05

D-dimer, mg/L 1.3 (0.2-20.0) 0.5 (0.1-20.0) <0.05 1.7 (0.2-20.0) 0.6 (0.1-20.0) 0.120 0.4 (0.2-1.3) 0.4 (0.2-8.7) 0.679

525.0 (203.0-
Creatine kinase, U/L 400.0 (203.0-12216.0) 58.5 (8.8-212.0) <0.001 64.0 (8.8-212.0) <0.001 231.0 (206.0-1260.0) 57.5 (19.0-184.0) <0.001
12216.0)
 442.0 (147.0-
Dehidrogenase laktat, U/L 415.0 (147.0-743.0) 229.0 (2.2-908.0) <0.001 285.0 (2.2-880.0) <0.01 315.0 (210.0-666.0) 213.0 (2.5-908.0) <0.05
743.0)

Alanin aminotransferase, U/L 44.0 (14.0-173.0) 25.0 (5.0-1933.0) <0.01 50.0 (14.0-173.0) 30.0 (5.0-1933.0) <0.05 28.0 (16.0-63.0) 23.0 (6.0-261.0) 0.495

Aspartat aminotransferase, U/L 46.0 (22.0-209.0) 25.0 (8.0-8191.0) <0.001 53.0 (26.0-209.0) 31.0 (8.0-8191.0) <0.001 34.5 (22.0-60.0) 23.0 (9.0-244.0) 0.065

Nitrogen Urea Darah, mmol/L 4.8 (2.0-48.1) 4.1 (1.5-19.1) <0.05 4.8 (2.4-48.1) 4.6 (1.5-19.1) 0.256 5.9 (2.0-10.6) 3.8 (1.6-13.7) 0.264

Kreatinin, µmol/L 80.5 (43.7-1299.2) 66.9 (35.9-9435.0) <0.01 81.5 (43.7-1299.2) 68.4 (35.9-9435.0) <0.05 77.4 (60.7-229.1) 65.1 (39.4-215.3) 0.050

Nilai P menunjukkan perbedaan antara pasien dengan dan tanpa cedera otot. P <0,05 dianggap signifikan secara statistik.
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Neurological Manifestations of Hospitalized Patients with COVID-19

in Wuhan, China: a retrospective case series study

Ling Mao*, Mengdie Wang*, Shengcai Chen*, Quanwei He*, Jiang Chang*,

† † †
Can-dong Hong, Yifan Zhou, David Wang, Yanan Li , Huijuan Jin , Bo Hu

Department of neurology (Prof. LM, MW Ph.D., SC Ph.D., Prof. QH, Prof. YL,

Prof. HJ, Prof. BH), Union hospital, Tongji medical college, Huazhong university

of science and technology, Wuhan, 430022, China;

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and

Health, School of Public Health (Prof. JC), Tongji medical college, Huazhong

univer-sity of science and technology, Wuhan, 430022, China;

Neurovascular Division, Department of Neurology, Barrow Neurological Insti-

tute/Saint Joseph Hospital Medical Center Phoenix, AZ 85013 USA (Prof. DW)

*
Contributed equally

†
Correspondence authors

Correspondence to:

Prof. Bo Hu, Department of neurology, Union hospital, Tongji medical

college, Huazhong university of science and technology, Wuhan, 430022,

China hubo@mail.hust.edu.cn

Or Prof. Huijuan Jin, Department of Neurology, Union hospital, Tongji medical col-

lege, Huazhong university of science and technology, Wuhan, 430022, China

jinhuijuan1983@163.com
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Or Prof. Yanan Li, Department of Neurology, Union hospital, Tongji medical college,

Huazhong university of science and technology, Wuhan, 430022, China

liyn@mail.hust.edu.cn
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

ABSTRACT

OBJECTIVE

To study the neurological manifestations of patients with coronavirus disease 2019

(COVID-19).

DESIGN

Retrospective case series

SETTING

Three designated COVID-19 care hospitals of the Union Hospital of Huazhong Uni-

versity of Science and Technology in Wuhan, China.

PARTICIPANTS

Two hundred fourteen hospitalized patients with laboratory confirmed diagnosis of

severe acute respiratory syndrome from coronavirus 2 (SARS-CoV-2) infection. Data

were collected from 16 January 2020 to 19 February 2020.

MAIN OUTCOME MEASURES

Clinical data were extracted from electronic medical records and reviewed by a

trained team of physicians. Neurological symptoms fall into three categories: central

nervous system (CNS) symptoms or diseases (headache, dizziness, impaired con-

sciousness, ataxia, acute cerebrovascular disease, and epilepsy), peripheral nervous

system (PNS) symptoms (hypogeusia, hyposmia, hypopsia, and neuralgia), and skele-

tal muscular symptoms. Data of all neurological symptoms were checked by two

trained neurologists.

RESULTS

Of 214 patients studied, 88 (41.1%) were severe and 126 (58.9%) were non-severe

patients. Compared with non-severe patients, severe patients were older (58.7 ± 15.0

years vs 48.9 ± 14.7 years), had more underlying disorders (42 [47.7%] vs 41
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

[32.5%]), especially hypertension (32 [36.4%] vs 19 [15.1%]), and showed less typi-

cal symptoms such as fever (40 [45.5%] vs 92 [73%]) and cough (30 [34.1%] vs 77

[61.1%]). Seventy-eight (36.4%) patients had neurologic manifestations. More severe

patients were likely to have neurologic symptoms (40 [45.5%] vs 38 [30.2%]), such

as acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]), impaired consciousness (13

[14.8%] vs 3 [2.4%]) and skeletal muscle injury (17 [19.3%] vs 6 [4.8%]).

CONCLUSION

Compared with non-severe patients with COVID-19, severe patients commonly had

neurologic symptoms manifested as acute cerebrovascular diseases, consciousness

impairment and skeletal muscle symptoms.

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Introduction

In December 2019, many unexplained pneumonia cases occurred in Wuhan, China,

and has rapidly spread to other parts of China, then to Europe, North America and

Asia. This outbreak was confirmed to be caused by a novel coronavirus (2019 novel

coronavirus, 2019-nCoV) [1]. 2019-nCov was reported to have symptoms resembled

that of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 [2]. Both

shared the same receptor, angiotensin-converting enzyme 2 (ACE2) [3]. Therefore,

this virus was named SARS-CoV-2, and recently WHO named it coronavirus disease

th
2019 (COVID-19). Until February 21 2020, there were 75569 confirmed cases of

COVID-19 and 2239 deaths in China [4].

Coronaviruses can cause multiple systemic infections or injuries in various animals

[5]. However, some of them can adapt fast and cross the species barrier, such as in the

cases of SARS-CoV and Middle East respiratory syndrome-CoV (MERS-CoV), caus-

ing epidemics or pandemics. Infection in human often leads to severe clinical symp-

toms and high mortality [6]. As for COVID-19, several studies have described clinical

manifestations including respiratory symptoms, myalgia and fatigue. COVID-19 also

has characteristic laboratory findings and lung CT abnormalities [7]. However, it has

not been reported that patients with COVID-19 had any neurological manifestations.

Here, we would like to report the characteristic neurological manifestation of SARS-

CoV-2 infection in 78 of 214 patients with laboratory-confirmed diagnosis of

COVID-19 and treated at our hospitals, which are located in the epicenter of Wuhan.

Methods

Study Design and Participants

This was a retrospective study. Data was reviewed on all patients with COVID-19

from January 16 to February 19, 2020 at three designated COVID-19 care hospitals of
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Union Hospital of Huazhong University of Science and Technology. All patients with

COVID-19 enrolled in this study were diagnosed according to the WHO interim

guideline [8]. Only those cases confirmed by a positive result to real-time reverse-

transcriptase polymerase-chain-reaction (RT-PCR) assay from throat swab specimens

were included in the analysis [9]. Union Hospital, located in the endemic areas of

COVID-19 in Wuhan, Hubei Province, is one of the major tertiary healthcare system

and teaching hospitals responsible for the treatments for SARS-CoV-2 infection as

designated by the government. The study was performed in accordance to the princi-

ples of the Declaration of Helsinki and was approved by the Research Ethics Commit-

tee of Tongji Medical College, Huazhong University of Science and Technology, Wu-

han, China. Verbal consent was obtained from patients before the enrollment.

Data Collection

The demographic characteristics, medical history, symptoms, clinical signs, labora-

tory findings, chest computed tomographic (CT) scan findings were extracted from

electronic medical records. The data were reviewed by a trained team of physicians.

Neurological symptoms were categorized into three main areas: central nervous sys-

tem (CNS) symptoms or disease, peripheral nervous system (PNS) symptoms and

muscular symptoms. Acute cerebrovascular disease included ischemic stroke and cer-

ebral hemorrhage diagnosed by head CT. Muscle injury was defined when a patient

had myalgia and elevated serum creatine kinase level above 200 U/L [7]. All neuro-

logical symptoms were reviewed and confirmed by two trained neurologists. The date

of disease onset was defined as the day when the symptom was noticed. The severity

of COVID-19 was defined by the international guidelines for community-acquired

pneumonia [10].
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Throat swab samples were collected and placed into a collection tube containing

preservation solution for the virus [9]. SARS-CoV-2 was confirmed by real-time RT-

PCR assay using a SARS-CoV-2 nucleic acid detection kit according to the manufac-

turer’s protocol (Shanghai bio-germ Medical Technology Co Ltd).

Statistical Analysis

Continuous variables were described as means and standard deviations, or medians

and interquartile range (IQR) values. Categorical variables were expressed as counts

and percentages. Continuous variables were compared by using the unpaired Wilcox

rank-sum test. Proportions for categorical variables were compared using the χ2 test.

All statistical analyses were performed using R (version 3.3.0) software. The signifi-

cance threshold was set at a P<0.05.

Results

Demographic and clinical characteristics

A total of 214 hospitalized patients with confirmed SARS-CoV-2 infection were in-

cluded in the present analysis. Their demographic and clinical characteristics were

shown in Table 1. Their average age was 52.7 ± 15.5 years, and 127 (59.3%) were fe-

males. Of these patients, 83 (38.8%) had at least one of the following underlying dis-

orders: hypertension (51 [23.8%]), diabetes (30 [14.0%]), cardiovascular disease (15

[7.0%]), and malignancy (13 [6.1%]). The most common symptoms at onset of illness

were fever (132 [61.7%]), dry cough (107 [50.0%]) and anorexia (68 [31.8%]). Sev-

enty-eight (36.4%) patients had nervons system symptoms: CNS (53 [24.8%]), PNS

(19 [8.9%]) and skeletal muscles (23 [10.7%]). In patients with CNS symptoms, the

most common complaints were dizziness (36 [16.8%] and headache (28 [13.1%]). In

patients with PNS symptoms, the most common complaints were hypogeusia (12

[5.6%]) and hyposmia (11 [5.1%]).

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

According to the diagnostic criteria, 88 (41.1%) patients were severe and 126

(58.9%) patients were non-severe, respectively. The patients with severe infection

were significantly older (58.2 ± 15.0 years vs 48.9 ± 14.7 years; P<0.001) and more

likely to have other underlying disorders (42 [47.7%] vs 41 [32.5%], P<0.05), espe-

cially hypertension (32 [36.4%] vs 19 [15.1%], P<0.001), and had less typical symp-

toms such as fever (40 [45.5%] vs 92 [73%], P<0.001) and dry cough (30 [34.1%]

vs 77 [61.1%], P<0.001). Moreover, nervous system symptoms were significantly

more common in severe cases as compared with non-severe cases (40 [45.5%] vs. 38

[30.2%], P<0.05). They included acute cerebrovascular disease (5 [5.7%] (4 patients

with ischemic stroke and 1 with cerebral hemorrhage who died later from respiratory

failure) vs. 1 [0.8%] (1 patient with ischemic stroke), P<0.05), impaired conscious-

ness (13 [14.8%] vs. 3 [2.4%], P<0.001) and muscle injury (17 [19.3%] vs. 6 [4.8%],

P<0.001).

Laboratory findings in severe patients and non-severe patients

Table 2 showed the laboratory findings in severe and non-severe subgroups. Severe

patients had more increased inflammatory response, including higher white blood

cell, neutrophil counts, lower lymphocyte counts and more increased C-reaction pro-

tein levels compared with those in non-severe patients (white blood cell: median, 5.4

[IQR, 0.1-20.4] vs 4.5 [IQR, 1.8-14.0], P<0.01; neutrophil: median, 3.8 [IQR, 0.0-

18.7] vs 2.6 [IQR, 0.7-11.8], P<0.001; lymphocyte: median, 0.9 [IQR, 0.1-2.6] vs 1.3

[IQR, 0.4-2.6], P<0.001; C-reaction protein: median, 37.1 [IQR, 0.1-212.0] vs 9.4

[IQR, 0.2-126.0], P<0.001). The severe patients had higher D-dimer levels than non-

severe patients (median, 0.9 [IQR, 0.1-20.0] vs 0.4 [IQR, 0.2-8.7], P<0.001), which

was indicative of consumptive coagulation system. In addition, severe patients had

multiple organ involvement, such as serious liver (increased lactate dehydrogenase,

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

alanine aminotransferase and aspartate aminotransferase levels), kidney (increased

blood urea nitrogen and creatinine levels) and muscle damage (increased creatinine

kinase levels).

Laboratory findings in patients with and without CNS symptoms

Table 3 showed the laboratory findings of patients with and without CNS symptoms.

We found that patients with CNS symptoms had lower lymphocyte, platelet counts

and higher blood urea nitrogen levels compared with those without CNS symptoms

(lymphocyte: median, 1.0 [IQR, 0.1-2.3] vs 1.2 [IQR, 0.2-2.6], P<0.05; platelet: me-

dian, 180.0 [IQR, 18.0-564.0] vs 227.0 [IQR, 42.0-583.0], P<0.01; blood urea nitro-

gen: median, 4.5 [IQR, 1.6-48.1] vs 4.1 [IQR, 1.5-19.1], P<0.05). For the severe sub-

group, patients with CNS symptoms also had lower lymphocyte, platelet counts and

higher blood urea nitrogen levels compared with those without CNS symptoms (lym-

phocyte: median, 0.7 [IQR, 0.1-1.6] vs 0.9 [IQR, 0.2-2.6], P<0.01; platelet: median,

169.0 [IQR, 18.0-564.0] vs 220.0 [IQR, 109.0-576.0], P<0.05; blood urea nitrogen:

median, 5.0 [IQR, 2.3-48.1] vs 4.4 [IQR, 1.5-19.1], P<0.05). For non-severe sub-

group, there were no significant differences in laboratory findings of patients with and

without CNS symptoms.

Laboratory findings in patients with and without PNS symptoms

Table 4 showed the laboratory findings of patients with and without PNS symptoms.

We found that there were no significant differences in laboratory findings of patients

with PNS and those without PNS. Similar results were also found in the severe sub-

group and non-severe subgroup, respectively.

Laboratory findings in patients with and without muscle injury

Table 5 showed the laboratory findings of patients with and without muscle injury.

Compared with the patients without muscle injury, patients with muscle injury had
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

higher neutrophil counts, lower lymphocyte counts and higher C-reactive protein lev-

els, D-dimer levels (neutrophil: median, 4.3 [IQR, 0.9-18.7] vs 2.9 [IQR, 0.0-13.0],

P<0.05; lymphocyte: median, 0.9 [IQR, 0.1-2.6] vs 1.2 [IQR, 0.1-2.6], P<0.01; C-re-

action protein: median, 56.0 [IQR, 0.1-212.0] vs 11.1 [IQR, 0.1-204.5], P<0.001; D-

dimer: median, 1.3 [IQR, 0.2-20.0] vs 0.5 [IQR, 0.1-20.0]). The abnormalities were

manifestation of increased inflammatory response and blood coagulation function. In

addition, we found that patients with muscle injury had multi-organ damage including

more serious liver (increased lactate dehydrogenase, alanine aminotransferase and

aspartate aminotransferase levels), and kidney (increased blood urea nitrogen and cre-

atinine levels) abnormalities.

For the severe subgroup, patients with muscle injury had increased inflammatory re-

sponse (decreased lymphocyte counts and increased C-reactive protein levels), and

more serious liver (increased lactate dehydrogenase, alanine aminotransferase and as-

partate aminotransferase levels), kidney (increased creatinine levels) and muscle dam-

age (increased creatinine kinase levels). For non-severe subgroup, patients with mus-

cle injury only had higher C-reactive protein and creatinine kinase levels compared

with those without muscle injury.

Discussion

This is the first report on detailed neurologic manifestations of the hospitalized

patients with COVID-19. As of February 19, 2020, of 214 patients included in this

study, 88 (41.1%) were severe and 126 (58.9%) were non-severe. Of these, 78

(36.4%) had various neurologic manifestations involved CNS, PNS and skeletal

muscles. Compared with non-severe patients, severe patients were older and had more

hypertension but less with typical symptoms such as fever and cough. Severe patients

were more likely to develop neurological symptoms, especially acute cerebrovascular

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

disease, conscious disturbance and muscle injury. Therefore, for patients with

COVID-19, we need to pay close attention to their neurologic manifestations,

especially for those with severe infectons, which may have contributed to their de-

mise. Moreover, during the epidemic period of COVID-19, when seeing patients with

these neurologic manifestations, doctors should consider SARS-CoV-2 infection as a

differential diagnosis so to avoid delayed diagnosis or misdiagnosis and prevention of

transmission.

Recently, ACE2 is identified as the functional receptor for SARS-CoV-2 [3], which

is present in multiple human organs, including nervous system and skeletal muscle

[11]. The expression and distribution of ACE2 remind us that the SARS-CoV-2 may

cause some neurological symptoms through direct or indirect mechanisms.

Neurological injury has been confirmed in the infection of other coronavirus such as

in SARS-CoV and MERS-CoV. The researchers detected SARS-CoV nucleic acid in

the cerebrospinal fluid of those patients and also in their brain tissue on autopsy [12-

13].

CNS symptoms were the main form of neurological injury in patients with COVID-

19 in this study. The pathological mechanism may be from the CNS invasion of

SARS-CoV-2, similar to SARS and MERS virus. Like other respiratory viruses,

SARS-COV-2 may enter the CNS through the hematogenous or retrograde neuronal

route. The latter can be supported by the fact that some patients in this study had

hyposmia. We also found that the lymphocyte counts were lower for patients with

CNS symptoms than without CNS symptoms. This phenomenon may be indicative of

the immunosuppression in COVID-19 patients with CNS symptoms, especially in the

severe subgroup. Moreover, we found severe patients had higher D-dimer levels than
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

that of non-severe patients. This may be the reason why severe patients are more

likely to develop cerebrovascular disease.

Consistent with the previous studies [7] muscle symptom was also common in our

study. We speculate that the symptom was due to skeletal muscle injury, as confirmed

by elevated creatine kinase levels. We found that patients with muscle symptoms had

higher creatine kinase and lactate dehydrogenase levels than those without muscle

symptoms. Furthermore, creatine kinase and lactate dehydrogenase levels in severe

patients were much higher than those of none-severe patients. This injure could be

related to ACE2 in skeletal muscle [14]. However, SARS-CoV, using the same

receptor, was not detected in skeletal muscle by post-mortem examination [15].

Therefore, whether SARS-CoV-2 infects skeletal muscle cells by binding with ACE2

requires to be further studied. One other reason was the infection-mediated harmful

immune response that caused the nervous system abnormalities. Significantly

elevated pro-inflammatory cytokines in serum may cause muscle damage.

This study has several limitations. First, only 214 patients were studied, which

could cause biases in clinical observation. It would be better to include more patients

from Wuhan, other cities in China, and even other countries. Second, all data were

abstracted from the electronic medical records, certain patients with neurological

problem might not be captured if their neurological symptoms were too mild, such as

with hypogeusia and hyposmia . Third, because most patients were still hospitalized

and information regarding clinical outcomes was unavailable at the time of analysis, it

was difficult to assess the effect of these neurologic manifestations on their outcome,

and continued observations of the natural history of disease are needed.

In conclusion, SARS-CoV-2 may infect nervous system, skeletal muscle as well as

respiratory tract. In those with severe infection, neurological involvement is more

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

likely, which includes acute cerebrovascular diseases, conscious disturbance and

skeletal muscle injury. Involvement of the nervous system carries a poor prognosis.

Their clinical conditions may worsen and patients may die soon. Therefore, for

patient with COVID19, physicians should pay close attention to any neurologic

manifestations in addition to the symptoms of respiratory system.

Funding

This work was supported by the National Key Research and Development Program of

China (No. 2018YFC1312200 to BH), the National Natural Science Foundation of

China (No. 81820108010 to BH, No.81974182 to LM, No.81671147 to JHJ）and

Major refractory diseases pilot project of clinical collaboration with Chinese & West-

ern Medicine (SATCM-20180339).

Reference

1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumo-nia

in China. N Engl J Med 2020; 20:382-8. doi:10.1056/NEJMoa2001017

2. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a

new coronavirus of probable bat origin. Nature 2020; published online 3

February. doi:10.1038/s41586-020-2012-7

3. Zhao Y, Zhao Z, Wang Y, et al. Single-cell RNA expression profiling of

ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv 2020, published

online 26 January. doi: 10.1101/2020.01.26.919985.

4. WHO. Coronavirus disease 2019 (COVID-19) Situation Report-32. January,

2020. https://www.who.int/docs/default-source/coronaviruse/situation-re-

ports/20200221-sitrep-32-covid-19.pdf?sfvrsn=4802d089_2 (accessed Feb

21, 2020).
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

5. Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and

pathogen-esis of coronaviruses. Trends Microbiol 2016; 24:490-502.

doi:10.1016/j.tim.2016.03.003

6. WHO. Middle East respiratory syndrome coronavirus (MERS-CoV). November,

2019. https://www.who.int/emergencies/mers-cov/en/ (accessed Jan 19, 2020).

7. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of 2019 novel

coronavirus infection in China. medRxiv 2020, published online 9 February.

doi:10.1101/2020.02.06.20020974.

8. WHO. Clinical management of severe acute respiratory infection when Novel

coronavirus (nCoV) infection is suspected: interim guidance. January, 2020.

https://www.who.int/internal-publications-detail/clinical-management- of-severe-

acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected

(accessed February 5, 2020)

9. Huang C, Wang Y, Li X, et al. Clinical features of patients with 2019 novel

coro-navirus in Wuhan, China. Lancet 2020; 10223:497-506. doi:

10.1016/S0140-6736(20)30183-5

10. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with

community-acquired pneumonia: An official clinical practice guideline of the

American Thoracic Society and Infectious Disease Society of America. Am J

Respir Crit Care Med 2019; 200:e45-e67. doi:10.1164/rccm.201908-1581ST

11. Hamming, W Timens, MLC Bulthuis, et al. Tissue distribution of ACE2 protein,

the functional receptor for SARS coronavirus. A first step in understanding SARS

pathogenesis. J Pathol 2004; 203:631–637. doi:10.1002/path.1570

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

12. Marc D, Dominique JF, Élodie B, et al. Human coronavirus: respiratory patho-

gens revisited as infectious neuroinvasive, neurotropic, and neurovirulent agents.

In: Sunit KS, Daniel R. Neuroviral Infections: RNA Viruses and Retroviruses.

Florida Boca Raton: CRC press 2013:93-122.

13. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East Respiratory Syndrome. N

Engl J Med 2017, 376:584-594. doi:10.1056/NEJMsr1408795

14. Cabello-Verrugio C, Morales MG, Rivera JC, et al. Renin-Angiotensin

System: An Old Player with Novel Functions in Skeletal Muscle. Med Res Rev

2015, 35:437–63. doi:10.1002/med.21343

15. Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syn-

drome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implica-

tions for pathogenesis and virus transmission pathways. J Pathol 2004; 203:622-

30. doi:10.1002/path.1560
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Table 1 Clinical characteristics of patients with COVID-19

Total Severe Non-severe

P
(n=214) (n=88) (n=126)

52.7±15.5 58.2±15.0 48.9±14.7

Age (y), means ± standard deviations

Age, n (%) <0.001

<50 y 90 (42.1) 24 (27.3) 66 (52.4)

≥50 y 124 (57.9) 64 (72.7) 60 (47.6)

Sex, n (%) <0.05

Female 127 (59.3) 44 (50.0) 83 (65.9)

Male 87 (40.7) 44 (50.0) 43 (34.1)

Comorbidities, n (%)

Any 83 (38.8) 42 (47.7) 41 (32.5) <0.05

Hypertension 51 (23.8) 32 (36.4) 19 (15.1) <0.001

Diabetes 30 (14.0) 15 (17.0) 15 (11.9) 0.287

Cardio cerebrovascular disease 15 (7.0) 7 (8.0) 8 (6.3) 0.651

Malignancy 13 (6.1) 5 (5.7) 8 (6.3) 0.841

Chronic kidney disease 6 (2.8) 2 (2.3) 4 (3.2) 0.694

Typical symptoms, n (%)

Fever 132 (61.7) 40 (45.5) 92 (73.0) <0.001

Dry cough 107 (50.0) 30 (34.1) 77 (61.1) <0.001

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Anorexia 68 (31.8) 21 (23.9) 47 (37.3) <0.05

Diarrhea 41 (19.2) 13 (14.8) 28 (22.2) 0.1730

Pharyngalgia 31 (14.5) 10 (11.4) 21 (16.7) 0.278

Abdominal pain 10 (4.7) 6 (6.8) 4 (3.2) 0.214

Nervous system symptoms,n (%)

Any 78 (36.4) 40 (45.5) 38 (30.2) <0.05

CNS 53 (24.8) 27 (30.7) 26 (20.6) 0.094

Dizziness 36 (16.8) 17 (19.3) 19 (15.1) 0.415

Headache 28 (13.1) 15 (17.0) 13 (10.3) 0.151

16 (7.5) 13 (14.8) 3 (2.4) <0.001

Impaired consciousness

6 (2.8) 5 (5.7) 1 (0.8) <0.05

Acute cerebrovascular disease

Ataxia 1 (0.5) 1 (1.1) 0 (0.0) NA

Epilepsy 1 (0.5) 1 (1.1) 0 (0.0) NA

PNS 19 (8.9) 7 (8.0) 12 (9.5) 0.691

Hypogeusia 12 (5.6) 3 (3.4) 9 (7.1) 0.243

Hyposmia 11 (5.1) 3 (3.4) 8 (6.3) 0.338

Hypopsia 3 (1.4) 2 (2.3) 1 (0.8) 0.365

Neuralgia 5 (2.3) 4 (4.5) 1 (0.8) 0.074

Muscle injury 23 (10.7) 17 (19.3) 6 (4.8) <0.001

 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Data are presented as means ± standard deviations and n/N (%).

Abbreviations: CNS, central nervous symptoms; PNS, peripheral nerves symptoms.

P values indicate differences between severe and non-severe patients. P<0.05 was considered

statistically significant.
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

Table 2 Laboratory findings of patients with COVID-19

Median (range) Total Severe Non-severe

P
(n=214) (n=88) (n=126)
White blood cell count,
4.9 (0.1-20.4) 5.4 (0.1-20.4) 4.5 (1.8-14.0) <0.01
9
×10 /L

Neutrophil, ×109/L 3.0 (0.0-18.7) 3.8 (0.0-18.7) 2.6 (0.7-11.8) <0.001

Lymphocyte count, ×109/L 1.1 (0.1-2.6) 0.9 (0.1-2.6) 1.3 (0.4-2.6) <0.001

209.0 (18.0- 204.5 (18.0- 219.0 (42.0-

9
Platelet count, ×10 /L 0.251
583.0) 576.0) 583.0)

C-reactive protein, mg/L 12.2 (0.1-212.0) 37.1 (0.1-212.0) 9.4 (0.4-126.0) <0.001

D-dimer, mg/L 0.5 (0.1-20.0) 0.9 (0.1-20.0) 0.4 (0.2-8.7) <0.001

64.0 (8.8- 83.0 (8.8- 59.0 (19.0-

Creatine kinase, U/L <0.01
12216.0) 12216.0) 1260.0)

Lactate dehydrogenase, 241.5 (2.2- 302.0 (2.2- 215.0 (2.5-

<0001
U/L 908.0) 880.0) 908.0)

Alanine aminotransferase, 26.0 (5.0- 32.5 (5.0- 23.0 (6.0-

<0.05
U/L 1933.0) 1933.0) 261.0)

Aspartate aminotransfer- 26.0 (8.0- 34.0 (8.0- 23.0 (9.0-

<0.001
ase, U/L 8191.0) 8191.0) 244.0)

Blood urea nitrogen,

4.1 (1.5-48.1) 4.6 (1.5-48.1) 3.8 (1.6-13.7) <0.001
mmol/L
 medRxiv preprint doi: https://doi.org/10.1101/2020.02.22.20026500. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without
permission.

68.2 (35.9- 71.6 (35.9- 65.6 (39.4-

Creatinine, µmol/L <0.05
9435.0) 9435.0) 229.1)

P values indicate differences between severe and non-severe patients. P<0.05 was considered

statistcally significant.
 Table 3 Laboratory findings of COVID-19 patients with CNS symptoms

Total Severe Non-severe

With CNS Without CNS With CNS Without CNS With CNS Without CNS
symptoms symptoms P symptoms symptoms P symptoms symptoms P
(n=53) (n=161) (n=27) (n=61) (n=26) (n=100)

Median (range)

White blood cell count, ×109/L 4.6 (0.1-12.5) 4.9 (1.8-20.4) 0.582 5.3 (0.1-12.5) 5.5 (1.9-20.4) 0.769 4.1 (2.4-11.0) 4.6 (1.8-14.0) 0.397

Neutrophil, ×109/L 2.6 (0.0-10.9) 3.1 (0.7-18.7) 0.413 3.8 (0.0-10.9) 3.6 (0.7-18.7) 1.000 2.2 (0.9-7.4) 2.8 (0.7-11.8) 0.106

Lymphocyte count, ×109/L 1.0 (0.1-2.3) 1.2 (0.2-2.6) <0.05 0.7 (0.1-1.6) 0.9 (0.2-2.6) <0.01 1.3 (0.7-2.3) 1.3 (0.4-2.6) 0.492

Platelet count, ×109/L 180.0 (18.0-564.0) 227.0 (42.0-583.0) <0.01 169.0 (18.0-564.0) 220.0 (109.0-576.0) <0.05 188.5 (110.0-548.0) 232.0 (42.0-583.0) 0.093

C-reactive protein, mg/L 14.1 (0.1-212.0) 11.4 (0.1-204.5) 0.307 48.6 (0.1-212.0) 26.1 (0.1-204.5) 0.677 7.4 (3.1-111.0) 9.8 (0.4-126.0) 0.817

D-dimer, mg/L 0.5 (0.2-9.7) 0.5 (0.1-20.0) 0.750 1.2 (0.2-9.7) 0.9 (0.1-20.0) 0.424 0.4 (0.2-6.4) 0.4 (0.2-8.7) 0.455

Creatine kinase, U/L 79.0 (8.8-12216.0) 60.5 (19.0-1260.0) 0.167 104.0 (8.8-12216.0) 64.0 (19.0-1214.0) 0.081 52.5 (28.0-206.0) 59.0 (19.0-1260.0) 0.561

Lactate dehydrogenase, U/L 243.0 (2.2-880.0) 241.0 (3.5-908.0) 0.766 334.0 (2.2-880.0) 299.0 (3.5-743.0) 0.324 198.0 (2.5-417.0) 226.0 (121.0-908.0) 0.142
Alanine aminotransferase, U/L 27.0 (5.0-261.0) 26.0 (6.0-1933.0) 0.214 35.0 (5.0-259.0) 31.0 (7.0-1933.0) 0.320 25.5 (13.0-261.0) 23.0 (6.0-135.0) 0.682

Aspartate aminotransferase, U/L 29.5 (13.0-213.0) 26.0 (8.0-8191.0) 0.1031 35.5 (14.0-213.0) 34.0 (8.0-8191.0) 0.319 23.0 (13.0-198.0) 23.5 (9.0-244.0) 0.575

Blood urea nitrogen, mmol/L 4.5 (1.6-48.1) 4.1 (1.5-19.1) <0.05 5.0 (2.3-48.1) 4.4 (1.5-19.1) 0.041 3.9 (1.6-9.4) 3.8 (1.7-13.7) 0.568

Creatinine, µmol/L 71.7 (37.1-1299.2) 66.3 (35.9-9435.0) 0.062 71.7 (37.1-1299.2) 68.4 (35.9-9435.0) 0.245 72.0 (40.3-133.6) 63.4 (39.4-229.1) 0.265

Abbreviations: CNS, central nerves system.

P values indicate differences between patients with and without CNS. P < 0.05 was considered statistically significant
 Table 4 Laboratory findings of COVID-19 patients with PNS symptoms

Total Severe Non-severe

With PNS Without PNS With PNS Without PNS With PNS Without PNS
symptoms symptoms P symptoms symptoms P symptoms symptoms P
(n=19) (n=195) (n=7) (n=81) (n=12) (n=114)
Median (range)

White blood cell count, ×109/L 4.8 (2.8-7.5) 4.9 (0.1-20.4) 0.744 4.5 (3.1-6.8) 5.6 (0.1-20.4) 0.105 4.9 (2.8-7.5) 4.4 (1.8-14.0) 0.273

Neutrophil, ×109/L 2.8 (1.5-5.4) 3.0 (0.0-18.7) 0.740 2.6 (1.5-5.3) 4.1 (0.0-18.7) 0.099 2.9 (1.9-5.4) 2.5 (0.7-11.8) 0.214

Lymphocyte count, ×109/L 1.2 (0.6-2.6) 1.1 (0.1-2.6) 0.433 1.2 (0.6-1.6) 0.9 (0.1-2.6) 0.257 1.2 (0.7-2.6) 1.3 (0.4-2.4) 0.917

Platelet count, ×109/L 204.0 (111.0-305.0) 213.0 (18.0-583.0) 0.564 204.0 (111.0-245.0) 205.0 (18.0-576.0) 0.558 214.5 (155.0-305.0) 219.0 (42.0-583.0) 0.806

C-reactive protein, mg/L 12.0 (3.1-81.0) 12.3 (0.1-212.0) 0.446 7.5 (3.1-76.4) 43.7 (0.1-212.0) 0.134 13.0 (3.1-81.0) 8.8 (0.4-126.0) 0.598

D-dimer, mg/L 0.4 (0.2-9.5) 0.5 (0.1-20.0) 0.399 0.5 (0.2-9.5) 1.3 (0.1-20.0) 0.272 0.4 (0.2-4.5) 0.4 (0.2-8.7) 0.989

Creatine kinase, U/L 67.0 (32.0-1214.0) 64.0 (8.8-12216.0) 0.413 105.0 (32.0-1214.0) 83.0 (8.8-12216.0) 0.761 66.0 (42.0-171.0) 57.5 (19.0-1260.0) 0.291
Lactate dehydrogenase, U/L 205.0 (2.5-517.0) 242.0 (2.2-908.0) 0.284 170.0 (46.0-517.0) 309.0 (2.2-880.0) 0.050 254.0 (2.5-481.0) 215.0 (2.9-908.0) 0.669

Alanine aminotransferase, U/L 26.0 (5.0-116.0) 27.0 (6.0-1933.0) 0.695 19.0 (5.0-80.0) 35.0 (8.0-1933.0) 0.232 26.0 (8.0-116.0) 23.0 (6.0-261.0) 0.555

Aspartate aminotransferase,
22.0 (8.0-115.0) 27.0 (9.0-8191.0) 0.288 22.0 (8.0-53.0) 35.5 (12.0-8191.0) 0.126 22.0 (14.0-115.0) 23.5 (9.0-244.0) 1.000
U/L

Blood urea nitrogen, mmol/L 4.1 (1.6-8.8) 4.1 (1.5-48.1) 0.764 4.2 (3.5-8.8) 4.7 (1.5-48.1) 0.963 3.7 (1.6-5.3) 3.9 (1.7-13.7) 0.660

Creatinine, µmol/L 62.5 (48.1-121.4) 68.3 (35.9-9435.0) 0.455 71.4 (58.3-121.4) 71.7 (35.9-9435.0) 0.717 59.9 (48.1-77.3) 66.6 (39.4-229.1) 0.235

Abbreviations: PNS, peripheral nerves system.

P values indicate differences between patients with and without PNS. P<0.05 was considered statistically significant.
 Table 5 Laboratory findings of COVID-19 patients with muscle injury

Total Severe Non-severe

With muscle Without muscle With muscle Without muscle Without muscle
With muscle injury
injury injury P injury injury P injury P
(n=6)
(n=23) (n=191) (n=17) (n=71) (n=120)

Median (range)

White blood cell count, ×109/L 6.0 (2.3-20.4) 4.8 (0.1-15.6) 0.248 6.7 (2.3-20.4) 5.2 (0.1-15.6) 0.269 4.3 (2.4-6.1) 4.5 (1.8-14.0) 0.618

Neutrophil, ×109/L 4.3 (0.9-18.7) 2.9 (0.0-13.0) 0.031 5.5 (0.9-18.7) 3.5 (0.0-13.0) 0.076 2.6 (1.1-4.5) 2.6 (0.7-11.8) 0.945

Lymphocyte count, ×109/L 0.9 (0.1-2.6) 1.2 (0.1-2.6) 0.002 0.8 (0.1-2.6) 0.9 (0.1-2.5) <0.05 1.2 (1.0-2.1) 1.3 (0.4-2.6) 0.846

Platelet count, ×109/L 185.0 (82.0-436.0) 215.0 (18.0-583.0) 0.224 182.0 (82.0-436.0) 209.0 (18.0-576.0) 0.407 223.0 (122.0-304.0) 219.0 (42.0-583.0) 0.688

C-reactive protein, mg/L 56.0 (0.1-212.0) 11.1 (0.1-204.5) <0.001 70.8 (0.1-212.0) 21.0 (0.1-204.5) 0.078 18.1 (9.7-126.0) 8.1 (0.4-123.0) <0.05

D-dimer, mg/L 1.3 (0.2-20.0) 0.5 (0.1-20.0) <0.05 1.7 (0.2-20.0) 0.6 (0.1-20.0) 0.120 0.4 (0.2-1.3) 0.4 (0.2-8.7) 0.679

525.0 (203.0-
Creatine kinase, U/L 400.0 (203.0-12216.0) 58.5 (8.8-212.0) <0.001 64.0 (8.8-212.0) <0.001 231.0 (206.0-1260.0) 57.5 (19.0-184.0) <0.001
12216.0)
 442.0 (147.0-
Lactate dehydrogenase, U/L 415.0 (147.0-743.0) 229.0 (2.2-908.0) <0.001 285.0 (2.2-880.0) <0.01 315.0 (210.0-666.0) 213.0 (2.5-908.0) <0.05
743.0)

Alanine aminotransferase, U/L 44.0 (14.0-173.0) 25.0 (5.0-1933.0) <0.01 50.0 (14.0-173.0) 30.0 (5.0-1933.0) <0.05 28.0 (16.0-63.0) 23.0 (6.0-261.0) 0.495

Aspartate aminotransferase, U/L 46.0 (22.0-209.0) 25.0 (8.0-8191.0) <0.001 53.0 (26.0-209.0) 31.0 (8.0-8191.0) <0.001 34.5 (22.0-60.0) 23.0 (9.0-244.0) 0.065

Blood urea nitrogen, mmol/L 4.8 (2.0-48.1) 4.1 (1.5-19.1) <0.05 4.8 (2.4-48.1) 4.6 (1.5-19.1) 0.256 5.9 (2.0-10.6) 3.8 (1.6-13.7) 0.264

Creatinine, µmol/L 80.5 (43.7-1299.2) 66.9 (35.9-9435.0) <0.01 81.5 (43.7-1299.2) 68.4 (35.9-9435.0) <0.05 77.4 (60.7-229.1) 65.1 (39.4-215.3) 0.050

P values indicate differences between patients with and without muscle injury. P<0.05 was considered statistically significant.