Perubahan ini berkaitan dengan sitokin proinflamasi yaitu interleukin (IL)-

6, IL-10 and tumor necrosis factor α, granulocyte colony stimulating

factor, monocyte chemoattractant protein 1, macrophage inflammatory
protein 1α, and increased expression of programmed cell death 1, T-cell
immunoglobulin and mucin domain 3 (Tim-3) [9].

Ketika virus masuk ke dalam sel, antigen virus akan dipresentasikan ke antigen presentation
cells (APC). Presentasi antigen virus terutama bergantung pada molekul major
histocompatibility complex (MHC) kelas I. Namun, MHC kelas II juga turut berkontribusi.30
Presentasi antigen selanjutnya menstimulasi respons imunitas humoral dan selular tubuh yang
dimediasi oleh sel T dan sel B yang spesifik terhadap virus.30

Virus memiliki mekanisme untuk menghindari respons imun pejamu.

SARS-CoV dapat menginduksi produksi vesikel membran ganda yang tidak
memiliki pattern recognition receptors (PRRs) dan bereplikasi dalam
vesikel tersebut sehingga tidak dapat dikenali oleh pejamu. Jalur IFN-I juga
diinhibisi oleh SARS-CoV dan MERS-CoV. Presentasi antigen juga
terhambat pada infeksi akibat MERS-CoV.30

Sistem tubuh dan organ yg terpengaruh

Sistem respirasi adalah sistem utama yang terpengaruh oleh SARS-CoV-2
dan banyak infiltrat yang ditemukan pada kedua paru.
Real-time Polymerase Chain Reaction (RT-qPCR) dengan swab nasofaring
atau sputum dibutuhkan untuk diagnosis.
Pada awal infeksi, tes PCR memungkinkan hasil negatif.
Gejala klinis dapat berupa sesak napas, peningkatan frekuensi napas,
penurunan saturasi oksigen, dan peningkatan protein C-reactive, tidak
spesifik. Tes lain seperti antibodi IgM dan IgG melawan SARS-CoV-2,
CD4+ dan CD8+ juga dapat dilakukan.
CD4+ dan CD8+ akan bernilai rendah pada SARS-CoV-2.
Patologi paru-paru menunjukkan kerusakan alveolar mikroskopis bilateral
difus, infiltrat fibromiksoid seluler dan infiltrat inflamasi mononuklear
interstisial dengan dominasi limfosit [10].
Pada sistem kardiovaskuler juga dapat terpengaruh oleh infeksi COVID-19.
Biomarker seperti peningkatan troponin-T yang sangat sensitif, peptida
natriuretik, dan IL-6 bersifat prognostik, dan peningkatan progresifitasnya
dikaitkan dengan hasil yang buruk. Peradangan sistem vaskular
menghasilkan perubahan berikut: trombus mikroangiopati difus, radang otot
jantung (miokarditis), dan aritmia jantung, gagal jantung, dan sindrom
koroner akut. Komplikasi kardiovaskular ini dapat menyebabkan kematian
[11,12].
Limfositopenia yang diamati selama infeksi berpotensi melibatkan CD4+
dan beberapa sel T CD8+. Perubahan ini mengganggu respon imun bawaan
dan didapat, menyebabkan pembersihan virus tertunda dan makrofag dan
neutrofil hiperstimulasi. Sinyal notch dikenal sebagai pengatur utama fungsi
kardiovaskular, dan juga terlibat dalam beberapa proses biologis yang
memediasi infeksi virus. Baru-baru ini telah diperdebatkan apakah
menargetkan pensinyalan Notch dapat mencegah infeksi SARS-CoV-2 dan
mengganggu perkembangan patogenesis penyakit jantung dan paru-paru
terkait COVID-19 [13].

Manifestasi gastrointestinal yang dilaporkan dari COVID-19 termasuk

diare, mual, muntah, dan sakit perut. RNA SARS-CoV-2 telah diisolasi dari
spesimen tinja dan dari swab yang mengambil sampel anus/rektum [14].
ACE2 telah ditemukan diekspresikan dalam sel epitel saluran pencernaan,
menunjukkan masuknya virus melalui reseptor ACE2 dan replikasinya
menyebabkan perubahan inflamasi dan gejala pasien. SARS-CoV-2 juga
menyebabkan kerusakan hati, yang bermanifestasi sebagai peningkatan
kadar serum alanin aminotransferase dan aspartat aminotransferase [15].
Peningkatan ringan bilirubin serum dan -glutamil transferase juga telah
dilaporkan pada beberapa pasien dengan infeksi COVID-19. Dalam
kebanyakan kasus, cedera hati bersifat sementara dan ringan. Namun,
disfungsi hati yang parah atau cedera telah dilaporkan pada pasien dengan
penyakit parah. Tingkat tinggi alanine aminotransferase lebih dari 7500 U/L
telah dilaporkan dalam sebuah penelitian di Cina [17]. Secara mikroskopis,
steatosis mikrovesikular hati dan cedera lobular ringan telah ditemukan
pada paten yang terinfeksi COVID-19 [16]. Tidak jelas apakah cedera hati
terkait SARS-CoV-2 yang diamati disebabkan oleh cedera virus langsung
atau jika terkait dengan obat-obatan hepatotoksik, perubahan inflamasi
sistemik yang menyertai, sepsis, hipoksia yang diinduksi sindrom gangguan
pernapasan, atau kegagalan organ multipel [18 ].

Ada bukti klinis bahwa SARS-CoV-2 memiliki potensi sifat neuropatik.

Beberapa gejala yang berhubungan dengan neurologis telah dilaporkan,
termasuk sakit kepala, pusing, kejang, penurunan tingkat kesadaran,
ensefalopati nekrosis hemoragik akut [19], agitasi dan kebingungan.

FIX

Internalization : The entering of cells by viruses following VIRUS ATTACHMENT.

This is achieved by ENDOCYTOSIS, by direct MEMBRANE FUSION of the viral
membrane with the CELL MEMBRANE, or by translocation of the whole virus
across the cell membrane.

Pada manusia, SARS-CoV-2 terutama menginfeksi sel-sel pada saluran

napas yang melapisi alveoli. SARS-CoV-2 akan berikatan dengan reseptor-
reseptor dan membuat jalan masuk ke dalam sel. Glikoprotein yang terdapat
pada envelope spike virus akan berikatan dengan reseptor selular berupa
ACE2 pada SARS-CoV-2. Di dalam sel, SARS-CoV-2 melakukan
duplikasi materi genetik dan mensintesis protein-protein yang dibutuhkan,
kemudian membentuk virion baru yang muncul di permukaan sel.20, 24
Coronavirus masuk ke sel inang bergantung pada ikatan antara spike
glikoprotein ke reseptor seluler dan ikatan protein S dengan protease pada
sel inang.
SARS-CoV dan SARS-CoV-2 menggunakan reseptor ACE2 dan
TMPRSS2 protease serin untuk protein S berikatan. (Hoffmann et al. 2020).
Interaksi antar virus dengan ACE2 mengakibatkan penurunan fungsi anti-
inflamasi dan peningkatan efek angiotensin II. [7].
Pada pengobatan pasien COVID-19 dengan hipertensi diberikan blocker
reseptor angiontensin II tipe 1 dan inhibitor ACE.
Serta, rekomendasi dari Council on Hypertension of the European Society
of Cardiology pada pasien hipertensi dapat tetap mengonsumsi
antihipertensi karena tidak mengganggu pengobatan COVID-19. [8].
Persebaran SARS-CoV-2 mirip dengan SARS-CoV yang disebabkan hasil
ekspresi dari reseptor ACE2.
Namun berbeda dengan SARS-CoV, SARS-CoV-2 memiliki afinitas 10-20
kali lebih tinggi. (Wrapp et al. 2020).
Ikatan protein S dengan reseptor ACE2 menghasilkan penyatuan envelop
pada virus dengan sel inang membrane sehingga virus dapat masuk dengan
jalur endosomal. (Coutard et al. 2020; Matsuyama and Taguchi 2009).
Selain fusi membran, terdapat juga clathrindependent dan clathrin-
independent endocytosis yang memediasi masuknya SARS-CoV ke dalam
sel pejamu.33
Sama dengan SARS-CoV, pada SARS-CoV-2 diduga setelah virus masuk
ke dalam sel, genom RNA virus akan dikeluarkan ke sitoplasma sel dan
ditranslasikan menjadi dua poliprotein dan protein struktural. 31
RNA virus yang masuk ke sitoplasma inang akan ditranslasi dan
menghasilkan poliprotein replikase pp1a dan pp1b yang selanjutnya
dipecah oleh proteinase yang dikodekan oleh virus menjadi protein kecil.
Perakitan virion terjadi melalui interaksi RNA virus dan protein pada
retikulum endoplasma (ER) dan kompleks Golgi. Virion ini kemudian
dilepaskan dari sel melalui vesikel (Gbr. 3.3) (Hoffmann et al. 2020).
Proses invasi pada sel paru, miosit, dan sel endotel pada pembuluh darah
mengakibatkan terjadinya edema, degeneraasi dan nekrosis.
Perubahan ini berkaitan dengan sitokin proinflamasi yaitu interleukin (IL)-
6, IL-10 and tumor necrosis factor α, granulocyte colony stimulating
factor, monocyte chemoattractant protein 1, macrophage inflammatory
protein 1α, and increased expression of programmed cell death 1, T-cell
immunoglobulin and mucin domain 3 (Tim-3) [9].
Faktor virus dan pejamu memiliki peran dalam infeksi SARS-CoV.35 Efek
sitopatik virus dan kemampuannya mengalahkan respons imun menentukan
keparahan infeksi.36
Disregulasi sistem imun kemudian berperan dalam kerusakan jaringan pada
infeksi SARS-CoV-2. Respons imun yang tidak adekuat menyebabkan
replikasi virus dan kerusakan jaringan. Di sisi lain, respons imun yang
berlebihan dapat menyebabkan kerusakan jaringan.35

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189391/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403867/
file:///Users/puticallistha/Downloads/
Coronavirus_Disease_2019_Tinjauan_Literatur_Terkin.pdf
https://pubmed.ncbi.nlm.nih.gov/32142651/
https://pubmed.ncbi.nlm.nih.gov/32075877/
https://pubmed.ncbi.nlm.nih.gov/32308263/
Zoonotic transmission initially appeared to be a plausible cause as majority of early cases had
a history of exposure to wet markets. However, by the end of January 2020, the number of
people who developed the disease without exposure to the market or another person with
respiratory symptoms increased. The spread of the disease among persons who did not visit
Wuhan and among healthcare workers suggested a person-to-person spread of the virus. The
exact mode of transmission of this virus is unknown. But, as with other respiratory viruses,
droplet borne infection, either directly or indirectly, through fomites is probably the
predominant mode of transmission.
https://sci-hub.se/10.1055/s-0040-1712187

animal-animal
These viral etiologies has confirmed that the bats were the reservoir
hosts of both SARS-CoV33 and MERS-CoV,34 which subsequently use
civet cats and dromedary camels as mediator hosts previous to spreading to
humans. Several theories on the origin of SARS-CoV-2 illness exist;
initially, it was believed to be originated from bats, seafood and snakes that
had spread among people visiting or residing in Wuhan, China and recently
it is suggested to have transmitted from pangolins to humans.

Animal-human
Direct contact with mediator host, exposure to animals or urine of
animals, consumption of milk or unprocessed meat of the infected animals
were considered to be the key routes of these HCoV transmissions to
humans. SARS-CoV, MERS-CoV and SARS-CoV-2 were transmitted
directly to humans from market civet cats, dromedary camels and
pangolins, respectively.

Human-human
SARS-CoV, MERS-CoV and SARS-CoV-2 are transmitted by humanto-human contact, or
by touching surfaces contaminated by the infected person and through aerosol
transmission.38 Transmission through direct human-to-human contact is most commonly
reported among health care employees and primary caregivers of the diseased patient.39
These viruses spread through the respiratory droplets while sneezing or coughing, that stays
on the surfaces. Human transmission can also occur upon contact with such contaminated
surfaces.40
https://sci-hub.se/10.1016/j.cegh.2020.100694
Efforts have been made to search for a reservoir host or intermediate carriers from which the
infection may have spread to humans. Initial reports identified two species of snakes that
could be a possible reservoir of the COVID-19. However, to date, there has been no
consistent evidence of coronavirus reservoirs other than mammals and birds [10,18].

This is supported by cases that occurred within families and among people who did not visit
the wet animal market in Wuhan [13,21]. Person-to-person transmission occurs primarily via
direct contact or through droplets spread by coughing or sneezing from an infected
individual. In a small study conducted on women in their third trimester who were confirmed
to be infected with the coronavirus, there was no evidence that there is transmission from
mother to child. However, all pregnant mothers underwent cesarean sections, so it remains
unclear whether transmission can occur during vaginal birth. This is important because
pregnant mothers are relatively more susceptible to infection by respiratory pathogens and
severe pneumonia (Rothan, Hussin A, 2020).
https://sci-hub.se/10.1016/j.jaut.2020.102433
 Cross sectional :
 Penelitian Analitik Cross Sectional adalah penelitian observaional dimana cara pengambilan
data variabel bebas dan variabel tergantung dilakukan sekali waktu pada saat yang bersamaan
 Populasinya adalah semua responden baik yang mempunyai kriteria variabel bebas dan
variabel tergantung maupun tidak
 Contoh: Hubungan antara Depo Provera dengan Obesitas pada Wanita Usia Subur
 Jika penelitian menggunakan pendekatan Cross Sectional, maka populasinya adalah:
 Semua Wanita Usia Subur (baik yang ikut depo provera maupun tidak, serta baik yang
obesitas maupun tidak)
 Cara pengambilan data, setiap responden diambil datanya untuk dua variabel sekaligus
 Setiap responden (WUS), dilakukan pengambilan dua data sekaligus, yaitu data tentang
memakai depo propera atau tidak, sekaligus diukur sedang mengalami obesitas atau tidak

Cohort study : karena ada pembeda ibu covid dan ibu non covid
Trus di liat mana yang NLRnya kondisinya lebih tinggi/rendah
Untuk determine mana yang keparahan covid??

Retr
ospective study : karena dengan pengambilan medical recods
Retrospective cohort studies, also known as historical cohort studies,
are carried out at the present time and look to the past to examine medical events or
outcomes.
DISAD : The existing data may be incomplete, inaccurate, or inconsistently measured
between subjects
We conducted a prospective cohort study of COVID-19 patients who received medical
treatment at the Third People’s Hospital of Yichang, Hubei Province, from January 9 to
February 26, 2020. All patients who were confirmed by laboratory tests (positive for RT-PCR
of nasal and pharyngeal swab specimens and/or specific IgM/G antibody assay of serum)
before admission were recruited for the study. Basic information (e.g., age, sex, smoking,
drinking, and history of comorbidities) was collected through face-to-face interviews with the
patients or their families using a standardized questionnaire [2]. Routine blood examinations,
including complete blood cell counts, coagulation profiles and serum biochemical tests, were
conducted at hospital admission. Patients with missing neutrophil and/or lymphocyte records
at hospital admission were excluded from the study.

Case control : bisa mengukur exposurenya dan membandingkan nlrnya antara

case dan control

Kaplan meier curves :

The Kaplan-Meier estimate is the simplest way of computing the survival over time in spite
of all these difficulties associated with subjects or situations. For each time interval, survival
probability is calculated as the number of subjects surviving divided by the number of
patients at risk.
https://pogi.or.id/publish/wp-content/uploads/2020/10/Rekomendasi-Covid-Maternal-
POGI.pdf
SKRINING DAN DIAGNOSIS COVID-19 PADA MATERNAL 1. Skrining Universal
untuk Covid-19 pada semua ibu hamil yang akan melahirkan perlu dilakukan secara
rutin. Hal ini berdasar temuan pada studi di New York, dari 215 ibu yang melahirkan, 15.3%
(33 kasus) yang positif, dengan mayoritas kasus yang positif tersebut (88%) tanpa gejala (2).
2. Idealnya semua ibu hamil yang akan melahirkan dilakukan pemeriksaan Reverse
Transcription Polymerase Chain Reaction test (RT-PCR) yang didapat melalui swab
nasopharing dan oropharing sehingga bisa dilakukan penegakan diagnosis pasti
("Universal testing dengan Swab RT-PCR"). Hal ini sesuai dengan rekomendasi
terbaru dari RCOG yang menyarankan bahwa semua pasien yang masuk rumah sakit
harus ditawarkan tes RT-PCR (3). Namun jika di fasilitas kesehatan tersebut tidak
memiliki kemampuan untuk melakukan hal ini, dapat dilakukan skrining terlebih
dahulu dengan metode lain. 3. Pemeriksaan RT PCR merupakan standar baku (gold
standard) untuk diagnosis Covid-19. 4. Skrining dikerjakan pada saat awal ibu hamil
yang akan melahirkan datang ke rumah sakit (di Instalasi Gawat Darurat/Unit Gawat
Darurat) 5. Rekomendasi skrining pada ibu bersalin secara umum tidak dibedakan
dengan skrining Covid-19 secara khusus, yaitu dengan melakukan penapisan
anamnesis dan pemeriksaan fisik terhadap gejala ISPA (demam [>38'C], batuk, sesak
dan gejala flu lainnya) serta riwayat kontak erat dan atau riwayat domisili atau
perjalanan ke daerah dengan transmisi lokal Covid-19. 6. Skrining secara umum ini
dapat menapis pasien bergejala. Kondisi ini akan sangat ideal dilakukan pada daerah
dengan prevalensi gejala yang rendah dan transmisi lokal Covid-19 yang dapat terkontrol
(contoh: Negara Malaysia). Namun perlu dipahami bahwa skrining ini tidak dapat
mengidentifikasi kasus tanpa gejala yang tentunya ditambah dengan kesulitan untuk
mengevaluasi riwayat kontak erat di masyarakat terutama di daerah dengan transmisi lokal
Covid-19 yang masih tinggi dan luas maka diperlukan strategi tambahan untuk melakukan
skrining Covid-19 pada kasus maternal yang mayoritas ditemukan dalam kondisi
asimptomatik. 7. Sebagai tambahan maka dapat dilakukan pemeriksaan penunjang
untuk meningkatkan sensitivitas metode skrining tersebut, meliputi: tes serologis
(darah lengkap dan rapid test Covid), CT scan thoraks atau foto thoraks 19 8.
Pemeriksaan serologis antibodi Covid-19 dengan metode ELISA juga perlu dikerjakan
untuk skrining awal. Antibodi Ig M dan Ig A terdeteksi dengan median 5 hari (Inter
Quartile Range/IQR: 3-6 hari), dan Ig dideteksi setelah 14 hari (IQR: 10-18 hari) (4).
Pada jurnal ini juga disebutkan bahwa IgM, IgA dan IgG pada beberapa kasus dapat
terdeteksi pada hari pertama gejala timbul untuk menunjukkan bahwa skrining dengan rapid
ini ‘masih bisa digunakan’ dan ‘hasilnya sulit diprediksi’ Sehingga dapat digunakan sebagai
alternatif skrining pada RS yang tidak dapat melakukan testing universal karena keterbatasan
sumber daya. 9. Pemeriksaan darah lengkap yang dapat digunakan sebagai penunjang
diagnosis Covid-19 meliputi: Limfopenia dan Neutrofil/limfosit rasio (NLR) > 5.8
(sesuai Covid-19 Early Warning Score) 10. CT scan thoraks memiliki sensitivitas tinggi
dalam mendeteksi dini Covid 19. Idealnya pada RS dengan fasilitas CT Scan thoraks
melakukan pemeriksaan ini sebagai bagian dari skrining awal Covid-19 pada ibu yang
mau melahirkan. 11. Gambaran Pneumonia pada CT Scan atau Foto thoraks
mendukung kecurigaan ke arah Covid-19. Pada CT Scan biasanya didapatkan
gambaran Ground Glass Opacities (GGO) atau konsolidasi multilobar bilateral,
sedangkan pada foto thoraks didapatkan gambaran ruang udara perifer berbayang
(peripheral airspace shadowing) (5). 12. Jika RS tidak memiliki fasilitas CT Scan thoraks
atau sulit melakukan pemeriksaan ini secara rutin, maka metode ini dapat digantikan dengan
pemeriksaan foto thoraks. Saat ini sedang dikembangkan kecerdasan buatan berbasis CT scan
untuk meningkatkan akurasi diagnosis Covid 19 menggunakan foto toraks. 13. Penggunaan
CT-Scan low dose dan foto thoraks dalam satu kali pemeriksaan memiliki paparan
radiasi yang cukup rendah dan aman untuk ibu hamil. 14. Di RS dengan satuan tugas
khusus Covid-19 atau ada dokter spesialis Paru, hasil pemeriksaan skrining bisa dikonsulkan
kepada yang bersangkutan untuk memastikan kategori kasus. 15. Dari hasil skrining pasien
dapat dikategorikan sebagai kasus non covid, suspek atau konfirmasi. 16. Pasien dengan
salah ssatu item pemeriksaan skrining yang positif dapat dikategorikan sebagai kasus suspect
(suspected cases). 17. Berdasarkan ‘Pedoman Pencegahan dan Pengendalian Covid-19 revisi
5 Kemenkes’ jika didapatkan kasus suspek dari evaluasi skrining diatas maka dilakukan
pemeriksaan diagnostik covid-19 dengan swab RT-PCR 20 18. Pasien suspect perlu
dimasukkan di ruang isolasi/ruang khusus di IGD/UGD untuk mencegah penularan kepada
pasien maupun tenaga kesehatan sambil menunggu pemeriksaan diagnostik lanjutan.
Upayakan untuk mempersingkat waktu pasien berada di ruang publik di IGD/UGD. 19.
Pasien suspect perlu dilakukan diagnosis dengan pemeriksaan PCR COVID-19 dari swab
nasopharing dan oropharing. 20. Pasien suspect harus diperlakukan sebagai pasien
Covid-19 positif sebelum ada hasil pemeriksaan PCR yang menyatakan sebaliknya.
Sehingga perawatannya di ruang isolasi dan jika diperlukan penatalaksanaan
persalinan yang tidak dapat ditunda, maka dilakukan penatalaksanaan persalinan
sesuai dengan tatalaksana persalinan Covid-19. 21. Pasien dengan kegawatdaruratan
obstetrik atau dengan gejala Covid-19 sedang/berat perlu dilakukan perawatan di RS
(hospitalisasi). 22. Penentuan kriteria hospitalisasi pada pasien dengan gejala Covid-19
tanpa ada masalah obstetrik dapat menggunakan Modified Early Obstetrics Warning
Score (MEOWS)(6) (tabel 3.1) atau melihat dari severitas gejala Covid(7) (tabel 3.2).
Pasien dengan skor MEOWS > 4 wajib mendapat perawatan di rumah sakit
(hospitalisasi). 23. Pasien dengan gejala ringan (tidak ada sesak dan tanda vital stabil),
tanpa komorbiditas, tanpa kegawatdaruratan obstetri dapat melakukan isolasi mandiri
di rumah atau tempat khusus dengan pengawasan parameter klinis harian. Pasien
dengan gejala sedang atau berat harus segera dirawat di ruang isolasi khusus di rumah
sakit.
Gejala Klinis
Gejala klinis COVID-19 sangat beragam, mulai dari asimptomatik, gejala sangat
ringan, gejala berat, hingga kondisi yang mengharuskan untuk mendapat
perawatan khusus seperti kegagalan respirasi akut (Huang et al., 2020).Gejala klinis
yang biasanya terjadi pada kasus COVID-19 adalah demam, batuk kering dan
sesak napas. Berdasarkan penelitian pada pasien, gejala yang paling sering muncul
adalah demam (98%), batuk (76%), dan myalgia atau kelemahan (44%), sakit kepala 8%,
batuk darah 5%, dan diare 3% (Huang et al., 2020). Gejala lain yang timbul adalah gejala
yang menyerang pencernaan dengan hasil penelitian sebagai berikut, 2,7% pasien
mengalami sakit abdominal, 7,8% pasien mengalami diare, 5,6% pasien mengalami
mual dan/atau muntah (Kumar et al., 2020).
(Arianda Aditia, 2021).
http://jurnal.globalhealthsciencegroup.com/index.php/JPPP/article/view/574/410

Clinical manifestation and diagnosis The complete clinical manifestation is not clear yet, as
the reported symptoms range from mild to severe, with some cases even resulting in death
[3]. The most commonly reported symptoms are fever, cough, myalgia or fatigue,
pneumonia, and complicated dyspnea, whereas less common reported symptoms
include headache, diarrhea, hemoptysis, runny nose, and phlegmproducing cough [3,
16]. Patients with mild symptoms were reported to recover after 1 week while severe
cases were reported to experience progressive respiratory failure due to alveolar
damage from the virus, which may lead to death [13]. Cases resulting in death were
primarily middle-aged and elderly patients with pre-existing diseases (tumor surgery,
cirrhosis, hypertension, coronary heart disease, diabetes, and Parkinson’s disease) [13].
Case definition guidelines mention the following symptoms: fever, decrease in lymphocytes
and white blood cells, new pulmonary infiltrates on chest radiography, and no improvement
in symptoms after 3 days of antibiotics treatment [2]. For patients with suspected infection,
the following procedures have been suggested for diagnosis: performing real-time
fluorescence (RT-PCR) to detect the positive nucleic acid of SARS-CoV-2 in sputum, throat
swabs, and secretions of the lower respiratory tract samples [13, 14, 43].
(Adhikari, Sasmita P, et.al, 2020).
file:///Users/puticallistha/Downloads/COVID-19_ScopingReview.pdf

General Symptoms The majority of patients with COVID‐19 present common symptoms that
include fever, shortness of breath, cough (either with or without sputum), sore throat, nasal
congestion, dizziness, chills, muscle ache, arthralgia, weakness, fatigue or myalgia, chest
tightness, excessive mucus production with expectoration, hemoptysis, and dyspnea [36–42].
Even though fever is not the only initial clinical manifestation of SARS‐CoV‐2 infection, it is
considered to be critical [43,44]. Fever, cough, and fatigue are the three most prevalent
symptoms in COVID‐19 patients [25,45]. Other less characteristic symptoms include
headache, diarrhea, abdominal pain, vomiting, chest pain, rhinorrhoea, or pharyngalgia [46–
49]. Approximately 90% of the patients present more than one symptom [50,51]. An
approximate proportion of severe versus common cases of COVID‐19 is estimated to 1:4
[52]. It is suggested that an early onset of shortness of breath constitutes a poor
prognostic factor for patients. Among 81 fatal cases of patients from Wuhan, the most
common cause of death was a respiratory failure (46.91%), followed by septic shock
(19.75%), multiple organ failure (16.05%), and cardiac arrest (8.64%). Rarer death
causes were acute coronary syndrome, malignant arrhythmia, or disseminated
intravascular coagulation (DIC) [53]. Zhou et al. reported a case of a COVID‐19 patient
with a spontaneous pneumomediastinum and subcutaneous emphysema [54]. Clinical
characteristics might differ between critically ill and non‐critically ill patients [55,56].
(Baj, Jacek, et al., 2020).
file:///Users/puticallistha/Downloads/jcm-09-01753.pdf
NLR

NLR indicates the balance between innate and adaptive immune responses and it is an
excellent indicator of infl ammation and stress together. The opposite changes in
neutrophil and lymphocyte counts are a multifactorial dynamic process depending on
finetuning and regulation of various immunologic, neuroendocrine, humoral and
biologic processes such as margination/ demargination, mobilization/redistribution,
accelerated/delayed apoptosis, infl uence of stress hormones and
sympathetic/parasympathetic imbalance of the vegetative nervous system.

Elevated values of NLR, high activity of neutrophils and lower activity of lymphocytes
(immune supression) and eosinophils are associated with higher volume and
distribution widths of the blood cells size (RDW% – red cell distribution widths, MDW
% – monocyte distribution widths %) are now well measured by fl owcytometry of the
new type of hematologic cell analyzers (Crouser et al, 2017). NLR is influenced by many
conditions including age, race, medications (corticoids), and chronic diseases such as
ischemic heart disease, chronic heart disease, anemia, diabetes, obesity, depression
disorders and cancer, i.e, those affecting the function, activity, behavior and dynamic
changes in neutrophil and lymphocyte counts (Fisher et al, 2016).
The priority of the article was clear, namely to postulate that the increase in NLR measures
the severity of immune-infl ammatory response and in general refl ects the intensity of
supraphysiological insults, severity of ongoing disease, and pathological state in general.
Simply, high NLR values are associated with severe infl ammation, stress, injury,
trauma or major surgery, or cancer, and marks the worsening of the prognosis
regarding morbidity or mortality.

The risk factors like smoking, obesity and diabetes mellitus were associated with mild
elevation in NLR

The level of stress, major injury and/or infl ammation and severity of clinical state are easily
derived from increasing values of NLR. NLR is helpful in differentiating a more severe
disease from a milder one. NLR is a very rapid and valid immunologic marker of
ongoing infl ammation, infection, tissue injury, stress response to a disease, and organ
dysfunction, as well as refl ects the severity of the disease per se.

NLR COVID 19
The neutrophil-to-lymphocyte ratio (NLR) is a simple, available and valid index of
immune-infl ammatory response, neuroendocrine stress and severity of illness. It is a
very sensitive but less specifi c hematologic parameter that refl ects the intensity of
systemic infection/ inflammation, stress and severity of diseases of various origins,
including COVID-19 infection.
Patients infected with COVID-19 exhibited higher leukocyte counts, abnormal respiratory
findings, and mildly or moderately increased plasma levels of proinfl ammatory
cytokines. Patient sputum showed positive polymerase chain reactions for novel coronavirus
SARS-CoV-2. The patients with COVID-19 infection had significantly higher values of
NLR (5.00; IQR 2.3–13.9) than non-COVID patients.
Severely ill patients with COVID-19 infection had severe lymphocytopenia, higher NLR
ratio (≥ 5–7), lower platelet counts, higher erythro cyte sedimentation rate (ESR),
mildly to moderately increased Creactive protein and procalcitonin, and elevated LDH,
whereas the cytokines such as IL-2, IL4, IL-6, IL-10 and IFN-gamma were not
increased or only moderately increased.
NLR can be used as an objective parameter for the purpose of stratification of patients
with COVID-19 infection. Not only the initial value of NLR and D-dimer levels are
important for stratification, the dynamic changes of NLR values during hospital stay are of
importance too. A progressive increase in NLR during the clinical course is associated
with the severity of COVID-19 disease, and poor clinical outcome (Fu et al, 2020, Ma et
al, 2020).
The major pathogenesis of viral respiratory infection is inflammation of respiratory
pathways, which in case of severe COVID-19 manifests as severe, unilateral or bilateral
pneumonia and is associated with severe hypoxemia and dyspnea. Severe cases are
coupled with leukocytosis and NLR values increased above 3.13 (Liu et al, 2020), or
above 5.0 (Song et al, 2020). The severe course of COVID-19 is associated with the
development of a severe acute respiratory syndrome (SARS).

The bad prognosis of COVID-19 is characterized by ongoing severe bilateral pneumonia,

development of acute respiratory failure or ARDS with severe hypoxemia and very low
oxygenation index (paO2 /FiO2 < 150–100 mmHg), which should be treated by non-invasive
or artifi cial mechanical ventilation. Neutrophil-to-lymphocyte ratio is an emerging
biomarker of the systemic infl ammation and severity of illness, which can be used alone or
together with other biomarkers such as D-dimer levels, serum ferritin, lactate
dehydrogenase, troponins and blood levels of CRP, PCT, and IL-6 for screening, early
diagnosis/stratifi cation and prognosis of COVID-19.

NLR UNTUK CLINICAL PRACTICE

The concept of NLR has brought about a new and deep insight of the dynamic course of
immune-infl ammatory response as a reaction between innate and adaptive cell immune
systems during various pathological states and illnesses. The unique position of NLR as a
simple, cheap and easily available parameter is that it refl ects the complex relations and
physiological cooperation among three suprasystems: vegetative nervous system,
neuroendocrine and immune systems. NLR itself integrates the general activity of these
suprasystems, however, under clinical condition we cannot differentiate between the
contribution of each of them. The clinical interpretation should be very careful, only in
clinical context, while taking in mind the infl uence of the neuroendocrine stress (Kalelioglu,
2019), and many other factors such as anemia, age and comorbidities (Fisher et al, 2019). The
normal range of NLR is in the range of 1–2 (0.8–2.2). The values above 3.0 and below 0.7 in
adults are pathological. NLR in grey zone of the range of 2.3–3.0 may serve as a warning that
there is a pathological process present in organism, such as cancer, atherosclerosis or
ischemic heart disease, psychiatric disorders, subclinical infection and/or infl ammation (Fig.
1, Tab. 4). NLR may help clinicians in the process of stating the right diagnosis or deciding
for online monitoring of immune-infl ammation response or reaction to various insults. The
twenty-year experience of using NLR as a prognostic marker provides wealth of evidence for
routine clinical use. The parameter of NLR parameter can be used for screening, early
warning, stratifi cation according to the severity of disease, prediction and prognosis.
However, its correct employment in clinical practice needs few important issues to be
accounted for (Tabs 5–7), namely longer time for reading, understanding and right
interpretation. NLR assessments should be done at serial time points. The change in NLR
(∆NLR) may be used for prediction and prognosis. The heterogeneity of many diseases
(cancer, ischemic heart disease) and syndromes (including SIRS and sepsis) are affected by
the strong infl uence of genotype and phenotype (epigenetics). Due to this fact, NLR should
be used as part of a panel of other biomarkers (Tabs 3 and 4). NLR is a novel parameter that
is opening a new dimension in clinical medicine, while improving the understanding of the
biology of infl ammation, pathophysiology of cellular immune response, coupling and
antagonism between innate and adaptive immunity and its clinical consequences for health
and disease. NLR is a novel marker of cellular immune activation, a valid index of stress and
systemic infl ammatory response syndrome of various origins. The utility of NLR is
summarized in Table 8. It can be used for stratifi cation and evaluation of the severity of
disease in many clinical disciplines (Tab. 4). NLR is a cheap, simple and easily available
parameter with high sensitivity and lower specifi city. It is a dynamic parameter with a quick
response to insults, it refl ects improvement or deterioration of the clinical status. It can be
used as part of a panel with valid biomarkers of infection /infl ammation. NLR alone or along
with other markers may be helpful in the process of decision making and management of
various acute and/or chronic diseases.

(R. Zahorec, 2021).

http://www.elis.sk/download_file.php?
product_id=7271&session_id=rrdpels1p3265dd1kgusu7tja0

The pathophysiology of the high pathogenicity of this unusual highly contagious SARS-
CoV2 could not be fully understood yet. Inflammation plays an important role in
infectious diseases. Accumulating evidence has shown the importance of inflammation
in the progression of viral pneumonia, including in coronavirus disease 2019 (COVID-
19) cases8 . Pro-inflammatory cytokines have been shown to increase in sera of patients
with pulmonary inflammation9 . The white blood cell (WBC) count, neutrophil,
lymphocyte count, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio
(PLR) are markers of systemic inflammation10,11. These markers are useful predictors
for the prognosis and follow-up of patients with viral pneumonia. NLR is a very useful,
rapid, and inexpensive indicator, the significance of which has been shown in bacterial
pneumonia12 and viral infections13. This retrospective, single-center study was conducted
to investigate the complete blood count parameters, NLR, PLR, C-reactive protein (CRP),
and the other infection bio-markers and biochemical data of a total of 80 COVID-19 positive
and negative cases.

The patients were divided into two groups, i.e., COVID-19 (+) and COVID-19 (-).
Neutrophil, lymphocyte, platelets, MPV, hemoglobin, and CRP values of all patients
were recorded, and the NLR and PLR values were calculated.
Therefore, CoV-induced inflammation-related lymphopenia increased NLR. In the only
study conducted before ours, the optimal threshold of 3.3 for NLR showed a superior
prognostic possibility of clinical symptoms for change from mild to severe7 . Our study
was among the first studies in the literature. We found NLR to be high and the likelihood
of COVID-19 was 20-fold greater when NLR was ≥2.4.

However, NLR is a rapid, inexpensive, and useful indicator that could be estimated via
the complete blood count. The clinical use of NLR has been shown in bacterial
pneumonia12 and viral infections13. The surveillance of NLR and lymphocyte subsets is
helpful in the early screening of critical illness, diagnosis, and treatment of COVID-19.

In conclusion, we found that NLR was significantly elevated in COVID-19 patients. We

also provided a cut-off for this readily available test and showed that patients with NLR
≥2.4 were 20.5 times more likely to have COVID-19 compared to patients whose NLR
was ≤2.4. Similarly, the likelihood of COVID-19 was 10.5-fold greater when fever was ≥36.8
°C. This study indicates that high fever and NLR are independent biomarkers for
COVID-19 patients. Our findings may also help in the early diagnosis of COVID-19.

(Nalbant, Ahmet et al. 2020).

file:///Users/puticallistha/Downloads/1806-9282-ramb-66-6-07461.pdf
This hyper-inflammation and immunological parameter changes raise a significant
issue in patients with confirmed COVID-19 infection. Previous studies have reported
neutrophil-lymphocyte-ratio (NLR) and platelet-lymphocyte-ratio (PLR) may be used
to evaluate immunological and inflammation status in confirmed patients. Coagulation
status and its complications can be assessed using Ddimer.13 However, these studies were
primarily based in China, which may differ from other countries. Therefore, the author
would like to analyse the association between NLR, PLR, and D-dimer levels to predict
and the prognosis of patients with early COVID-19 infection in order to provide a
better and more effective treatment.

We compared patients’ age, haemoglobin, leukocyte, platelet, neutrophil count,

lymphocyte count, albumin, NLR, PLR, and d-dimer between those who finished the
hospitalisation group and patients who died during the hospitalisation group using the
unpaired Ttest, Mann-Whitney, and Chi-Square tests. Each variable’s optimal cut-off
values were analysed using receiver operator curve (ROC) analysis with a confidence
interval of 95%.
file:///Users/puticallistha/Downloads/215-984-2-PB.pdf

NLR and PLR have proven to be reliable markers in several diseases that go with systemic
inflammation. As shown, they have a higher value in COVID 19 patients, and even more, they
correlated with classical inflammatory markers such as CRP, ESR, and with those specific to
SARS-cov2 infection.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252599#sec006

The neutrophil to lymphocyte ratio (NLR), easily calculated from a routinely blood test
by dividing absolute neutrophil count by absolute lymphocyte count, has been reported
of having great value in indicating a patient’s overall inflammatory status.1 Increasing
NLR is a risk factor of mortality not only in infectious diseases but also in malignancy,
acute coronary syndrome, intracerebral hemorrhage, polymyositis and
dermatomyostis.2-5 A recent research has exhibited that severe cases of COVID-19
tended to have higher NLR.6 Whether NLR could be an independent predictor of
mortality in hospitalized COVID-19 patients needs to be further elucidated.

This retrospective cohort study included 245 COVID-19 patients, and the total in-hospital
mortality was 13.47%. We found that higher NLR significantly associated with an
increased risk of all-cause death during hospitalization. Older age and high level of D-
dimer are considered independent predictors of in-hospital death.13 We adjusted age, D-
dimer concentrations and other covariates to minimize the potential impact of confounding.
Moreover, features that, when added to the model, changed the odds ratio by at least 10
percent have been added to the multiple logistic regression models. Compared with crude
regression analyses, this association still persisted when adjusting for demographic and
clinical variables in the multivariable regression analyses. According to the stratified
analysis, the risk of mortality tended to be higher as NLR increased in male patients.

Several studies have addressed the difference of baseline leukocyte counts between the
clinical stages in COVID-19 patients. Qin C et al.6 reported that severe cases of COVID-
19 were likely to have higher neutrophil count but lower lymphocyte count compared
with non-severe patients, thus the NLR tended to be higher in severe infection patients.
Mo P et al.14 investigated 155 patients with COVID-19 and found that refractory patients
had higher level of neutrophils in comparison with general patients. Moreover, some
researchers evaluated the clinical characteristics of the SARS-CoV2 reactivation. The study
included 5 reactivated patients, among which one patient had progressive lymphopenia and
progressive neutrophilia indicating the potential value of leukocyte counts on COVID-19
reactivation.15 Limited by the number of patients, difference of clinical outcome and lack of
follow-up, the specific risk factors for in-hospital mortality remain to be identified.

In this study, we found that patients with increased NLR had a higher risk for mortality
during hospitalization after adjustment for other cofounders, meanwhile, the male had
a more significant association with the risk of mortality than the female. This finding is
consistent with the results concluded by Mo P et al.14 that male patients have a higher
incidence of disease refractoriness. Further research should be conducted to confirm this
result and determine the differences in the pathophysiological mechanisms between male and
female with COVID-19.

NLR has taken both the levels of neutrophils and lymphocytes into account, and been
proposed as a new biomarker for systemic inflammation. The high NLR results from
increased neutrophil count and decreased lymphocyte count. The inflammatory response
could stimulate the production of neutrophils and speed up the apoptosis of lymphocytes.
Dysregulated immune cell responses and consequently immunologic abnormality are
believed to play remarkable roles in the severity of virus-induced disease.16 When
immune response is dysregulated, it would result in an excessive inflammation, even
death. One of the most prominent factors associating with the severity and outcomes of the
Middle East respiratory syndrome coronavirus (MERS-CoV) disease is the hematological
change in leukocyte populations.17 leukocytosis characterized by increased neutrophils and
monocytes was primarily observed in several MERS-CoV patients, and all the deceased
patients showed rapid drops of lymphocyte counts.18,19 Recent studies showed that higher
levels of inflammatory cytokines, chemokines and NLR in infected patients were
correlated with the severity of the disease than did those non-severe patients, suggesting
the involvement of cytokine storm in disease severity.6,20 These findings are consistent
with our results. Furthermore, patients with severe virus infection are more likely to co-
infected with bacteria due to low immune functions, which would be another possible
reason to explain the increased level of neutrophils, C-reactive protein and
procalcitonin shown in our study.

The results of this study have several clinical implications and strengths. Since NLR
could be quickly calculated based on a blood routine test on admission, clinicians may
identify high risk COVID19 patients at an early stage. Thus, treatments can be modified
accordingly to reduce the in-hospital death. As this is an observational study and
susceptible to various confounders. We adopted strict methods of statistical adjustment to
minimize potential confounding. In addition, we tested the robustness of the results by
repeating the analyses with tertiles of the NLR and in different subgroups of gender, age,
body mass index and history of hypertension.

There are some limitations that should be noted meanwhile. First, the number of observed
events is to some extent small which limits the statistical power of this explorative study.
However, the sample size of this research is sufficient to draw a conclusion. Statistical
analyses with tertiles of the NLR and in subgroups have ensured the reliability of the results.
Second, since all subjects in our study were hospitalized Chinese patients diagnosed with
COVID-19, results of this study might not directly be applied to other ethnicities. Third,
although we have adjusted for multiple potential confounders, residual and unmeasured
confounding might not be fully considered.

In conclusion, this retrospective cohort study performed in the Chinese population revealed
that the NLR is an independent risk factor for the in-hospital mortality. Further researches are
needed to confirm our findings in other cohorts and to compare the predictive ability of
baseline NLR and the change in NLR under treatments
https://sci-hub.se/10.1016/j.jinf.2020.04.002

Systemic inflammation induces an increase in neutrophils and platelets count

accompanied by a decrease in lymphocyte count making their ratio (neutrophil-
tolymphocyte ratio and platelets-to-lymphocyte ratio) a useful tool in the diagnosing
chronic inflammatory diseases [5, 7]. In bronchiectasis the inflammation is primarily
neutrophilic and it’s due to persistent bacterial infection [8]. Excessive neutrophilic
inflammation is linked to an increased frequency of exacerbations and rapid lung function
decline through degradation of airway elastin, among other mechanisms [1-5]. NLR is
assessing both the inflammatory status and cell-mediated immunity and it’s increase in
several systemic diseases, cancer, COPD, asthma, obstructive sleep apnea [5,7, 9-19].
Platelets have an important role in the immune system due to the surface receptors that enable
them to recognize pathogens and immune complexes. Activated and adherent platelets release
cytokines, including chemokines that stimulates inflammatory recruitment of immune cells
[20, 21]. The aim of this study is to evaluate the utility of NLR and PLR as inflammatory
markers in patients with exacerbation of bronchiectasis compared with classical markers such
as C-reactive protein, erytrocite sedimentation rate and white blood cells. As a second
objective we wanted to see if in patients with COPD and bronchiectasis these markers are
higher, considering that both conditions are associated systemic inflammatory status.

The NLR ratio was defined as the absolute count of neutrophils divided by the absolute
count of lymphocytes.

In recent years, multiple studies have been carried out to evaluate the utility of NLR and PLR
as markers of systemic inflammation as they are more accessible and cheaper blood test.
While NLR has been proven to be a reliable inflammatory marker in solid tumors, COPD,
sleep apnea and several of other disease the importance of PLR is still [17-23]. NLR is an
independent prognostic factor in many solid tumors (eg, pulmonary, gastric). It is
associated with disease severity, hospitalization, malnutrition, recurrence, and mortality
in various chronic diseases such as cardiovascular or renal disease and has recently
been studied as a predictive factor. of exacerbations and mortality in COPD. Thus, it
was observed that NRL increases significantly in exacerbations compared to stable periods
and that there are significant positive correlations between NLR, CRP and white blood cells.
In the case of bronchiectasis, Nacaroglu et al [5] observed in a retrospective study that
followed 50 pediatric patients that only absolute numbers of neutrophils and NLR can be
used as biomarkers in acute exacerbations, the ratio does not have higher values. In our study
COPD stage 2 patients had higher vales of both NLR and PLR when compared with other
stages. It is well known that these patients represent a particular group as they have higher
decline rate and higher risck to develop cancer. One possible explanation could be that in this
particular subgroup of COPD patients the inflammation is more important
https://www.revistadechimie.ro/pdf/23%20MOTOC%20N%2011%2019.pdf
NLR is an easy parameter to perform, the complete blood count being one of the standard,
mandatory tests for any hospitalized patient, so it can be widely used to assess the severity of
sepsis or septic shock. Furthermore, using the cut-off value of 10, as obtained in our study
and suggested by other authors [3], may help for a faster, mental calculation of the potential
sepsis severity. Nevertheless, larger studies which will include more patients are needed to
positively demonstrate the effectiveness of NLR in predicting the severity of sepsis, as well
as assessing the risk of mortality in these patients

However, since NLR lacks high sensitivity, further research is certainly required to
confidently prove its effectiveness in predicting sepsis severity
file:///Users/puticallistha/Downloads/biomedicines-10-00075-v2.pdf
IBU HAMIL DAN COVID
Keadaan khusus dijumpai pada beberapa laporan penelitian. Penyakit dari virus corona
seperti MERS, SARS dan COVID-19 pada masa kehamilan membuat respon imun
seluler menjadi kacau. Pada infeksi virus SARS-CoV terjadi limfopenia berat, Infeksii
MERS-CoV terjadi inhibisi respon limfosit T dan pada infeksi SARSCoV-2 terjadi
penurunan jumlah sel T CD4+ dan CD8+ (21). Keadaan khusus lainnya di-kemukakan
oleh penelitian Slutsky, et al terdapat perbedaan aktifitas sel T CD4+ dan CD8+ pada saat
melahirkan prematur dibandingkan dengan melahirkan cukup bulan. Hasil yang
diperlihatkan pada wanita yang melahirkan prematur adalah meningkatnya sel T naif
dan juga peningkatan proliferasi sel T CD4+ dan CD8+ jika adanya inflamasi plasenta.
15 Dari penjelasan sebelumnya dapat dilihat bahwa ibu dan janin sangat rentan
mengalami infeksi, maka seorang wanita hamil harus menjaga kesehatannya dengan
pola hidup bersih dan sehat karena perlindungan tubuh sedang tidak adekuat untuk
menjalankan berbagai fungsi fisiologis. 22 Imunitas dari wanita hamil bisa menyerang
janin jika berada dalam kondisi inflamasi. Hal tersebut bisa mengganggu perkembangan
janin, menyebabkan kelainan permanen pada janin dan juga bisa sampai janin gugur karena
proses inflamasi. Ibu hamil juga akan lebih mudah untuk mengalami komplikasi lewat
berbagai penyakit yang diderita selama kehamilan. Vaksinasi belum bisa menjadi solusi
untuk meningkatkan imunitas karena perbedaan kondisi imunitas seluler wanita yang
menyebabkan respon tubuh ibu hamil terhadap vaksinasi berbeda jika dibandingkan
dengan pada wanita tidak hamil. 13,14
file:///Users/puticallistha/Downloads/31796-70107-2-PB.pdf

Although pregnant women show symptoms similar to nonpregnant women for

Coronavirus, some points should be considered, such as complications during
pregnancy and postpartum [90–92]. The risk of viral pneumonia is significantly higher
among pregnant women compared to the general population, especially when there is
no antiviral therapy [2]. There are no reports for vertical transmission, however, some
newborns developed severe retardation in intrauterine growth and life-threatening
gastrointestinal complications [3]. As the SARS-CoV-2 appears to have similar
pathogenicity to SARS-CoV and MERS-CoV, pregnant women may be at high risk to
develop serious infections.

In summary, the study conducted by Li et al.

https://www.annualreviews.org/doi/10.1146/annurev-virology-110615-042301
[77] revealed that the ACE2 receptor used by SARS-CoV-2 was widely distributed in
specific cell types of the maternal-fetal interface cells and fetal organs. Regarding
maternal-fetal interface, ACE2 was found highly expressed in these cells, including
stromal cells, perivascular cells of decidua and cytotrophoblast, and
syncytiotrophoblasts in the placenta. In addition, ACE2 was also expressed in specific
cell types of human fetal heart, liver, and lung, but not in the kidneys. Although
previous clinical studies have not observed vertical transmission of SARS-CoV-2 among
limited cases, this phenomenon still needs to be investigated more carefully in clinical
practice. Corroborating this study, the study conducted by Schwartz [102] showed that all
neonatal samples tested, including in some cases placentas, were negative for SARS-CoV-2
by RT-PCR. Thus, at this point in the global pandemic of Covid-19, there is no evidence
that the SARS-CoV-2 virus undergoes intrauterine or transplacental transmission from
infected pregnant women to their fetuses. A case of neonatal SARS-CoV-2 infection in
China with pharyngeal swabs was reported with a positive RT-PCR test 36 h after
birth. However, it has not been confirmed yet if the case is a mother-to-child vertical
transmission [103]. In addition, two cases of SARS-CoV-2 were reported during the third
trimester of pregnancy, in which mothers and newborns had excellent results and the virus
has not been identified in all conception products and in the newborns. This reinforces once
again that there is evidence of a low risk of intrauterine infection by vertical transmission of
SARS-CoV-2 [104]. During the Hong Kong outbreak, a cohort study of five babies born alive
to pregnant women with SARS-CoV was conducted. A systematic search through perinatal
examinations for transmission of the SARS-associated coronavirus, including RT-PCR
assays, viral cultures, and paired serological titers. The virus was not detected in any of the
babies' samples.. In addition, none of the babies developed clinical, radiological,
hematological, or biochemical evidence suggestive of SARS [105]. Likewise, as there is no
evidence that also SARS-CoV-2 can be transmitted transplacentally from the mother to the
baby the treatment strategy for children with Covid-19 is based on the adult experience. It is
also important to highlight that the disease condition of most children is mild and, to date,
few deaths in the pediatric age group have been reported [106].
https://sci-hub.se/10.1016/j.jogoh.2020.101846

Immunologic alterations during pregnancy may help explain the altered severity of and
susceptibility to infectious diseases during pregnancy. As pregnancy progresses,
hormone levels change dramatically and are considerably higher than at any other
time.49 The interplay between sex hormones and the immune system is complex and
multifactorial, and it affects many organ systems (Fig. 1). In humans, estradiol can enhance
several aspects of innate immunity and both cell-mediated and humoral adaptive
immune responses.51,52 In general, low estradiol concentrations promote CD4+ type 1
helper T-cell (Th1) responses and cell-mediated immunity, and high estradiol
concentrations augment CD4+ type 2 helper T-cell (Th2) responses and humoral
immunity.52 Progesterone can suppress the maternal immune response and alter the
balance between Th1 and Th2 responses.49,53,54 Increasing estrogen and progesterone
concentrations with advancing pregnancy lead to a reversible thymic involution. The
mechanisms of estrogen and progesterone modulation of individual components of the
immune system have been extensively studied in vitro but not in humans. There is evidence
that aspects of innate immunity (phagocytic activity, α-defensin expression, and numbers of
neutrophils, monocytes, and dendritic cells) are maintained or enhanced during pregnancy,
particularly during the second and third trimesters.50,55 Conversely, the number of CD3+ T
lymphocytes (both CD4+ and CD8+) decrease during pregnancy56,57 as do Th1 and Th2
responses to mitogenic or antigenic lymphocyte stimulation.55,58 However, there is limited
information on the longitudinal trends of such alterations during pregnancy. Levels of several
cytokines are altered: levels of interferon-γ, monocyte chemoattractant protein 1, and eotaxin
are decreased in most pregnant women, whereas tumor necrosis factor α, interleukin-10, and
granulocyte colony-stimulating factor levels rise.50 In general, levels of inflammatory
cytokines are reduced, whereas levels of cytokines that induce phagocytic-cell recruitment or
activity increase; these alterations do not necessarily follow a clear Th1 or Th2 phenotype.50
Regulatory T cells become more numerous.59

Several theories have been proposed to explain the immunologic alterations that occur during
pregnancy. It was initially thought that pregnancy confers general immunosuppression to
ensure tolerance of the semiallogeneic fetus.60 However, data indicating that fetus-specific
cytotoxic T-cell responses can be generated during pregnancy without loss of the fetus,61 as
well as data from studies of pregnant mice showing normal memory T-cell development after
lymphocytic choriomeningitis virus infection,62 contradict the idea of systemic
immunosuppression during pregnancy. Adequate immunologic responses to vaccination in
pregnant women have been demonstrated in several studies and for several pathogens.63-66
The fact that pregnant women do not seem, on the basis of epidemiologic evidence, to be
more susceptible to infections in general also contradicts this theory. A more recent theory
proposed a shift from Th1 to Th2 immunity during pregnancy.67 Th2 cells stimulate B
lymphocytes, increase antibody production, and suppress the cytotoxic T-lymphocyte
response, decreasing the robustness of cell-mediated immunity. A shift to Th2 immunity is
postulated to be responsible for altered responses to respiratory viral infections or
autoantigens during pregnancy and could explain the increased severity of infections such as
influenza or coccidioidomycosis, in which cellmediated immunity is important.5,50,68

Elucidation of the immunologic alterations and adaptations that occur during pregnancy
suggests that older concepts of pregnancy as a state of systemic immunosuppression are
oversimplified. A more useful model may be the view of pregnancy as a modulated
immunologic condition, not a state of immunosuppression.50 Decreases in adaptive
immunity seen in later stages of pregnancy are consistent with the observed increase in the
severity of certain infectious diseases during later pregnancy. Decreases in the numbers and
function of CD4+, CD8+, and natural killer cells could affect antiviral, antifungal, or
antiparasitic responses and delay clearance of the offending microorganism. However, the
increases in innate immunity observed during pregnancy may help to prevent acquisition of
infection and thus explain the absence of increased susceptibility to infections.

Furthermore, the placenta is an active immunologic site, capable of interacting with and
responding to pathogens. The placental tropism of specific pathogens (e.g., listeria or P.
falciparum) affects the susceptibility to and severity of certain infectious diseases during
pregnancy, as well as pregnancy outcomes.54 Placental infection that elicits the production of
inflammatory cytokines may activate the maternal immune system and lead to placental
damage and miscarriage or preterm labor.69 Although a viral infection of the placenta that
triggers a mild inflammatory response may not terminate the pregnancy, it can activate the
maternal immune system or that of the fetus, potentially promoting an inflammatory response
that may lead to long-term neurodevelopmental or other sequelae,70 including diseases in
adulthood,54 in the offspring.

Given the hormonal shifts during pregnancy and the resultant effects on the immune system,
efforts to reduce the pathogenesis of infectious and other diseases by modulating the
hormonal environment locally or systemically warrant consideration. Approaches that boost
pathogen-specific immunity or particular components of the immune system (e.g., alterations
in certain cytokines and in regulatory T-cell subsets) may provide new prophylactic and
therapeutic pathways. Interfering with the special interactions between some pathogens and
the placenta may also offer a potential strategy for prophylaxis or therapy. Vaccination before
and during pregnancy, which has proved safe and effective for a number of infectious agents,
could one day be expanded to include vaccines against other relevant pathogens, such as
HSV, HEV, and malaria parasites. The beneficial effects of maternal vaccination may not be
limited to the mother but, by reducing fetal and placental inflammation, may also provide
longterm benefits for the child. The education of pregnant women about prevention of
infections and the early identification and appropriate treatment of infectious diseases during
pregnancy remain important strategies for protecting maternal and infant health.
https://sci-hub.se/10.1056/NEJMra1213566

Pregnancy is a unique immunological state. The maternal immune system faces great
challenges: establishing and maintaining tolerance to the allogeneic fetus while
preserving the ability for protection against microbial challenges. A successful
pregnancy relies on finely tuned immune adaptations both systemically and locally.
Instead of keeping immune suppression, maternal immunological states actively adapt
and chang with the growth and development of fetus at different gestational stage: from
a pro-inflammatory state (beneficial to the embryo implantation and placentation) in
the first trimester to an anti-inflammatory state (helpful for the fetal growth) in the
second trimester, and finally reaching a second pro-inflammatory state (preparing for
the initiation of parturition) in the third trimester (Mor et al., 2017).

The maternal immune system is well-prepared to defend the invasion of foreign

pathogens. Innate immune cells, such as NK cells and monocytes, respond more
strongly to viral challenges, while some adaptive immune responses are down-regulated
during pregnancy, e.g. decreased numbers of T and B cells (Aghaeepour et al., 2017).
Besides, during pregnancy, the upper respiratory tract tends to be swollen by a high level of
estrogen and progesterone, and restricted lung expansion makes the pregnancy woman
susceptible to respiratory pathogens.

Although current evidence is limited, we can not ignore the potential risk of infected
pregnant women and the fetus. Recent literature indicates that in severe cases, COVID-
19 infection is associated with a cytokine-storm, which is characterized by increased
plasma concentrations of interleukins 2 (IL2), IL-7, IL-10, granulocyte-colony
stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein
1, macrophage inflammatory protein 1 alpha, and tumor necrosis factor α (TNF-α)
(Huang et al., 2020), which may be caused by ADE (Tetro, 2020). Based on the
knowledge that pregnant women in their first and third trimester are at the pro-
inflammatory state, the cytokine-storm induced by SARSCoV-2 may induce more
severe inflammatory state in these women. Moreover, the occurrence of maternal
inflammation as a result of viral infection during pregnancy can affect several aspects of
fetal brain development and may lead to a wide range of neuronal dysfunctions and
behavioral phenotypes that are recognized later in postnatal life (Mor et al., 2017).

One news-network reported that a pregnant woman with COVID-19 at 28 gestational weeks
had been cured and discharged from a hospital in Wuhan of China (Gong, 2020). Timely
intervention with individualized approach should be given to these women according to the
severity of the disease and advancement of pregnancy (the trimester of the pregnancy). In
particular, more attention should be paid to pregnant women with COVID-19 in the first and
second trimester. Although there is no reliable evidence to support the possibility of vertical
transmission of COVID-19 from the mothers to the baby, existing research suggests that even
though the virus does not reach the fetus, the maternal infection and inflammation that
occurred in response to the viral infection could affect the developing fetus (Mor et al., 2017).
Early detection and intervention of COVID-19 may reduce potential obstetrical complications
such as pregnancy loss, intrauterine growth restriction, and preterm delivery, and may be
beneficial for improving pregnancy outcomes. Anti-viral therapy for COVID-19, such as
lopinavir and ritonavir, should be determined by weighing the risks and benefits. Treatment
can be initiated when the potential benefits outweigh the potential risks to the fetus. Even
after the viral infection is controlled, the intrauterine development of the fetus should be
closely monitored since the early gestation data is lacking, and placental inflammation may
persist for a prolonged time. Pregnant women with COVID-19 should be carefully
monitored throughout pregnancy and the postpartum period since they had anti-viral
drug therapy and radiation exposure from CT examinations.

Conclusion
Since SARS-CoV-2 is a novel virus, herd immunity is not present, which makes all
populations susceptible. Pregnant women are more susceptible to respiratory
pathogens; hence, they may be more susceptible to COVID-19 infection than the general
population. Moreover, due to the characteristic immune responses during pregnancy
and potential risks from the cytokine-storm by COVID-19 infection, pregnant women
with COVID-19 may face severe morbidity and even mortality. Although existing
evidence does not support the intrauterine vertical transmission, the maternal infection
and inflammation occurred in response to COVID-19 could affect the developing fetus
and even postnatal life. With the continuing pandemic of COVID-19, more efforts
should be made to protect both mothers and fetuses. Further studies are warranted to
investigate the pregnant women with COVID-19 in the first and second trimester and
follow-up the pregnancy outcomes and postnatal development of the fetus.
https://sci-hub.se/10.1016/j.jri.2020.103122

Immunological stages of pregnancy

Inflammation has been mostly associated with negative pregnancy outcomes. Its
occurrence has been thought to cause abortion, preterm birth and even pre-
eclampsia20. As such, a healthy pregnancy has been defined as an anti-inflammatory or
TH2-type condition, and it was thought that a sudden shift towards a pro-inflammatory
TH1-type immune response could lead to pregnancy complications, such as recurrent
abortion and preterm birth20,21. Current studies, however, argue against this concept and
have shown that a TH1-type tissue environment is found in healthy pregnancies22–24. These
conflicting findings may be explained by the consideration of pregnancy as a single
homogeneous event instead of as a developmental process with different immunological
stages. It should be acknowledged that implantation and placentation, fetal growth, and
parturition are distinct processes, that each of these stages requires a unique immune
environment and, more importantly, that each stage is confronted with different
immunological challenges. Therefore, a successful pregnancy depends on the ability of
the maternal immune system to change and adapt to each specific developmental
stage25. We describe below three distinct immunological states that correspond to the
stages of fetal development: first, a pro-inflammatory stage that is associated with
implantation and placentation; second, an anti-inflammatory stage that is associated
with fetal growth; and third, a second pro-inflammatory stage that is responsible for the
initiation of parturition25,26 (FIG. 4).

Implantation and placentation: a pro-inflammatory stage.

The initial attachment of the blastocyst to the epithelial lining of the uterus during
implantation and the subsequent placentation that occurs involve the active breakdown and
restructuring of the decidua by the invasive trophectoderm. The stage of implantation and
early placentation thus resembles the process of tissue injury and subsequent repair. At the
implantation site, inflammation is characterized by the presence of interleukin-6 (IL-6), IL-8,
IL-15, granulocyte– macrophage colony-stimulating factor (GM-CSF), CXCchemokine
ligand 1 (CXCL1; also known as GROα), CC-chemokine ligand 4 (CCL4; also known as
MIP1β), osteopontin and tumour necrosis factor (TNF), which are derived from both
endometrial stromal cells and infiltrating immune cells27. The inflammatory environment
during this stage is crucial for the following processes: the transfer of stored adhesion
molecules to the cell surface of epithelial cells at the uterus lumen and the expression of new
adhesion molecules; the removal of the pre-existing layer of mucins present at the luminal
surface epithelium of the uterus, as these mucins prevent blastocyst adhesion; the increased
affinity of adhesion molecules on the uterine epithelium, such as L-selectin, following initial
contact with the blastocyst; and the reorganization of adhesion molecules on the apical
surface of the epithelium of the lumen to ensure blastocyst attachment (FIG. 5). These events
are required for endometrial receptivity and for successful implantation and placentation, and
studies demonstrate that they occur secondary to the inflammatory environment created by
immune infiltrates28,29. The requirement for such a pro-inflammatory environment is
supported by studies showing that performing endometrial biopsies, a process that causes
local injury and inflammation, increases uterine receptivity28. In addition, it has been shown
that the presence of CD11c+ DCs is crucial for implantation and early placentation, as the
depletion of these cells in mouse models leads to failed implantation30. Uterine DCs seem to
govern uterine receptivity by regulating tissue remodelling and angiogenesis30. Furthermore,
as uterine DCs do not migrate to the lymph nodes, they can have an early role in the process
of promoting tolerance to paternal antigens31. Taken together, these findings highlight the
importance of local inflammation in the receptivity of the maternal decidua, and in
determining the success of implantation and early placentation.

An anti-inflammatory stage of fetal growth.

Following successful implantation and placentation, there is a stage of rapid fetal growth and
development. At this stage, the mother, placenta and fetus are symbiotic, and the predominant
milieu is that of a TH2-type or an antiinflammatory environment (FIG. 4). This is the longest
period of the pregnancy (lasting from week 13 to week 27), and many studies examining the
immunology of pregnancy have used blood samples obtained during this period; this has led
to the generalization that pregnancy is characterized by a TH2-type tissue environment32.
Indeed, any ongoing pro-inflammatory signals at this stage can lead to miscarriage, and any
ensuing pro-inflammatory insult — such as infection — can lead to preterm birth20,33.
Several immune cell types — including macrophages, decidual NK cells and Treg cells —
contribute to the establishment of an anti-inflammatory microenvironment at this stage of the
pregnancy34. Decidual macrophages have an M2-like phenotype that is associated with tissue
renewal, and they predominantly secrete antiinflammatory cytokines35; these cells are
important for tissue renewal during trophoblast invasion and placental growth. Due to their
high phagocytic capacity, decidual macrophages efficiently remove dying trophoblast cells,
thus preventing the release of paternal antigens that could trigger a maternal immune
response against the fetus36. Decidual NK cells differ from peripheral blood NK cells in
terms of both their phenotype and their function37. Decidual NK cells are identified by their
unique phenotype; they are CD56bright and CD16-negative, show low cytotoxicity, and have
been shown to interact with CD14+ decidual macrophages and induce the generation of Treg
cells38. The roles and characteristics of decidual NK cells have been extensively discussed
elsewhere8,39. Treg cells are key players in the tissue repair process owing to their anti-
inflammatory and anti-apoptotic capacities. During pregnancy, Treg cells have a central role
in maintaining an anti-inflammatory environment by preventing effector-type immune
responses against paternal antigens40. A systemic expansion of Treg cells specific for
paternally derived antigens is observed in early pregnancy, indicating that their function is to
protect fetal cells that express paternal antigens from rejection by the maternal immune
system41. Treg cells are also present in the decidua of healthy pregnant women, and they
persist after delivery and rapidly accumulate during subsequent pregnancies, which indicates
a memory-type regulatory response41. Infertility has been proposed to be associated with
reduced expression of the transcript encoding the Treg cell-associated transcription factor
forkhead box protein P3 (FOXP3) in endometrial tissue42,43.

Similarly, spontaneous abortion has been shown to correlate with lower numbers of systemic
Treg cells than are found in healthy pregnancies44,45. A population TH17 cells is also
present in the uterus, and this population expands during pregnancy, although not to the same
extent as do CD4+ CD25+ Treg cell populations. As they are generally pro-inflammatory in
nature, these TH17 cells may help to protect the maternal–fetal interface from microbial
infections, whereas the Treg cells may serve to regulate TH17 cell function. In support of this
idea, altered numbers of TH17 cells and an altered ratio of TH17 cells to Treg cells in the
uterus or maternal circulation are associated with pregnancy complications, such a
spontaneous abortion, pre-eclampsia and preterm birth32.

A pro-inflammatory switch is necessary for labour.

Once the fetus has completed its development, a switch to a pro-inflammatory environment
has been shown to be indispensable for labour (FIG. 4). The pro-inflammatory nuclear factor-
κB (NF-κB) signalling pathway has been shown to initiate labour, and it is crucial for the
continued progress of labour and delivery46,47. The nuclear translocation of the p50 and p65
subunits of NF-κB has been shown to occur during the initiation of labour, and intra-amniotic
injection of the NF-κB inhibitor peptide SN50 has been shown to delay the onset of labour in
pregnant mice46. The influx of immune cells into the myometrium is crucial in order to
promote the contraction of the uterus, delivery of the baby and separation of the placenta. The
activation of the NF-κB signalling pathway should therefore be temporally controlled, and its
induction has been shown to occur as a result of Toll-like receptor 4 (TLR4) activation by
ligands such as surfactant protein A (a protein secreted by the fetal lung)48 and endogenous
damage-associated molecular patterns (DAMPs), such as high mobility group box 1
(HMGB1)49–51, which are present in high levels towards the end of the pregnancy52. Thus,
pregnancy is a process that engages at least three phases that each have unique inflammatory
profiles and that correspond to the stages of gestation. As discussed below, the normal milieu
is created in part by the normal microbiota and can be disrupted by external stimuli such as
infections. The success of pregnancy thus highly depends on the ability of the immune
system to maintain the status quo of each particular stage. The process of immune regulation
during pregnancy is complex and involves epigenetic modifications53, microRNAs54,
autophagy and histocompatibility antigens55; unfortunately, due to space limitations, we do
not discuss these aspects here.
https://sci-hub.se/10.1038/nri.2017.64

Wanita hamil menjadi kelompok yang rentan terhadap patogen penyebab penyakit
pernafasan dan pneumonia. Hal ini dapat terjadi karena saat hamil, wanita hamil
berada pada keadaan imunosupresif dan mengalami perubahan fisiologis kehamilan,
seperti peningkatan diafragma, peningkatan konsumsi oksigen, dan edema mukosa
saluran pernafasan yang dapat membuat rentan terhadap hipoksia. Selain itu, imunitas
ibu hamil yang menurun dapat menyebabkan peningkatan kerentanan terhadap infeksi
penyakit.

Proses persalinan secara normal ataupun caesar tidak menjadi suatu akibat dari infeksi
COVID19 pada ibu. Persalinan prematur yang terjadi pada ibu terinfeksi COVID-19
dapat disebabkan oleh stres atau tekanan psikis selama kehamilan akibat sang ibu
terinfeksi COVID-19 (Khan et al., 2020). Persalinan caesar juga tidak dapat dihubungkan
akibat ibu terinfeksi COVID-19. Terdapat beberapa indikasi kehamilan yang menyebabkan
harus menjalani proses persalinan secara caesar, seperti preeklampsia berat, memiliki riwayat
operasi caesar, dan kasus gawat janin. Selain itu, persalinan prematur juga dapat disebabkan
oleh komplikasi kehamilan seperti terjadinya pre-eklamsi atau sebabsebab lainnya (Chen et
al., 2020).

Penelitian yang dilakukan oleh London, dkk menyebutkan bahwa dari sembilan kasus
persalinan prematur, delapan diantaranya mengalami iatrogenik (tujuh kasus gangguan
pernafasan dan satu kasus akibat penurunan gerakan janin) (London et al., 2020). Penelitian
Yan, dkk. melaporkan terdapat satu kasus bayi asfiksia dan satu kasus kematian neonatal.
Pada kasus kematian neonatal, sebelumnya ibu dari bayi tersebut mengalami kasus
pneuomonia berat dan syok septik sehingga memerlukan perawatan di ICU (Yan et al., 2020).
Kasus asfiksia pada bayi baru lahir dapat dispekulasi akibat infeksi COVID-19 pada ibi yang
menyebabkan peningkatan hipoksemia sehingga berdampak pada asfiksia (Huang et al.,
2020).

Meskipun beberapa penelitian melaporkan kasus ibu hamil terinfeksi COVID-19 pada
trimester akhir kehamilan, hingga saat ini masih belum ada bukti bahwa COVID-19
dapat menjadi penyebab timbulnya dampak yang parah akibat transmisi vertikal
intrauterin . Penelitian yang telah dilakukan oleh Chen, dkk mengambil sampel dari cairan
ketuban penderita COVID-19 pada saat persalinan. Selain itu sampel berupa darah tali
pusat, swab tenggorokan neonatal dan ASI juga dikumpulkan untuk dilakukan
pemeriksaan. Sampel diperiksa di laboratorium milik School of Basic Medical Sciences
di Universitas Wuhan. Hasilnya seluruh sampel dinyatakan negatif COVID-19 (Chen et
al., 2020). Penelitian yang dilakukan Yan, dkk, mengambil sampel dari sekresi vagina
dan hasil yang ditunjukkan juga negatif COVID-19 (Yan et al., 2020).

Kelompok ibu hamil menjadi kelompok yang rentan terhadap infeksi Covid-19. Hal ini
disebabkan oleh karena dalam keadaan hamil hamil, tubuh berada pada keadaan
imunosupresif dan mengalami perubahan fisiologis kehamilan, seperti peningkatan
diafragma, peningkatan konsumsi oksigen, dan edema mukosa saluran pernafasan yang dapat
membuat rentan terhadap hipoksia. Gejala dan tanda yang timbul akibat infeksi COVID-19
dapat berbeda pada masing-masing individu. Gejala yang timbul pada ibu hamil tidak
memiliki perbedaan yang signifikan dibandingkan dengan gejala yang terjadi pada
populasi umum dengan infeksi COVID-19.
Sampai saat ini sejumlah studi telah dilakukan untuk mengetahui adanya transmisi vertikal
COVID-19 dari ibu ke janin. Sejumlah sampel seperti darah tali pusat, cairan ketuban, swab
tenggorokan neonatal, ASI, dan sekresi vagina telah diambil untuk dilakukan pemeriksaan
dan menunjukkan hasil negatif. Kasus komplikasi dan kematian yang terjadi tidak memiliki
hubungan dengan infeksi COVID-19. Diharapkan adanya studi lebih lanjut mengenai
transmisi vertikal. Pada ibu hamil dengan kasus COVID-19 diharapkan untuk menjalani
perawatan secara intensif untuk meminimalisasi dampak yang mungkin timbul akibat
infeksi COVID-19.
file:///Users/puticallistha/Downloads/2253-9518-1-PB%20(1).pdf

Maternal COVID-19 infection is associated with an approximately doubled risk of

stillbirth and may be associated with an increased incidence of small-for-gestationalage
babies. The preterm birth rate in women with symptomatic COVID-19 appears to be two to
three times higher than the background rate; these are primarily iatrogenic preterm births.

Vaccination in pregnancy against COVID-19 is strongly recommended and should be

offered at the same time as the rest of the population based on age and clinical risk

COVID-19 vaccines can be given at any time in pregnancy, or postpartum (including

after an uncomplicated instrumental birth or caesarean section), and preference is to
offer the Pfizer-BioNTech or Moderna vaccines

In women with symptomatic COVID-19, there may be an increased risk of fetal

compromise in active labour and caesarean birth. Women with symptomatic suspected
or confirmed COVID-19 should be advised to labour and give birth in an obstetric unit
with continuous electronic fetal monitoring. This is not required for asymptomatic
infection.

Senior obstetric and medical input for a woman with severe or critical COVID-19
should be sought, particularly for decision making about birth.

The level of personal protective equipment (PPE) required by healthcare professionals

caring for a woman with COVID-19 who is undergoing a caesarean birth should be
determined by the risk of her requiring intubation for a general anaesthetic.

Water birth is not contraindicated for women who are asymptomatic of COVID-19,
providing adequate PPE can be worn by those providing care. Women with
symptomatic COVID-19 should not labour or birth in water.
https://www.rcog.org.uk/globalassets/documents/guidelines/2022-01-11-coronavirus-covid-
19-infection-in-pregnancy-v14.3.pdf

Creating a ‘COVID-protected’ elective pathway

A true planned/elective pathway includes a 14-day period of household isolation prior to

the admission. It is recognised that this cannot commonly be achieved prior to hospital
admissions for maternity care: essential care, including the 38 week visit for
primiparous women, precludes this being possible.

For this reason, the majority of women admitted for maternity care will need to be cared for
according to the recommendations for individuals admitted through urgent/emergency
pathways.

However, units may still be able to create a ‘COVID-protected’ pathway, that is a pathway
for women admitted for an elective procedure or birth who have had a negative test for
COVID-19 in the 72 hours prior to admission, and, due to having isolated for a period
beforehand, are unlikely to develop COVID-19 during admission. This may be
particularly suitable for women undergoing elective caesarean birth whose intended
birth partner is within her household.

The following conditions should be met before creating such a pathway:

- The availability of the test result should provide improved safety for the woman
and/or the hospital setting, for example by enabling safer cohorting or by
enabling an operation to take place in a ‘COVIDfree’ theatre setting.
- It should be possible for women identified as ‘COVID-protected’ to be cohorted
during their entire hospital stay together (i.e. in ‘COVID-protected’ bays and/or
siderooms).
- If women are to be admitted for birth, it should be possible for testing of birth
partners to occur in line with testing for the woman.
For the pathway to be offered:
- Women and their intended birth partner should be able to isolate, together with
their household(s), for a period of 14 days prior to admission to hospital.
Women and their partners can be presumed to be ‘COVID-protected’ and cohorted together
if:
- both they and their birth partner have met the period of household isolation
prior to admission,
- both they and their birth partner have remained asymptomatic during the
period and received a negative SARS-CoV-2 test result within the 72 hours prior
to admission can be presumed ‘COVIDprotected’ and can be cohorted together.

Women should not experience any change to their care beyond practical alterations (such as
cohorting by possible infection status or scheduling at the end of a caesarean birth list where
appropriate) if they are unable to isolate together with their household prior to admission.

Care in labour
Women who are confirmed COVID-19-positive or in whom COVID-19 infection is
considered possible (e.g. symptomatic of COVID-19, or recent household exposure)
should be treated as potentially or confirmed positive COVID-19 with regard to labour
care. Further advice on the care of women with COVID-19 is available in the
RCOG/RCM guidance on COVID-19 in pregnancy. 2

Women who are risk assessed as unlikely to be currently infected with SARS-CoV-2 who do
not yet have a test result should be treated as though they do not have COVID-19 when in
labour. Their care should follow a similar plan to that prior to the pandemic.

For all women, appropriate PPE should continue to be worn by staff. Local guidance may be
used to supplement national guidance to decide what PPE should be used for women without
a test result who are unlikely to be currently infected with SARS-CoV-2 (if they should be
treated as a ‘possible case’). This will take into account many factors, including current local
population prevalence.

https://www.rcog.org.uk/globalassets/documents/guidelines/2020-05-29-principles-for-the-
testing-and-triage-of-women-seeking-maternity-care-in-hospital-settings-during-the-covid-
19-pandemic.pdf
PEMERIKSAAN
Generally, COVID‐19 patients tend to have normal or decreased white blood cell counts,
lymphopenia, or thrombocytopenia [67,68]. Zhang et al. showed that patients with high
leukocyte count (>10 × 10^9/L), higher neutrophil count (>7 × 10^9/L), and lower
lymphocyte count (150 mg/L) and increased D‐dimer levels (>1 mg/L) are also strongly
associated with an increased risk of COVID‐19 pneumonia and the composite endpoint.
Additional laboratory indicators of increased risk are higher alanine aminotransferase (ALT)
activity (>80 U/L), higher aspartate aminotransferase (AST) activity (>80 U/L), higher  α—
hydroxybutyrate dehydrogenase activity (>540 U/L), higher lactate dehydrogenase activity
(>720 U/L), higher creatine kinase activity (>600 U/L), and lower total protein level (So far,
researchers have not observed a significant statistical association between altered platelet
counts and creatinine levels with an increased risk of COVID‐19‐related pneumonia. As
opposed to numerous studies, Zhang et al. showed that COVID‐19 pneumonia and composite
endpoint are associated with leukocytosis rather than leukopenia [69]. However, the
abovementioned results differ among COVID‐19 patients. Du et al. observed that the
majority of COVID‐19 patients (81.2%) had lowered eosinophil count and
many patients had decreased hemoglobin and hematocrit, as well as decreased activated
partial prothrombin time (APTT) and increased prothrombin time (PT) [53]. Among studied
patients, 22.4% had increased procalcitonin levels and elevated levels of blood urea nitrogen
or serum creatinine. It is still speculated whether eosinophilopenia might constitute a
prognostic factor for COVID‐19 patients. Some patients present progressive lymphopenia
with a concurrent progressive neutrophilia [70]. However, among the most common reported
laboratory findings, those of the highest prevalence include elevated levels of C‐reactive
protein and erythrocyte number, as well as increased myohemoglobin, liver enzymes, and
muscle enzymes [25]. Additionally, patients with a severe course of COVID‐19 usually have
elevated D‐dimer levels, increased procalcitonin, increased leukocyte number, and
lymphocytopenia [29,71]. In some cases, lymphocytes and white blood cell levels might
remain within physiological ranges. The decrease in the number of lymphocytes is generally
observed in the CD4+ subpopulation. No significant changes are stated in the case of CD8+
and B cell subpopulations [72]. Further, interleukin 10 (IL‐10), interleukin 6 (IL‐6),
interleukin 1 (IL‐1), interleukin 2R (IL‐2R), and tumor necrosis factor alpha (TNF‐α) levels
might exceed the upper limit in COVID‐19 patients [73–76]. Chemokines, such as interferon
gamma‐induced protein 10 (IP‐10) and monocyte chemoattractant protein 1 (MCP1), are also
overexpressed during the course of COVID‐19 [74]
(Baj, Jacek, et al., 2020).
file:///Users/puticallistha/Downloads/jcm-09-01753.pdf
Ada beberapa pemeriksaan yang dilakukan untuk mendeteksi COVID-19. Penelitian
Bernheim et al.,(2020) dan Caruso et al.,(2020) melakukan pemeriksaan CT-Thoraks pada
pasien COVID-19 hasilnya paru–paru pasien mengalami gangguan berupa konsolidasi,
penyakit bilateral dan perifer, adanya kekeruhan dan seluruh paru mengalami
gangguan. Penelitian lainnya mengatakan RealTime Polymerase Chain Reaction (RT-
PCR) dapat mendeteksi pasien COVID-19 setelah dilakukan tes pertama kali sebanyak
70.58% (Fang et al., 2020). Penelitian He et al., (2020) membandingkan CTThoraks dan
PCR hasilnya bahwa keduanya memiliki sensitivitas yang baik dalam mendeteksi COVID-
19. Oleh karena itu, tujuan dari studi literature ini untuk mengetahui pemeriksaan diagnostik
yang digunakan untuk mendeteksi COVID-19.
https://core.ac.uk/download/pdf/327263764.pdf

Pemeriksaan sensitivitas Real-Time Polymerase Chain Reaction (RT-PCR) dan CT-

Chest
Penelitian (He et al., 2020) di China menemukan dari 34 pasien saat pemeriksaan awal RT-
PCR sebanyak 27 orang COVID-19 dan hasil CT-chest COVID-19 26 pasien. Sehingga
sensitivitas PCR (79%) dan CT-Chest (77%), Spesifitas PCR (100%) dan CT-Chest (96%),
dan akurasi PCR (92%) dan CT-Chest (88%). Penelitian lainnya (Fang et al., 2020) di China
mendapatkan perbedaan hasil positif COVID-19 pada awal pemeriksaan dimana CTChest 50
orang dan RT-PCR 36 orang. Penggunaan CT-Chest lebih sensitive dibandingkan RT-PCR.
Penelitian (Long et al., 2020) di China menemukan dari 36 kasus COVID-19 dengan
pneumonia CTChest menemukan 35 pasien memiliki CT abnormal sedangkan hasil RT-PCR
mendapatkan 30 pasien positif. Sensitivitas pemeriksaan CT-Chest (97,2%) dan RT-PCR
(84,6%). Pemeriksaan CT-Chest sensitive dalam mendeteksi virus sedangkan RT-PCR
menghasilkan negatif palsu. Penelitian (Ai et al., 2020) di China dari 1014 pasien meliputi
601 orang positif RT-PCR dan 580 dari 601 CT-Chest positif, 413 negatif RT-PCR dan 308
dari 413 positif CTChest. CT-Chest memiliki sensitivitas tinggi untuk diagnosis COVID-19.
Penelitian lainnya (Liu et al., 2020) di China menemukan hasil specimen pernapasan di uji
menggunakan RT-PCR dari 4880 sebanyak 1875 (38,42%) positif dengan uji RT-PCR
dengan spesimen pernapasan. Virus NAT (Nucleat Acid test) adalah diagnosis laboratorium
yang cepat, mudah dilakukan, dan banyak digunakan untuk deteksi infeksi SARS-CoV-2.

Pemeriksaan CT-Chest
Penelitian (K. Wang et al., 2020) di China terkait CT-Chest mengungkapkan bayangan paru
abnormal pada 110 pasien COVID-19. Spiral CT adalah metode pemeriksaan sensitif, yang
dapat diterapkan untuk membuat diagnosis dini dan untuk evaluasi perkembangan, dengan
sensitivitas dan akurasi diagnostik yang lebih baik daripada deteksi asam nukleat. Penelitian
lainnya (Ding, Xu, Zhou, & Long, 2020) di China menemukan dari sampel sebanyak 112
pasien diperiksa CT-Chest sesuai dengan waktu setelah timbulnya gejala awal didapatkan
frekuensi crazy-paving pattern, konsolidasi dan opasitas linear memuncak pada tahap-3
(62,7%), tahap-4 (75,0%) dan tahap-5 (83,1%), dan menurun setelahnya. CT dapat
memberikan analisis semi-kuantitatif keparahan kerusakan paru-paru. Penyakit ini berubah
dengan cepat pada tahap awal, kemudian cenderung stabil dan bertahan lama. Penelitian
(Zhao, Zhong, Xie, Yu, & Liu, 2020) di China dari 101 kasus pneumonia COVID-19
sebagian besar pasien memiliki fitur pencitraan yang khas, seperti ground-glass
opacities(GGO) 87 pasien (86,1%) atau GGO campuran dan konsolidasi 65 pasien (64,4%),
pembesaran vaskular pada lesi 72 pasien (71,3 %), dan traksi bronkiektasis 53 pasien
(52,5%). Lesi yang ada pada gambar CT lebih cenderung memiliki distribusi perifer 88
pasien (87,1%) dan keterlibatan bilateral 83 pasien (82,2%) dan menjadi dominan paru-paru
yang lebih rendah 55 pasien (54,5%) dan multifokal 55 pasien (54,5%). CT involvement
score dapat membantu dalam evaluasi tingkat keparahan dan luasnya penyakit. Penelitian
(Dai et al., 2020) menemukan bahwa CT-Chest menunjukkan abnormal attenuation pada
beberapa lobus paru bilateral, didistribusikan di bagian bawah dan/atau pinggiran paru-paru
(94,98%), dengan berbagai bentuk Penampilan klinis pasien dengan COVID-19, sebagian
besar dengan riwayat epidemiologi dan gejala tipikal, sangat berharga dalam diagnosis
COVID-19. Sementara HRCT dada memberikan distribusi, bentuk, atenuasi dan luasnya lesi
paru-paru, serta beberapa tanda CT khas pneumonia COVID-19. Penelitian lainnya (Farid,
Selim, & Khater, 2020) di Arab menggunakan dataset CT-Images benchmark pada kombinasi
yang diusulkan dari empat filter gambar dengan composed hybrid feature selection(CHFS)
untuk mendiagnosis COVID-19. Model yang diusulkan menunjukkan lebih baik daripada
pendekatan klasifikasi tradisional untuk pemilihan fitur optimal dan peningkatan proses
klasifikasi dan secara efektif mengurangi tingkat falsenegative dengan akurasi tinggi.

Pemeriksaan Rapid Test (IgG dan IgM)

Penelitian (Jia, Zhang, Tian, & Wang, 2020) di China tentang hasil uji asam nukleat dari 57
pasien suspek COVID-19 pada pemeriksaan pertama kali sebesar 42,10% (24 pasien positif
dan 33 pasien negative). Presentasi hasil pemeriksaan kombinasi IgM dan IgG untuk pasien
dengan tes asam nukleat negatif COVID-19 (33 pasien) adalah sebesar 72,73% dan 87,50%
dinyatakan positif COVID-19. Hasil pemeriksaan darah didapatkan peningkatan yang
signifikan nilai CRP dan AST pada pasien positif COVID-19. Berdasarkan hasil penelitian
tersebut peneliti merekomendasikan untuk menggabungkan pemeriksaan asam nukleat, IgM,
IgG, CT scan dan hasil karakteristik klinis untuk menegakkan diagnosis pasien. Penelitian
(Dohlan et al., 2020) di Jerman mengevaluasi tes cepat berbasis IgG/IgM dengan waktu
pemeriksaan 20 menit. Sampel dalam penelitian ini sebanyak 39 orang yang dipilih secara
acak, dan dilakukan pemeriksaan tes cepat (rapid test) dan juga qPCR secara bersamaan.
Hasil penelitian menunjukkan dari 39 orang, 22 orang dinyatakan positif melalui test qPCR
dan hanya 8 orang terdeteksi positif melalui rapid test. Penelitian (Gozes et al., 2020)
mengevaluasi efektivitas pemeriksaan yang tersedia secara komersial yakni rapid test (15
menit) spesifik IgG dan IgM. Sampel dalam penelitian ini sebanyak 153 orang yang terdiri
dari 29 orang positif COVID-19 (berdasarkan pemeriksaan PCR) dan 124 orang yang sehat.
Penelitian ini menunjukkan hasil klasifikasi untuk kasus COVID-19 vs Non COVID-19 per
studi CT toraks 0,996 AUC (95% CI: 0,989-1,00) pada pasien yang terinfeksi. Hasil
pemeriksaan CT thorak memiliki sensitivitas 98,2%, spesifisitas 92,2%. Hasil penelitian
(Wang, 2020) didapatkan sensitivitas pemeriksaan kombinasi uji IgG dan IgM (88,66%) dan
spesifisitas (90,63%). Dari 397 pasien positif (terkonfirmasi dari pemeriksaan PCR)
didapatkan 352 positif dari hasil test IgG/IgM, sedangkan 128 pasien negatif didapatkan 12
positif dengan test IgG/ IgM. Uji kombinasi IgG dan IgM memiliki utilitas dan sensitivitas
yang lebih baik dibanding dengan uji IgG atau IgM secara tunggal.
https://core.ac.uk/download/pdf/327263764.pdf

a.Metode Molekuler
Next generation sequencing(NGS) juga disebut sebagaiHigh throughput sequencing(HTS).
Metode ini dipakai untuk menentukan urutan genomik, digunakan lebih dari 1 juta pasang basa dalam
satu kali pemeriksaan. Teknik ini, mampu mendiagnosis penyakit herediter, kanker, dan penyakit
infeksi serta untuk melacak wabah Methicillin ResistantStaphylococcus aureus(MRSA) di rumah
sakit.13,14Metode ini memiliki akurasi yang tinggi dan pelacakan yang baik untuk menelusurisumber
penularan. Namun, penggunaan metode tersebutmembutuhkan keahlian khusus dan biaya yang cukup
mahal.14Saat ini, quantitativeRT-PCR (qRT-PCR) merupakan pemeriksaan yang umum
digunakan untuk diagnosis COVID-19 dan merupakan baku emas untuk diagnostik molekuler
dari berbagai jenis virus atau bakteri patogen yang fastidious.15Kuantitatif RT-PCR memiliki
beberapa kelebihan yaitu lebih spesifik, konsisten, dapat digunakan dengan mudah, hanya
memerlukan primer-probetertentu yang dirancang dan disintesis sesuai gen target. 15,16Setelah hasil
primer virus SARSCoV-2 dari China dipublikasikan, alat tes diagnostik selain rRT-PCRdirancang
dan dikembangkan para peneliti lainnya.9Berbagai lembaga atau produsen telah memilih paduan
gen target yang berbeda dari banyak gen SARS-CoV-2 (gen ORF-1a, gen ORF-1b, gen RdRp, gen N,
gen E dan lainnya), sehingga setiap alat tes memiliki variasi tingkat sensitivitas. Selain masalah
sensitivitas yang bervariasi, qRT-PCR memiliki beberapa kelemahan seperti bahaya biosafetydan
biosecurity yang mungkin terjadi selama pemrosesan sampel, transportasi, proses ekstraksi
asam nukleat, dan kebutuhan peralatan laboratorium yang mumpuni untuk melakukan pemeriksaan
qRT-PCR seperti kabinet biosafety, ruangan yang memiliki tekanan negatif dan peralatan
pendukung lainnya. Peralatan dan standar ruangan harus dipenuhi, agar keamanan dan
keselamatan petugas terjaga demikian juga kualitas mutu hasil pemeriksaan. 16,17Semua
kelemahan tersebutharus dapat diatasi pada keadaan darurat kesehatan atau situasi wabah
global seperti saat ini. Selain itu, alat PCR dapat digunakan untuk mendeteksi tidak hanya target
virus, tetapi juga dapat melakukan deteksi beberapa virus pernapasan secara bersamaan yang
menyebabkan peningkatan adanya risiko positif palsu atau negatif palsu. 18Loop-mediated isothermal
amplification(LAMP) merupakan salah satu teknik molekuler yang relatif baru untuk diagnosis
COVID-19. Metode ini juga menggunakan teknik amplifikasi molekuler yang dapat mendeteksi materi
genomik dengantingkat efisiensi tinggi dan waktu yang lebih singkat.Perbedaan LAMP dengan RT-
PCR terletak pada suhu reaksi dan jumlah primernya. Pada LAMPsintesis DNA target dilakukan pada
suhu konstan 60–65oC menggunakan enzim DNA polimerase dan empat primer yang dirancang
khusus untuk mengenal sekuens DNA target.Penggunaan suhu konstan ini memperpendek
durasi proses amplifikasi,sehingga durasi hasil tes dapat keluar lebih cepat dibandingkan metode PCR.
Metode ini sangat spesifik dan memiliki sensitivitas yang tinggi, cepat dan lebih ekonomis.

b.Metode Deteksi Berbasis Reaksi Antigen-Antibodi/Imunoserologi

Metode pengujian berbasis serologis biasanya mendeteksi virus sebagai antigen atau mendeteksi
antibodinya dari sampel darah.Sampel darah mengandung konsentrasi antibodi atau antigen
spesifik virus yang signifikan dan terukur. Dua jenis antibodi utama dalam darah yang dimaksud
adalah imunoglobin G (IgG) dan imunoglobulin M (IgM). IgM muncul dalam beberapa hari dan
bertindak sebagai sistim imunaktif yang pertamakali timbul,laludiikuti oleh produksi IgG yang bekerja
mengeliminasi infeksi. Tes darah untuk COVID-19 bertujuan mendeteksi protein (antigen/biomarker
khas) atau antibodi khusus terhadap virus SARS-CoV-2 yang bersifat spesifik. 21Rapid
Antigen SARS-COV2merupakan metode pemeriksaan imunoserologi dengan format tes alur
lateral yang mudah digunakan dan umum dipakai untuk tes HIV, malaria, dan influenza. Antigen-
Rapid Detection Test(Ag-RDT) biasanya terdiri dari kaset plastik dengan rongga sampel dan penyangga
serta strip matriks nitroselulosa disertai penanda berupa garis uji. Target antigen akan terikat menjadi
kompleks antigen-antibodi terkonjugasi. Target dari Ag-RDT biasanya berupa protein nukleokapsid virus
yang berjumlah lebih banyak dari target antigen lainnya. Sampel yang dipakai untuk Ag—RDT
adalah sampel usapan nasal atau nasofaringeal.Para peneliti terus melakukan penelitian agar
dapat menggunakan jenis sampel alternatif seperti air liur, cairan oral, agar memudahkan pengambilan
sampel sehingga mudah mendeteksi pelacakan kasus secara efisien dan efektif tanpa mengesampingkan
kualitas mutu pemeriksaan.Salah satu kelebihan metode Rapid Antigen SARS-COV2 yaitu tes
lebih sederhana, mudahdilakukan, sertawaktu pemeriksaan yang cepat sekitar10-30 menit. Akan
tetapi rapid antigen memiliki sensitivitas yang lebih rendah daripada metode molekuler.22Hal
tersebut didukung oleh studi yang dilakukan oleh Kosacket al. (2017) dalam mengevaluasi rapid
antigen, yang menunjukkan bahwa sensitivitas uji cepatantigen lebih rendah dibandingkan dengan
metode kultur dan metode molekuler.23Hal tersebut dikarenakan uji cepatantigen memerlukan target
jumlah virus tertentu untuk dapat terdeteksi antigen proteinnyasebagai hasil positif atau artinya, uji
cepatantigen memiliki batas deteksiminimum jumlah virus. Beberapa penelitian lain juga menunjukkan
bahwa sensitivitas Ag-RDT terhadap sampel dari saluran pernapasan atas (usap nasal atau
nasofaringeal) tampakberbeda-beda jika dibandingkan NAAT, dengan rentang 0-94% tetapi
spesifisitasnya konsisten dilaporkan tinggi (>97%). Berdasarkan hasil ini, maka pemeriksaan Ag-
RDT dapat digunakan untuk telusur kontak pada kelompok kecil yang semi closedyaitu bilamana
ditemukan hasil reaktif pada beberapa orang dalam kelompok tersebut. Hasil ini juga sebaiknya
dikonfirmasi dengan pemeriksaan RT-PCR walaupun tidak merupakan prioritas. Sebaliknya bilamana
didapati hasil negatif maka harus diprioritaskan untuk dilakukanpemeriksaan konfirmasi dengan
RT-PCR.Sejumlah Point of Care Testing(POCT) berdasarkan IgM atau IgG yang didesain dengan
prinsip imunokromatografiberbasis ELISA telah dikembangkan secara komersil. Uji ini mudah dilakukan,
dan tidak memerlukan keahlian khusus untuk melaksanakannya serta dapat dengan mudah digunakan di
lingkungan rumah sakit, di laboratorium atau di sisi tempat tidur pasien. Kit deteksi berbasis
ELISA ini umumnya menggunakan antigen dari protein N dan protein S dan menunjukkan sensitivitas
yang baik untuk SARS-CoV yaitu masing-masing 94,7% dan 58,9%. 19Akan tetapi, diagnosis
berdasarkan antibodi kurang tepat biladigunakan pada saat awalinfeksi COVID-19, karena antibodi
baru terbentuk7 hari atau lebih setelah infeksivirusatau setelah timbul gejala dantidak dapat digunakan
untuk memonitor pengobatan karena antibodi IgG akan terus bertahansetelah pasien sembuh. Metode
POCT atau yang sering kita sebut uji cepat inimasih lazim digunakan karena ujiini dapat
memberikan hasil dalam waktu 10-30 menit.

c.Radiografi/CT-ScanCT
Scan juga merupakan salah satu teknik diagnosis yang sensitivitasnyatinggi karena banyak
peneliti merekomendasikan penggunaannya sebagai salah satu metode diagnostik
tambahan yang diperlukanuntuk mendiagnosisCOVID-19. Hasilnya pun sudah dapat diketahui
sebelum gejala klinis muncul. Gambaranumum CT daripasien COVID-19 menunjukkan gambaran
opakmulti-lobar bilateral dengan distribusi yang berbeda di posterior dan juga di pinggiran, sub-
pleura, septa lobular menebal dengan pengisian alveolar yang bervariasi, dan efusi. 25,26CT
dada resolusi tinggi terbukti sebagai alat penting untuk mendeteksi SARS-CoV-2, pada
tahap awal dan untuk mengambiltatalaksana intervensi yang cepat dan diperlukan.27Oleh
karena itu, berbagai penelitian baru-baru ini menggunakan gambar CT dada untuk menunjang
diagnosis COVID-19.27-29Gambar CTdadapasien yang terinfeksi COVID-19bersifat khas. 29Sesuai
temuan ini, CT scan ditemukan sebagai alat diagnostik yang bagus untuk skrining
pasien COVID-19 terutama di daerah prevalensi atau pandemi yang tinggi. Akan tetapi CT
scan hanyalah alat indikatif dan tidak dapat digunakan untuk mengonfirmasi patogenpenyebab
penyakitdalam diagnosis COVID-19. Terlebih lagi, CT scan juga memiliki beberapa kekurangan
seperti ketidakmampuan untuk memisahkan kasus pneumonia lain (virus atau non-virus)
dan histeresis pencitraan CT abnormal.9

d.GeNose
GeNose merupakan salah satu metode terbaru dalam mendeteksiinfesi COVID-19 yang
dikembangkan oleh peneliti dari salah satu universitas di Indonesia. Metode ini mendeteksi
Volatile Organic Compound(VOC) yang terbentuk karena adanya infeksi COVID-19.
VOCdikeluarkanbersama hembusan nafas ke dalam kantong khusus. Selanjutnyahembusan udara yang
tertampung dalam kantong plastik akandiidentifikasi melalui sensor-sensor dan diolah datanya dengan
bantuan kecerdasan buatan(Artificial Intelligence).Alat ini mampu mendeteksi dalam waktu kurang
dari 2 menit. Sebelum diedarkan, alat ini dilakukan uji validasi untuk memetakan pola yang jelas
dari COVID-19, dan pola dari orang-orangyang sakit non COVID-19. Sampel uji validasi menggunakan
685 sampel napas dan di antaranya terdapat 382 sampel napas berpola COVID-19. Data 382 sampel
napas berpola COVID-19 ini dijadikan sebagai data atau otak dari alat deteksi GeNose.Hasil uji validasi
dilanjutkan dengan uji klinik dan komparasi langsung dengan uji RT-PCR yang menjadi pemeriksaan baku
emas untuk COVID-19. Uji klinis ini dilakukan di delapan rumah sakitdengan total sampel
1999. Hasil uji klinis menunjukkan bahwa alat ini memiliki sensitivitas antara 89-92% dengan
spesifitas 95-96%.30

e.Metode Lain Dalam Pengembangan

Saat ini beberapa pendekatan diagnosis berbasis biosensor canggih telah banyak digunakan.
Metode ini dapat mengatasi kelemahan deteksi PCR yang panjang. Salah satu biosensor yang paling
banyak digunakan yaitu nano-biosensor. Nano-biosensor merupakan biosensor yang
menggunakan aptamer, suatu alat analitik yang ampuh untuk diagnosis penyakit yang cepat
dengan sensitivitas dan spesifisitas yang tinggi dengan cara yang efektif dan
mudahpenggunaannyadibandingkan dengan metode konvensional.31Sensor nano semacam
itu akan memiliki potensi besar untuk mendeteksi SARS-CoV2 bahkan bagi yangtanpa gejala
dengan sensitivitas, spesifisitas, dan selektivitas tinggi hanya untuk COVID-19.9

Perangkatberbasis kertas merupakan metode lain yang juga sedang dikembangkan untuk
diagnosis COVID-19. Metode ini merupakan integrasi dari berbagai fungsi yang berbeda seperti untuk
ekstraksi, elusi, pemurnian, amplifikasi dan deteksi, semua diproses dalam suatu jenis kertas, sekali
pakai dan dicetak dengan lilin di permukaannya dalam bentuk zona. Perangkat tersebut
diharapkan dapat menyelesaikan seluruh proses pengujian dengan sumber daya yang minimal,
sehingga lebih bermanfaat daripada teknik lainnya yang mahal dan rumit. Perangkat analitik ini
menggunakan metodemicrofluidiscberkualitas tinggi, cepat, dan tepat untuk deteksi, serta biaya
produksi yang rendah dan mudah digunakan.32,33Feses dan urin dari penderita COVID-19, juga
merupakan limbah yang dapat mengandung virus, dan virus ini dapat tetap aktif di lingkungan
yang sesuai selama beberapa hari.32,33Hasil penelitian menunjukkan potensi kuat dari
perangkat berbasis kertas ini untuk melacak penularan COVID-19 melalui air limbah di
masyarakat melalui analisis SARS-CoV-2 dalam feses, urin dan ekskreta manusia lainnya.9

Metode lainnya yang sedang dikembangkan untuk mendiagnosis COVID-19secara cepatialah

menggunakan CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats). 34Sistem ini
bekerja berdasarkan sistem imun yang adaptif dari bakteri terhadap genetikbenda asing seperti faga.
Prinsip yang digunakan adalah protein yang telah disiapkan khusus akan melekat pada target pilihan
melalui RNA untuk pembelahan target sekuens. Beberapa protein yang dibuat seperti protein
Cas13a yang bekerja pada RNA diharapkan akan lebih mudah untuk mendeteksi SARS-CoV-
2.35,36Metode ini masih dalam proses pengembangan untuk dapat digunakan secara luas.

Pemilihan Metode yang Tepat

Pemilihan metode yang tepat saat melakukan pemeriksaan laboratorium COVID-19 sangat perlu
diperhatikan untuk menjamin ketepatan diagnostik dan pengobatan. 23,38Hal-hal yang perlu diperhatikan
saat melakukan pemilihan metode yaitu:tujuan dari dilakukannya pemeriksaan menjadi pertimbangan
dalam melakukan pemilihan metode pemeriksaan. Pemeriksaan yang dilakukan apakah bertujuan
untuk skrining, diagnostik atau monitoring pengobatan. Jenis metode yang digunakan dapat
berbeda sesuai dengan tujuannya.23Saat ini, infeksi COVID-19 memiliki gejala yang luas dan
terkadang asimptomatik. Gambar 3mendeskripsikan secara skematis respon antibodi terhadap infeksi
SARS-COV-2. Berdasarkan gambar skematis tersebut,dapat digunakanuntuk mendeteksi adanya infeksi
SARS-CoV-2 dan perlu memperhatikan tahapan infeksi dan tujuan pemeriksaan. 19Apabila
bertujuan untuk skrining atau penapisan, metode deteksi cepat menggunakan rapid test baik yang
berbasis deteksi antibodi maupun yang berbasis deteksi antigen lebih cocok digunakan karena
hasil lebihcepatdan pengambilan sampelpun lebih mudah. Akan tetapi bila bertujuan untuk
mendeteksi atau mendiagnosis infeksi SARS-CoV-2 sebaiknya menggunakan metode molekuler
yang lebih spesifik. Untuk pemeriksaan yang bertujuan monitoring pengobatan dapat
digunakan metode berbasis reaksi antigen-antibodi seperti ELISA.

Munculnya gejala (0 hari) biasanya muncul 5 hari setelah infeksi (0 –5 hari).

Pada fase awal cenderung tidak timbul gejala, viral loadberada di bawah batas
thresholddari RT-PCR dan hasil tes kemungkinan bernilai negatifpalsu. Hal yang
sama juga terjadi pada fase akhir penyakit, ketika pasien pulih. Serokonversi
biasanya terdeteksi 5-7 hari dan 14 hari setelah muncul gejala, sehingga pada fase
pertama penyakit, tes serologi lebih sering memberikan hasil negatif palsu. Garis
titik-titik warna hitam pada grafik mengilustrasikan sensitivitas dari
chemiluminescent assaysebagai turunan dari data tes komersial (Abbot
Diagnostics, USA)Hal penting lainnya yang harus diperrhatikansaat memilih
suatu metode ialah metode tersebut sudah disetujui atau dianjurkan oleh
organisasi nasional seperti Kemenkes RI maupun organisasi internasional
seperti FDA atau WHO serta sebaiknya memenuhi standar ISO
13485.38Selanjutnya, harus dilakukan evaluasi untuk meninjau performa
pemeriksaan pada saat kondisi normal seperti melakukan proses penjaminan mutu
internal sebelum alat tes digunakan untuk pemeriksaan rutin.Beberapa
penelitian telah dilakukan untuk mengetahui akurasi sejumlah metode
pemeriksaan baik tes serologi maupun molekuler.21-22,39Semakin tinggi tingkat
akurasi suatu metode makin baik
http://ejournal.ukrida.ac.id/ojs/index.php/Meditek/article/view/2036/2129

Penelitian Tang YW et al tahun 2020 mendapatkan PCR menjadi pilihan utama karena
memiliki keunggulan dalam pemeriksaan amplifikasi dan analisisnya. 14 Penelitian
Tahamtan A et al tahun 2020 pemeriksaan ini mengungguli pemeriksaan lainnya karena
memiliki sensitivitas dan spesifisitas yang tinggi. 15 Penelitian Iglói Z et al tahun 2020
menunjukan bahwa semua kit RT-PCR yang disertakan dalam penelitian ini
menunjukan efisiensi PCR 90%, sementara sebagian besar tes menunjukkan
sensitivitas yang baik untuk setidaknya satu dari target yang dimasukkan. 27 Sejalan
dengan itu penelitian Sidiq Z et al tahun 2020 bahwa metode ini memiliki keuntungan yaitu
dapat menganalisis dan amplifikasi sampel dalam sistem yang tertutup secara bersamaan
sehingga menurunkan angka positif palsu yang dapat timbul karena kontaminasi dari
amplifikasi. 22 Penelitian Petrillo S et al tahun 2020 memaparkan bahwa pemeriksaan ini
sering digunakan karena sensitivitas yang tinggi. 25

Di sisi lain, dalam beberapa literaturliteratur yang direview menyebutkan bahwa negatif palsu
ataupun positif palsu pada pemeriksaan PCR dapat terjadi, dikarenakan oleh beberapa faktor,
sejalan dengan penelitian Tahamtan A et al tahun 2020 mendapatkan bahwa pemeriksaan
dengan metode PCR dapat menimbulkan hasil positif palsu dan negatif palsu. Banyak
kasus yang dilaporkan sebagai suspek COVID-19 dengan gejala klinis yang khas dan CT-
Scan yang spesifik tapi tidak didiagnosis sebagai COVID-19. Beberapa faktor berpengaruh
terhadap tidak konsistennya hasil real time RT-PCR, pengambilan spesimen dari tempat yang
salah dan waktu yang tidak tepat juga berpengaruh terhadap hasil negatif palsu pada
pemeriksaan ini. Begitu juga dengan cara pengambilan sampel dan transportasi sampai ke
laboratorium juga cara pengerjaan spesimen dalam laboratorium yang memiliki teknik dan
cara tertentu dapat menentukan hasil akhir dari tes. Menjalankan standar laboratorium sesuai
protokol dan keselamatan, pengambilan spesimen bukan hanya di satu bagian tubuh namun
lebih dari satu, tidak hanya pada saluran napas atas tapi juga saluran napas bawah. Sedangkan
untuk menghindari terjadinya positif palsu, yang sering berhubungan dengan kontaminasi
sampel spesimen maka laboratorium tetap menjalankan standar protokol tes sesuai dengan
alur pemeriksaan yang ada. Proses pemeriksaan spesimen yang sesuai prosedur, standard
laboratorium yang baik, kualitas kit real time RT-PCR dapat mempengaruhi dan
menurunkan ketidakakuratan yang dapat ditimbulkan. 15 Penelitian Lai CKC dan Lam
W et al tahun 2020 kinerja RT-PCR berdasarkan waktu sejak onset gejala atau paparan,
perkiraan tingkat hasil negatif palsu adalah 100% pada hari paparan, 38% pada hari ke 5
(estimated as the first day of symptoms / perkiraan sebagai gejala hari pertama), 20% pada
hari ke-8, dan 66% pada hari ke21. 16 Penelitian Chirumbolo S tahun 2020 menjelaskan dari
subjek asimtomatik, menunjukkan tingkat kegagalan yang jelas tinggi, karena banyak terkait
bias dan kesalahan analitis. 17 Penelitian Habibzadeh P et al tahun 2020 mengingat
sensitivitas rendah (tingkat negatif palsu yang tinggi) dari tes RT-PCR untuk diagnosis
COVID19 dalam sampel nasofaring. 20 Penelitian Caruana G et al tahun 2020 mendapati
bahwa hasil negatif palsu dapat terjadi karena beberapa faktor seperti tidak adekuatnya
sampel yang diambil melalui hidung, tingkat virulensi yang rendah, waktu pengambilan
sampel, tipe spesimen (NP swab, OP swab, feses, sputum), dan transportasi (suhu, container).
21 Penelitian Alteri C et al tahun 2020 tetapi pemeriksaan ini belum optimal dalam deteksi
virus penyebab COVID-19 karena adanya angka negatif palsu yang cukup tinggi yaitu 20-
30% dengan tingkat virulensi rendah merupakan penyebab utama terjadinya bias dalam
pemeriksaan RT-PCR ini. 23 Penelitian Petrillo S et al tahun 2020 menjelaskan bahwa
meskipun pemeriksaan ini sering digunakan karena sensitivitas yang tinggi, namun hasil
negatif palsu juga banyak timbul terutama pada pasien dengan tingkat virulensi yang rendah.
25 Penelitian Zafar H tahun 2020 mendapati bahwa meskipun demikian dalam pemeriksaan
PCR dapat terjadi hasil yang meragukan karena adanya kemungkinan positif palsu dan
negatif palsu. Sehingga perlu dilakukan tes sebanyak minimal 2x yang berjarak 1 minggu
untuk pemeriksaan molekular berupa PCR maupun pemeriksaan serologis. Penyimpanan
spesimen juga berpengaruh terhadap hasil dari pemeriksaan, dimana spesimen harus
disimpan dalam suhu beku -70 ℃ atau lebih untuk menjaga viabilitas dari isolasi virus. 26
https://rsud-kelet.jatengprov.go.id/elibrary/assets/file_pdf/document_(1).pdf
RT PCR

WHO merekomendasikan pengujian menggunakan nucleic acid amplification test (NAAT)

untuk mengonfirmasi kasus Covid-19 (World Health Organization, 2020). NAAT merupakan
pengujian molekuler yang dikerjakan pada laboratorium klinis untuk deteksi dan identifikasi
organisme. NAAT merupakan pengujian di mana susunan asam nukleat spesifik pada sampel
yang diuji akan diamplifikasi atau direplikasi. Identifikasi organisme kemudian dilakukan
dengan mendeteksi amplikon yang dihasilkan. Salah satu metode NAAT yang digunakan
adalah dengan PCR (Goldenberg, 2013).
file:///Users/puticallistha/Downloads/29823-122469-2-PB.pdf

Real time reverse transcription polymerase chain reaction (RT-qPCR) in respiratory samples
is the current recommended laboratory method to diagnose SARS-CoV-2 acute infection
3,4 However, performing RT-qPCR requires special equipment and skilled laboratory
personnel familiar with molecular techniques.
https://sci-hub.se/10.1016/j.jcv.2020.104455

Real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay of nasal and
pharyngeal swab specimens is currently the gold standard for the diagnosis of COVID-19.2
However, it generally takes several hours before the results of RT-PCR testing become
available, and its sensitivity is insufficient to reliably exclude COVID-19 due to factors like
sampling or laboratory errors.3-6 RT-PCR testing therefore should be repeated in those
individuals with a persistent clinical suspicion of COVID-19 infection.3-6 Altogether,
RTPCR testing is rather time-consuming and suboptimal for the rapid triaging of patients.
https://journal.chestnet.org/article/S0012-3692(20)31733-5/pdf
Meanwhile, positive RT-PCR results were found not only in the respiratory tract but
also in GI tract specimens including faeces (29%–53.42%positivity rate),4 5 anal swabs6
and endoscopic biopsy specimens from stomach, duodenum, ileum and rectum.7 Stool viral
RNA was detected in 38.5% of those with diarrhoea, and 8.7% in the non-diarrhoea group,8
meaning that even in the absence of diarrhoea, faecal specimen RT-PCR may still be
diagnostic for COVID-19.

Nasopharyngeal swab was done by entering the swab straight along the floor of the nose
until resistance was met, indicating that the swab had reached the posterior
nasopharynx. The swab was then rotated several times and withdrawed. After
collection, swab sticks were inserted into viral transport medium tube.
Cut-off cycle threshold (CT) value of the kit was 40, which means if CT value below 40
and amplification curve was present, the sample was valued as positive, and if
otherwise, negative.

RT-PCR from nasopharyngeal specimen is still the gold standard for the diagnosis of SARS
CoV-2. However, the sensitivity varies, depending on the timing of the test relative to
exposure.

RT-PCR anal swabs is a good confirmatory test for COVID-19 cases (specificity 93.8%).
https://bmjopengastro.bmj.com/content/bmjgast/8/1/e000590.full.pdf

Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse
transcriptase polymerase chain reaction (RT-PCR) are often used to rule out infection among
high-risk persons, such as exposed inpatients and health care workers. Hence, it is critical to
understand how the predictive value changes in relation to time since exposure or symptoms,
especially when using the results of these tests to make decisions about whether to stop using
personal protective equipment or allow exposed health care workers to return to work. The
sensitivity and specificity of PCRbased tests for SARS-CoV-2 are poorly characterized, and
the “window period” after acquisition in which testing is most likely to produce false-
negative results is not well known.

As RT-PCR–based tests for SARS-CoV-2 are becoming more available, they are
increasingly being used to rule out infection to conserve scarce personal protective
equipment and preserve the workforce. When exposed health care workers test negative,
they may be cleared to return to work; similarly, when exposed patients test negative,
airborne or droplet precautions may be removed. If negative results from tests done during
the window period are treated as strong evidence that an exposed person is SARS-CoV-2–
negative, preventable transmission could occur. It is critical to understand how the
predictive value of the test varies with time from exposure and symptom onset to avoid
being falsely reassured by negative results from tests done early in the course of
infection. The goal of our study was to estimate the false-negative rate by day since
infection.

Over the 4 days of infection before the typical time of symptom onset (day 5), the probability
of a falsenegative result in an infected person decreased from 100% on day 1 to 68% on day
4. On the day of symptom onset, the median false-negative rate was 38%. This decreased to
20% on day 8 (3 days after symptom onset) then began to increase again, from 21% on day 9
to 66% on day 21. The false-negative rate was minimized 8 days after exposure—that is, 3
days after the onset of symptoms on average. As such, this may be the optimal time for
testing if the goal is to minimize false-negative results. When the pretest probability of
infection is high, the posttest probability remains high even with a negative result.
Furthermore, if testing is done immediately after exposure, the pretest probability is equal to
the negative posttest probability, meaning that the test provides no additional information
about the likelihood of infection.

Since the outbreak began, concerns have been raised about the poor sensitivity of RT-PCR–
based tests (18); 1 study has suggested that this might be as low as 59% (19). We have
designed a publicly available model that provides a framework for estimating the
performance of these tests by time since exposure and can be updated as additional data
become available.

Tests for SARS-CoV-2 based on RT-PCR added little diagnostic value in the days
immediately after exposure. This is consistent with a window period between acquisition of
infection and detectability by RT-PCR seen in other viral infections, such as HIV and
hepatitis C (20, 21). Our study suggests a window period of 3 to 5 days, and we would not
recommend making decisions regarding removing contact precautions or ending quarantine
on the basis of results obtained in this period in the absence of symptoms. Although the
falsenegative rate is minimized 1 week after exposure, it remains high at 21%. Possible
mechanisms for the high false-negative rate include variability in individual amount of viral
shedding and sample collection techniques.

One consideration is whether serial testing would offer any benefit in test performance
compared with a single test. If we assume independence of the test results, serial testing
would almost certainly reduce the false-negative rate; however, without more data on the
underlying mechanism for the high false-negative rate.

Further studies to better characterize the underlying mechanism for poor diagnostic
performance of SARS-CoV-2 RT-PCR are needed to inform testing strategies.

The relationship between a false-negative result and infectiousness is unclear, and patients
who test negative on samples from nasopharyngeal swabs may be less likely to transmit the
virus regardless of true case status. We found an increase in the false-negative rate starting 9
days after exposure; however, it is possible that some of the later results were not actual false
negatives but rather represented clearance of the infection. Thus, interpretation later in the
clinical course depends on the purpose of testing: If the goal is to clear a patient from
isolation, these negative results may be correct, although more data are needed given studies
showing viral replication in other sites. However, if the goal of the test is to evaluate whether
additional follow-up is needed or whether the patient should be treated as SARS-CoV-2–
positive for the purpose of contact tracing, the test may not be providing the desired
information and caution should be used in decision making. Because antibodies appear later
in the course of infection, a combination of antibody testing and RTPCR might be most
useful for patients more remote from symptoms or exposure.

In summary, care must be taken when interpreting RT-PCR tests for SARS-CoV-2 infection,
particularly early in the course of infection and especially when using these results as a basis
for removing precautions intended to prevent onward transmission. If clinical suspicion is
high, infection should not be ruled out on the basis of RT-PCR alone, and the clinical and
epidemiologic situation should be carefully considered. In many cases, time of exposure is
unknown and testing is done on the basis of time of symptom onset. The falsenegative rate is
lowest 3 days after onset of symptoms, or approximately 8 days after exposure. Clinicians
should consider waiting 1 to 3 days after symptom onset to minimize the probability of a
false-negative result. Further studies to characterize test performance and research into
higher-sensitivity approaches are critical.
https://sci-hub.se/10.7326/M20-1495

According to the latest guideline of Diagnosis and Treatment of Pneumonitis Caused by

2019-nCoV (trial sixth version) published by the China government (5), the diagnosis of
COVID-19 must be confirmed by the reverse transcription polymerase chain reaction (RT-
PCR) or gene sequencing for respiratory or blood specimens, as the key indicator for
hospitalization. However, with limitations of sample collection and transportation, and kit
performance, the total positive rate of RT-PCR for throat swab samples was reported to be
about 30% to 60% at initial presentation (6). In the current emergency, the low sensitivity
of RT-PCR implies that many COVID-19 patients may not be identified and may not
receive appropriate treatment in time; such patients constitute a risk for infecting a
larger population given the highly contagious nature of the virus. Chest CT, as a routine
imaging tool for pneumonia diagnosis, is relatively easy to perform and can produce fast
diagnosis. In this context, chest CT may provide benefit for diagnosis of COVID-19. As
recently reported, chest CT demonstrates typical radiographic features in almost all COVID-
19 patients, including ground-glass opacities, multifocal patchy consolidation, and/or
interstitial changes with a peripheral distribution (7). Those typical features were also
observed in patients with negative RT-PCR results but clinical symptoms. It has been noted
in small-scale studies that the current RT-PCR testing has limited sensitivity, while chest CT
may reveal pulmonary abnormalities consistent with COVID-19 in patients with initial
negative RT-PCR results (8, 9).

viral nucleic acid test by RT-PCR assay plays a vital role in determining hospitalization and
isolation for individual patients. However, its lack of sensitivity, insufficient stability, and
relatively long processing time were detrimental to the control of the disease epidemic.
https://sci-hub.se/10.1148/radiol.2020200642

Metode pengujian untuk identifikasi SARS-CoV-2 yang digunakan saat ini umumnya
merupakan metode berbasis realtime Reverse Transcription (rRT)-PCR. RTPCR merupakan
pengembangan metode PCR di mana RNA dari suatu sampel akan direaksikan terlebih
dahulu sebelum diamplifikasi. Reaksi yang terjadi adalah reverse transcription di mana RNA
untai tunggal akan diubah menjadi complementary DNA (cDNA), yang merupakan untai
DNA dari RNA. cDNA ini kemudian digunakan sebagai cetakan untuk proses amplifikasi
(Bachman, 2013). Sementara itu, real-time PCR merupakan pengembangan lainnya dari PCR
di mana proses amplifikasi dapat dipantau dengan melihat jumlah amplikon yang telah
dihasilkan. Jumlah amplikon ini dapat terlihat dengan bantuan probe yang akan terintegrasi
pada amplikon. Probe ini kemudian dideteksi dengan bantuan fluorosensi sehingga akumulasi
amplikon dapat dilihat dalam bentuk grafik berupa jumlah amplikon terhadap waktu
(Maddocks & Jenkins, 2016).

Saat ini terdapat beberapa protokol pengujian SARS-CoV-2 dengan gen target yang berbeda.
Salah satu protokol yang telah dipublikasikan dikembangkan oleh Corman, et al. Metode ini
menguji dua gen target pada SARS-CoV-2 yakni gen envelope protein (E) dan gen RNA-
dependent RNA polymerase (RdRp) dengan metode (rRT)-PCR. Pengujian ini dilakukan
dengan tiga tahap. Pertama dilakukan pengujian terhadap gen E dan bila ditemukan hasil
positif dilanjutkan pengujian terhadap gen RdRp menggunakan dua jenis probe (RdRp-P1
dan RdRp-P2). Bila pengujian kedua menunjukkan hasil yang positif, maka dilanjutkan
dengan pengujian terhadap gen RdRp kembali dengan menggunakan RdRpP2. Hasil studi
menunjukkan bahwa RdRp-P2 hanya mengamplifikasi sampel SARS-CoV-2 dan tidak
bereaksi dengan penyakit saluran pernafasan atas infeksi lainnya. Perlu diketahui bahwa
metode ini dikembangkan dan divalidasi tanpa menggunakan sampel klinis dari pasien
Covid-19 (Corman, et al., 2020).
Chan, et al. mengembangkan metode baru dengan menguji gen RNA-dependent RNA
polymerase/helicase (RdRp/Hel) dan dibandingkan terhadap metode Corman, et al.
Ditemukan bahwa pengujian terhadap gen RdRp/Hel lebih sensitif dibandingkan pengujian
terhadap gen RdRp-P2 (Chan, et al., 2020). Metode pengujian lainnya yang telah
dikembangkan adalah dengan menggunakan gen target nsp2 dengan kelebihan berupa waktu
reaksi hanya satu jam dan lebih cepat dibandingkan pengujian RdRp/Hel (Yip, et al., 2020).

Pengujian lain dikembangkan dengan menggunakan gen target berupa gen ORF1b dan gen N
(Chu, et al., 2020). Berdasarkan penelitian oleh Li, et al. kedua gen ini memiliki potensi
untuk digunakan sebagai acuan untuk mengkonfirmasi kasus Covid-19 . Metode pengujian
ini dikembangkan untuk mampu bereaksi dengan beberapa jenis coronavirus karena saat
tahap desain penelitian belum banyak informasi terkait SARS-CoV-2 yang dapat diakses.
Meskipun demikian, ditemukan bahwa pengujian ini mampu mendeteksi spesimen klinis dari
pasien Covid-19 dan tidak bereaksi terhadap beberapa penyakit pernafasan lainnya (Chu, et
al., 2020).

Protokol pengujian yang digunakan oleh Nao, et al (Nao, et al., 2020). melibatkan pengunaan
nested PCR dan RT-PCR. Untuk metode nested PCR, digunakan gen target berupa gen
ORF1a dan gen S. Untuk metode RT-PCR, digunakan gen N. Nested PCR merupakan
modifikasi lain dari PCR yang dilakukan untuk meningkatkan sensitivitas dan spesifisitas
dari reaksi. Dengan metode ini, digunakan dua pasang primer dengan dua reaksi. Pada reaksi
pertama, sepasang primer akan menempel pada urutan basa di posisi upstream dari pasangan
primer kedua. Pada reaksi kedua, pasangan primer kedua akan mengamplifikasi amplikon
hasil reaksi pertama. Meskipun mampu meningkatkan spesifisitas dan sensitivitas dari reaksi
PCR, metode ini juga meningkatkan kemungkinan terjadinya kontaminasi bawaan hasil dari
reaksi sebelumnya (Grody, et al., 2010).

Pengembangan teknologi PCR lain adalah mobile PCR. Salah satu contoh mobile PCR di
antaranya melibatkan peralatan PCR standar dengan kondisi laboratorium yang dapat
dipindahkan seperti di dalam mobil atau pun di dalam kapal. Menggunakan metode ini,
proses pengujian sampel dapat langsung dilakukan di lokasi pengambilan sampel dan
memotong waktu yang dibutuhkan untuk mendapatkan hasil (Marx, 2015). Meskipun
menjanjikan untuk mempercepat proses identifikasi SARS-CoV-2, perlu dipertimbangkan
bahwa penanganan spesimen klinis untuk pengujian molekuler harus dilakukan dengan
fasilitas yang memenuhi atau setara dengan Biosafety Level 2 (BSL-2) (World Health
Organization, 2020).
file:///Users/puticallistha/Downloads/29823-122469-2-PB.pdf

Sejak awal pandemi COVID-19, laboratoriumlaboratorium telah terus menggunakan tes

amplifikasi asam nukleat (NAAT) seperti real time reversetranscription polymerase chain
reaction (rRT-PCR) untuk mendeteksi SARS-CoV-2, virus penyebab penyakit tersebut. Di
banyak negara, akses pada bentuk tes ini menjadi tantangan. Tes diagnostik deteksi antigen
spesifik infeksi SARS-CoV-2 yang lebih andal tetapi lebih terjangkau dan cepat sedang
dikembangkan dan dicari. Tes diagnostik deteksi antigen dirancang untuk secara langsung
mendeteksi protein SARS-CoV-2 yang dihasilkan oleh virus yang bereplikasi di sekresi
saluran pernapasan. Tes ini dikembangkan untuk penggunaan berbasis laboratorium dan
dekat pasien dan disebut tes diagnostik cepat, atau RDT. Lanskap pengembangan tes
diagnostik ini bersifat dinamis di mana hampir seratus perusahaan mengembangkan atau
membuat tes cepat untuk deteksi antigen SARS-CoV-2 (1)
https://www.who.int/docs/default-source/searo/indonesia/covid19/deteksi-antigen-dalam-
diagnosis-infeksi-sars-cov-2-menggunakan-imunoasai-cepat.pdf?sfvrsn=222f2be3_2

https://ec.europa.eu/health/system/files/2022-02/covid-19_rat_common-list_en.pdf
https://www.cdc.gov/zika/pdfs/trioplex-real-time-rt-pcr-assay-instructions-for-use.pdf

RAPID TEST

Sebagian besar Ag-RDT untuk COVID-19 menggunakan metode imunodeteksi sandwich

dengan format tes alur lateral yang mudah digunakan dan umum dipakai untuk tes HIV,
malaria, dan influenza. Ag-RDT biasanya terdiri dari kaset plastik dengan rongga
sampel dan penyangga dan strip matriks nitroselulosa dengan garis tes dengan antibodi
terikat untuk kompleks antigenantibodi terkonjugasi target dan garis kontrol dengan
antibodi terikat untuk antibodi terkonjugasi. Dalam hal RDT SARS-CoV-2, analit
targetnya seringkali protein nukleokapsid virus tersebut yang berjumlah lebih banyak.
Biasanya, semua material yang diperlukan untuk melakukan tes, termasuk material
pengambilan sampel selain penghitung waktu, disediakan di dalam alat yang dijual di
pasaran.

Setelah spesimen saluran pernapasan diambil dan dioleskan ke strip tes, hasilnya
dibaca oleh operator dalam waktu 10 sampai 30 menit dengan atau tanpa bantuan
instrumen pembaca. Penggunaan pembaca menstandardisasi interpretasi hasil tes sehingga
mengurangi perbedaan interpretasi asai oleh operator yang berbeda, tetapi memerlukan
perlengkapan pendukung. Sebagian besar tes yang saat ini diproduksi memerlukan
sampel usapan nasal atau nasofaringeal, tetapi perusahaan-perusahaan sedang meneliti
kinerja tes mereka jika menggunakan jenis sampel alternatif seperti air liur, cairan
oral, dan sistem-sistem pengambilan sampel untuk dapat memperluas opsi penggunaan
dan untuk memfasilitasi tes yang aman dan efisien. Secara umum, kemudahan
penggunaan dan singkatnya waktu ketersediaan hasil Ag-RDT berpotensi memperluas
akses pada tes dan mengurangi penundaan diagnosis dengan cara bergeser ke tes
pasien dengan gejala awal secara terdesentralisasi. Sisi sebaliknya dari kemudahan
pengoperasian Ag-RDT adalah sensitivitas yang lebih rendah dibandingkan NAAT.
Sangat sedikit Ag-RDT SARS-CoV-2 yang sudah menjalani kajian regulasi ketat. Hanya
empat tes yang telah menerima Emergency Use Authorization (EUA/izin penggunaan
darurat) United States Food and Drug Administration (US FDA), dan hanya dua tes lain yang
telah disetujui oleh Pharmaceutical and Medical Devices Agency Jepang. Hanya tiga
perusahaan yang telah menyerahkan dokumen untuk prosedur Emergency Use Listing
(EUL/daftar penggunaan darurat) WHO (2, 3).

Data tentang sensitivitas dan spesifisitas Ag-RDT untuk SARS-CoV-2 yang sekarang ada
diambil dari penelitianpenelitian yang memiliki desain penelitian dan merek sasaran evaluasi
yang beragam. Penelitian-penelitian ini menunjukkan bahwa sensitivitas Ag-RDT terhadap
sampel dari saluran pernapasan atas (usap nasal atau nasofaringeal) tampak banyak berbeda-
beda jika dibandingkan NAAT, dengan rentang 0-94% (4-13) tetapi spesifisitasnya konsisten
dilaporkan tinggi (>97%). Meskipun lebih banyak bukti aspek kinerja dan operasional di
lapangan masih diperlukan, Ag-RDT paling mungkin bekerja dengan baik pada pasien
dengan jumlah virus tinggi (nilai Ct ≤25 atau >106 salinan genomik virus/mL), yang
biasanya terjadi pada fase prasimtomatik (1-3 hari sebelum munculnya gejala) dan fase
simtomatik awal (dalam waktu 5-7 hari pertama penyakit) penyakit ini (14, 15). Hal ini
menjadi Data tentang sensitivitas dan spesifisitas Ag-RDT untuk SARS-CoV-2 yang
sekarang ada diambil dari penelitianpenelitian yang memiliki desain penelitian dan merek
sasaran evaluasi yang beragam. Penelitian-penelitian ini menunjukkan bahwa sensitivitas Ag-
RDT terhadap sampel dari saluran pernapasan atas (usap nasal atau nasofaringeal) tampak
banyak berbeda-beda jika dibandingkan NAAT, dengan rentang 0-94% (4-13) tetapi
spesifisitasnya konsisten dilaporkan tinggi (>97%). Meskipun lebih banyak bukti aspek
kinerja dan operasional di lapangan masih diperlukan, Ag-RDT paling mungkin bekerja
dengan baik pada pasien dengan jumlah virus tinggi (nilai Ct ≤25 atau >106 salinan genomik
virus/mL), yang biasanya terjadi pada fase prasimtomatik (1-3 hari sebelum munculnya
gejala) dan fase simtomatik awal (dalam waktu 5-7 hari pertama penyakit) penyakit ini (14,
15). Hal ini menjadi kesempatan untuk diagnosis awal dan interupsi transmisi melalui isolasi
terarah dan penentuan kohort kasus-kasus yang paling infeksius dan kontak-kontak eratnya
(16). Pasien yang menunjukkan presentasi lebih dari 5-7 hari sejak munculnya gejala lebih
mungkin membawa jumlah virus yang lebih rendah, dan kemungkinan hasil negatif palsu Ag-
RDT lebih tinggi.

Meskipun kinerjanya diperkirakan mengalami batasanbatasan ini, jika digunakan dan

diinterpretasikan dengan tepat Ag-RDT dapat memainkan peran penting dalam memandu
tatalaksana pasien, pengambilan keputusan kesehatan masyarakat, dan surveilans COVID-19.
Setidaknya, Ag-RDT perlu mengidentifikasi jauh lebih banyak kasus daripada yang terlewat
(sensitivitas ≥80%) dan memiliki spesifisitas yang sangat tinggi (≥97-100%). Berdasarkan
parameter-parameter kinerja ini, panduan interim ini mengajukan beberapa potensi peran Ag-
RDT dan memberikan rekomendasi-rekomendasi umum untuk pemilihan tes serta
pertimbangan-pertimbangan utama untuk implementasinya.

Penggunaan Ag-RDT dapat dipertimbangkan di negara atau daerah di mana terjadi transmisi
komunitas meluas, di mana sistem kesehatan kelebihan beban, dan di mana tidak
memungkinkan melakukan tes atas semua kasus suspek atau kasus suspek satu pun dengan
NAAT. Seperti semua tes diagnostik, tetapi terutama seperti tes diagnostik dengan
sensitivitas dan/atau spesifisitas yang suboptimal, agar hasil tes RDT dapat diinterpretasikan
dan dijadikan dasar tindakan, prevalensi penyakit (menurut standar referensi) harus
diperkirakan berdasarkan surveilans, karena prevalensi ini menentukan nilai prediktif positif
(NPP) dan negatif (NPN) RDT (lihat Lampiran). Proses yang diusulkan untuk pemanfaatan
Ag-RDT untuk tatalaksana kasus COVID-19 di tempat dengan transmisi komunitas meluas
ditunjukkan di Gambar 1. Di tempat tersebut, probabilitas COVID-19 sebelum tes
(kemungkinan pasien terkena COVID-19 sebelum hasil tesnya diketahui, berdasarkan faktor-
faktor epidemiologis dan klinis) relatif tinggi, dan hasil tes positif memiliki nilai prediktif
yang tinggi. Demikian juga, di tempat dengan transmisi komunitas, nilai prediktif hasil RDT
negatif mungkin rendah, bahkan dengan adanya indikatorindikator epidemiologis atau klinis
pajanan atau penyakit COVID-19.

Faktor-faktor yang memengaruhi kinerja tes

Sebagaimana disebutkan di atas, banyak faktor dapat berdampak pada kinerja Ag-RDT.
Karena itu, temuan klinis dapat bervariasi. Hal-hal berikut harus dipertimbangkan:

• faktor-faktor pasien seperti waktu sejak munculnya penyakit dan tipe sampel status imun;
• Jenis (saluran pernapasan atas atau bawah), kualitas, dan pengolahan sampel, termasuk
kondisi penyimpanan dan pelarutan di dalam media transportasi virus;
• faktor-faktor virus seperti konsentrasi dan masa peluruhan antigen virus dan variasi
struktural pada antigen target, reaktivitas silang dengan virus lain.
• Target protein khusus, karena beberapa antigen diproduksi dengan konsentrasi yang lebih
tinggi dibandingkan antigen lain, misalnya nukleokapsid atau protein spike;
• isu desain atau kualitas produk, seperti:
- jumlah antibodi atau afinitas antigen (-antigen) sasaran tidak mencukupi;
- pengemasan buruk dan pajanan pada panas dan kelembapan saat dipindahkan dan/atau
disimpan dengan tidak tepat, sehingga merusak antibodi alat tes; dan
- instruksi yang tidak jelas yang dapat berdampak pada kinerja alat tes; dan

• pelatihan atau kompetensi operator tes yang tidak memadai, yang dapat mengakibatkan
kekeliruan dalam persiapan Ag-RDT, pelaksanaan tes, atau interpretasi hasilnya, sehingga
kesimpulan keliru
https://www.who.int/docs/default-source/searo/indonesia/covid19/deteksi-antigen-dalam-
diagnosis-infeksi-sars-cov-2-menggunakan-imunoasai-cepat.pdf?sfvrsn=222f2be3_2

Moreover, molecular tests are costly and often time consuming. COVID-19 Ag Respi-Strip
(Coris BioConcept, Gembloux, Belgium) is a dipstick immunochromatographic test designed
to detect SARS-CoV-2 antigens in nasopharyngeal secretions within 15 minutes. This rapid
test was approved by the belgian Federal Agency of drugs and health products (AFMPS) and
included in the first line of diagnostic tests for COVID19 by the public health institute in
Belgium (Sciensano

COVID-19 Ag Respi-Strip (CORIS Bioconcept, Gembloux, Belgium) is a ready to use test

based which allows rapid and qualitative detection of SARS-CoV-2 antigen in
nasopharyngeal secretions. This test, based on a membrane technology with colloidal gold
nanoparticules, uses monoclonal antibodies to detect highly conserved SARS-CoV and
SARS-CoV-2 nucleoprotein antigen. Another monoclonal antibody is conjugate to colloidal
gold nanoparticules. These antibodies are immobilized onto the nitrocellulose membrane. The
test was performed according to manufacturer’s instruction by mixing 100 µL of
nasopharyngeal secretions with 4 drops (approximately 100 µL) of LY-S dilution buffer in a
tube and the strip was added. When the nasopharyngeal secretions come into contact with the
strip, passive diffusion allows the solubilized conjugate to migrate with the sample and react
with the anti-SARS-CoV-2 antibodies immobilized onto the membrane. A control line is
included in the strip to assess the correct migration of the sample. Visual interpretation of the
result is performed after 15 minutes. Two versions of the test were evaluated. On the second
version, conjugate was coupled on a different way and the control line was optimized.

In the ongoing pandemic context of COVID-19, diagnostic testing for SARS-CoV-2 is

crucial in order to limit the spread of the virus as well as appropriately manage infected
patients. Different diagnostic test manufacturers have developed rapid tests based on
SARS-CoV-2 proteins detection in respiratory samples. However, the analytical
performances of these rapid antigenic tests depend on different factors including the
viral load, the quality of the specimen and how it is processed. The performances also
depend on the setting of patients tested. Although the COVID-19 Ag Respi-Strip has
several advantages such as the ease and fast achievement of the test, the rapid answer,
the lower cost and the non-requirement of special equipment or skills compared with
molecular techniques, data presented here suggested that this rapid test is suffering
from poor sensitivity. The rapid antigen detection test is able to detect SARS-CoV-2 with
high sensitivity in nasopharyngeal samples with high viral load equivalent at least to 1.7 x
105 copies/mL (Ct <25), but the sensitivity declines substantially when the viral load
decreases with Ct values over 30, cquivalent to 9.4 x 10 copies/mL, which is often the case in
patients suffering of COVID-19.Actually, in our study, while the specificity was 100%, the
overall sensitivity of the COVID-19 Ag Respi-Strip was 30.2%. This lack of sensitivity of
rapid diagnostic tests for virus detection was already observed during the Influenza A (HIN1)
pandemic [5]. Ensuring accurate diagnosis is essential to limit the spread of the virus. The
poor sensitivity of the COVID-19 Ag Respi-Strip leads to false negative results, which in
these times of pandemic can be of great consequence. This rapid test was thought to be
used as a first line COVID-19 diagnostic test in Belgium in order to possibility reduce
the number of RT-qPCR testing in case of positive results, but requiring confirmation
for negative results. However, because negative results cannot rule out SARS-CoV-2
infection, this test is of little use in a pandemic setting. Pending more evidence of their
performances, our data suggest that COVID19 Ag Respi-Strip should not be used alone for
COVID-19 diagnosis and shows no benefit in reducing the use of RT-qPCR.
https://sci-hub.se/10.1016/j.jcv.2020.104455

Although these RATs might be useful for the identification of COVID-19 patients in
local clinics, their sensitivity is important in determining usage strategies.

Therefore, these RATs may be suitable for the detection of COVID-19 in individuals who are
shedding a large amount of SARS-CoV-2; that is, they may be useful to identify patients with
a high likelihood of transmitting the virus to others.

. The recommended samples for these RATS are nasopharyngeal swabs not saliva, and some
of the saliva samples from which SARS-CoV-2 was isolated gave negative results with all of
the RATs tested here. Nonetheless, these RATs need to be improved with respect to their
sensitivity.
https://sci-hub.se/10.3390/v12121420

COVID-19 infection would not be detected in patients in the early or late phase of the
infection typically associated with a low viral load. However, differentiation between
contagious and non-contagious individuals may be possible with this assay. Samples with Ct-
values >30 usually do not allow culturing of the virus indicating low infectivity. Such
individuals may be regarded non-contagious despite carrying low virus loads. This
differentiation of individuals may be of particular importance for the decision on access to
susceptible individuals e.g. in nursing homes or at many other circumstances.

The significance of this assay's results is, as the significance of any other assay aiming at
determination of the SARS-CoV-2 infection status, severely affected by the method of
sample collection. The viral load of a specimen does not necessarily reflect the viral load in
the patient's respiratory tract. Meaningful results can only be obtained with an efficient
sample collection method. Otherwise the viral load in the patient may be underestimated.
Taken together, we conclude that sensitivity and specificity of the antigen assay is inferior to
the PCR assay. However, the antigen assay may be a quick and easy-toperform approach to
allow differentiation of individuals contagious for SARS-CoV-2 from non- or less contagious
individuals.
https://sci-hub.se/10.1016/j.jviromet.2020.114024

A number of antigen-detecting rapid diagnostic tests (Ag-RDTs) for severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) are now commercially available and can result in
rapid decisions on patient care, isolation and contact tracing at the point of care [1]. Two Ag-
RDTs using nasopharyngeal (NP) swab samples meet World Health Organization (WHO)
targets and are now approved through the WHO Emergency Use Listing procedure

NP swab samples are frequently perceived as uncomfortable by patients and must be

collected by trained healthcare personnel with protective equipment. A more complex
sampling technique could also result in an incorrect performance in clinical reality, with a
possible consequence for test sensitivity. Evidence supports the use of alternative sampling
methods for RT-PCR, including nasal swabs collected by patients, and some tests have
received regulatory approval with nasal samples [5, 6]. The term nasal sampling is often not
used uniformly but can be differentiated in anterior nasal and nasal mid-turbinate sampling
[6]. Considering the ease-of-use of Ag-RDTs, a reliable, simple sampling method would not
only allow self-sampling, but may also pave the way for self-testing.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736752/
CT SCAN

In the initial screening, computed tomography (CT) examination is needed for the auxiliary
diagnosis.3 The diagnosis is then confirmed by the positive results of the nucleic acid
amplification test (NAAT) of the respiratory tract or blood specimens using reverse
transcription real-time fluorescence polymerase chain reaction (RT-PCR).2 However, this
diagnosis method is highly limited: (1) When the viral load is low, the detection rate is low,
leading to false-negative results. (2) Only a positive diagnosis can be made, but the severity
of COVID-19 and its progression cannot be judged (in contrast, CT imaging can reveal
disease progression). (3) The supply of the reagents cannot keep up with the demand, and the
quality of new products of major companies awaits to be studied and improved. (4) It takes 1
day or longer to obtain the results after sampling. For these reasons, Chinese researchers
strongly recommend CT imaging as the main basis for the diagnosis of COVID-19 in the
current situation.4 An academician of the American Society for Radiation Oncology called
for the immediate establishment of a CT-based diagnostic method for COVID-19 and
improvement of the detection rate of the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).5 If a patient with clinically suspected COVID-19 has negative NAAT results
but positive imaging results, the patient should be isolated and treated as soon as possible.
The advantage of CT examination in the diagnosis of COVID-19 is obvious. Below, we
analyze some typical patients who were examined and diagnosed by our institution.

Case 1 was a 52-year-old male who had long been working in Wuhan, China. He arrived in
Shenzhen, China, on January 22, 2020. He sought treatment in our hospital due to fever for
half a day, with nasal congestion and headache but without rhinorrhea, pharyngalgia, cough,
expectoration, or diarrhea. Laboratory tests showed a low lymphocyte count (0.58 109 /L), a
high neutrophil percentage (81.3%), a high procalcitonin concentration (0.130 ng/mL), a high
high-sensitivity C-reactive protein (hs-CRP) concentration (7.80 mg/L), a normal white blood
cell (WBC) count (6.62 109 /L), and normal concentrations of creatine kinase-myocardial
band, cardiac troponin I, and myoglobin. Unenhanced CT scan revealed patchy pure ground-
glass opacities (GGOs) at the lateral basal segment of the right lower lobe and vascular
dilation inside the lesion (Figure 1). The patient was suspected to have early-stage COVID-
19. The NAAT result obtained by RT-PCR detection of SARS-CoV-2 from respiratory tract
specimens of the patient was positive, and the patient was diagnosed with COVID-19.

Case 2 was a 63-year-old male who took a high-speedtrain from Wuhan to Beijing on
January 10, 2020, and arrived in Shenzhen by plane from Beijing on January 26, 2020. He
was hospitalized dueto fever for 5 days after catching cold, with a highest body temperature
of 37.7C, occasional cough, and myalgia but without expectoration or dyspnea. Laboratory
tests showed elevated hs-CRP (33.57 mg/L), normal procalcitonin (0.072 ng/mL), a normal
neutrophil count (2.50 109 /L), a normal lymphocyte count (1.11 109 /L), a normal WBC
count (3.99 109 /L), and a normal lymphocyte percentage (27.8%). Unenhanced CT scan
showed multiple pure GGOs in the right lower lobe, a distribution of lesions in the subpleural
area and lung periphery, a ‘‘crazy-paving’’ pattern, and interlobular septal thickening (Figure
2). On the basis of CT findings, the patient was suspected to have advanced-stage COVID-
19. The NAAT result obtained by RT-PCR detection of SARS-CoV-2 from blood specimens
of the patient was positive, and the patient was diagnosed with COVID-19.

Case 3 was a 48-year-old male patient who was quarantined at home after driving by himself
from Wuhan to Shenzhen on January 24, 2020. He was hospitalized due to pharyngalgia for 4
days and fever for 1 day. The patient’s temperature at admission was 38.5C. He had no
cough, expectoration, headache, myalgia, nasal congestion, rhinorrhea, or dyspnea.
Laboratory tests showed elevated serum hs-CRP (73.99 mg/L), increased procalcitonin
concentration (0.100 ng/mL), a decreased lymphocyte count (0.92 109 /L), and a normal
WBC count (5.54 109 /L). The unenhanced CT scan showed multiple GGOs in multiple lobes
of both lungs, interlobular septal thickening, and a crazy-paving pattern (Figure 3). On the
basis of CT findings, the patient was suspected to have advanced-stage COVID-19. The
NAAT result obtained by RT-PCR detection of SARS CoV-2 from pharyngeal swabs of the
patient was positive, and the patient was diagnosed with COVID-19.

Case 4 was a 47-year-old male resident of Shenzhen who had recently been in close contact
(distance <2m) with a driver from Wuhan. He had fever for 4 days even though he used
nonprescription antipyretic medications, so he sought treatment in our hospital. He had a
body temperature up to 40C and diarrhea twice but had no cough, expectoration, myalgia,
dysuria, or dyspnea. Laboratory tests showed a low percentage of lymphocytes (14.4%), a
low lymphocyte count (0.90 109 /L), a high hs-CRP concentration (136.51 mg/L), a high
procalcitonin concentration (0.180 ng/mL), a normal neutrophil percentage (72.2%), and a
normal WBC count (6.27 109 /L). Unenhanced CT scan showed patchy consolidations on the
left upper lobe, partially consolidated lung tissue, GGOs on the edge, and air bronchograms
in the lesion (Figure 4). The NAAT result obtained by RT-PCR detection of SARS-CoV-2
from blood specimens of the patient was positive, and the patient was diagnosed with
COVID-19.

Computed tomography imaging does have the limitation that some imaging signs of COVID-
19 are the same as those of other lung diseases. The following 2 patients had suspected
COVID-19 in our institution and were paid special attention but were finally diagnosed with
other diseases.

Case 1 was a 60-year-old female who had no recent history of exposure to the epidemic area.
She was admitted to the hospital due to cough for 10 days, chest pain and wheezing for 3
days, and yellow sputum. She took cephalosporin antibiotics by herself before seeking
treatment in our hospital, but her symptoms were not relieved. She had no fever, headache,
rhinorrhea, nausea, vomiting, or hemoptysis. She had a history of rheumatoid arthritis for
more than 10 years. Laboratory tests showed a normal WBC count (4.96 109 /L), a normal
neutrophil percentage (48.6%), a normal procalcitonin concentration, and a normal
lymphocyte count. Plain chest CT scan revealed extensive patchy exudates and consolidation
of both lungs, faint GGOs on the edge, and interlobular septal thickening (Figure 5). The
NAAT result obtained by RT-PCR detection of SARS-CoV-2 from respiratory tract
specimens of the patient was negative. Additional laboratory tests showed high hs-CRP
(40.20 mg/L), high D-dimer (2.22 mg/L), high immunoglobulin G (19.3 g/L), and positive
rheumatoid factor. The patient was diagnosed with rheumatic pneumonia.

Case 2 was a 58-year-old female from Henan who recently passed through Wuhan. She had
recurrent chest pain for 1 month. She was admitted to our hospital 2 hours after aggravation
of chest pain. She had no fever, cough, dizziness, or headache but a previous history of
hypertension for more than 10 years. Chest CT showed extensive GGOs in both lungs, which
were mainly distributed along the hila, interlobular septal thickening, and interlobar pleural
thickening (Figure 6). Computed tomography findings could not rule out the possibility of
COVID-19. The NAAT result obtained by RT-PCR detection of SARS-CoV-2 from
respiratory tract specimens of the patient was negative. Laboratory tests showed no
abnormality in D-dimer concentration, WBC count, or hs-CRP concentration.
Echocardiography indicated low-amplitude left ventricular wall motion and low diastolic
function. Electrocardiography showed ST elevation in lead aVR of 0.05 mV and multilead
ST depression of 0.1 to 0.2 mV. Digital subtraction angiography suggested occlusion of the
left anterior descending coronary artery. Eventually, the patient was diagnosed with heart
failure and pulmonary edema caused by coronary heart disease and acute myocardial
infarction.

To date, our institution has examined a total of 50 suspected patients with COVID-19, 15 of
whom were diagnosed with COVID-19. The main clinical manifestations of confirmed cases
have been fever (100%; >38C in most cases and >37.5C in a few cases), cough and
expectoration (46.7%), headache (20%), and diarrhea (13.3%). No confirmed patients have
had dyspnea. Imaging findings have mainly included single or multiple lesions, patchy or
segmental GGOs (93.3%), and reticular markings that mainly followed peribronchovascular
and subpleural distributions. Interlobular septal thickening might be present, and pleural
effusion and enlarged mediastinal lymph nodes were rarely seen.

Currently, 90% to 95% of the medical imaging examinations for suspected patients with
COVID-19 are chest CT, which has a high detection rate of viral pneumonia. In contrast, the
quality of available SARS-CoV-2 nucleic acid detection kits differs greatly, and the
reliability of NAAT is still questionable. Moreover, NAAT has a low detection rate for
SARSCoV-2 and thus needs to be repeated 2 to 3 times in many cases. Some patients had
negative NAAT results for the detection of SARS-CoV-2 from pharyngeal swabs but positive
NAAT results for the detection of SARS-CoV-2 from bronchoalveolar lavage, leading to
false-negative results. Second, the number of people awaiting NAATs for the detection of
SARS-CoV-2 greatly exceeds the capacity of medical institutions. Many patients have not
been diagnosed in a timely manner and thus have missed the chance of early isolation and
early treatment. Compared with various limitations of NAAT, chest CT examination is timely
and rapid and has a high positive rate.1 The extent of lung lesions is closely related to clinical
symptoms. Therefore, chest CT examination is irreplaceable in the preliminary screening of
COVID-19.

Coronavirus disease 2019 has different imaging manifestations at different stages, which are
mainly related to pathogenesis. The lesions at the early stage of COVID-19 are relatively
localized and mainly manifest as inflammatory infiltration restricted to the subpleural or
peribronchovascular regions of one lung or both lungs, exhibiting patchy or segmental pure
GGOs with vascular dilation (Figure 1). Very few cases have negative CT findings at the
early stage. In the progressive stage, CT shows mainly an increased range of pure GGOs
(Figure 2), the involvement of multiple lobes (Figure 3), consolidations of some lesions, and
GGOs surrounding consolidated lesions (the characteristic change of the progressive stage).
Interlobular septal thickening and an obvious crazy-paving pattern are often present, and air
bronchograms are common (Figure 4). At the advanced stage, the CT manifestations of
patients are similar to those in other types of pneumonia and mainly include diffuse lesions in
both lungs, which are mostly consolidated lesions, and GGOs surrounding consolidated
lesions, which are mostly accompanied by parenchymal bands and occasionally by a small
amount of pleural effusion. This CT appearance is called lung whiteout. Different imaging
manifestations at different stages may be associated with the pathological mechanism of viral
pneumonia, which at first is prone to affect the terminal bronchioles and their surrounding
pulmonary parenchyma and then develop into infiltration of pulmonary lobules and, lastly,
diffuse alveolar damage.6

In imaging diagnosis, COVID-19 is difficult to distinguish from pneumonias caused by

influenza A virus, influenza B virus, cytomegalovirus, adenovirus, respiratory syncytial virus,
SARS-CoV, MERS coronavirus, and other viral pneumonias as well as bacterial pneumonia.2
Luckily, their treatment methods are similar. There are no medicines specifically targeting
COVID-19. Viral pneumonias other than COVID-19 mainly manifest as peribronchial and
perivascular interstitial inflammation that moves toward the inner part of the pulmonary
interstitium, and their CT manifestations are multiple interlaced or parallel high-attenuation
fibrous streaks or highattenuation reticular patterns caused by infiltration of the interlobular
septa. The lesions mainly occur in the hilar and subpleural regions.7 If the pneumonia is
secondary to bronchitis and does not involve the alveoli, inflammation often further develops
into the bronchial wall. When the bronchioles are partially or completely blocked, CT images
show localized pulmonary edema and/or atelectasis. The occurrence of viral pneumonia is
correlated with the virulence of the virus, the transmission route, and the age and
immunological status of the host. In general, the incidence of viral pneumonias is higher in
children than in adults. In contrast, COVID-19 commonly occurs in 40- to 60-year-old
patients with multiple comorbidities. Compared to patients with SARS and MERS, patients
with COVID-19 have no obvious complications or infections, and the disease progression is
relatively slow.8

Coronavirus disease 2019 also needs to be differentiated from bacterial pneumonia,

mycoplasma pneumonia (MPP), and chlamydia pneumonia.9 Bacterial pneumonia occurs in
the lung parenchyma and mainly manifests as bronchial pneumonia or lobar pneumonia with
many inflammatory secretions in the bronchioles and alveoli. Its CT manifestations are
mainly extensive patchy consolidations of the lung parenchyma, and GGOs are less common.
Mycoplasma pneumonia commonly occurs in school-age children and adolescents but rarely
occurs in adults. The chest CT findings of MPP in adults are mostly bronchial wall thickening
and centrilobular nodules; bronchial wall thickening is considered the manifestation of
lobular pneumonia, and centrilobular nodules are small airway lesions. The proportion of
lung consolidation is as high as 61% in MMP. In contrast, CT manifestations of COVID-19
are mainly pure GGOs at the early stage and visible consolidations in the center of the lesions
at the progressive stage, but the proportion of consolidations in COVID-19 is less than that in
MMP. In addition, COVID-19 needs to be differentiated from lung disease caused by other
diseases.10 For example, the 2 suspected patients reported above were given completely
different treatments, which mainly aimed to control pneumonia and primary diseases. Heart
failure–induced pulmonary edema manifests differently at different stages of the disease. It
can be divided into 2 subtypes: pulmonary alveolar edema (type I) and interstitial pulmonary
edema (type II). Computed tomography manifestations of type I pulmonary edema mainly
include local or multiple GGOs, patchy high-attenuation patterns, and large patchy high-
attenuation patterns in both lungs, which typically exhibit the highattenuation butterfly sign
with both hila as the center, accompanied by signs of interstitial pulmonary edema such as
sporadic or local interlobular septal thickening. Computed tomography manifestations of type
II pulmonary edema mainly include extensive or local interlobular septal thickening in both
lungs, peribronchial cuffing, and redistribution of blood flow in both lungs, which may be
accompanied by signs of pulmonary alveolar edema, including high-attenuation patterns such
as GGOs.11

Although various types of pneumonias have certain imaging features, COVID-19 and other
viral pneumonias, bacterial pneumonia, and some lesions share some common imaging
features.12 In some cases, it is difficult to differentiate COVID-19 from them by imaging
alone, and first clinical manifestations, contact history, and laboratory tests should also be
considered to make the final diagnosis. The conclusions are listed in Table 1.

In conclusion, in contrast to NAAT of SARS-CoV-2, which is restricted by false-negative

results and detection limitations, chest CT, which is simple to perform and readily available,
can quickly detect lung lesions and make imaging diagnoses at the early stage. Therefore, it
has great value in early screening, differential diagnosis, and disease severity assessment of
COVID-19. For patients with fever as the first symptom and with a history of exposure to
COVID-19, chest CT examination should be performed as soon as possible. If imaging shows
the presence of typical manifestations of 2019-nCoV, even if the NAAT result for the
detection of SARS-CoV-2 is unavailable or negative, it is still necessary to take isolation
measures to avoid the spread of the epidemic.
https://journals.sagepub.com/doi/pdf/10.1177/0846537120913033

X-ray and CT Scan The x-ray equipment used in this case series was Polymobil Plus Mobile
X-ray (Siemens Healthineers, Erlangen, Germany). Chest X-ray images were taken on AP
supine projection with exposure factors of 100-110 kVp and 4-8 mAs. The CT equipment
used in this case series was SOMATOM Definition AS 64 slices (Siemens Healthineers,
Erlangen, Germany) with parameters of 120 kV, 124 mAs, and 5 mm image thickness
continued with lung and mediastinum window reconstruction. Images were sent to INFINITT
PACS (INFINITT Healthcare, Korea) to be read by the radiologists. Senior radiologists with
practical experience of 20 years provided expertise for both CXR and chest CT images of
each patient. The patients in this case series were all males with an age range of 37-57 years
old. All three had mild to moderate symptoms with the most common symptom being fever.
Two out of the three patients had lymphocytopenia, while only the first patient had decreased
white blood count and platelets. The first and second patient had a significantly high level of
CRP, especially the second patient with CRP levels of approximately 20 times over the
normal range. The CXR of all three patients showed bilateral infiltrates, suggestive of
pneumonia. Chest CT of all three patients showed bilateral subpleural ground glass opacity
with interlobular septal thickening, also suggestive of pneumonia. RT-PCR for the first and
second patient was confirmed positive for SARS-CoV-2. As of the writing of this paper, the
RT-PCR result of the third patient is yet to be released. The mean duration of hospitalization
was 12.3 days.

To our knowledge, as of the writing of this paper, this is the first case series in Indonesia that
discusses the importance of chest CT in diagnosing COVID-19. The median age in this study
was 42 years old, which is younger than that reported by Guan et al.6 (47 years old), Wang et
al.7 (56 years old), Zhou et al.8 (56 years old), and Zhang et al.9 (57 years old). In
accordance with recent studies, the most common clinical symptom in this report was fever,
while gastrointestinal symptoms only appeared in one patient in the form of early onset
diarrhoea.6-9 However, out of the three patients, only one manifested dry cough, which, in
tandem with fever, were the two most dominant clinical characteristics as reported by several
recent studies.6-9 All three patients had mild to moderate symptoms, most likely due to their
relatively young age, with the oldest patient being 57 years old. Studies have shown that
older patients tend to manifest more severe symptoms, while younger patients tend to
manifest mild to moderate symptoms.7-10 The mean duration of hospitalization was 12.3
days, quite similar to the data reported by Guan et al.6 (12.8 days), and Zhou et al.8 (11.0
days). The patients were discharged based on clinical, laboratory, and radiological
improvements. Ideally, two consecutive negative RT-PCR results should be the decisive
factor in the discharge of COVID-19 patients. However, due to the continually increasing
number of confirmed patients, and limited access to RT-PCR results, physicians adapted and
discharged patients based on the improvements of the patients’ general conditions and
minimalized the chance of transmission by monitoring the number of days since the first
onset of their illness.

Although the three patients manifested different clinical symptoms that are mostly mild and
different laboratory findings that are not specifically indicative of COVID-19, all three chest
CT scans had uniformed results which point to the diagnosis of COVID-19. Physicians
should be aware and not be misled by vague laboratory findings of the patients. Such as in the
case of the first patient, where the Tubex®TF rapid typhoid test even suggested a strong
positive result for typhoid. The patient received antibiotics prescribed for typhoid, but the
fever persisted, and CRP levels kept increasing. Only after the patient received a new therapy
regiment (Hydroxychloroquine 2 x 400mg, Azythromycin 1 x 500mg, Vitamin C 2 x
2000mg) did the fever subside and CRP levels started decreasing. To the authors’ knowledge,
there is no study yet reporting a false positive for Salmonella sp. IgM in COVID-19 patients.

The chest CT findings in this case series were largely consistent with those found in recent
studies, with the hallmark of novel coronavirus pneumonia (NCP) being the presence of a
bilateral subpleural distribution of ground-glass opacity accompanied by interlobular septal
thickening.5,11 All three patients had positive chest CT findings for COVID-19 before RT-
PCR confirmed the diagnosis a few days after, indicating that chest CT is a swift screening
tool for COVID-19. Moreover, chest CT has also been exhibited to be able to diagnose
COVID-19 accurately, with a sensitivity of over 97% and a specificity of approximately
25%.(3, 4) The study of Fang et al. has even argued that chest CT is a more reliable
alternative to RT-PCR in diagnosing COVID-19 patients, due to various variables that could
potentially render the results of RTPCR invalid.4 While Shi et al.5 proposed that chest CT
could be used to screen asymptomatic COVID-19 patients, the study of Ai et al.3 has
suggested that there is a mean delay of around 5 days for serial RT-PCR test to turn from
initial negative to positive. As a delay in diagnosis could translate into a delay in proper
patient management, a swift and accurate diagnostic tool is desperately needed, especially in
a pandemic such as this. Nevertheless, as essential of a modality CT is, the safety and health
of the radiographers, radiologists, healthcare workers and patients are of the utmost
importance, as per the current statement from the American College of Radiology. Therefore,
precautionary steps should be taken to limit the spread of COVID-19 and to ensure minimal
radiation exposure to both patients and healthcare workers.
The authors are aware that there are still limitations to this study. First, the population of this
study was small, and might not represent a genuine condition in a natural environment. The
inclusion of more patients would naturally paint a more comprehensive picture of the
importance of chest CT findings in COVID-19 patients. Second, this study only fixated on
the baseline chest CT findings that the physicians first encountered, without including
findings from follow-up CT scans. The inclusion of follow-up CT scans could potentially
highlight the importance of chest CT in following disease progression. Third, this study only
included the baseline laboratory results of the patients on admission, excluding other
laboratory exams that the physicians initially deemed unnecessary before the confirmation of
the diagnosis of COVID-19. More comprehensive laboratory findings could give a more
vivid understanding of the overall condition of the patients, and insight to prognosis.
file:///Users/puticallistha/Downloads/1430-5093-2-PB.pdf

Sebagai infeksi saluran pernapasan, pencitraan dada dengan CT-scan memainkan peran
penting dalam deteksi, evaluasi keparahan, dan tindak lanjut perjalanan penyakit. CT-scan
toraks telah terbukti sebagai teknik pilihan dalam pencitraan infeksi paru. 4 Salah satu
modalitas pencitraan utama yang menjadi pilihan untuk pemeriksaan COVID-19 ialah CT-
scan toraks.2

Penelitian oleh Xia et al5 dilakukan di Rumah Sakit Anak, Wuhan, terhadap pasien laki-laki
berusia 1-10 tahun dan pada pasien perempuan berusia 8-14 tahun. Kesemuanya
memperlihatkan gambaran CT-scan toraks berupa GGO. Pada pasien perempuan berusia 8
tahun didapatkan gambaran GGO di lobus inferior paru kiri; dan pada pasien perempuan
berusia 14 tahun didapatkan GGO yang tersebar di lobus inferior paru kanan, terletak
subpleural atau meluas dari lesi subpleural.

Wang et al6 melakukan penelitian terhadap pasien laki-laki berusia 22-78 tahun dan pasien
perempuan berusia 21 tahun. Kesemuanya memperlihatkan adanya gambaran GGO dengan
beberapa variasi, berupa: GGO soliter; beberapa area GGO di bagian bawah bilateral lobus
paru; GGO dengan dilatasi vaskular; GGO dengan bronkodilatasi vaskular; GGO yang tidak
merata; GGO dengan vasodilatasi dan konsolidasi; dan GGO dengan halo sign di lobus kanan
bawah.

Pada penelitian oleh Cui et al7 terhadap pasien laki-laki berusia 28-67 tahun dan pasien
perempuan berusia 45-69 tahun didapatkan juga gambaran GGO yang bervariasi, berupa:
GGO yang tidak merata (setelah 3 hari masuk rumah sakit/MRS) yang berlanjut peningkatan
area GGO subpleural secara bilateral disertai dengan konsolidasi dan bayangan seperti kabel
serta penebalan septum interlobular (setelah 6 hari MRS); GGO di sepanjang berkas vaskular
di daerah subpleural segmen lingula lobus kiri atas (setelah 2 hari MRS) yang berlanjut
menjadi GGO yang meluas disertai konsolidasi, selanjutnya area lesi meningkat secara
bermakna dengan peningkatan konsolidasi yang tidak merata (setelah 9 hari /MRS), dan CT
toraks setelah 15 hari MRS menunjukkan kepadatan GGO menurun; GGO tersebar di kedua
paru; beberapa GGO subpleural bilateral dan setelah 7 hari MRS gambaran CT-scan toraks
menunjukkan GGO difus bilateral dan subpleural yang melibatkan beberapa lobus paru;
GGO yang tidak merata dan perubahan seperti jaringan secara bilateral di area subpleural dari
pinggiran paru, CT-scan toraks diambil setelah 3 hari MRS menunjukkan peningkatan GGO
yang tidak merata secara bilateral di pinggiran paru disertai dengan konsolidasi, GGO dan
bayangan seperti jaringan di dalam paru disertai penebalan septum interlobular.
Pada penelitian oleh Zhu et al8 terhadap pasien laki-laki berusia 41-67 tahun dan pasien
perempuan berusia 43-57 tahun didapatkan gambaran GGO yang bervariasi, berupa: GGO
dengan konsolidasi di lobus kanan bawah, disertai air bronchogram; GGO dengan konsolidasi
streak dan garis subpleural di paru kiri bawah; GGO yang terdistribusi di sekitar pinggiran
dengan pola retikuler atau gambaran sarang lebah; GGO dengan konsolidasi beruntun yang
terdistribusi di daerah perifer dan garis subpleural di lobus kanan atas; GGO perifer
berbentuk bulat dengan sedikit konsolidasi di lobus kanan bawah; serta beberapa GGO yang
tersebar di area perifer, GGO dengan konsolidasi di lobus bawah, GGO dengan gambaran
vakuola di segmen atas paru kiri, dan GGO dengan penebalan septum interlobular di lobus
inferior kanan.

Penelitian oleh Gu et al9 terhadap pasien laki-laki berusia 46-70 tahun dan mendapatkan
gambaran GGO pada lobus kanan disertai nodul; distribusi campuran bilateral dari GGO
dengan kelainan yang terjadi secara bersamaan meliputi pola sarang lebah dan penebalan
interlobular.

Penelitian oleh Li et al10 dilakukan pada pasien laki-laki berusia 1-4 tahun. Pada pasien laki-
laki usia 1 tahun 5 bulan, CTscan toraks setelah 4 hari menunjukkan adanya GGO yang tidak
merata pada lobus kanan atas, namun setelah 5 hari didapatkan penampilan menjadi normal.
Demikian pula pada seorang pasien laki-laki berusia 3 tahun, CT-scan toraks setelah 9 hari
gejala menunjukkan adanya GGO yang tidak merata di lobus kiri bawah, namun setelah 7
hari kemudian didapatkan tampilan normal. Hal yang serupa didapatkan juga pada seorang
pasien laki-laki berusia 4 tahun, CTscan toraks setelah 2 hari MRS memperlihatkan adanya
GGO yang tidak merata di lobus kiri bawah, namun CT-scan toraks setelah 5 hari kemudian
memperlihatkan tampilan normal.

Penelitian oleh Steinberger et al11 dilakukan pada pasien laki-laki berusia 8-18 tahun dan
pasien perempuan berusia 14 tahun. Hasil penelitiannya mendapatkan gambaran GGO pada
semua kasus dengan variasi untuk masing-masing kasus. Pasien laki-laki usia 8 tahun, CT-
scan toraks menunjukkan GGO minimal pada lobus kanan bawah dan kiri dan tidak
didapatkan konsolidasi. Pada seorang pasien laki-laki berusia 15 tahun, CT-scan toraks
menunjukkan GGO bilateral dan konsolidasi dalam pola predominan perifer dan basilar yaitu
pola yang dapat dilihat pada cedera paru dengan pengorganisasian akut. Pada seorang pasien
laki-laki berusia 18 tahun, CT-scan toraks menunjukkan distribusi perifer dan basilar yang
dominan dari GGO disertai area GGO di lobus kiri atas dengan konsolidasi perifer. Pada
seorang pasien perempuan berusia 14 tahun, CT-scan toraks menunjukkan distribusi bilateral
dan perifer dari GGO dengan tanda halo sign di lobus kiri bawah, sedangkan lobus atas dan
lobus tengah kanan tidak menunjukkan kelainan.

Pada penelitian yang dilakukan oleh Zhang et al12 terhadap pada pasien laki-laki berusia 20-
35 tahun. Hasil penelitiannya mendapatkan gambaran GGO pada semua kasus. Pada pasien
laki-laki usia 20 tahun, CT-scan toraks menunjukkan GGO di paru kanan bawah, kemudian
setelah 4 hari CTscan toraks menunjukkan peningkatan GGO. Pada pasien laki-laki berusia
35 tahun dengan CT -scan toraks yang menunjukkan lesi GGO dengan satu nodul padat kecil
di dalamnya di lobus paru kiri bawah, dan setelah 5 hari CT -scan toraks menunjukkan
peningkatan lesi dan tanda pembuluh darah membesar serta tanda bronkogram.

Pada penelitian yang dilakukan oleh Jiang et al13 terhadap pasien laki-laki berusia 66 tahun
dan pasien perempuan berusia 57- 86 tahun. Didapatkan seorang pasien lakilaki usia 66 tahun
CT -scan toraks pada hari ke-5 menunjukkan GGO dan setelah hari ke 11, 15, 19 dan 23
menunjukkan ukuran dan kepadatan lesi pada kedua paru secara bertahap dan bermakna
menurun. Pada seorang pasien perempuan berusia 57 tahun, CTscan toraks awal dilakukan
pada hari pertama menunjukkan GGO multifokus dan konsolidasi kemudian setelah hari ke-7
dan 14 hari menunjukkan lesi paru sembuh secara bermakna. Pada seorang pasien perempuan
berusia 57 tahun, CT-scan toraks awal dilakukan pada hari ke-4 menunjukkan GGO
multifokus dan konsolidasi kemudian setelah hari ke-10 dan 20 menunjukkan lesi paru
sembuh secara bermakna. Demikian pula pada seorang pasien perempuan berusia 65 tahun,
CT-scan toraks dilakukan hari ke7 setelah onset penyakit menunjukkan GGO yang tidak
merata terlihat di area subpleural lobus kanan bawah paru dan pada hari ke-15, CT-scan
toraks menunjukkan lesi telah sembuh dengan jelas dan ukurannya berkurang. Pada seorang
pasien laki-laki berusia 67 tahun, CT-scan toraks dilakukan hari ke8 setelah onset penyakit
menunjukkan GGO yang tidak merata terlihat di area subpleural lobus kanan bawah paru dan
pada hari ke-15, CT-scan toraks menunjukkan lesi telah sembuh dengan jelas dan ukurannya
berkurang. Pada seorang pasien perempuan berusia 86 tahun CT-scan toraks awal dilakukan
pada hari pertama menunjukkan GGO di daerah subpleural lobus kanan atas paru kemudian
pada hari ke-7 CT-scan toraks menunjukkan ukuran lesi membesar dan GGO baru diamati di
area subpleural lobus kiri atas paru yang artinya hasilnya telah berkembang, kemudian pada
hari ke-27, CT-scan toraks menunjukkan kepadatan lesi menurun secara bermakna yang
berarti hasilnya telah terjadi pengurangan, 13

Pada penelitian oleh Linjun et al14 terhadap 49 pasien, 35 pasien tipe ringan tanpa komorbid,
dan 14 pasien tipe parah dengan komorbid. Hasil CT-scan toraks memperlihatkan bahwa
pada pasien dengan tipe ringan ditemukan GGO murni (34 pasien), konsolidasi (9 pasien),
GGO dengan konsolidasi (19 pasien), dan fibrosis (15 pasien). Pada tipe parah ditemukan
GGO murni (14 pasien), konsolidasi (4 pasien), GGO dengan konsolidasi (12 pasien), dan
fibrosis (11 pasien). Pasien dengan tipe parah lebih cenderung menyandang penyakit
hipertensi. CT-scan toraks menunjukkan tidak terdapat perbedaan bermakna antara tipe
ringan dan tipe parah dengan adanya GGO murni pada 48 pasien. Pada pasien tipe parah, CT-
scan toraks menunjukkan lebih banyak GGO dan konsolidasi dibandingkan pada pasien tipe
ringan; selain itu pasien tipe parah memiliki lebih banyak fibrosis dibandingkan pasien tipe
ringan.

Hasil kajian literatur menunjukkan air bronchogram, konsolidasi, dan GGO merupakan fitur
pencitraan yang paling sering dilaporkan. Pada penelitian ini didapatkan bahwa GGO
merupakan temuan CT-scan toraks yang khas dengan morfologi bulat dan distribusi paru
perifer, juga didapatkan GGO yang lebih luas dari pada konsolidasi. 12 Salah satu penelitian
menyatakan bahwa CT-scan toraks dapat secara akurat mengevaluasi fitur dan luas lesi paru.
Pada penelitian itu juga dikatakan bahwa tanda CT-scan toraks yang khas ialah GGO, GGO
dengan konsolidasi campuran, penebalan pleura yang berdekatan, penebalan septum
interlobular, dan bronkogram udara. 14

Pada pasien anak sampai dengan dewasa, CT-scan toraks dapat menunjukkan perubahan
karakteristik. Umumnya pada anak ditemukan bentuk ringan karena tidak memiliki riwayat
penyakit bawaan, dengan GGO unilateral atau bilateral. 5 Penelitian lainnya melaporkan
bahwa tidak terdapat perbedaan bermakna dari CT-scan toraks untuk pasien usia muda dan
lanjut, tetapi pada pasien usia lanjut, CT-scan toraks menunjukkan rasio garis subpleural dan
ketebalan pleura yang lebih tinggi dibandingkan pasien berusia muda, terlebih lagi seluruh
lobus paru lebih mungkin dapat terlibat. 8
Berdasarkan jenis kelamin, temuan CT- scan toraks menunjukkan bahwa tidak terdapat
perbedaan bermakna antara kedua jenis kelamin.10 Penelitian ini juga mendapatkan bahwa
tidak ada perbedaan bermakna berdasarkan jenis kelamin. Selain itu hasil menunjukkan
bahwa fitur pencitraan mirip satu sama lain dan memiliki GGO bilateral dan perifer di paru.
13

Temuan CT-scan toraks yang dilakukan jika ditinjau berdasarkan komorbid menunjukkan
bahwa tidak terdapat perbedaan bermakna pada pasien dengan dan tanpa komorbid, namun,
pasien dengan komorbid memiliki lebih banyak GGO dan konsolidasi dibandingkan pasien
tanpa komorbid. 14

Gambaran CT-scan toraks pada pasien COVID-19 memperlihatkan adanya air bronchogram,
konsolidasi, dan ground-glass opacities. Tidak terdapat perbedaan bermakna dari gambaran
CT-scan toraks berdasarkan usia, jenis kelamin, dan komorbid.

Diharapkan adanya penelitian lebih lanjut dan mendalam mengenai gambaran hasil CT-scan
toraks yang lebih spesifik dengan komorbid seperti penyakit hipertensi, penyakit ginjal, dan
penyakit hati.
file:///Users/puticallistha/Downloads/32416-67726-1-PB.pdf

Meanwhile, several reports have indicated a possible role for chest CT scans in the diagnosis
of this disease.3,7-9 Chest CT scanning may be used for the diagnosis of COVID-19
infection in several settings. First, health care institutions that adopt a strategy of containment
may decide to use chest CT scanning for the evaluation of patients in whom COVID-19
needs to be excluded, in addition to RT-PCR. Second, chest CT scanning may have a
potential role as a problem-solving diagnostic tool in patients in whom RT-PCR testing
remains negative, despite persistent clinical suspicion. Third, CT scans that are performed as
part of standard clinical care, for reasons other than COVID-19 evaluation (eg, oncologic
follow-up CT scans), may reveal lung abnormalities that can suggest the diagnosis of
COVID-19, even in asymptomatic individuals.3,7-9 Given the diagnostic potential of chest
CT scanning, it is imperative for radiologists to have knowledge of the typical imaging
characteristics of COVID-19 infection. Although several previous studies have described
chest CT characteristics of COVID-19 infection, these individual studies may suffer from low
sample sizes and differences in study design and methods. Of interest, the Fleischner Society
recently published an expert opinion statement on the use of chest imaging (including
radiography and CT scanning) in patient treatment during the COVID-19 pandemic, with the
intent to offer guidance to physicians on the use of thoracic imaging across a breadth of
health care environments.10 However, the Fleischner Society also acknowledged that the
evidence base that supported the use of imaging across the scenarios presented was scant and
that their advice may undergo refinement through rigorous scientific investigation.10 A
systematic review and meta-analysis is required to overcome the limitations of individual
studies and to provide an up-to-date overview that can be used to optimize the diagnostic
interpretation of chest CT scanning for COVID-19 infection.

The purpose of this study was to review systematically and meta-analyze the chest CT
imaging signature of COVID-19 infection.

The number of studies on chest CT imaging in COVID19 has increased rapidly since the
pandemic outbreak of this disease. However, both individual studies, nonsystematic reviews,
and expert opinion articles may contain claims that are not substantiated by evidence. This is
potentially dangerous because health care providers need to be provided with unbiased,
reliable data to make the right clinical decisions. For other diseases that are already known
and that do not pose an imminent threat to humanity, scientific evidence can be accumulated
and reflected on at a relatively slower pace. However, COVID-19 does not provide this
relative luxury, hence the potentially higher risk for health care providers to make clinical
decisions based on missing, incomplete, or incorrect information. Because of the potential of
chest CT scanning in adjunct to clinical examination and RT-PCR for the diagnosis of
COVID19 and the rapid proliferation of studies on this topic, a systematic review and a meta-
analysis were performed to assess the methodologic quality of these studies and to determine
the frequency of different chest CT imaging findings that are found in this disease.

Twenty-seven of 28 studies (96%) that were included had a retrospective design.

Methodologic quality concerns were present in all 28 included studies. Methodologic
concerns were a failure to report whether patient recruitment was consecutive or random
(13/28 [46%] of studies), the exclusion of patients without any abnormalities on CT imaging
(8/28 [29%] of studies), a failure to report the time interval between CT and RTPCR/gene
sequencing (24/28 [86%] of studies) or a time interval of up to 7 or 14 days (2/28 [7%] of
studies), a lack of information on observer agreement variability in the interpretation of chest
CT (27/28 [96%] of studies), and a failure to report whether the chest CT image was
interpreted without knowledge of CT and RT-PCR/gene sequencing results (14/28 [50%] of
studies). Importantly, some journals provide so-called “ultra-rapid” peer review services
(within 24 hours) for COVID-19-related research.42 It has been reported that such a service
may result in a series of high-quality research publications with downloads that are 6 to 30
times greater than the average articles that are published in the same journal and that several
of these COVID-19 publications have been in the top two or three trending articles on
PubMed.42 However, the results of the present study challenge the claim that only high-
quality research is published with such a policy. In fact, the results indicate the lack of a solid
scientific foundation for chest CT scanning in COVID-19 and the need for more highquality
studies. Our findings resonate with a previous review that concluded that the published
literature reporting on chest CT features in COVID-19 consisted of limited retrospective
studies with methodologic quality issues.43

Within the boundaries of the available evidence, a critical finding of this systematic review
and meta analysis was that 10.6% of patients with proven COVID-19 (almost all of these
patients were symptomatic) had normal chest CT imaging findings. The substantial
prevalence of normal chest CT imaging findings is clinically relevant because it implies that a
negative chest CT scan cannot exclude COVID-19 with sufficient certainty, not even in
symptomatic patients. Although it has been reported that normal findings at chest CT
scanning may occur more frequently in the first days after symptom onset,44 a nonnegligible
number of symptomatic patients with normal chest CT imaging findings are observed during
the later stage of the infection.44-46 Therefore, it is questionable whether chest CT images
can be used for accurate stratification of patients in a screening setting that aims strictly to
isolate individuals with COVID-19 from those without. Importantly, six imaging findings
were observed in >70% of COVID-19-confirmed cases; these included posterior predilection,
ground-glass opacity, bilateral abnormalities, left lower lobe involvement, vascular
thickening, and right lower lobe involvement, in order of decreasing frequency. In geographic
regions in which COVID-19 is endemic, the observation of these chest CT imaging findings
should raise the suspicion of possible COVID-19 infection. On the other hand, several
imaging findings were observed in #5% of COVID-19-positive cases; these included pleural
effusion, lymphadenopathy, airway secretions/tree-inbud sign, central lesion distribution,
pericardial effusion, and cavitation/cystic changes, in order of decreasing frequency. The
isolated observation of one or more of these chest CT imaging findings therefore may be
suggestive of another diagnosis, although it should be noted that COVID-19 cannot be
eliminated completely from the differential diagnosis. Altogether, the aforementioned chest
CT imaging findings on both sides of the spectrum regarding observed frequencies in
COVID-19 may be helpful to imaging physicians to determine the likelihood of COVID-19.
However, some caution is warranted, because these chest CT imaging findings were extracted
from studies that generally provided no to little information on the presence and types of
pulmonary comorbidities (which may cause CT scanning abnormalities that are not related to
COVID-19) in the patients who were included. Finally, other chest CT imaging findings were
found to be of relatively lower value in terms of true-positive or false-negative rates.

This systematic review and meta-analysis had some limitations. First, only RT-PCR-
confirmed COVID-19 cases were included. Chest CT features of COVID-19 may overlap
with those of other entities, which include, but are not limited to, other viral and (atypical)
bacterial pneumonias, interstitial lung diseases, drug-induced lung disease, alveolar
hemorrhage, and pulmonary edema due to a wide range of cardiogenic or other
noncardiogenic causes.47 The individual chest CT scan abnormalities that were retrieved by
our analysis are nonspecific; if a mixed group of infections were studied (as would be typical
in most settings, except in the epicenter of a COVID-19 outbreak), it can be expected that
specificity will be further compromised. Future studies are required to test which chest CT
criteria achieve optimal sensitivity and specificity in differentiating COVID-19 from other
entities in different clinical settings and with different disease prevalence rates. Second, the
various chest CT imaging findings based on the Fleischner Society’s glossary terms were
assessed individually and pooled regarding frequency of appearance in COVID-19. However,
a combination of chest CT imaging findings will likely be necessary to establish an
appropriate confidence scale for the diagnosis of COVID-19. Of interest, a Radiological
Society of North America Expert consensus statement on reporting chest CT imaging
findings related to COVID-19 was published recently.48 Four categories for reporting CT
imaging findings potentially attributable to COVID-19 were proposed, and three of these
categories used a combination of chest CT imaging findings.48 Furthermore, there are no
published studies yet that have evaluated this chest CT classification scale, to our knowledge.
However, this categorization and the corresponding CT criteria were based on a limited
number of studies that were selected by an expert committee.48 The findings of the present
systematic review and meta-analysis may be helpful to further develop existing confidence
scales for COVID-19, such as the one that was issued recently under auspices of the
Radiological Society of North America.48 The presented data may also serve as an input for
machine learningbased diagnostics. Third, the majority of studies that were included
originated from China. Nevertheless, there is no a priori assumption as to whether chest CT
imaging findings in COVID-19 would be different in non-Chinese populations. Fourth,
temporal changes on chest CT imaging during the course of disease could not be assessed.
Although several of the studies that were included also reported some information on
temporal changes on chest CT images during the course of disease,15,22,27,28,32,34-38,40
they had from a considerable amount of flaws and limitations in the analysis of temporal
changes on chest CT images. None of these studies described sufficient details of the patients
who underwent chest CT imaging at different time points to understand potentially
confounding factors on the temporal course of chest CT imaging findings (such as pulmonary
comorbidities and therapies that were administered). Time points of chest CT imaging during
the course of disease were dissimilar among all studies, and all studies provided mere
descriptive data without performing comprehensive statistical analyses to assess for
differences in chest CT imaging findings between different time points.15,22,27,28,32,34-
38,40 Furthermore, one study compared different patients who underwent chest CT imaging
at different time points rather than evaluating the time course of chest CT imaging findings in
the same patients.15 In the other studies that did perform an intrapatient evaluation during the
course of disease, either only a subset of patients underwent followup chest CT imaging,
which caused selection bias,22,27,28,32,34-38 or chest CT imaging findings were
insufficiently reported.40 Consequently, the available data on temporal changes on chest CT
images are unreliable, lack clinical applicability, and cannot be summarized systematically.
The same concerns apply to the studies that were excluded from this systematic review and
metaanalysis. A prospective well-designed study is still required to determine the natural
evolution of chest CT imaging findings in COVID-19.

In conclusion, studies on chest CT imaging findings in COVID-19 suffer from methodologic

quality concerns. More high-quality research is necessary to establish diagnostic CT imaging
criteria for COVID-19. Based on the available evidence that should be interpreted with
caution, several chest CT imaging findings appear to be suggestive of COVID-19, but normal
chest CT imaging findings do not exclude COVID-19, not even in symptomatic patients.
https://journal.chestnet.org/article/S0012-3692(20)31733-5/pdf
PEMERIKSAAN LAB

The leukocyte formula also showed a significant association between the five
components (neutrophils, eosinophils, basophils, lymphocytes and monocytes) and
COVID-19 patients. The most represented neutrophils and, to a lesser extent,
lymphocytes, were lower in the positive group.

The leukocyte formula also showed a significant association between the five components
and COVID-19-positive patients. However, although basophils, eosinophils and monocytes
showed a significant decrease with relatively low p-values (Table 2), their count, even in
healthy individuals, is rather low and might be affected by a large variability regardless of the
pathological situation. Thus, they might not have a clinical implication in the COVID-19
diagnosis.

Transaminase and LDH were strongly associated with the COVID-19 disease (Table 2).
High levels of AST and ALT have been observed previously in hospitalized COVID
patients [16]; however, to the best of our knowledge, they were never compared with
patients affected by pulmonary diseases but COVID-19 negative. The strong association
between LDH and the COVID-19 disease (Table 2) might be explained by the facts that this
enzyme is known to be a marker of lung damage [17] and that COVID-19 primarily infects
the lower respiratory tracts.

We also observed a gender discrepancy between the two groups which cannot be attributed to
a bias in the selection of patients. However, due to the limited number of patients enrolled in
the study, we need more data in order to verify whether the large difference between males
and females in the positive group was just a causality or could be an important factor to be
considered when discriminating between positive and negative COVID-19 patients.

By empirically using cutoff levels for LDH and AST, we were able to identify, with an error
rate similar to that observed for rRT-PCR [15], the COVID-19 positivity/negativity in almost
70% of the patients. We believe that by using a larger dataset and appropriate software to
combine multiple variables (including gender) it should be possible to identify a panel of
analytes with appropriate cutoffs, able to identify, with high accuracy, patients infected by
COVID-19.

It must be noted that our study suffers from a few limitations like the relatively limited
number of patients and the absence of recorded patients’ clinical signs which can help in
discriminating between positive and negative COVID-19 patients

By comparing the routine blood analysis of 207 patients who were rRT-PCR tested, after
being admitted to the emergency room with COVID-19 symptoms, we found statistically
significant differences in the plasma levels of WBC, CRP, AST, ALT and LDH between
those who were positive at the genetic test and those who were negative. Using rRT-PCR as
the gold standard, almost 70% of the patients could be classified as COVID-19 positive
or negative on the basis of their hematological parameters. Thus, a simple blood test
might help in identifying false-positive/negative rRT-PCR tests but also might be used
in developing countries and in those countries suffering from a shortage of rRT-PCR
reagents and/or specialized laboratories as an inexpensive and available alternative to
identify potential COVID-19 patients

Recent studies showed that a few hematologic parameters were clearly altered in COVID-19
patients [9, 10]. For instance, Liu et al. [11] showed a high level of transaminases and LDH
in Chinese COVID-19 patients.

In our study, we analyzed the blood test results of 207 patients who, after being admitted to
the San Raffaele Hospital (Milan, Italy) emergency room with COVID-19 symptoms, were
tested for rRT-PCR. Of them, 105 tested positive whereas 102 tested negative. We analyzed
the plasma levels of white blood cells (WBCs), platelets, C-reactive protein (CRP), aspartate
aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT),
alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in the two groups, with the aim
of highlighting statistically significant differences which could be useful for the identification
of positive and negative COVID-19 patients. Thus, a simple blood test might help in
identifying false-positive/negative rRT-PCR tests as well as play a crucial role in the mass
screening of potential COVID19-infected individuals in those countries which suffer from a
large shortage of rRT-PCR reagents and/or specialized laboratory.

WBCs were measured in all of the 207 patients and were significantly different between the
two groups (Table 2). The p-value as low as < 0.001 indicated a strong association between
COVID-19-positive patients and a low WBC count (Table 2). The leukocyte formula also
showed a significant association between the five components (neutrophils, eosinophils,
basophils, lymphocytes and monocytes) and COVID-19 patients (Table 2). The most
represented neutrophils and, to a lesser extent, lymphocytes, were lower in the positive group.

No association (p-value: 0.072) was observed between platelets and the disease (Table 2),
whereas CRP was significantly higher in the positive group (Table  2). High values of the
pyridoxal phosphatedependent enzymes AST and ALT were significantly associated with the
COVID-19 disease (Table 2). In contrast, ALP and GGT showed a p-value higher than 0.05
indicating no association between these two analytes and the pandemic disease (Table 2). A
strong association was observed for LDH as well (p-value: < 0.001) (Table 2). Unfortunately
not all patients underwent a complete blood test analysis and a few analytes were measured in
a limited number of patients (Table 2). For instance, AST was measured in all of the patients
while LDH was measured in 141 only. Such patients were called the “LDH group” (78 and
63 from the positive and negative groups, respectively) (Table 2).

In order to tentatively develop a COVID-19 diagnostic method based on routine blood

test analysis, we empirically adopted cutoff levels of 210 U/L and 35 U/L for LDH and
AST, respectively, for COVID-19 positivity. In the LDH group, 66 patients had both LDH
and AST above the cutoffs and 55 of them (PPV: 83.3%) tested positive at the rRT-PCR test
(Table 3). In contrast, by considering patients with an AST level lower than 25 U/L as a
marker of COVID-19 negativity, regardless of the LDH measurement, of the 141 patients, 32
fell in this group and 29 of them (NPV: 90.6%) were indeed rRT-PCR negative (Table 3).
The remaining 43 patients having AST between 25 and 35 U/L could not be classified. Thus,
in the LDH group, on the basis of their blood test results, 98 patients (69.5%) could be
identified as either COVID-19 positive or negative with a PPV and an NPV of 83.3% and
90.6%, respectively. When extending the AST < 25 U/L to the whole group (207 patients),
we identified 54 patients and 48 of them tested negative (NPV: 88.9%) at the rRT-PCR test
(Table 3).

Interestingly, even though the patients were randomly selected, a gender discrepancy was
observed between the two groups: the negative group had a similar number of males and
females (52% and 48%, respectively), whereas the positive group was mostly composed of
males (70.5%).

However, although basophils, eosinophils and monocytes showed a significant decrease with
relatively low p-values (Table 2), their count, even in healthy individuals, is rather low and
might be affected by a large variability regardless of the pathological situation. Thus, they
might not have a clinical implication in the COVID-19 diagnosis.

Transaminase and LDH were strongly associated with the COVID-19 disease (Table 2). High
levels of AST and ALT have been observed previously in hospitalized COVID patients [16];
however, to the best of our knowledge, they were never compared with patients affected by
pulmonary diseases but COVID-19 negative. The strong association between LDH and the
COVID-19 disease (Table 2) might be explained by the facts that this enzyme is known to be
a marker of lung damage [17] and that COVID-19 primarily infects the lower respiratory
tracts.

By comparing the routine blood analysis of 207 patients who were rRT-PCR tested, after
being admitted to the emergency room with COVID-19 symptoms, we found statistically
significant differences in the plasma levels of WBC, CRP, AST, ALT and LDH between
those who were positive at the genetic test and those who were negative. Using rRT-PCR as
the gold standard, almost 70% of the patients could be classified as COVID-19 positive or
negative on the basis of their hematological parameters. Thus, a simple blood test might help
in identifying false-positive/negative rRT-PCR tests but also might be used in developing
countries and in those countries suffering from a shortage of rRT-PCR reagents and/or
specialized laboratories as an inexpensive and available alternative to identify potential
COVID-19 patients.
https://sci-hub.se/https://doi.org/10.1515/cclm-2020-0398

COVID-19 plays a critical role in the host immune response in disease pathogenesis and clinical
manifestation. It triggers the antiviral immune system to produce an uncontrolled inflammatory
response that may lead to cause hematological abnormalities such as lymphopenia,
lymphocytes, and abnormalities in granulocyte and monocyte. These hematological
abnormalities can facilitate the infection by other microorganisms, septic shock, and multi-organ
dysfunction. Moreover, individuals with comorbid diseases such as hypertension, obesity, diabetes,
etc., are at higher risk of coronavirus infection. Most comorbidities are frequently associated with
excessive body fat mass [8]. As a result, it alters various hormonal, metabolic, and inflammatory
functions. Also, adipose tissue may involve in the pathogenesis of COVID-19, where obesity plays an
important role [9]. Hypertension is also a risk factor for coronavirus infection. COVID-19 patients with
hypertension might increase severity and mortality rates. Hypertension should consider as a clinical
predictor for the severity of COVID-19 both in adults and children [10]. Also, diabetes is another
comorbidity to increase the COVID-19 disease burden and mortality worldwide [11, 12]. It plays a
primary role in the development of pneumonia and sepsis due to the virus infection. A study showed
that diabetic patients are at higher risk of coronavirus infection. Also, they have an increased chance
of COVID-19 severity and mortality [13]. However, some COVID-19 patients with comorbid diseases
are recovering. Unfortunately, it might create an increased burden for them due to post-COVID
complications.
We presented the hematological alterations of the cohort in Table 2. First, we compared
hematological variations between SCP and NSCP. The SCP had lower RBC and Hb levels than
NSCP. The NSCP showed significantly lower WBC, neutrophils, platelet, CRP, ferritin, d-dimer,
creatinine, SGPT, SGOT, and bilirubin levels than SCP. However, we observed the electrolyte
levels (Na+, K+, Cl-, and HCO3) were higher in NSCP than SCP. We demonstrated the changes of
hematological parameters in two different disease states using box-plot graphs

SCP : severe COVID-19 patient

NSCP : non severe COVID-19 patient

We conducted this observational cohort study to assess the connection of hematological

abnormalities with the severity of hospitalized COVID-19 patients with complications. Amidst the
increasing rate of COVID-19 transmission [31], it is vital to generate comprehensive information
regarding the COVID-19 severity to measure the mortality risks. Hematological parameters and
comorbid disease can help to measure COVID-19 severity [32]. Therefore, we can assess patient’s
severity and mortality risks by easily monitoring those potential indicators. In our findings, we
analyzed some hematological parameters in different severity stages of hospitalized COVID-19
patients. Among the parameters, we found a decreased level of Hb, RBC, packed cell volume
(PCV), mean corpuscular volume (MCV), lymphocytes, eosinophils, and increased level of
WBC, neutrophils in SCP than NSCP. Also, we observed increased CRP, ferritin, d-dimers,
SGOT, and SGPT levels and decreased Na+, K+, CI-, and HCO3 levels in SCP than NSCP.
However, the values of most parameters were within normal ranges. Therefore, these parameters
might have statistical significance but not clinical significance. According to our knowledge, this is the
first-ever study in Bangladesh to find an association of hematological abnormalities in COVID-19
patients with diagnostic performance analysis. Also, we validated the present study findings using
ROC analysis which was absent in most earlier studies. Inconsistent with our findings, speculated
evidence indicates that hematological abnormalities are very prevalent in SCP and increases the
requirement of hospital stay and ICU support otherwise accelerate lethality. Different hematologic
parameter level irregularities are associated with the risk of COVID-19 severity [33–35]. Terpos et al.
reviewed hematological parameters in COVID patients and observed some abnormalities in SCP than
NSCP [36]. Also, some other studies supported the present findings describing the evidence of the
correlation between elevated CRP and ferritin levels in SCP [37–39].

After the SARS-CoV-2 entrance into the blood, it primarily affects the angiotensin-converting enzyme
(ACE2), a receptor of the SARS-CoV-2 expressed in various organs like the liver, heart,
gastrointestinal tract. After 7–14 days of infection, the CT scan report shows changes in the
worsening situation. At this stage, lymphocyte count decreases, and inflammatory cytokine increases
that deteriorate the condition of patients [40]. Lymphopenia is common in critically ill patients that
correlate with the severity of COVID-19 [35, 37, 41]. Moreover, along with the increased leukocytes,
reduced basophils, monocytes, lymphocytes, eosinophils, and platelets are frequently observed in
SCP [42, 43]. According to studies, neutrophilia occurs in COVID-19 patients who required ICU
support. Therefore, the neutrophil-to-lymphocyte ratio can serve as an indicator for the severity of
COVID-19 patients [34, 44]. Several studies observed the incidence of thrombocytopenia due to
decreased platelet count in a significant portion of patients who needed to admit to the hospital
[35, 37]. Lippi et al. accumulated four different studies where it has been showing that the Hb level of
COVID patients is in descending tendency and a contributor for worse advancement [45]. A meta-
analysis of 21 studies on 3,377 patients reported the significant association of abnormal
hematological parameters among SCP [46]. So, the hematological abnormalities have a close
association with the severity of COVID-19, prolongation of hospitalization, and the requirement
of ICU supports.
Based on the above discussion, we noticed that several previous studies recognized the
hematological abnormalities in SCP. But we cannot use these changes for the assessment of COVID
severity due to their absence of predictive performance [34–39]. Initial alterations of any blood
parameters may not serve as a diagnostic predictor until these changes not validated for sensitivity
and specificity. In the present study, we observed a lot of parameters altered in blood levels. But only
CRP and ferritin showed good predicting performances for COVID-19 severity based on the
diagnostic performance evaluation by ROC analysis. These three parameters demonstrated good
sensitivity and specificity. Therefore, we recommend these three factors together can serve as
differentiation factors for SCP and NSCP.

Moreover, coagulation frequently occurs among SCP [38, 47]. Coagulation is associated with a higher
level of d‐dimer and prothrombin time prolongation. These are frequently encountered in severe
stages of COVID-19 and are also considered a prime reason for death [34, 47]. Many past studies
have presumed the elevated d-dimer levels responsible for altered coagulation in COVID-19 patients
[35, 48–50]. Thus d-dimer, a fibrin degradation product, is a possible predictive factor for
COVID-19 severity. In the early stage of the COVID-19 pandemic, a study found elevated d-
dimer levels in 260 COVID-19 patients out of 560 in China [35]. Also, scientific evidence
revealed that patients who died in COVID-19 had a higher level of d-dimer [51]. Besides,
significant increased d-dimer levels were in ICU patients or patients with critical conditions in different
studies [34, 42]. However, the increased level of d-dimer found in hospitalized COVID patients had a
significant predictive performance for the COVID severity in our country. Changes in the immune
system and lung damage are some of the prime abnormalities in COVID-19 patients. It is well
established that cytokine storm causes to increase several inflammatory biomarker’s levels in
SCP [52, 53]. Another cohort study showed that the augmented risks of developing ARDS in SCP
were associated with elevated ferritin, CRP, and other biomarkers levels [54]. Ferritin is a protein that
stores iron. The increased serum ferritin levels reflect the iron level. Another study revealed that
patients who died in COVID-19 had higher ferritin levels and had to stay in hospital for a longer time
[55]. Therefore, elevated serum ferritin induces cytokine storms and severity of COVID-19 patients
[56, 57]. Thus, ferritin levels can serve as a factor for monitoring COVID-19 severity [46]. A
study reported high levels of CRP in SCP. The higher levels of CRP may cause cytokine storms
and affect liver function. Therefore, hepatic abnormalities worse the situation of SCP [58]. Ferritin is
an independent risk factor for the severity of COVID-19. However, there is a positive relationship
between ferritin and CRP in COVID fatality [59]. CRP is a marker of severe infections and
inflammatory responses [60, 61]. Many past studies reported the association between CRP levels and
lung lesions in the severe stage of hospitalized COVID-19 patients [62, 63].

Additionally, COVID-19 is a systemic infection responsible for several clinical appearances [64]. In the
present study, we observed that age, sex, obesity, and comorbid diseases were significantly
associated with the risks for developing severity among COVID-19 patients. Several retrospective
studies also demonstrated increased mortality and morbidity rates in older adults with underlying
comorbidities. Myocardia injuries are also a consequence of hematological abnormalities. The recent
data supports abnormal levels of leukocyte, lymphocyte, platelet counts were predominant in patients
with COVID-19 who had myocardia injuries [65]. One study found that associated comorbidities and
recent history of chemotherapy can potentiate viral load. Therefore, the death rate was 35% for those
COVID-19 patients [66]. Another study conducted in the USA showed that most COVID-19 patients
with comorbid diseases were treated in the ICU by mechanical ventilation [67]. A French study found
that COVID-19 patients with abnormal BMI had 7-fold higher chances to get admitted into the
hospitals for ICU support than non-obese patients [68].

Moreover, several studies showed no significant associations of CRP with the incidence of diabetes
[69, 70]. Other studies reported a high-CRP association only with diabetes-induced complications, like
nephropathy and cardiovascular risk. Ethnic group differences were evident in detecting the
association of CRP levels with hypertension [71]. No correlation was found between CRP and
hypertension levels in Bangladeshi [72], and Chinese participants, except Hispanic participants [73]. A
study showed that an increased CRP level would not result in a higher CKD risk [74]. Evidence
reported an association of CRP levels with the severity of asthma and COPD. We found a general
increase of CRP in all SCP with or without comorbid diseases compared to NSCP, suggesting that
CRP is a crucial factor in determining the severity of COVID patients [75, 76]. Patients with diabetes
had generally higher d-dimer levels. A study showed increased plasma d -dimer levels in patients with
impaired fasting glucose [77], which is because of developing a hypercoagulable state [78]. Increased
level of d-dimer was reported in patients with hypertension [79], CKD [80], and COPD [81]. Increased
level of ferritin predicts the severity of COVID-19 diseases. A high level of ferritin is independently
associated with the prevalence of diabetes [82], hypertension [83], CKD [84], COPD, and worse
asthma symptoms because of a strong correlation with systemic inflammation. The present found an
increase of ferritin levels in SCP regardless of comorbid diseases. The increased ferritin levels may
worsen COVID-19 symptoms by contributing to the cytokine storm.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255379

Blood tests have an important role in early diagnosis of the disease, considering the
information they provide to physicians regarding the inflammatory process. This
information includes leukocyte count and characteristics such as neutrophil- or
lymphocyte-dominance, inflammation (CRP), collateral organ damage (acute renal
failure, acute liver failure) and the severity of the disease. Furthermore, biomarkers
provide information regarding the nature of pneumonia, meaning that physicians can
determine whether a disease is bacterial or due to other etiologies by analyzing blood test
results [8].

Complete blood counts (CBC) are easily performed and inexpensive. Included in the
CBC are values such as white blood count, neutrophil, lymphocyte and platelet count (PLT),
mean platelet volume and certain ratios of these values. These can be used as inflammatory
markers. Neutrophils are the most characteristic cell type among the white blood cells and are
an important component of the immune system. Regulated by mast cells, epithelial cells and
macrophages, neutrophils also take part in inflammatory processes. The role of lymphocytes
in both inflammation and infections is evident. Additionally, thrombocytes also have
importance in the regulation of various inflammatory processes. While these parameters may
be used as inflammatory markers by themselves, their ratios to one another may also be
indicators of early inflammation [9–11]. Circulating leukocytes respond to stress by
increasing neutrophils and reducing lymphocytes; the ratio of these two parameters is
also used as an inflammatory marker [12].

Considering previous research, the use of circulating biomarkers representing inflammation

and the immune system have been considered as a prognostic indicator in COVID-19-
positive patients. However, their utility in terms of diagnosis has not been explored [13]. In
this study, the roles of biomarkers from a peripheral blood sample in the diagnosis of
COVID-19 patients who have gone to the emergency room (ER) of a second level state
hospital have been examined.

Systemic inflammatory index (SII) = thrombocyte count × neutrophil count/lymphocyte

count. Neutrophil lymphocyte ratio (NLR) = absolute neutrophil count/absolute lymphocyte
count. Platelet lymphocyte ratio = absolute PLT/absolute lymphocyte count.
Comparisons made according to the RT-PCR test results revealed that while no statistically
significant difference was observed between test result groups (negative or positive)
regarding lymphocyte and platelet lymphocyte ratio values (p > 0.05), a statistically
significant difference (p < 0.05) was found between the test result groups regarding platelet,
hemoglobin, leukocyte, neutrophil, NLR and SII values. In patients with negative test results,
it was found that platelet, leukocyte, neutrophil, NLR and SII values were higher, whereas
hemoglobin was found to be higher in patients with positive test results. Also, hemoglobin
was found to be higher in male patients who tested positive for COVID-19 (Table 2).

Considering the high infectivity and mortality rates of COVID-19, early diagnosis of the
disease is essential. The definitive diagnosis of this disease is made by proving a viral
presence in real-time PCR analyses. Due to factors such as the high number of samples,
limited number of staff trained in performing the aforementioned tests and insufficient lab
capacities, the time it takes to receive results can be prolonged. Therefore, every parameter
allowing for early diagnosis is vital. In this study, the possibility of diagnosing COVID-19
early in ER visits by a simple, inexpensive, easily accessible test, such as a CBC, has been
examined.

In the results of this study, which are also consistent with previous research, low
thrombocyte, leukocyte and neutrophil counts were revealed in COVID-19 positive patients.
Thus, it can be said that thrombocytopenia, leukopenia and neutropenia may be indicative of
COVID-19 disease. Likewise, thrombocytopenia and leukopenia were noted in Guan et al.’s
study [15]. The thrombocyte count was also found to be low in the study by Assiri et al. [19]
and leukopenia was noted in another study conducted by Xu et al. [17]. In general, while the
leukocyte count was lower than 10,000 in viral pneumonias, leukocytosis was seen in
bacterial pneumonias with a leukocyte count of more than 50,000 [20]. Additionally, Xu et al.
revealed in their study that thrombocyte counts are significantly low in pneumonia patients
and that this decrease is directly proportional to the patients’ clinical status [21]. In a study by
Fan et al. mild thrombocytopenia and leukopenia was observed in some patients at first
admission who were COVID-19 positive [22]. The effects of viral pneumonia on the immune
system show a decrease in thrombocyte, leukocyte and neutrophil counts.

Also, hemoglobin levels in COVID-19 positive patients were found to be significantly higher
than in COVID19-negative patients. While no significant difference was observed among
females regarding hemoglobin, higher hemoglobin levels were seen in COVID-19 positive
male patients. It is possible that these results are also affected by other reasons, such as the
presence of comorbidities or anemia, and habits such as cigarette smoking. The patient files
used for this study did not include a detailed patient history, and thus, their effect on
hemoglobin levels were not accounted for. Also, the normal hemoglobin level in the female
population is lower than that of males [23]. Since around 70% of the positive patient group is
comprised of males in this study, this is likely to also have an effect on the results.

An apparent relationship, although not certainly proven, exists between a bacterial infection
and neutrophilia, and a viral infection and lymphocytosis. Accordingly, NLR of peripheral
blood has been used to distinguish between these types of infections [24,25]. In a
retrospective study concerning hospitalized patients with a fever of an unknown origin, it has
been shown that NLR is higher in those with fever due to bacterial infections than those with
fever due to a viral etiology [26]. In the study by Zhang et al., NLRs were used as an early
diagnostic marker for aiv-H7N9 patients [27]. Ai-Ping Yang et al. found an AUC of 0.743,
with a cut-off of 3.3, specificity of 0.636, and a sensitivity of 0.88 for NLR in determining the
prognosis for seriously ill COVID-19 patients [18]. Moreover, in the study conducted by Sun
et al., an AUC of 0.88 for NLR was found for serious COVID-19 positive patients at their
first visit to the ER [28]. Similarly, this study found a significantly lower NLR at first visit to
the ER for patients with positive test results. Low NLR levels can therefore possibly be used
as a diagnostic marker for COVID-19. The following has been observed for NLR: AUC =
0.739, cut-off = 1.8, specificity = 0.765 and sensitivity = 0.595.

A recently proposed prognostic score is the SII, which relies on thrombocytes, neutrophils
and lymphocytes. As an index defining the instability in the inflammatory response, the SII
has been proposed as a prognostic indicator in the follow-up of sepsis patients [29]. In
addition, SII has been found to be useful in predicting the prognosis of small cell lung cancer
and hepatocellular carcinoma [30,31]. In this study, SII was found to be significantly low for
COVID-19-positive patients, meaning that it can also be used while diagnosing COVID-19.
The cut-off value for SII was noted as being ≤479.1, and the AUC = 0.760 with a sensitivity
of 74.9%, and a specificity of 68.9%.
https://sci-hub.se/10.2217/bmm-2020-0317
KLASIFIKASI PDP, ODP, OTG
2.1.1 Pasien Dalam Pengawasan (PDP) 1) Orang dengan Infeksi Saluran Pernapasan Akut
(ISPA) yaitu demam (≥38oC) atau riwayat demam; disertai salah satu gejala/tanda penyakit
pernapasan seperti: batuk/sesak nafas/sakit tenggorokan/pilek/pneumonia ringan hingga
berat# DAN tidak ada penyebab lain berdasarkan gambaran klinis yang meyakinkan DAN
pada 14 hari terakhir sebelum timbul gejala memiliki riwayat perjalanan atau tinggal di
negara/wilayah yang melaporkan transmisi lokal*. 2) Orang dengan demam (≥380C) atau
riwayat demam atau ISPA DAN pada 14 hari terakhir sebelum timbul gejala memiliki
riwayat kontak dengan kasus konfirmasi COVID-19. 3) Orang dengan ISPA berat/pneumonia
berat** yang membutuhkan perawatan di rumah sakit DAN tidak ada penyebab lain
berdasarkan gambaran klinis yang meyakinkan.

2.1.2 Orang Dalam Pemantauan (ODP) 1) Orang yang mengalami demam (≥380C) atau
riwayat demam; atau gejala gangguan sistem pernapasan seperti pilek/sakit
tenggorokan/batuk DAN tidak ada penyebab lain berdasarkan gambaran klinis yang
meyakinkan DAN pada 14 hari terakhir sebelum timbul gejala memiliki riwayat perjalanan
atau tinggal di negara/wilayah yang melaporkan transmisi lokal*. 2) Orang yang mengalami
gejala gangguan sistem pernapasan seperti pilek/sakit tenggorokan/batuk DAN pada 14 hari
terakhir sebelum timbul gejala memiliki riwayat kontak dengan kasus konfirmasi COVID-19.

2.1.3 Orang Tanpa Gejala (OTG) Seseorang yang tidak bergejala dan memiliki risiko tertular
dari orang konfirmasi COVID-19. Orang tanpa gejala (OTG) merupakan kontak erat dengan
kasus konfirmasi COVID-19.
(Kemkes, 2020).
https://infeksiemerging.kemkes.go.id/download/REV-04_Pedoman_P2_COVID-
19__27_Maret2020_TTD1.pdf
The characteristics of the patients were described using the frequency and percentage
parameters. For numerical data, the normality test was performed first using the Shapiro Wilk
test, then descriptively presented in the form of mean and standard deviation if the data were
normally distributed or median and ranges (minimum-maximum) if the data were not
normally distributed. To observe the difference in the neutrophil lymphocyte ratio in Covid-
19 patients with mild and moderate-severe symptoms, the unpaired t-test was used, if the data
were normally distributed and the Mann Whitney test if the data were not normally
distributed. The result of the statistical test was significant if p< 0.05. The analysis was
performed using the SPSS statistical program.
file:///Users/puticallistha/Downloads/2255-13778-1-PB%20(1).pdf

*G.DEFINISI OPERASIONAL VARIABEL PENELITIAN* - SALMA

1. variabel bebas
Penyakit paru obstruktif kronis (PPOK) merupakan penyakit yang kompleks akibat adanya
keterbatasan aliran udara schingga menimbulkan keluhan di sistem pcrnapasan manusia.
(Global Initiative for Chronic Obstructive Lung Disease, 2020)
*Cara pengukuran : Melihat data rekam medis pasien*
*Alat ukur : Rekam medis*
*Skala pengukuran : Nominal (PPOK dan non PPOK)*

2. variabel terikat
Derajat penyakit COVID-19 merupakan klasifkasi untuk
mengukur tingkat keparahan berdasarkan gejala klinis yang dialami oleh pasien. Gejala klinis
yang dialami oleh pasien didapat dari hasil anamnesis maupun pemeriksaan fisik maupun
pemeriksaan penunjang yang selanjutnya akan dituliskan pada *rekam medis.* Derajat
penyakit COVID-19 menurut PDPI et al., (2020) pada pasien dewasa dibagi menjadi :
tabel derajat keparahan covid 19
*cara pengukuran : melihat data rekam medis*
*alat ukur : rekam medis*
*skala pengukuran : ordinal (ringan, sedang, berat, kritis)*
*Definisi operasional variabel penelitian* - MBA ARIVA
1. Nilai NLR
Dalam penelitian ini yang dimaksud peneliti adalah nilai NLR
yang diperoleh dari pengecekan darah lengkap pada pasien ibu hamil terinfeksi SARS-CoV-
2. Data yang digunakan merupakan data sekunder yang diperoleh dari catatan rekam medik
pasien di Rumah Sakit UNS.

TEKNIK ANALISIS DATA

Untuk menganalisis data dalam penelitian ini, dilakukan analisis univariat dan bivariat.
Dimang analisis univariat untuk menampilkan informasi berupa karakteristik demografi
dari masing-masing varibel. Selanjutnya dilakukan analisis bivariat dengan uji chi-
square guna mencari hubungan antara variabel yakni *penyakit paru obstruktif kronis
(skala nominal)* dengan derajat keparahan pasien COVID-19 (skala ordinal).
Keseluruhan hasil data yang diperoleh dari penelitian akan diolah menggunakan
bantuan perangkat Iunak yakni Statistical Product and Service Solution (SPss) *for
Windows.*

Pada penelitian ini, peneliti akan melakukan dua teknik analisis data yaitu analisis
univariat dan bivariat. Analisis univariat dilakukan untuk melihat gambaran dari
variabel yang diteliti. Data yang dianalisis merupakan data deskriptif. Selanjutnya,
dilakukan analisis bivariat dengan menggunakan uji Chi-square. Uji Chi-square
adalah uji statistik non-parametrik yang digunakan untuk menilai hubungan antara
variabel yang berskala nominal maupun ordinal (McHugh, 2013).

a. Chi-square(x3)
Ukuran statistik ini merupakan ukuran asosiasi yang
berusaha untuk menguji hipotesis bahwa antara variabel independen dan variabel
dependen terdapat hubungan yang signifikan. Namun, mengingat uji statistik ini
hanyalah uji independensi, hanya sedikit memberikan informasi mengenai kekuatan
atau bentuk asosiasi di antara dua variabel. Nilai chi-square ini pun juga akan
bergantung pada ukuran sampel. Semakin besar jumlah sampel, nilai chi-square juga
 akan bertambah, dan sebaliknya, semakin kecil jumlah sampel, nilai chi-square juga
akan semakin kecil. (Priyono, 2008)

LAPORAN
Tipe betacoronavirus telah menyebabkan beberapa penyakit sebelum COVID-19,
yaitu SARS pada tahun 2002 dan MERS pada tahun 2004 (Zeinab Abdelrahman et al
2020). Kedua penyakit ini menyebabkan komplikasi yang berat pada ibu di masa
kehamilan. Berdasarkan hasil penelitian Wong SF, Chow KM, Leung TN, et al tahun
2004 pada 12 ibu hamil yang positif SARS-cov dinyatakan bahwa 4 dari 7 ibu pada
trimester pertama mengalami keguguran, 2 dari 5 ibu pada trimester kedua sampai
ketiga mengalami gangguan pertumbuhan janin, 5 bayi terlahir prematur, dan 3 ibu
meninggal selama kehamilan. Sedangkan review Alfaraj SH, Al-Tawfiq JA, Memish
ZA tahun 2019 pada 11 ibu hamil yang positif MERS-cov dinyatakan bahwa 10 ibu
mengalami kondisi buruk dengan 6 neonatus perlu dirawat di intensive care unit (ICU),
3 naonatus meninggal, 2 neonatus dilahirkan premature (Favre G et al. 2020).

Pada pasien yang positif COVID-19 dapat melakukan metode deteksi molekuler / Nucleic
Acid Amplification Test (NAAT) yang dianjurkan oleh WHO (World Health Organization,
2020). Selain itu, pemeriksaan hematologi juga perlu dilakukan untuk mengevaluasi
komponen darah sehingga dapat menilai keparahan COVID-19 yang diderita (Yusra dan
Pangestu N, 2020).

JENIS PENELITIAN (SEBELUM REVISI)

Penelitian ini merupakan penelitian observasional analitik dengan
pendekatan cross-sectional. Penelitian observasional analitik dilakukan untuk
mengetahui korelasi antara variabel terikat dan bebas. Desain termasuk cross-sectional
karena dalam meneliti korelasi antara variabel terikat dan bebas ini dilakukan dalam
satu waktu tertentu (Masturoh and Anggita, 2018).
 MEOW SCORE
MEOW Score 3 2 1 0 1 2 3
Saturasi O2 (%) 85 86-89 90-95 96
Laju Nafas (x/menit) <10 10-14 15-20 21-29 30

Nadi (x/menit) <40 41-50 51-100 101-110 110-129 130

Tekanan darah sistolik 70 71-80 81-100 101-139 140-149 150-159 160
(mmHg)

Tekanan darah 49 50-89 90-99 100-109 110

diastolic (mmHg)
Diuresis (ml/jam) 0 20 35 35-200 200
Sistem saraf pusat Agitasi Sadar Respons Respons Tidak ada
hanya hanya respons
terhadap terhadap
stimulus stimulus
verbal nyeri

Suhu (‘C) 35 35-36 36-37.4 37.5-38.4 38.5

MEOWS 0-1 Normal
MEOWS 2-3 Normal dan stabil, laporan kondisi pasien bisa dalam 1 hari
MEOWS 4-5 Abnormal dan tidak stabil, harus dievaluasi dalam 30 menit
MEOWS 6 Abnormal dan tidak stabil, harus dievaluasi dalam 10 menit