FACTORS ASSOCIATED WITH DEATH IN COVID-19 PATIENTS INJAKARTA,
INDONESIA: AN EPIDEMIOLOGICAL STUDY
Anna Rozaliyani1,2, Ary I. Savitri3, Findra Setianingrum2, Titania N. Shelly3,Vini Ratnasari4, Romala Kuswindarti5,
Ngabila Salama6, Dwi Oktavia6, Widyastuti6, Diah Handayani1,7
1 National Medical Team COVID-19, the Indonesian Society of Respirology, Jakarta, Indonesia.
2 Department of Parasitology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
3 Siena Clinical: Academic Research Organization, Jakarta, Indonesia.
4 Regional Public Hospital of Pasar Rebo, Jakarta, Indonesia.
5 Regional Public Hospital of Ciracas, Jakarta, Indonesia.
6 Provincial Health Office of Special Capital Region of Jakarta, Jakarta, Indonesia.
7Department of Pulmonology and Respiratory Medicine, Faculty of Medicine Universitas Indonesia, PersahabatanHospital, Jakarta, Indonesia.
Corresponding Author:
Anna Rozaliyani, MD., PhD. Indonesian Society of Respirology. Jl. Cipinang Baru Bunder No.19, Cipinang, Jakarta13340, Indonesia.
email: [email protected].
ABSTRAK
Latar belakang: penyakit Coronavirus 2019 adalah penyakit sistem pernapasan yang baru saja muncul dan
menjadi pandemi. Indonesia mengalami peningkatan jumlah kasus yang cukup drastis tetapi data lokal
terkait hal ini masih jarang didapatkan. Metode: analisis dalam riset ini menggunakan data rekapitulasi
Penelusuran Epidemiologi (PE) yang dikeluarkan oleh Pemerintah Daerah Khusus Ibukota Jakarta dari 2
Maret hingga 27 April 2020. Hasil: dari total 4.052 pasien, 381 (9,4%) pasien meninggal. Analisis
multivariabel menunjukkan bahwa kematian berhubungan dengan usia tua (odds ratio [OR] 1,03; 95%
confidence interval [CI] 1,02, 1,05, peningkatan usia per tahun; p<0,001), sesak napas (OR 4,83; 95% CI
3,20, 7,29; p <0,001), pneumonia (OR 2,46; 95%CI 1,56, 3,88; p<0,001), dan riwayat hipertensi (OR 1,86;
95%CI 1,24, 2,78; p=0,003). Angka kematian tertinggi terjadi pada 6 April 2020 dan menurun di beberapa
pekan selanjutnya, setelah pembatasan sosial berskala besar diberlakukan. Kesimpulan: usia tua, sesak
napas, pneumonia, dan riwayat hipertensi berhubugan dengan risiko kematian. Mortalitas tergolong tinggi
tetapi mungkin dapat dikurangi dengan pembatasan interaksi sosial.
Kata kunci: COVID-19, kematian, Indonesia, Jakarta, karakteristik pasien.
ABSTRACT
Background: Coronavirus Disease 2019 is an emerging respiratory disease that is now a pandemic. Indonesia
is experiencing a rapid surge of cases but the local data are scarce. Methods: this is an analysis using data
fromthe ongoing recapitulation of Epidemiological Surveillance (ES) by the Provincial Health Office of Jakarta
from March 2nd to April 27th 2020. We evaluated demographic and clinical characteristics of all confirmed
cases in association with death. Results: of the 4,052 patients, 381 (9.4%) patients were deceased.
Multivariable analysis showed that death was associated with older age (odds ratio [OR] 1.03; 95%
confidence interval [CI] 1.02, 1.05, per year increase; p<0.001), dyspnea (OR 4.83; 95% CI 3.20, 7.29;
p<0.001), pneumonia (OR 2.46; 95%CI 1.56, 3.88; p<0.001), and pre-existing hypertension (OR 1.86; 95%
CI 1.24, 2.78; p=0.003). Death was highest in the week of April 6th 2020 and declined in the subsequent
weeks, after a large-scale social restrictioncommenced. Conclusion: older age, dyspnea, pneumonia, and
pre-existing hypertension were associated withdeath. Mortality was high, but may be reduced by lockdown.
Keywords: COVID-19, death, Indonesia, Jakarta, patient characteristics.
INTRODUCTION DATA COLLECTION
Coronavirus Disease 19, or widely known as Data were collected using Epidemiological
COVID-19 is a new emerging respiratory Surveillance (Penyelidikan Epidemiologi/PE)
disease that can cause respiratory failure due forms which were distributed to all healthcare
to severe pneumonia.1 This viral infection was facilities in the province, including all public
first reported in December 2019 in Wuhan, primary care centres (Puskesmas) and public
China and suspected to be transmitted through and private hospitals. Doctors or nurses who
zoonotic origin, followed by human to human provided care for patients suspected with
transmission.2 By May 22nd 2020, a total of COVID-19 infection were obliged to fill in thePE.
4,993,470 confirmed cases have been reported The PE forms were later being submitted to
globally and the disease has spread rapidly Dinkes Provinsi DKI Jakarta.
throughout at least 215 countries, including The PE form consists of questions related to
Indonesia.3 patient demographic characteristics and clinical
The first two cases in Indonesia were identified information. Signs and symptoms that were askedin
in West Java Province on March 2nd 2020.4 the questionnaire included body temperatureand
Thenceforth, the number of COVID-19 cases in the presence of fever, cough, cold, sore throat,
the country increased remarkably, reaching dyspnea, chills, headache, malaise, myalgia,
20,796 confirmed cases on April 22nd 2020. At the nausea and emesis, abdominal pain and
time of preparing this manuscript,the number of diarrhea. Other conditions and comorbidities that
COVID-19 cases and mortality rates in were asked included the presence history of
Indonesia are still increasing and the end of diabetes, heart disease, hypertension, malignancy,
the epidemic is still uncertain.5,6 Published immunologic disorder, chronic kidney failure,
reports on the epidemiology and clinical chronic liver failure, and chronic obstructive
characteristics of COVID-19 cases fromIndonesia pulmonary disease (COPD). In case patients
are scarce. High-quality evidence is important were hospitalized, the start and end date of
for understanding the disease, improving the hospitalization were recorded together with
quality of care of patients and could serve as a whether there was admission to the intensive care
basis for policy making. In thisstudy, we analyze unit (ICU), intubation performed, and the use of
demographic and clinicalparameters associated extracorporeal membrane oxygenation (ECMO)
with the mortality of laboratory-confirmed cases machine. The end date of hospitalization was also
with COVID-19 inDKI Jakarta, Indonesia. recorded and data about the clinical outcomes
were collected.
METHODS
This is a retrospective cohort study using data Age was classified into 5 groups; 0-9 years, 10-
from the ongoing recapitulation of 19 years, 20-49 years, 50-69 years, and older
Epidemiological Surveillance (ES) conducted by than 70 years. Patient’s address was classified
the Provincial Health Office of Capital Special into 6 groups; including 5 areas of Jakarta
Region of Jakarta (Dinas Kesehatan/ Dinkes (South, West, East, North, and Central) and
Provinsi DKI Jakarta). outside Jakarta if patients had non-Jakarta
The laboratory-confirmed patients are defined as address. Within subjects with available data of
patients with a positive result on real-time body temperature, we categorized them into4
reverse transcription polymerase chain reaction groups (<37oC, 37.3–38oC, 38.1– 39oC, and
(RT-PCR) for the presence of SARS-CoV-2 in >39oC). The time from the onset of the symptomsto
either the nasal or pharyngeal swab specimens, nasal and/or throat swab tests were used asa
irrespective of the clinical signs and symptoms. proxy for patient’s access to a health facility with
All confirmed cases of COVID-19 in Jakarta a shorter number represents better access.
between March 2nd 2020 and April 29th 2020
were included in the analysis. This study was
approved by The Ethics Committee of Faculty of
Medicine University of Indonesia (No: KET-506/
UN2.F1/ETIK/PPM.00.02/2020).
OUTCOME MEASURES than 70 years groups dying. There were more
Death was considered as the main outcome in male patients in the total population and among
this study. All deaths that occurred after the those who died. The majority of the patients had
diagnosis of COVID-19 were considered to be non-Jakarta addresses and death rates were
the consequence of the infection. This clinical significantly different depending on the area
outcome was followed up until April 29th 2020. where they lived.
Among all the comorbidities, hypertension was
DATA ANALYSIS revealed to be the most common disease
Patients’ demographic information and clinical reported (18.3%), followed by diabetes (11.1%),
characteristics were tabulated for descriptive heart disease (6.9%), and COPD (5.6%). Among
purposes. All these variables were 800 patients with the non-missing data on the
considered as potential predictors of death existence of all comorbidities, 83.6% were
during the follow-up time. Univariable regression reported to having at least one comorbidity. The
was first performed to evaluate the unadjusted proportion of patients with hypertension,
relation between each predictor and the diabetes, heart disease, and renal diseases
occurrence of death. We selected the weresignificantly higher in those who died.
statistically significant predictors from the Cough (61.0%), fever (53.0%), malaise (32.4%)
univariable analysis and evaluated them using and dyspnea (30.2%) were the most commonly
multivariable logistic regression. Results are reported symptoms, while pneumonia occurred in
expressed as odds ratios (ORs) with 95% 41.1% of patients. The proportion ofpatients with
confidence intervals (CIs) and corresponding these symptoms and pneumonia was also
p values. Statistical significance was considered significantly higher among those who died.
to be a 2-sided p value <0.05. All analyses were Within 655 patients with reported body
performed using SPSS Version25.0 for Mac temperature, the majority had a body
(SPSS Inc., Chicago, IL, USA). temperature between 37.3 – 38.0oC.
The mean duration between symptom onset and
RESULTS swab test in the total population was 7 days(SD
Of the 4,052 COVID-19 patients included in the 6.0) and was significantly different between those
study, 381 (9.4%) patients were deceased, while who died and those who survived (9.9 days vs 8
3670 (90.6%) patients survived (TableAmong days, p < 0.001). The following procedures were
the surviving patients, 412 (11.2%)patients were also more common in those who died as
cured, 2,012 (54.8%) patients were still compared to those who survived; ICU admission
hospitalised, and 1,246 (33.6%) patients were in (20 [16.0%] vs 17 [1.2%], p < 0.001), intubation
self-isolation. (17 [13.8%] vs 11 [0.8%], p < 0.001), and ECMO (7
[5.9%] vs 4 [0.3%], p < 0.001).
Table 1 shows the demographic and clinical
characteristics of the study population in total In Table 2, we show that in the univariable
and separately for those who died and those analysis, older age, being older than 70 years,
who survived. The mean age of the patients was male, residing in Central or South Jakarta, having
45.8 years. The majority of the patients were symptoms of cough, fever, malaise, dyspnea,
from age groups of 20 to 49 years and50 to headache, nausea/emesis, sore throat, chills, and
69 years (51.2% and 37.6% respectively, from pneumonia were significantly associated with a
the total population). Those who died were higher risk of death. Deaths were also more
significantly older than those who survived. likely with higher body temperature, pre-existing
Similarly, analysis by age groups also showed comorbidities (mainly hypertension, diabetes,
significant differences in the risk of death with heart disease, renal disease, and immunological
more patients in the 50 to 69 years and older disorder).
When all significant demographic and clinical The number of confirmed cases and death due
characteristics (p < 0.05) were included in the to COVID-19 showed an increased surge
multivariable analysis, we show that most during the observation period. The weekly
associations between these characteristics number of new confirmed cases was consistently
and the occurrence of deaths became non- increasing during the observation period
significant. The characteristics which remained (Figure 1). The weekly number of deaths, on
significantly associated with higher mortality the other hand, reached its peak in the week of
were older age(OR 1.03, one year increment), April 6th 2020 and dropped in the following
dyspnea (OR 4.83), evidence of pneumonia weeks. This is as shown in Figure 2 where the
(OR 2.46), and pre-existing hypertension (OR slope becomes lesssteep in the following weeks
1.86). Based on the total number of deaths afterApril 6th 2020.
and confirmed cases, the case fatality rate
(CFR) in Jakarta was estimated to be 9.4%.
.
DISCUSSION
In th e present study we provided evidence suggesting that among laboratory-confirmed cases of
COVID-19 in Jakarta, the odds of deathwere greater if patients were older, had dyspnea,pneumonia, and
pre-existing hypertension.To the best of our knowledge, this is the
Figure 1. Weekly cumulative number of COVID-19 cases in Jakarta, Indonesia.
Figure 2. Weekly cumulative number of deaths in patients with COVID-19 in Jakarta, Indonesia.
first and largest analysis using epidemiological the present study a total of 41% patients were
surveillance data to assess risk factors for reported with pneumonia and 30% had dyspnea.
mortality in laboratory-confirmed COVID-19 The proportions are higher than in China where
patients in Indonesia. The study population was less than 20% confirmed cases had pneumonia
comprised of people living in the epicenter of and only 14% had dyspnea.13
local transmissions, the urban setting of Jakarta This study revealed pre-existing hypertension was
and its surrounding area (Jabodetabek) with independently associated with mortality in
relatively good access to the healthcare facility.In COVID-19 patients in Jakarta. Earlier studies
terms of time, this study captured the initial also reported that hypertension was the most
phase of the epidemic in Indonesia (within 2 common underlying disease of the COVID-19
months after the first case of COVID-19 in patients, especially in fatal cases.8,11,14 Disruption
Indonesia was reported). The data comprising of the renin-angiotensin system may explain this
the entire population with laboratory confirmed phenomenon.15 It is postulated that pre-existing
COVID-19 in the area were included in the cardiovascular disease, including hypertension,
analysis. contributes to the occurrence of pneumonia and
Our finding that older age was related withhigher fatal symptoms in COVID-19.16 Our analysis
mortality in COVID-19 patients is in concordance showed that COVID-19 patients with pre-
with several previous studies.7,8 Mortality was existing hypertension have an approximately 2-
higher by 10% per year increasein these studies fold risk of death as compared to patients
as compared to 3% in the present study. This without. This is relatively comparable to the
difference might be attributed to thefact that only increased risk of developing severe COVID-19
adult patients were included in the previous (OR:2.92) estimated by a large meta-analysis
study. Our finding also confirms previous studies from China.17
that showed significant increased risk of death in The unadjusted analyses showed that diabetes
patients aged >65 years.9,10 Due to impaired increased risk of death in COVID-19 patients but
immune response, older patients tend to have a this association became non-significant after
more serious condition and poorer response to adjustment for other characteristics (age, sex,
treatments. symptoms, and other comorbidities). This finding
Pneumonia and dyspnea (shortness of breath)have suggests that diabetes itself may not have direct
been reported to be associated with death in the implication on infection severity, butrather present
previous studies.11,12 The latter was associatedwith coexisting with other worsening factors such as
the occurrence of acute respiratory distress older age and hypertension. This is in line with
syndrome (ARDS) in COVID-19 patients.8 In previous studies which showed no significant
addition, an earlier study also revealed thatearly association between diabetes and mortality of
onset of dyspnea may be a marker of poor COVID-19 patients when other factors such as
prognosis.11 These findings are also supported age, sex, other comorbidities were taken into
by a meta-analysis which suggested that patients account in the analyses.18,19
with dyspnea showed worse clinical outcomes.12 In
We showed a case fatality rate (CFR) of number of weekly death cases dropped to 25
9.4% in our study population, which was among patients in the period between April 20th andApril
the highest in the world. This rate leads among 26th 2020. This number was lower than in the
countries in Southeast Asia, higher than in previous weeks and in the early days of PSBB(82
Wuhan, China (4.3% of confirmed cases) and is patients between 6 April – 13 April 2020). These
almost twice the global mortality rate of results are preliminary but indicate the
5.97%.20,21 The high CFR in our population might effectiveness of the large-scale social restrictionin
partially be explained by the limited capacityof controlling the spread and mitigating the
PCR testing which resulted in serious under- catastrophe of COVID-19. The mathematical
reporting.22 It is estimated that only 0.03 tests modeling suggested that quarantine, school
were done daily per thousand people.20 Patients closure and social distancing had an impact in
with more pronounced symptoms and therefore a the reduction of COVID-19 cases.25,26 India,
more severe condition were more likely to seek which adopted early social distancing and social
help and therefore had better access to PCR tests. lockdown had lower mortality (3%) due to
Nonetheless, the high CFR might also reflect COVID-19 compared to Spain (12%) and France
poorer healthcare capacity in responding to the (19.9%).3,27 Australia experienced success in
epidemic. Data from the Provincial Health Officeof decreasing the rate of COVID-19 cases together
Special Capital Region of Jakarta revealed the with low mortality rate (1.4% per 10 May 2020)as
death cases during February 2020 were 5792 an impact of international travel restrictions and
people, markedly increased from January 2020 social distancing.28 This study has several
(3072 deaths).23 This might indicate undetected limitations. First, no data were available
deaths related to COVID-19 before the first case regarding the diagnostic and treatment received
was diagnosed in Indonesia. by the patients. Diagnostic and therapeutic
About one third of patients in this study had a measures, notably, may have asignificant role in
registered address outside Jakarta. This finding modifying the clinical course of the disease and
might indicate the urban problem of Jakarta and its outcomes. Laboratory and radiologic findings
public health problems. Many people possibly may provide insights into the course of the
work and live in Jakarta while still maintaining disease and severity of the condition. In the
their “outside Jakarta” address on their ID card. absence of such information, interpretation of
Additionally, people who live in the surrounding our findings needs to be done with caution.
areas near Jakarta mightprefer to go to Jakarta Secondly, some information in the PE form was
when seeking medical services. Therefore, missing because it was left empty by the
basing the calculation of healthcare services interviewer. Proper training of the healthcare
demand solely on the number of Jakarta providers might increase the quality of the PE
inhabitants would result in serious form database.
overestimation of Jakarta’s preparedness forthe
pandemic. CONCLUSION
A large-scale social restriction (pembatasansosial We identified older age, dyspnea, pneumonia, and
berskala besar or PSBB) has been imposed in pre-existing hypertension as predictors for
Jakarta since April 10th 2020.24 The PSBB in mortality among the laboratory confirmed cases of
Jakarta seems to create an impact in reducing COVID-19 in DKI Jakarta, Indonesia. The
the curve slope of both the cumulative numberof mortality rate was high at 9.4%. The research
confirmed cases and the number of deaths has also shown the apparent beneficial impact
(Figure 1 and 2). The number of weekly new of PSBB in reducing the spread of COVID-19.
confirmed cases dropped to 651 patients in the
period between April 20th and April 26th 2020,10 ACKNOWLEDGMENTS
days after PSBB was applied. This number was We gratefully acknowledge the Provincial Health
lower than in the previous weeks and in the Office of Special Capital Region of Jakarta for
early days of PSBB (833 patients between April providing the database of Epidemiological
6th – April 13th 2020). In line with this, the Surveillance as the source of this study.
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CARDIAC INJURY IS ASSOCIATED WITH MORTALITY AND CRITICALLY ILL
PNEUMONIA INCOVID-19: A META-ANALYSIS
Anwar Santoso, MD, Ph.D. a,⁎, Raymond Pranata, MD b, Arief Wibowo, MD, Ph.D. c,
Makhyan Jibril Al-Farabi, MD, MSc, M Biomed d, Ian Huang, MD b, Budhi Antariksa, MD, Ph.D e
a Department of Cardiology – Vascular Medicine, Universitas Indonesia, Harapan Kita Hospital – National Cardiovascular
Centre, Jalan Letjen S. Parman kav 87, Jakarta 11420, Indonesia.
b Faculty of Medicine, Universitas Pelita Harapan, MH Thamrin Boulevard 1100, Tangerang 15811, Indonesia.
c Department of Cardiology – Vascular Medicine, Padjadjaran University, Dr. Hasan Sadikin Hospital, Jalan Pasteur No: 38,
Bandung 40161, Indonesia.
d Department of Cardiology – Vascular Medicine, Airlangga University, Soetomo Academic and General Hospital, Jalan
Mayjen Moestopo No: 6-8, Surabaya 60286, Indonesia.
e Department of Pulmonology and Respiratory Medicine, Universitas Indonesia, Persahabatan Hospital, Jalan Persahabatan
Raya No: 1, Jakarta 13230, Indonesia.
Article Info
Article history : Received 2 April 2020, Received in revised form 13 April 2020, Accepted 14 April 2020, Available online xxxx
Keywords: Cardiac, Injury, Coronavirus, COVID-1,Troponin,Mortality
ABSTRACT
Background: In this systematic review and meta-analysis, we aimed to explore the association
between cardiac injury and mortality, the need for intensive care unit (ICU) care, acute respiratory
distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19) in patients with COVID-
19 pneumonia.
Methods: We performed a comprehensive literature search from several databases. Definition of
cardiac injuryfollows that of the included studies, which includes highly sensitive cardiac troponin I (hs-
cTnl) N99th percen- tile.The primary outcome was mortality, and the secondary outcomes were ARDS,
the need for ICU care, and se- vere COVID-19. ARDS and severe COVID-19 were defined per the
World Health Organization (WHO) interim guidance of severe acute respiratory infection (SARI) of
COVID-19.
Results: There were a total of 2389 patients from 13 studies. This meta-analysis showed that cardiac
injury was associated with higher mortality (RR 7.95 [5.12, 12.34], p b 0.001; I2: 65%). Cardiac injury
was associated with higher need for ICU care (RR 7.94 [1.51, 41.78], p = 0.01; I2: 79%), and
severe COVID-19 (RR 13.81 [5.52,34.52], p b 0.001; I2: 0%). The cardiac injury was not significant for
increased risk of ARDS (RR 2.57 [0.96, 6.85], p = 0.06; I2: 84%). The level of hs-cTnI was higher in
patients with primary + secondary outcome (mean differ-ence 10.38 pg/mL [4.44, 16.32], p = 0.002;
I2: 0%). Conclusion: Cardiac injury is associated with mortality, need for ICU care, and severity of
disease in patients with COVID-19.
1. INTRODUCTION aimed to explore the association between
A series of pneumonia cases of unknown acute cardiac injury and mortality, the needfor
origin emerged in Wuhan,the Hubei province of Intensive Care Unit (ICU) care, acute
China, in December 2019, and the clinical respiratory distress syndrome (ARDS), and
presen- tations were most similar to viral severe COVID-19 in patients with COVID-19.
pneumonia [1]. This pneumonia is a newly
recognized illness that has spread rapidly 2. METHODS
across the country and around the world. A few This meta-analysis was accomplished in
days after the initial outbreak, Chinese sci- agreement with the pre-ferred reporting items
entists managed to identify a novel for systematic reviews and meta-analysis
coronavirus [1], which was later named (PRISMA) statement [7].
severe acute respiratory syndrome—
coronavirus 2 (SARS-CoV- 2). This virus is 2.1Eligibility criteria
classified as a ß CoV of group 2B and has at We included all research articles in adult
least similar- ity in genetic sequence to severe patients diagnosed with COVID-19 with
acute respiratory syndrome—coronavi- rus information on hs-cTnl, cardiac injury, and
(SARS-CoV-1). SARS is a zoonosis caused by clinical grouping or outcome of the clinically
SARS-CoV-1, which first appeared in China in validated definition of mortality, the need for
2002 and spread to 29 countries in 2003, ICU care, acute respiratory distress syndrome
causing aglobal outbreak with 8903 cases [2]. (ARDS), or severe COVID-19. The following
Coronaviruses are viruses with single-stranded types of the article were excluded: arti- cles
RNA enveloped by afat-coated substance. This other than original research (e.g., case report or
virus belongs to the Coronaviridae family and is series, review arti- cles, letters to editor,
encountered in humans and mammals. editorials or commentaries), duplicate
Although coronavirus infec- tion is generally publication,and non-English articles.
mild, the previous two betacoronavirus
epidemics, namely SARS-CoV-1 and Middle 2.2Search strategy and study selection
East respiratory syndrome coronavirus (MERS- We systematically searched PubMed,
CoV), has caused a cumulative case of SCOPUS, EuropePMC, ProQuest, and
10,000 patients with a10% case fatality rate for Cochrane Central Databases with the search
SARS-CoV-1 and 37% for MERS-CoV [3,4]. The terms “COVID-19” or “SARS-CoV-2” and
clinical spectrum of SARS-CoV-2 pneumonia “Cardiac Disease” and “CardiovascularDisease”
ranges from mild to critically ill cases. The and “Acute Cardiac Injury” and “ARDS” and
previous studies reported only the epidemiologi- “critically ill COVID-19”; search results were
cal findings, the clinical presentation, and the limited to the year 2020. Duplicate re- sults
clinical outcomes. How- ever, more specific were removed. The remaining articles were
information identifying critically ill patients independently screened for relevance by its
remains unknown. Recently, cardiac injury has abstracts with two authors. The remaining
been reported to be as- sociated with mortality investigators read full selected articles that met
[5]. The mortality of critically ill patients with the requirements and provided final
SARS-CoV-2 pneumonia is substantial [6]. suggestions. These articles were thoroughly
Older patients with comor- bidities and adult read, and those that fulfilled our criteria were
respiratory distress syndrome (ARDS) are at included in the study. The final in- clusion of
increased risk of death [6]. Therefore, studying studies was merely based on the agreements
the association of acute cardiac in- jury with the of all investiga- tors; then, any disagreement
mortality in COVID-19 is essential and justified was resolved by consensus. The full text of
for preven-tion and preparation in the hospitals residual articles was assessed according to the
facing these global pandemics. In this inclusion and exclusion criteria. The search
systematic review and meta-analysis, we was finalized on March 29th, 2020.
2.3Data extraction
Data extraction was performed independently by two authors, and we used standardized forms that
include authors, year of the study, study design, age, gender, hs-cTnl (including its cut-off point),
history
Fig. 1. PRISMA study flow diagram.
of hypertension, history of coronary The primary outcome was mortality, and the
artery/cardiovascular diseases, car- diac injury, secondary outcomes were ARDS, the need for
mortality, ARDS, need for ICU care, and severe ICU care, and severe COVID-19. Acute
COVID-19. Definition of cardiac injury follows respiratory distress syndrome was defined as
that of the included studies, which includes per the World Health Organization (WHO)
highly sensitive cardiac troponin I (hs-cTnl) interim guidance on Severe Acute Respiratory
N99th per- centile, regardless of Infection (SARI) of COVID-19, including the
electrocardiography and echocardiography. acute onset, chest imaging, origin of pulmo-
As aresult, studies that reported elevation of hs- nary infiltrates, and oxygenation impairment [8].
cTnl above the 99th percen- tile were Severe COVID-19 was defined as patients who
considered as a cardiac injury. had any of the following features at the time of,
or after, admission: (1) respiratory distress (≥30
breaths per min); (2) ox- ygen saturation at rest outcome. We also performed qualitative
≤93%; (3) ratio of the partial pressure of arterial assessment for publication bias by using
ox- ygen (PaO2) to the fractional concentration inverted plot analysis, an asymmetrical shape
of oxygen inspired air (fiO2) ≤300 mmHg; or (4) indicates publication bias.
critical complication (respiratory failure, septic
shock, and/or multiple organ 3. RESULTS
dysfunction/failure) [9]. 3.1Baseline characteristics and study
selection
2.4Statistical analysis We found a total of 157 records, and 147
To perform a meta-analysis, Review Manager remained after the removal of duplicates. One
5.3 (Copenhagen: The Cochrane Collaboration, hundred and twenty-one records were
2014) and Stata version 16 (StataCorp LP, Texas excluded after screening the title/abstracts.
77845, USA) were used. The continuous After assessing 26 full-text for eligibility, we
variables were reported as means with excluded 13 full-text articles because: 1) no
standard deviations (SDs) and were dichotomous outcome of interest (elevated
calculated using theinverse-variance method. troponin/cardiac injury) and/or hs-cTnI (n =
Dichotomous variables were calculated using 11), and 2) specific population (myocarditis
the Mantel-Haenszel formula. Random effects and cardiovascular manifesta- tion) (n = 2).
models were used regardless of We included 13 studies in qualitative
heterogeneity. Mean differences (MDs) and synthesis and 12 in meta-analysis (Fig. 1).
risk ratios (RRs) were reported with 95% There were a total of 2389 patients from 13
confidence intervals (CIs) for continuous and studies [5,11-24]. The baseline characteristics
dichotomous variables, respectively. The P- of the included studies are presented in Table
value was two-tailed, and the statistical 1. All of the studies were retrospective
significance set at ≤0.05. Sensitivity analysis observa- tional. Most of the included studies
by leave-one-out was performed to single out defined cardiac injury as hs-cTnI el- evation
heterogeneity. above 99th percentile.
Heterogeneity was assessed with the Q-statistic There are studies that did not specify their
test and the I2 test. The I2 statistic measured definition of cardiac injury, however, these
the percentage of total variation across the studies presumably used similar definition to
studies due to clinical or methodological the existing studies (Fig. 2).
heterogeneity instead of chance. If the
significant Q statistics (P b 0.05) indicated 3.2Cardiac injury and mortality
heterogeneity across the studies, a random This meta-analysis showed that cardiac injury
effect model was utilized for meta- analysis. was associated with higher mortality (RR 7.95
Otherwise, a fixed-effect model was utilized. [5.12, 12.34], p b 0.001; I2: 65%, p = 0.009).
Substantial het- erogeneity was represented Sensitivity analysis showed that heterogeneity
by I2 for N50% [10]. To assess the small-study for mortality outcomes could be reduced by
effect and publication bias, we performed the removal of Zhou 2014 et al. study (RR 7.22
regression-based Egger's test for continuous [4.97, 10.47], p b 0.001: I2: 54%, p = 0.05).
variable and Harbord's test for a binary
Authors Table 1 Troponin Troponi Male Age HTN CAD (%) Outcome
Characteristics of the included studies ncut-off (%) (%)
Study design Samples Cardiac injury definition
Chen T Observational 274 hs-cTnl above 99th hs-cTnl N15.6 pg/mL 73 vs 68.0 (62.0–77.0) vs 48 vs 16 vs 7 Mortality
(113/161) percentile hs-cTnl N34.2 pg/mL 55 51.0 (37.0–66.0) 24 9 vs 0
2020 retrospective 32 Unspecified hs-cTnl N40 pg/mL 73 vs 69 (57–78) vs 51 45 vs 16 vs 6.6 Mortality
(11/21) hs-cTnl Unspecified 22 (33–70) 19 N/A
Li K 2020 Observational 403 Unspecified hs-cTnl 57 vs 71 (65–80) vs 49 60 vs Mortality
(100/303) hs-cTnl 44.9 (37–62) 17.5
retrospective 416 hs-cTnl above 99th hs-cTnl N/A N/A N/A Mortality, ARDS,
hs-cTnl severe COVID-19
Luo XM Observational percentile Mortality, ICU care,
188 Unspecified
2020 retrospective ARDS,
Need for ICU care
Shi S 2020 Observational
Mortality
retrospective
Severe COVID-19
Wu C Observational ≥6.126 pg/mL N/A N/A N/A N/A
2020a retrospective
Wang D Observational 138 hs-cTnl above 99th ≥26.2 pg/mL 61.1 vs 66 (57–78) vs 51 58.3 vs 25 vs 10.8
(36/102) percentile N26 pg/mL 52 (37–62) 21.6 (CVD)
2020 retrospective 48 hs-cTnl above 99th N26.2 pg/mL 70.6 vs 78.65 ± 8.31 vs 70.6 vs 23.5 vs 29
(17/31) percentile (N26 pg/mL) 67.7 66.16 ± 13.66 64.5
Zhang F Observational 221 hs-cTnl above 99th 63.6 vs 62.0(52.0–74.0) vs 47.3 vs 23.6 vs 5.4
(55/166) percentile 44 51.0 (36.0–64.3) 16.9
2020 retrospective
Zhang Observational
Guqin retrospective
2020
Zhou 2020 Observational 191 hs-cTnl above 99th hs-cTnl N28 pg/mL 70 vs 69.0 (63.0–76.0) vs 48 vs 24 vs 1 Mortality
percentile hs-cTnl N28 pg/mL ICU Care
retrospective hs-cTnl N0.04 pg/mL 59 52.0 (45.0–58.0) 23 Severe COVID-19
41 hs-cTnl above 99th hs-cTnl N/A Mortality
Huang Observational (13/28) percentile hs-cTnl N50 pg/mL 85 vs 49.0 (41.0–61.0) vs 15 vs 23 vs 11 Severe COVID-19
323 Unspecified
2020 retrospective (172/151) 68 49.0 (41.0–57.5) 14 (CVD)
36 Unspecified
Hu L 2020 Observational (16/20) 52.9 vs 65 vs 56 38.3 vs 19.2 vs 5.3
78 Unspecified
retrospective (20/58) 49.7 25.8 (CVD)
Hu B 2020 Observational 68.8 vs 66.5 (61.3–75.0) vs 50 vs 43.8 vs 0
retrospective 65 56.0 (48.5–67.5) 40 (CVD)
Zhao W Observational 55 vs 69 ± 15 vs 45 ± 17 40 vs 30 vs 5.3
2020 retrospective 40.4 14 (CVD)
CAD: Coronary artery disease; COVID-19: Coronavirus disease 2019; cTnI: Cardiac troponin I; CVD:
Cardiovascular Disease; hs-cTnI: Highly sensitive cardiac troponin I; ICU: Intensive Care Unit; N/A:
Not available. a Group was not poor outcome vs good outcome (high troponin vs low-moderate troponin; cardiac injury vs no
cardiac injury).
Fig. 2. Cardiac injury and mortality. Cardiac injury was associated with increased mortality.
3.3Cardiac injury and secondary outcome 3.4Highly sensitive cardiac troponin I and
Cardiac injury was associated with a higher primary + secondary outcome
need for ICU care (RR 7.94 [1.51, 41.78], p =
0.01; I2: 79%, p = 0.009) and severe COVID- The level of hs-cTnI was higher in patients with
19 (RR 13.81 [5.52, 34.52], p b 0.001; I2: 0%, primary + second- ary outcome (mean
p = 0.38) (Fig. 3). Cardiac injury was not difference 10.38 pg/mL [4.44, 16.32], p =
significant for an increased risk of ARDS (RR 0.002; I2:0%, p = 0.92) (Fig. 4).
2.57 [0.96, 6.85], p = 0.06; I2:84%, p = 0.01).
The removal of the Wu et al. study reduced 3.5Publication bias
heterogeneity for the need for ICU care The funnel-plot analysis showed an
(RR 16.85 [4.93,57.62], p b 0.001; I2: 0%, p asymmetrical shape for all outcomes (Fig.
= 0.36). 5A, B, and C), indicating possible publication
bias. Regression-based Harbord's test
showed no indication of small-studyeffects for findings are beneficial and should be
mortality (p = 0.882). Egger's test showed an considered in clinical man- agement,
indication of small-study effects for sensitive prevention, and preparation for patient safety
troponin I and primary + secondary outcome issues in the hospital in the setting of the
(p = 0.035). COVID-19 global pandemic. As previously
reported, the mortality of critically ill patients
4. DISCUSSION with COVID-19 pneumonia is high. The
This meta-analysis demonstrated that acute survival period of the non-survivors is likely to
cardiac injury, repre- sented by elevated be within 1 to 2 weeks after ICU admission.
troponin concentration, was associated with Elderly patients with comor- bidities and ARDS
in- creased mortality, the need for ICU care, are at increased risk of mortality. Consequently,
and severe COVID-19. Although the the severity of COVID-19 pneumonia poses a
association between cardiac injury and high burden to hospital care resources, and a
ARDS did not show statistical significance, it is shortage of medical personnel [25].
essential from a clinical standpoint. These
Fig. 3. Cardiac injury and secondary outcome. Cardiac injury was associated with an increased need
for ICU care and severe COVID-19. The association was not significant for ARDS. ARDS: Acute
Respiratory Distress Syndrome, ICU: Intensive Care Unit.
Fig. 4. Highly-sensitive troponin I and primary + secondary outcome. Elevated hs-cTnI was
associated with poor outcome. hs-cTnI: Highly-sensitive Troponin I.
Fig. 5. Funnel-plot analysis. Funnel-plot analysis showing asymmetrical funnel plot for mortality.
Previously, a letter to the editor reporting a the effect esti- mate in dichotomous form as RR
meta-analysis of 4 stud- ies showed that (also applicable for the secondary out- come).
troponin levels were associated with the The present meta-analysis showed that
severity of the disease (presented as cardiac injury is associated with RR of 8 for
standardized mean difference). The result mortality. This result gave clinicians more in-
fromthe subgroup analysis of cardiac injury and formation on the impact and clinical
severe COVID-19 further supported this importance of cardiac injury.
notion. To the best of the authors'
knowledge, this study is the first meta-analysis Mortality from COVID-19, as shown in the
that evaluates the relationship between cardiac study, is likely due to cy- tokine storm
injury and mortality in COVID-19 and presents syndrome and fulminant myocarditis.
Fulminant myocar- ditis is primarily caused by expres- sion [36]; this is further reflected by a
a viral infection. It arises quickly, progresses meta-analysis of six studies show- ing that
rapidly, and results in severe heart failure and patients with cardiovascular, metabolic
circulatory failure. The clinical presentation is disease were at risk for increased severity
hypotension and cardiogenic shock, with a [37]. However, the rise of troponin in cardiac
mor- tality rate as high as 50%–70% injury was also paralleled by the increase in
[26,27]. In a portion of patients with COVID- inflammatory biomarkers which may indicate
19, interstitial mononuclear cells were shown the role of cytokine storm in addition to direct
to infiltrate myo- cardium in autopsies [28]. cardiac in- jury [38]. Such manifestation may
Case reports on COVID-19-induced myocar- explain why the cardiac injury is po- tentially
ditis are also available [29,30]. While the linked to ARDS, which might a be a
exact mechanism is still unknown, surrogate marker for cytokine storm or vice
myocardial damage might be due to the versa [39].
direct injury from the virus and exacerbated
by the host's secondary immune response. 4.1The implication for clinical practice
Such a phenomenon has been observed in Our meta-analysis suggests elevated
viral myocarditis of other causes and troponin and cardiac injury were associated
possibly also applies to COVID-19 [31,32]. with poor outcomes. Nevertheless, troponin
and car- diac injury can be a marker of poor
Following spike protein activation by prognosis in patients with COVID-19. We
transmembrane protease ser- ine 2 simply encourage the inclusion of troponin
(TMPRSS2), the viral surface spike (S) when constructing a prognostication model
protein binds to Angiotensin-converting for a patient with COVID-19. During a
Enzyme 2 (ACE2) [33]. The receptor-binding pandemic, risk stratification in triage is
domain (RBD) in the SARS-CoV-2 S protein necessary, and troponin can be a potential
has a higher binding affinity for human ACE2 indicator of high-risk patients.
and is significantly higher compared to SARS-
CoV-1 [34,35]. Although ACE2 is only slightly 4.2Limitation
expressed in the cardiomyocyte, it was highly The limitation of this study is first, the presence
expressed in the pericytes. COVID-19 may of publication bias; this is possibly due to the
attack pericytes, which is essential for shortage of studies pertinent to the issues.
endothelial stability, causing capillary Most of the articles included in the study were
endothelial dysfunction, which leads to preprints; nevertheless, the authors have
microcirculatory disorders [36]. This ex- made exhaustive efforts to ensure that only
plains why, although ACE2 is only slightly sound studies were included. Most of the
expressed in the cardiomyocytes, COVID-19 studies are from China; the patients might
may cause cardiac injury. Patients with car- overlap across the reports. Second, the
diovascular comorbidity such as heart failure included studies were alsomostly retrospective
are thought to be more susceptible to cardiac in design.
injury due to significantly increased ACE2
Anwar Santoso : Conceptualization,
5. CONCLUSION Methodology, Data curation, Investigation,
Cardiac injury is associated with mortality, need Writing original draft, Writing review & editing,
for ICU care, and se- verity of disease in Supervision. Raymond Pranata :
patients with COVID-19. The high mortality in Conceptualization, Methodology, Data curation,
COVID-19 is very likely due to cytokine storm and Formal analysis, Investigation, Writing original
fulminant myocarditis. draft. Arief Wibowo : Data curation, Writing
Credit Authorship Contribution Statement
original draft. Makhyan Jibril Al-Farabi : Data Project administration.Budhi Antariksa:Investi-
curation, Writing original draft. Ian Huang : Data gation, Writing review & editing.
curation, Investigation, Writing original draft,
acute-respiratory-infection- when-novel-
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The ACE2 expression in human heart
SCHOOL REOPENING: EVIDENCE-BASED RECOMMENDATIONS DURING COVID-
19 PANDEMIC IN INDONESIA
Raden Yuli Kristyanto1,4* Lily Chandra,2 Hermawan Hanjaya,2 Mohamad Saifudin Hakim,3 Dian Kesumapramudya Nurputra 1,2,4*
1 Department of Child Health, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta,
Indonesia
2 COVID-19 Working Task Group, Bhayangkara Police Hospital, Yogyakarta, Indonesia
3 Department of Microbiology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta,
Indonesia
4 Dr. Sardjito General Hospital, Yogyakarta, Indonesia
ABSTRACT Since the first Coronavirus Disease to do to prepare in advance for the up-coming
2019 (COVID-19) case was reported, it has run decision to reopen schools.
amok and caused global changes. It has
affected human lives in almost every aspect, KEYWORDS: COVID-19, New normal School
including education. In response to COVID-19, reopening, Indonesian Education Policy, School
governments and policy-makers decided to shift safety
the educational activities into online learning and
institute school closure. As of March 2020, many 1. Introduction
countries worldwide have implemented school The newly identified strain of Coronavirus,
closure, including Indonesia. Large scale social Severe Acute Respiratory Syndrome
distancing and stay-at-home policies have Coronavirus 2 (SARS-CoV-2) has made its
begun to negatively impact society’s physical severe health impact worldwide.1 Coronavirus
and mental health. As people start to adapt to Disease 2019 (COVID-19) is transmitted via
the first wave of the COVID-19 pandemic, respiratory droplets and by direct contact with
policy- makers and the government need to infected persons or by contact with
consider how to reopen the schools and its contaminated objects and surfaces.2 Wildly
system to keep students and staff safe. School contagious, various systemic manifestations,
reopening is an important step toward loosening and fast clinical deterioration are several
the lockdown. Schools play a crucial role in challenges faced in handling patients with
preserving children’s well-being. The objective of COVID-19. Due to the widespread transmission
this review was to give a recommendation to of COVID-19 found in almost every province in
facilitate school reopening. Research articles Indonesia, the Indonesian government decided
were gathered and assessed based on the to temporarily close all schools according to the
themes of the articles. Forty articles were found transmission patterns in every region. The policy
reflecting SARS-CoV-2 and school reopening. is not only intended to protect children from
Findings were adapted and modified according COVID-19, but it also helps to prevent SARS-
to Indonesian situations during the SARS-CoV-2 CoV-2 transmission among children, their
pandemic. Indonesia is currently preparing the families and community.3 However, the school
first steps toward school reopening. For schools closure policy imposes several risks which need
to be reopened, there are several health to be considered. Prolonged school closure can
measurements that need to be considered. A affect children’s development and psychological
good collaboration between various authorities well-being as well as cause several unwanted
and stakeholders is essential in school economic effects.4
reopening so that children’s safety and disease To date, after three months of school closure, in
mitigation strategies remain stable. This review regard to educational and economic aspects, the
presents insights and recommendations for Ministry of Education and Culture of Indonesia
every element involved in school safety decided to take a measured step toward
including the government, schools, teachers, reopening schools in early July 2020. The new
parents and students including what each needs policy was commendable for addressing each
regional government, school administration, and 3. Result
parents’ preparedness to reopen the schools. Although school closure policy has been
However, the picture of the policy is too general. addressed as one of the disease mitigation
It lacks a deep understanding and appears to strategies, new obstacles have emerged.
disregard the present prediction of possible in- Evidences and recommendations have reported
the-field problems. Several aspects, including negative effects regarding children’s
the increasing number of new COVID-19 cases, development, education, and psychology.
uneven dynamics of additional new cases Prolonged school closure brought tremendous
throughout most regions in Indonesia, and impact to parent’s economic status. On the other
suboptimal tracing, reporting, and mitigating of hand, reopening school policy without judicious
COVID-19 cases, are important to be judgement might eventually lead to other more
considered. Accordingly, our review provides harmful effects. Evidences and
and offers further evaluation and consideration recommendations are reported as follows.
of additional education system measures, risks,
and impacts which are needed in preventing and 3.1The Negative Effects Of School Closure
lowering the transmission risks of COVID-19, 3.1.1 The Negative Effects On Children’s
once schools are in the process of reopening. All
findings are summarized in several easy-to-use Development And Education
checklists. Hence, the government is expected From the children’s developmental point of view,
to weigh the risks and benefits of every policy it is undeniable that schools are considered to
which will be made or planned, respectively. be one of the most systematic and scientific
institutions to stimulate and facilitate their
2. Method development. Education at school is one of the
2.1Search Strategy fundamental needs of children especially in
A literature review was performed to assess the fulfilling their right to education5. The core
recommendation of school reopening during the educational values consist of improving
“New Normal” era. Electronic search from children’s academic and life skills ranging from
databases such as PubMed, Embase, Science basic physical, social, and character building
Direct, and Google Scholar was completed and through developmentally appropriate
articles were assessed and selected from the psychological, intellectual, and spiritual aspects.
search. The following are the search criteria: During this modern era, the family remains the
‘school reopen’ or ‘school reopening’ or ‘school mainstay in children’s character development,
closure’ or ‘school’ or ‘children’ or ‘child’ AND which will continue in formal education at school
‘COVID-19’ or ‘pandemic’ or ‘quarantine’ or to improve cognitive and behavioral aspects.6
‘psychology’ or ‘mental health’ or ‘development’ Aside from a place to study, school is also a
or ‘recommendation. Forty papers were selected place for children to make friends with others of
to be reviewed. Articles gathered are ranging the same age. Indeed, children may still be able
from 1994- 2020, with seven papers ranging to study at home but a gap exists.7 Meanwhile,
from 1994-2019, and thirty-four papers are social interaction during studying, direct contact
recent studies from 2020. The literature was type of playing and communication with other
reviewed by the authors, resulting in the children of the same age are still necessary in
selection of those appearing in this paper. social skill improvement and remain important
Among the reviewed articles, risk assessment for the optimal development in children.5,8
protocols and recommendations were Therefore, school closure during this COVID-19
extrapolated and modified in accordance with pandemic could potentially disturb this
situations in Indonesia. Thus, this fundamentally essential education in children.
comprehensive approach can give an update for Prolonged use of electronic media also has
the newly adapted strategies for school detrimental effect on child development, such as
reopening in Indonesia. obesity, sleep disturbance, online activities,
decreased interest in offline or “real life”
relationships, unsuccessful attempts to decrease With the recent school closure policy, children
gadget use, and withdrawal symptoms.9 from impoverished families could suffer more
set-backs in education and developmental
3.1.2 The Negative Effects On Children’s aspects because of insufficient social
Psychology environment and lack of parental support.17,18
The COVID-19 pandemic also results in a global
It is in almost all children’s nature every day to economic recession which in turn disrupts a
enjoy outdoor activities and to play with other family’s income. This dilemma further adds to
children of the same age. This daily interaction parents’ distress and might also lead to new
results in a higher probability of children conflicts between parents and their children. The
contracting and transmitting the virus. Children’s worst scenario which needs more attention is
lack of understanding in the importance of the higher probability of child abuse17. Studies
staying at home, school closing, and maintaining in developed countries showed that many
social distancing will result in children having parents need to leave their job in order to take
difficulty to obey these rules. The older children care of their children during school closure time
might try to understand ‘what is going on’ during in a pandemic. This unemployed status will
this dangerous time of school closure. However, affect both the family’s income and the
younger children will have questions and doubts availability of human labor at the workplace.19–
regarding the need for staying at home, school 21 In Indonesia, many children are nurtured not
closing, and social distancing will eventually only by their parents but also by their family
arise. Furthermore, this lack of understanding in relatives or by paid caregivers. This cultural
younger children will result in discomfort and consideration makes it harder in determining the
frustration while obeying the rules.10,11 effects from school closure on parents’ work and
Isolation and lack of social interaction with their economical status.
peers will lead to psychological stress in children
and teenagers.12,13 Prolonged boredom could 3.2The negative effects of schools
lead to children and teenagers leaving home to reopenings
play somewhere unsafe and to gather in large
groups, which is known to be unfavorable in 3.2.1 Risk of SARS-CoV-2 infection in
preventing transmission of COVID-19.14 children
3.1.3 The Negative Effects On Economical It is assumed that children are less likely to
Aspect contract SARS-CoV-2 infection since the
children’s age group constitute only 1-2% of total
Shifting of traditional education media into online COVID-19 patients.22,23 However, there is a
education media needs parents’ preparedness, possibility that the reported numbers in previous
especially in providing and using electronic studies are not representative of the actual
devices appropriately, as well as spending extra numbers of children cases. One study in China
expenses for stable Internet connection. If the found that about 86% of patients with SARS-
government does not help to provide equal CoV-2 remained undiagnosed during the early
facilities in fulfilling children’s education needs, stage of this global pandemic.24 Most pediatric
prolonged school closure could eventually lead patients with SARS-CoV-2 infection presented
to a wide disparity in learning opportunities and only with mild complaints and some were even
a significant gap in accessing education asymptomatic. Meanwhile, polymerase chain
outcomes between wealthy and impoverished reaction (PCR) tests from nasopharyngeal
families.4,15,16 swabs have been performed only in pediatric
For the impoverished family, schools and patients with moderate to severe symptoms.25
playfields might be the only place for their This pattern could lead to an underestimation of
children to play and study. This happens pediatric patients infected with SARS-CoV-2.
because their parents need to work and the Severe disease manifestations such as in Acute
residential area might not be sufficient in Respiratory Distress Syndrome (ARDS) and
providing a safe and good social environment. severe multiorgan dysfunction have been
reported.26,27 Based on a case report by the report study in China stated that an infected
Indonesian Pediatric Association (IDAI), there young person could transmit the disease to
were several COVID-19 pediatric cases in seven other teenagers.36 The transmission
Indonesia that presented with severe disease could occur before any fever or other clinical
manifestations and led to fatalities.28 Evidence manifestations were reported. Other studies also
suggests that in mild symptomatic and suggest that 40% of SARS-CoV-2 transmission
asymptomatic pediatric patients with COVID-19, occurred before manifestations of any clinical
systemic inflammation resembling Kawasaki symptoms.37
disease could be found. Some cases Transmission of COVID-19 disease occurs via
progressed into hyperinflammation shock and droplets excreted from the positive patient’s
eventually resulted in fatalities.29–32 The WHO respiratory tract during talking, sneezing, or
is currently investigating the emergence of coughing. The droplets will circulate in free air
SARS-CoV-2 infection in children with for around nine minutes before slowly coming
symptoms resembling Kawasaki disease. These down to the surface of an object.38 It will survive
facts are in contrast to the current incorrect for 4-72 hours on the surface.39 Therefore,
considerations for school reopening which contaminated objects and surfaces frequently
assume that COVID-19 infection in children is touched by children at school can be a potential
always presented with mild symptoms or even medium for SARS-CoV-2 transmission.
may be harmless. Evidence also suggests SARS-CoV-2
transmission via aerosol (droplet nuclei)40.
3.2.2 Risk Of SARS-Cov-2 Transmission In Aerosol is relatively smaller compared to
Children droplets and is generated during medical
procedures, such as, nebulization, intubation,
It has also been incorrectly proposed that and dental procedures.39 It has been proposed
pediatric patients with SARS-CoV-2 are less that droplet nuclei are also produced during
likely to transmit the disease since they usually coughing and speaking. Coughing produces
present with asymptomatic to mild symptoms as more concentrated droplets than speaking.41
well as less viral load. However, on the contrary, Nevertheless, the louder a person talks, the
evidence suggests that the viral load found in more droplet nuclei that are excreted. They
children are equal compared to adults.33 could survive for 8-14 minutes in the air of
Furthermore, there is no difference between confined space.42 Studies have found traces of
virus replication rate in culture medium taken SARS-CoV-2 RNA derived from droplet nuclei
from children’s swab tests compared to adults’ which circulated in the free air of confined
swab tests.34 Therefore, children are not any spaces.43,44 This evidence indicates that both
less likely to transmit the disease, even though infected teachers and students, who remain
they might have milder symptoms as compared mildly symptomatic or asymptomatic, can
to adults. transmit the virus via droplets and aerosols
During the previous SARS pandemic, virus produced during talking. It also indicates that the
transmission occurred once clinical droplet nuclei of SARS-CoV-2 can circulate for a
manifestations developed and reached its peak long period of time in the atmosphere in closed
once symptoms worsened. The mitigation classrooms lacking ventilation. Therefore, the
strategy using thermal scanning with a one meter apart seating plan inside the
thermometer was useful in containing disease classroom may be less useful than at first
transmission during the previous SARS believed in preventing SARS-CoV-2
pandemic. Unfortunately, during SARS-CoV-2 transmission.38
pandemic, this mitigation strategy is less Studies have shown that SARS-COV-2 RNA
effective since significant transmission could was detected in children's feces in a longer
happen from asymptomatic, presymptomatic or period compared to that of nasopharyngeal
mildly symptomatic children.35 While adult swabs.45,46 SARS-CoV-2 was also isolated
patients with COVID-19 have the potential to from a fecal sample taken from an asymptomatic
spread the virus to 2-3 people, a recent case
pediatric patient.47 Isolated virus remains alive laboratory examination in screening students at
during sample collection indicating that fecal oral school. Several reports from other countries
transmission could occur.48 This route of showed the occurrence of disease transmission
spreading will lead to a possibility of disease at school areas or rapid increase of new cases
transmission at schools via contaminated feces after school reopening. Most schools were
in unhygienic toilets at schools, poor hand reopened in France in May 2020. However, they
hygiene behavior, and also unhygienic and were closed again within one week after seventy
contaminated food at school.49 new cases were reported. It is believed that
Studies evaluating COVID-19 transmission in those 70 patients already had the disease
school facilities showed inconclusive results. A before entering school.52 This pattern indicates
study in Ireland on close contact tracing from six that it is highly important to ensure that teachers
COVID-19 positive cases related to school and students are completely free from the virus
opening found that there was no single before going back to school to minimize disease
confirmed case at school areas.50 Meanwhile, transmission. A report from Israel states the
in New South Wales, Australia, close contact need to periodically evaluate students’ and
tracing from 18 positive COVID-19 cases teachers’ disease’s status after school
showed additional two positive confirmed cases reopening.53,54 Meanwhile, in South Korea, the
at school areas.51 These varying results are plan for school reopening at Buncheon was
probably due to the fact that the PCR postponed after a new cluster of confirmed
examination was performed only in children with COVID-19 cases was found.55 Collectively,
a history of close contact with COVID-19 school reopening policy is dynamic, depending
patients, diverse health protocols at every on the numbers of new cases and disease
school and countries, and incomprehensive transmission patterns in the community.
4. Discussion
Considering the negative effects of school closure and reopening that are previously mentioned,
accordingly, we formulated several risk assessments,
Figure 1. Risk Assessment in School Reopening
modified from several guidelines which are needed to be considered in order to ensure safety once the
reopening process begins (Fig.1).
4.1 Regional Risk Assessment number of currently infected cases.
In the beginning, Indonesia has had quite low Effective reproductive number (Rt) can be used
PCR test capacity even though it has steadily as a parameter to assess the effectiveness of
increased to the ratio of 2,315 tests per 1 million mitigation measures implemented in a local
citizens. Due to limited resources and the region. The Rt numbers will decrease in
narrow window of time, only the PCR cost of a response to strict mitigation measures.56
small select number of people who fall under the However, when tracing and diagnostic testing
category to be clinically monitored and patients are not performed thoroughly, this then leads to
under supervision could be covered by the undetectable SARS-CoV-2 infection, and the Rt
Indonesian government. As a consequence, it value will be less than its actual number.57
has resulted in uneven coverage and Hence, procurement of PCR testing facilities and
inconsistent testing. The government policy extending the criteria for subjects to do the PCR
stated that only people with severe or moderate testing are the most important efforts to do by
symptoms with COVID-19 cases are to be the Indonesian government as a precondition to
tested with PCR. Even though it was not school reopening. If combined with an intensive
recommended due to its high false negative contact tracing, this ‘umbrella approach’ will help
results, antibody based measurements, or rapid to attain the precise number of infected cases.
diagnostic tests (RDT) were provided by the Determining the impact of COVID-19 is
government for those with mild symptoms or necessary for the government to accurately plan
contact without symptoms of the disease. their containment measures. COVID-19 impact
Hence, it is difficult to establish the precise can be divided into 3 classifications, in which
every classification has its own assessment, 8. Proportion of severe respiratory distress
including disease intensity, severity and impact cases of confirmed cases compared to all
on the health system.58 severerespiratory distress cases.
4.1.1 Disease Intensity 9. Proportion of severe respiratory distress
1. Proportion of confirmed cases as compared cases in confirmed cases according to
age compared to all severe respiratory
to all cases tested for PCR. All cases that distress cases according to age.
undergo PCR testing, whether symptomatic
suspected cases, asymptomatic, and close All those parameters’ data could be gathered
contact cases are included. A low proportion from respected health care facilities. They have
indicates improved conditions. to be carefully measured and used as basis of
2. Proportion of confirmed symptomatic suspect prediction by local authorities to mitigate the
cases compared to all symptomatic suspect possible reemerging cases if and when the
cases that were tested for PCR. Higher school does open.
numbers represent better case identification
methods. 4.1.3 Impact on health system
3. Proportion of respiratory tract symptoms in 1. Confirmed cases among health care
suspected cases tested for PCR compared to workers.
all cases with respiratory tract symptoms. 2. Confirmed death cases among health
This number reflects an adequate PCR test care workers.
capacity. 3. Sick health care workers that are on
4. Proportion of confirmed COVID-19 cases quarantine or self-isolation.
according to age groups. After school 4. Proportion of beds occupied for
reopening, if there is a surge of confirmed suspected or confirmed cases in the
COVID-19 cases in the school age group, hospital compared to allocated beds for
viral spreading in the school area is highly COVID-19 cases.
suspected. 5. Personal protective equipment (PPE)
5. Proportion of close contact that is traced availability. Mitigation on aforementioned
down and quarantined, compared to all close factors of the current health system may
contact cases. give a hint on the capacity of certain
6. Proportion of close contact cases tested with regions to overcome the secondary
PCR compared to all close contact cases. outbreak during and after school
reopening.
4.1.2 Disease severity
1. Total death cases. 4.2 School Risk Assessment
2. Total confirmed death cases. In addition to the regional risk assessment,
3. Proportion of confirmed death cases of several considerations at the school level should
COVID-19 compared to total death cases be made. School risk assessment has to be
in the period. performed once the regional risk assessment
4. Total confirmed or suspected cases has been completed. The Pennsylvania
admitted to the hospital. Department of Education had recommended
5. Total confirmed or suspected cases phases of the school reopening plan according
admitted to ICU/ HCU. to its new safety policy post COVID-19
6. Proportion of total confirmed death cases pandemic.
compared to total confirmed cases of
COVID-19. 1. Red phase: closed schools remain closed
7. Proportion of confirmed death cases of if new cases are still reported in the
COVID-19 according to age groups region. Remote learning is recommended
compared to confirmed cases according via online, both through digital and non-
to age groups. digital platforms. Additional student
services such as a school meal programs
at boarding schools should be provided Organization (WHO) recommendations.
as feasible. Essential requirements are protocols and
2. Yellow phase: as the number of new policies for school reopening, health facility
cases remain stable and additional cases preparedness, human resource preparedness,
per day are lessened, closed schools will funding, and communication and cooperation for
be reopened based on several school reopening. These requirements are
requirements. During this yellow phase, proposed tomaintain a safe and conducive
stay at home policies are lifted and large- learning environment while minimizing disease
scale social restrictions are loosened. transmission. Based on these
3. Green phase: outbreak parameters and recommendations, several adjustments at
the severity of outbreaks can be schools are required in accordance with the New
controlled. Most restrictions are eased, Normal policy post COVID-19 pandemic.
large-scale social restrictions are widely Summary recommendations of school reopening
loosened although social and physical policies and school facilities preparedness which
distancing measures are still applied. need to be reviewed are listed as follows (Figure
During the green phase, large group 2 and 3). The higher number of “yes” answers
social activities are executed based on on the checklist may indicate the readiness of
the ‘new normal’ policy. Schools within the school to initiate the reopening process. On
the green phase can be reopened based the contrary, more “no” answers may suggest
on several considerations.59 that the school needs to consider other
Several school reopening requirements should alternatives in establishing its curriculum and
be met based on the United Nations Children’s education process.
Fund (UNICEF) and the World Health
4.3 Individual Risk Assessments vision, awareness, and understanding
Human resources (students, teachers, and concerning SARS-CoV-2 infection. Once actions
parents) play a pivotal role to provide a safe and are taken based on the same shared
conducive learning environment at schools fundamental approach, schools are ready for
during the New Normal Era of post COVID-19 reopening based on the following individual risk
pandemic. All parties have to share the same
Figure 2. Health policies checklist for school reopening
Figure 3. School facilities checklist for school reopening
assessments (Figure 4, 5, and 6). during reopening process. Several changes on
Just as the previous checklists could be used to the number of “yes” and “no” answers could be
mitigate and assess a school’s readiness before expected during the reopening process and may
reopening, individual checklist assessments for be used to mitigate and decide whether the
students, parents and teachers could be used reopening could be continued or halted
not only for preparation but also for evaluation temporarily.
4.4 Alternative Strategies And Recommendations
Indonesian schools are currently facing a paramount obstacle to conduct their education activities. Both
safety and education quality have to be
Figure 4. Student checklist as risk assessment in school reopening
Figure 5. Parents checklist as risk assessment for school reopening
Figure 6. Teacher checklist as risk assessment for school reopening
guaranteed for the young students to survive in interactive, considering screen time and
the current pandemic situation. Accordingly, its limit in children. The 20-20- 20 rule is
various preparations and compliances to school recommended to prevent eye strain
facility preparedness for school reopening have caused by prolonged screen time.
to be performed. This approach is not only 2. Learning modules, target, and
intended to protect the students, but also all staff curriculum need to be modified
working at schools. Implemented strategies effectively and be timely in order to
should consider children’s needs holistically, meet learning objectives in shorter
including biomedical, social and psychological online learning duration.
perspectives. 3. Online learning modules should be
Several preparations should be made by innovative and creative, consisting of
schools and the government to ensure that the opening, main body, and closing with
upcoming strategies implemented for school interactive games being put in between
reopening are based on considerations to fulfill sessions. Learning modules are made
children basic needs and to prevent further to facilitate student’s autonomy.
transmission of the pandemic. However, schools 4. Learning modules are made as a
and the government are also expected to combination of online and offline
provide alternative learning strategies similar to learning.
the well-organized remote learning opportunities 5. Outcomes from online learning are
currently available online. Various evaluated based on learning objectives
recommendations are crucial in order to in accordance with the New Normal
evaluate both the health benefits and side situation.
effects of online learning such as:
1. Online learning activities with gadgets
should be effective, concise, and
5. Conclusion S, Miani A, Giannini S. Rethinking the role
Schools are required to identify and mitigate
disease transmission risk and to prepare school of the school after COVID-19 closure.
reopening regulations based on health regional
authorities. Good cooperation between various Lancet. 2020;(May
authorities and stakeholders are essential in
preventing further community disease 20):e370.doi:10.1007/s00134-020-05991-
transmission and in preventing the emergence
of new clusters of transmission. The Indonesian x. Bizzarro
Health Authorities are expected to be aware that
other measurements are needed outside of the 8. Sylva K. School influences on children’s
important health protocols to prevent the
emergence of new cases once schools have development. J Child Psychol
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Psychiatry.1994;35(1):135-170.
Conflicts Of Interest
Authors declare no potential conflict of interests. doi:10.1111/j.1469-7610.1994.tb01135.x
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SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 (SARS-COV-2): AN
OVERVIEW OF VIRAL STRUCTURE AND HOST RESPONSE
Indwiani Astuti*, Ysrafil
Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nurses, Universitas Gadjah Mada,
Yogyakarta, Indonesia
ABSTRACT
Background and aim: As a result of its rapid spread in various countries around the world, on March
11, 2020, WHO issued an announcement of the change in coronavirus disease 2019 status from
epidemic to pandemic disease. The virus that causes this disease is indicated originating from animals
traded in a live animal market in Wuhan, China. Severe Acute Respiratory Syndrome Coronavirus 2
can attack lung cells because there are many conserved receptor entries, namely Angiotensin
Converting Enzyme-2. The presence of this virus in host cells will initiate various protective responses
leading to pneumonia and Acute Respiratory Distress Syndrome. This review aimed to provide an
overview related to this virus and examine the body’s responses and possible therapies.
Method: We searched PubMed databases for Severe Acute Respiratory Syndrome Coronavirus-2,
Middle East respiratory syndrome-related coronavirus and Severe Acute Respiratory Syndrome
Coronavirus. Full texts were retrieved, analyzed and developed into an easy-to-understand review.
Results: We provide a complete review related to structure, origin, and how the body responds to this
virus infection and explain the possibility of an immune system over-reaction or cytokine storm. We also
include an explanation of how this virus creates modes of avoidance to evade immune system attacks.
We further explain the therapeutic approaches that can be taken in the treatment and prevention of this
viral infection.
Conclusion: In summary, based on the structural and immune-evasion system of coronavirus, we
suggest several approaches to treat the disease.
Keyword : COVID-19 SARS-CoV-2, Pandemic ACE2,Wuhan
1. Introduction accessory proteins [9]. The spike or S
Coronavirus disease 2019 (COVID-2019) is glycoprotein is a transmembrane protein with a
caused by a novel coronavirus known as Severe molecular weight of about 150 kDa found in the
Acute Respiratory Syndrome Coro- navirus 2 outer portion of the virus. S protein forms
(SARS-CoV-2) and was identified as a homotrimers protruding in the viral surface and
pandemic by the World Health Organization facilitates binding of envelope viruses to host
(WHO) on March 11, 2020 [1]. As of April 12, cells by attraction with angiotensin-converting
2020, more than 1.8 million people were enzyme 2 (ACE2) expressed in lower respiratory
confirmed to have been infected and tested tract cells. This glycoprotein is cleaved by the
positive for COVID-19, with over 114,000 deaths host cell furin-like protease into 2 sub units
worldwide [2]. This virus was first identified in namely S1 and S2. Part S1 is responsible for the
the respiratory tract of patients with pneumonia determination of the host virus range and
in Wuhan, Hubei China, in December 2019 cellular tropism with the receptor binding domain
which was then indicated as a newly identified b- make-up while S2 functions to mediate virus
coronavirus (nCoV) [3,4]. fusion in transmitting host cells [3,10,11].
SAR-CoV2 is an enveloped, non-segmented, The nucleocapsid known as N protein is the
positive sense RNA virus that is included in the structural compo- nent of CoV localizing in the
sarbecovirus, ortho corona virinae subfamily endoplasmic reticulum-Golgi region that
which is broadly distributed in humans and other structurally is bound to the nucleic acid material
mammals [5,6]. Its diameter is about 65e125 of the virus. Because the protein is bound to
nm, containing single strands of RNA and RNA, the protein is involved in processes related
provided with crown-like spikes on the outer to the viral genome, the viral replication cycle,
surface. SARS-CoV2 is a novel b-coronavirus and the cellular response of host cells to viral
after the previously identified SARS-CoV and infections [12,13]. N protein is also heavily
MERS-CoV which led to pulmonary failure and phosphorylated and suggested to lead to
potentially fatal respiratory tract infection and structural changes enhancing the affinity for viral
caused out- breaks mainly in Guandong, China RNA [10] (see Fig. 1).Another important part of
and Saudi Arabia. In COVID-19 research, many this virus is the membrane or M protein, which is
studies have demonstrated that bats are sus- the most structurally structured protein and
pected as the key reservoir of the viruses by plays a role in determining the shape of the virus
finding as much as96.2% identical genome envelope. This protein can bind to all other
sequencing of SARS-CoV-2 with bat CoV structural proteins. Binding with M protein helps
RaTG13 [3,7]. In this review, we hypothesize to stabilize nucleocapsids or N proteins and pro-
that since the COVID- 19 virus has several motes completion of viral assembly by stabilizing
complex immune-evasion components that N protein-RNA complex, inside the internal
contribute to its virulence, we suggest this more virion. The last component is the envelope or E
complete under- standing can be used to protein which is the smallest protein in the
develop an effective approach in the treatment SARS- CoV structure that plays a role in the
of diseases caused by this virus. production and maturation of this virus [12].
2. Origin And Structure Of SARS-Cov2 In supporting the process of entry of the virus
A sample isolation from pneumonia patients who into the host cell, SARS-CoV2 binds to the
were some of the workers in the Wuhan seafood ACE2 receiver that is highly expressed in the
market found that strains of SARS-CoV-2 had a lower respiratory tract such as type II alveolar
length of 29.9 kb [8]. Structurally, SARS-CoV-2 cells (AT2) of the lungs, upper esophagus and
has four main structural proteins including spike stratified epithelial cells, and other cells such as
(S) glycoprotein, small envelope (E) absorptive enterocytes from the ileum and colon,
glycoprotein, membrane (M) glycoprotein, and cholangiocytes, myocardial cells, kidney
nucleocapsid (N) protein, and also several proximal tubule cells, and bladder urothelial cells
[14]. Therefore, patients who are infected with Respiratory Distress Syndrome (ARDS), but
this virus not only experience respiratory
problems such as pneumonia leading to Acute also experience disorders of heart, kidneys, and
digestive tract.
Fig. 1. Structure of severe acute respiratory syndrome coronavirus 2 [12,13].
3. Entry And Life Cycle Of Coronaviruses expression throughout the respiratory tract [17].
As a member of the Nidovirus family, Furthermore, entered-SARS-CoV-2 will
coronavirus infection (SARS-CoV2) can be subsequently release its genomic material in the
contracted from animals such as bats, and cytoplasm and become translated in the nuclei
fellow humans. This virus can enter the human (see Fig. 2).
body through its receptors, ACE2 which are
found in various organs such as heart, lungs, The genomic material released by this virus is
kidneys, and gastrointestinal tract, thus mRNA that is ready to be translated into protein.
facilitating viral entry into target cells. The In its genome range, this virus is complemented
process of CoV entering into the host cell begins by about 14 open reading frames (ORF), each of
through the attachment of the S glycoprotein to which encodes a variety of proteins, both
the receptor, the ACE2 in the host cells (such as structural and non- structural that play a role in
in type II pneumocytes in the lungs) [15]. This its survival as well as virulence po- wer. In its
attachment occurs in the binding domain of S phase of transformation, the gene segments that
protein of SARS-CoV-2 receptors which are encode nonstructural polyproteins are the ones
present at 331 to 524 residues, and can bind this process first translates into ORF1a and
strongly to human ACE2 and bat ACE2 [13]. The ORF1b to produce two large overlapping poly-
entry and binding processes are then followed proteins, pp1a and pp1ab by contributing a
by fusion of the viral membrane and host cell ribosomal frame shifting event [19]. The
[11]. polyproteins are supplemented by protease
enzymes namely papain-like proteases (PLpro)
After fusion occurs, the type II transmembrane and a serine type Mpro (chymotrypsin-like
serine protease (TMPRSS2) that is present on protease (3CLpro)) protease that are encoded in
the surface of the host cell will clear the ACE2 nsp3 and nsp 5. Subsequently, cleavage occurs
and activate the receptor-attached spike-like, S between pp1a and pp1ab into nonstructural
proteins [15]. Activation of the S proteins leads proteins (nsps) 1e11 and 1e16, respectively.
to conformational changes and allows the virus The nsps play an important role in many
to enter the cells [16]. Both of these proteins processes in viruses and host cells (Table 1)
(TMPRSS2 and ACE2) are the main [10,20,21] (see Fig. 3).
determinants of the entry of this virus. Based on
the research of Sungnak et al. nasal epithelial Many of the nsps subsequently form replicase-
cells, specifically goblet/secretory cells and transcriptase complex (RTC) in double-
ciliated cells, display the highest ACE2 membrane vesicles (DMVs), which are mainly
an assembly by RNA-dependent RNA translated into struc- tural and accessories
polymerase (RdRp)- and helicase-containing proteins such as M, S, and E proteins that
subunits, the canonical RdRp domain residing of subsequently are insulated in the endoplasmic
CoV nsp 12 and AV nsp9. Furthermore, the reticulum and then moved to the endoplasmic
complex transcribes an endogenous genome reticulum-Golgi intermediate compartment
template of viral entry to negative-sense genes (ERGIC). Meanwhile, the previously replicated
of both the progeny genome and subgenomic genome program can directly join the N protein
RNA as intermediate products and followed by to the nucleocapsid form and move into the
transcription to positive-sense mRNAs that are ERGIC. In this compartment, nucleocapsids will
mainly mediated by RdRp [19,20,22]. meet with several other structural proteins and
form small wallet vesicles to be exported out of
Next, the subgenomic proteins become the cell through exocytosis [10,19].
Fig. 2. Genome and nonstructural proteins of Severe Acute Respiratory Syndrome Coronavirus-2 [18].
4. Immune Response To Coronavirus system cells via antigen presenting cells (APC),
Infection e.g. dendritic cells and macrophages as frontline
of the immune system [15,26]. APC have
Generally, the body’s immune response to Pattern Recognition Receptors (PRR) including
SARS-CoV2 and SARS-CoV is closely similar Toll-like receptors (TLRs), NOD-like receptors
being mediated by cytokines [23]. A case report (NLRs), RIG-I-like receptors (RLRs) and other
in Wuhan from 99 COVID-19 patients revealed small free molecules that are located in various
that there was an increase in the total number of places in host cells such as plasma membranes,
neutrophils, Interluekin-6 (IL-6) serum and c- endo- somal membrane, lysosomes,
reactive protein about 38%, 52% and 86%, endocytolysosomes, and cytosol. They
respectively and 35% decrease of total recognize PAMP comprised nucleic acids,
lymphocytes [24]. Other research found carbohydrate moi- eties, glycoproteins,
increased expression of proinflammatory lipoproteins and other small molecules that are
cytokines and chemokines IP-10, MCP-1, MIP- found in the structural components of viruses or
1A, and tumor ne- crosis factor-alpha (TNFa) [5]. intermediate products such as dsRNA and
The conditions are correlated with severity and induce cascade signaling to produce immune
mortality of this disease which suggest the system cell effectors. Each of the PRRs could
potential of cytokines forming as found occurring induce a different biological response to
in SARS-CoV and MERS-CoV infections [25]. subsequent protein activation [23,26].
The entry of the virus into the host cell triggers For example, Toll like receptor 4 (TLR-4) might
stimulation of the host’s immune response, recognize the outer component of CoV, the
which will first be encountered by innate immune
protein spike. Furthermore, through mediation of complexes with its receptors, IFNAR and
MyD88, this introduction will trigger the subsequently activate the JAK-STAT pathways.
activation of NF-kB transcription factors and the JAK1 and TYK2 kinases further phosphorylate
pathogen-activated protein kinases (MAPKs) STAT1 and 2 followed by its complexation with
pathway to induce proinflammatory proteins. IRF9, and together they migrate into the nucleus
Meanwhile, activation of endosomal receptors to initiate the transcription of IFN-stimulated
such as TLR-3 and TLR that could recognize the genes (ISGs) and lead to suppression of viral
RNA or dsRNA genome of coronavirus leads to replication and prevent the severity of the
recruitment of TRIF adapter protein directly. disease [25]. However, excess releasing of pro-
TRIF subse- quently activates the IRF3 and NF- inflammatory cytokines such as IFN-a, IFN-g, IL-
kB transcription factors to induce 1b, IL-6, IL-12, IL-18, IL-33, TNF-a, TGFb, and
proinflammatory cytokines such as interferon-a chemokines CCL2, CCL3, CCL5, CXCL8,
and TNF-b. Although the introduction of PAMP CXCL9, CXCL10 from immune effector cells
through TLR-4 can also recruit TRIF adapter causes hyperinflammation which will eventually
proteins, the recruitment must be mediated by lead to ARDS [28,29].
TRAM and TIRAM [15,25e27]. This secret of
proinflammatory cytokines is the initial response As the presenter of foreign antigens, the APC
in the first line of defense against virus infec- will present the
tion. Furthermore, type I INF in turn will form
antigen of CoV to the CD4 T-helper cells by as a co-stimulatory molecule to further stimulate
MHC class 1, and this leads to releasing of IL-12 the Th1 cell activation. In addition to Th1
stimulation, releasing of interleukin-12 and IFN- avoidance strategies through the formation of
a, an increase in MHC Class I expression and double vesicles on the outside of the cell. The
NK cell activation is also needed for resistance formation of these vesicles causes shield
of viral replication for the eradication of virus- recognition of cytosolic PRRs to dsRNA as an
infected cells. It also initiates production of intermediate product of replication virus [28].
proinflammatory cytokines via the NF-kB
signaling pathway. IL-17 is a proinflammatory In addition to the formation of a double vesicle,
cytokine that also is increased when SARS- this virus has 8 proteins capable of avoiding the
CoV2 infection occurs. These cytokines further immune system through the blocking of INF.
recruit neutrophils and monocytes to the site of Nsp1 is a non-structural group of proteins from
infection and activate several other pro- SARS-CoV that can suppress the work of INFeI
inflammatory cytokines and che- mokines through host translational machinery
including IL-1, IL-6, IL-8, IL-21, TNF-b, and inactivation, RNA-Host degradation and
MCP-1 [15,26,30,31]. inhibition of phosphorylation of STAT1. The
mechanism could cause INFeI failure to induce
Next, activation of Th1 cells could stimulate CD8 replication and dissemination of viruses at an
T cells, which are one of the effectors of T cells early stage and leads to increased severity of
that will target and kill cells infected with CoV. At disease [25,27]. The composition of the viral
the same time, CD4 T cells could stimulate RNA genome including SARS-CoV which has a
humoral immune responses by producing 5 0cap less than the host cell RNA makes it
antigen-specific antibodies via activating T- easy for immune system cells to recognize its
dependent B cells [15,28,30]. presence and induce an immune response. To
get around this, the virus developed a strategy
The antibodies produced are generally IgM and of mimicking the host capping machinery. This
IgG which have a unique presence pattern in strategy employs two non-structural proteins
response to the presence of coronavirus [28]. namely nsp 14 which initiates cap forma- tion,
Generally, this infection will produce a specific and subsequently follows modifying the cap of
IgM that can only last 12 weeks, but IgG with a viral RNAs by nsp 16 so that RNA viral seems
longer period. In addition to the formation of similar to host cell RNA and avoids any PRRs
antibodies, exposure to this virus also cause the recognition [27,34,35].
for- mation of CD4 T cells and CD8 memory that
can last for four years [32]. In fact, based on Other nonstructural proteins from coronavirus
findings in patients who recovered six year after that also have the ability to prevent this virus
coronavirus infection, T cell memory was still from immune responses are nsp3 that encoded
able to hit the peptide spike when the first two functional proteins, macrodomains and
exposure occurred [33]. This further explains PLpro (cleavage of nsps). Both of these proteins
and directs researchers to the development of appear to be employed as actors in the evading
vaccines against the corona virus, especially to of SARS-CoV from immune response-induce
SARS-COV-2, which is now a pandemic viruses. This possibility was supported by Fehr
outbreak in the worldwide [28]. et al. in their in vivo study in BALB/c mice that
were infected by SARS-CoV- lacking
5. Immuno-Evasion Of Coronaviruses macrodomains. The findings of this study
Generally, viruses including coronavirus have revealed that although there was an increase in
number of avoidance ways from onslaught of expression of type I IFN, ISG15, CXCL10 and
immune system cells to better survive and infect the proinflammatory cytokines IL-6 and TNF,
host cells [28,30]. The strategy can be applied to followed by significantly higher survival, there
various processes, both at the time of was no lung pathology development in the mice
introduction (before entering the cell) and when [36]. The finding is closely similar to other
it has entered the host cell. During the studies conducted in mice demonstrating a lack
recognition process, this virus can use of deubiquitinating enzyme (DUB) activity in
MERS-CoV. DUB is another role of PLpro to occurred before and since the death ratio
help coronavirus evade attack from a host’s caused by COVID 19 is quite high, miti- gation
immune response by antagonizing the IFN methods need to be developed, one of which is
response. From these findings, we hypothe- through the development of vaccines that have
sized that the decline in function of the two not yet been found. Specific vaccines could be
proteins may lead to the direct introduction and used to initiate the formation of specific anti-
sticking of immune troops to continu- ously bodies against the SARS-CoV2 virus. This
infected cells and prevented the replication of development is being temporarily developed in
the virus and the life cycle [37,38]. In addition to various parts of the world and is the focus of
using nonstructural proteins, SARS-CoV could today’s global efforts. In fact, according to a
utilize its protein accessories to avoid immune news release from Jakarta Globe on March 27,
responses. For example the gene segment 2019, the G20 has set aside about USD$ 4
located on ORF3b of this virus has the ability to billion for the development of the vaccine
antagonize the INF signaling pathway and cause [40,43].
inhibition of the effector cell activation cascade
for eradica- tion and inhibition of viral replication Spike or S protein-based vaccine is one
[39]. Equally of concern, the protein encoded in approach to developing vaccines that has
ORF6 could inhibit JAK-STAT signaling pathway attracted the attention of many researchers in
by binding to karyopherin-a2,and tethers the discovery of the coronavirus vaccine. S
karyopherin-b1 on internal membranes to lead to protein has an RBD located in the S1 subunit of
blocking nuclear translocation of the the virus that facilitates entry of the virus into the
transcription factor STAT1 [27]. host cell by binding to its receptors on the host
cell, ACE2. Furthermore, the existence of
6. Approach For SARS-Cov-2-Related mapping and genomic character- ization of
Disease Therapy these proteins has increasingly answered the
puzzle in the development of this vaccine
There is no specific treatment for eradication of [44,45]. Research by Yang et al. that used
the SARS-CoV2 virus in patients. Accordingly, combined DNA demonstrated protein S could
the therapeutic approach that can be done is to activate the immune response through T cell
use another b-coronavirus approach such as production that subsequently form antibodies
SARS-CoV or MERS-CoV treatments. Some which can neutralize the virus in mice. Another
possible therapies can be given ac- cording to study shown that this strategy was effective to
the approaches including lopinavir/ritonavir, elicit protective immunity producing neutralizing
chloro- quine, and hydroxychloroquine. Aerosol antibodies in mice [46,47]. Further studies with
inhalation of alpha- interferon twice per night closely similar results conducted by Gao et al.
also could be used. In some cases coro- and He et al. that used reconstructed vaccine
naviruses (such as MERS-CoV) have commonly which originated from S1 fragment of SARS-
used combinations of interferon-a combined with CoV revealed that it could stimulate immune
ribavirin [40,41]. This therapy seems to be able response and induce highly potent neutralizing
to give results at the beginning of therapy, that is antibodies to blocking S protein binding and
14 days after being diagnosed, but this effect prevent SARS-CoV entry [48,49].
disappears when entering day 28. Furthermore,
Loutfy et al. found that the combination of In addition, through recent developments in
interferon with steroid drugs can accelerate lung vaccine-based therapy for cancers and other
repair and in- crease oxygen survival levels. diseases, therapeutic development efforts also
Therapy using interferona is still confusing. focus on drug discovery that can stop the spread
Other studies have concluded that this therapy and replication of the virus in the host cell that is
does not have a beneficial effect on patients intended for patients who have already
[38,42]. contracted an infection. These include camostat
mesylate which is a serine protease inhibitor that
As a matter of fact, as with epidemics that have
can inhibit the performance of TMPRSS2 Declaration of competing interest
enzyme activity in the coronavirus entry process. None declared.
This drug has been used clinically in the
treatment of chronic pancreatitis so that it is References
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POSSIBLE SILENT HYPOXEMIA IN A COVID-19 PATIENT: A CASE REPORT
Siswantoa,*, Munawar Ganib, Aditya Rifqi Fauzic, Ririn Enggy Yuliyantic, Maria Patricia Inggrianic, Bagus Nugrohod, Denny
Agustiningsihe, Gunadic,**
a Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/UGM Academic
Hospital, Yogyakarta, 55291, Indonesia
b Pulmonology Division, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas
Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia
c Pediatric Surgery Division, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah
Mada/Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia
d Panti Rapih Hospital, Yogyakarta, 55223, Indonesia
e Department of Physiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, 55281,
Indonesia
ABSTRACT
Introduction: It has been hypothesized that silent hypoxemia is the cause of rapid progressive
respiratory failure with severe hypoxia that occurs in some COVID-19 patients without warning.
Presentation of case: A 60-year-old male presented cough without any breathing difficulty. Vital signs
showed blood pressure 130/75 mmHg, pulse 84x/minute, respiratory rate (RR) 21x/minute, body
temperature 36.5C,and oxygen saturation (SpO2) 75% on room air. RT-PCR for COVID-19 were
positive. On third day, he com- plained of worsening of breath shortness, but his RR was still normal
(22x/minute) with SpO2 of 98% on 3 L/ minute oxygen via nasal cannula. On fifth day, he experienced
severe shortness of breath with RR 38x/minute. He was then intubated using a synchronized
intermittent mandatory ventilation. Blood gas analysis showed pH 7.54, PaO2 58.9 mmHg, PaCO2 31.1
mmHg, HCO3 26.9mEq/L, SaO2 94.7%, FiO2 30%, and P/F ratio 196 mmHg. On eighth day, his
condition deteriorated with blood pressure 80/40 mmHg with norepinephrine sup- port, pulse
109x/minute, and SpO2 72% with ventilator. He experienced cardiac arrest and underwent basic life
support, then resumed strained breathing with return of spontaneous circulation. Blood gas analysis
showed pH 7.07, PaO2 58.1 mmHg, PaCO2 108.9 mmHg, HCO3 32.1mEq/L, SaO2 78.7%, FiO2 90%,
and P/F ratio 65 mmHg. Three hours later, he suffered cardiac arrest again and eventually died.
Discussion: Possible mechanisms of silent hypoxemia are V/Q mismatch, intrapulmonary shunting,
and intra- vascular microthrombi.
Conclusions: Silent hypoxemia might be considered as an early sign of deterioration of COVID-19
patients, thus, physician may be able to intervene early and decrease its morbidity and mortality.
Keywords: ARDS COVID-19, Early sign of deterioration, Respiratory failure with severehypoxia Silent
hypoxemia
1. Introduction respiratory failure causes an increase in
The SARS-CoV-2 virus that causes Coronavirus respiratory rate (RR), in some patients, a
Disease 2019 (COVID-19) was declared a persistent normal RR was found and
pandemic since the World Health Organi- zation inconsistent with the severity of hypoxia. Some
(WHO) decree on March 11, 2020, and has pa- tients with COVID-19 reported experiencing
infected more than 54 million people and caused rapid deterioration without warning. This reaction
more than 1.3 million deaths as of November 14, might be caused by ‘silent hypoxemia’.
2020 [1,2]. Research has shown that failure of pulmonary
oxygen diffusion causes a gradual decrease in
The early sign of severe disease of SARS-CoV- oxygen saturation [3,4]. Here, we reported one
2 infection is pneu- monia with respiratory COVID-19 case with the possibility of silent
failure, similar to Acute Respiratory Distress hypoxemia.
Syndrome (ARDS). Although hypoxic acute
2. Presentation Of Case bridging intervention to mechanical venti- lation.
A 60-year-old Javanese male came to outpatient His blood gas analysis showed respiratory
clinic in our hospital with complaints of cough alkalosis (pH 7.54, PaO2 58.9 mmHg, PaCO2
that was felt for two weeks before admission 31.1 mmHg, HCO3 26.9 mEq/L, SaO2 94.7%,
without any breathing difficulty. Complaints were FiO2 30%, P/F ratio 196 mmHg, indicating
accompanied by fever, runny nose and sore moderate ARDS). On the following day, his
throat. He had a comorbid condition of un- blood gas analysis showed compensated
controlled diabetes mellitus (DM). He was not a respiratory alkalosis (pH 7.45, PaO2 64.6
smoker and had no history of chronic pulmonary mmHg, PaCO2 42.9, HCO3 29.9 mEq/L, SaO2
disease. His vital signs examination showed 93.6%, FiO2 60%, P/F ratio of 111.5 mmHg,
blood pressure 130/75 mmHg, pulse 84 times indicating moderate ARDS). On the eighth day
per minute, normal respiratory rate (RR) of 21 of treatment, his condition deteriorated starting
times per minute, body temperature 36.5C, 75% in the morning, with blood pressure 80/40 mmHg
oxygen saturation on room air. His body mass with norepinephrine support, pulse 109 times
index is 28.04, categorized as overweight. On per minute, and 72% SpO2 with ventilator. In
physical examination, an increase in vesicular the afternoon, the patient experienced cardiac
sounds and crackles in both lungs were arrest and underwent basic life support, then
identified. Labora- tory tests showed an increase resumed strained breathing with return of
in C-reactive protein (CRP), neutrophil- spontaneous circulation. His laboratory results
lymphocyte ratio, aspartate transaminase (AST), showed leu- cocyte count of 21.33x103/μL, AST
and alanine aminotransferase (ALT) of 140 of 112 μ/L, ALT of 96 μ/L, blood urea nitrogen of
mg/L, 8.7, 88 μ/L, and 116 μ/L, respectively. 41.5 mg/dL, creatinine of 3.36 mg/dL, and CRP
Chest x-ray showed bilateral pneumonia (Fig. 1). of 140 mg/L. Blood gas analysis showed severe
Sputum and GeneXpert tests were performed, respiratory acidosis (pH 7.07, PaO2 58.1 mmHg,
and the results were negative for tuberculosis PaCO2 108.9 mmHg, HCO3 32.1 mEq/L, SaO2
infection. The nasopharyngeal and 78.7%, FiO2 90%, P/F ratio of 65 mmHg,
oropharyngeal swab real-time poly- merase indicating severe ARDS) (Fig. 2). Three hours
chain reaction tests for COVID-19 were positive. later, he suffered cardiac arrest again, but was
After admis- sion, the patient received antibiotics unable to be resuscitated. The patient eventually
and antiviral therapy based on the COVID-19 died.
Prevention and Control guidelines by the
Indonesian Ministry of Health [5], namely 3. Discussion
intravenous azithromycin 500mg once daily, oral Here, we discuss a case with COVID-19 with the
lopinavir/ritonavir 400/100mg twice daily, oral possibility of silent hypoxemia. Hypoxemia itself
chloroquine sulfate 150 mg twice a day, is defined as a potential life-threatening
intravenous meropenem 1 gr thrice daily, and condition characterized by a decrease in arterial
medications for his DM (Fig. 2). On the third day PO2 below the normal value. Hypoxemia
of treatment, the pa- tient complained of documentation can be done by checking pulse
worsening of shortness of breath, but his RR oximetry and arterial blood gas analysis.
was still normal with 22 times per minute with Hypoxemia occurs when PaO2 is less than 80
SpO2 of 98% on 3 L/minute oxygen via nasal mmHg, and severe hypoxemia is when it is less
cannula. On the fifth day of treatment, the than 60 mmHg. There are four main factors that
patient experienced severe shortness of breath can impair pulmonary gas exchange and cause
with a RR of 38 times per minute. The patient hypoxemia when breathing room water is at sea
was then intubated using a mechanical ventilator level: hypoventilation, diffusion limitation, shunt,
with synchronized intermittent mandatory and ventilation-perfusion (V/Q) mismatch [7–9].
ventilation. The patient was not in a prone
position. Moreover, continuous positive airway This unusual ‘silent hypoxemia’ phenomenon
pressure was not utilized in this patient as a showed it is possible that the virus has an
idiosyncratic effect on the respiratory control
sys- tem. Angiotensin-converting-enzyme 2 mismatch, however, at the same time, it also
(ACE2) receptors are highly expressed in the stimulates the pro-fibrotic effect, and both effects
carotid bodies, which are also the same sites are aggravated by the concomitant upregulation
where chemoreceptors sense oxygen. ACE2 of ACE2 [10–12].
receptors are also widely expressed in the nasal
mucosa. Symptoms of anosmia-hyposmia are Gattinoni et al. [13] suggested two primary
experienced by a third of patients with COVID- phenotypes of hypoxemia in patients with
19, and the olfactory bulb can be the entrance of COVID-19: type L and type H. Type L is caused
the virus to the brain and may also play a role in by loss of respiratory regulation and loss of
depressed dyspnea response [10,11]. hypoxic vasoconstriction. The condition of
hypoxemia is due to an increase in minute
Moreover, ACE2 counteracts the physiological ventilation, mainly by increasing the tidal volume
functions of ACE and results in the activation of (up to 15–20 ml/kg). Meanwhile, type H is a
the renin-angiotensin-aldosterone system transition from type L, which is associated with a
(RAAS) related to blood pressure regulation more negative intrathoracic inspiratory pressure.
through the conversion of Angiotensin I to Diffuse pulmonary micro- vascular thrombosis is
Angiotensin II and the electrolyte homeostasis. also believed to be the cause of hypoxemia in
During the hypoxia condition, Angiotensin II patients with COVID-19 [14].
induces vasoconstriction to improve the V/Q
Fig. 1. Chest x-rays: a) on the admission day indicated bilateral pneumonia, which is not compatible
with the relatively slight clinical manifestations of patient, b) on the third day, and c) on the eight day
also showed bilateral pneumonia.
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