Coronavirus
disease-2019 (COVID-19) is a global health crisis. The clinical
characteristics, disease progression and outcome in children and
young adults appear significantly milder compared to older
individuals. Since first being reported in Wuhan, China in
December 2019, COVID-19 has rapidly spread to affecting over 200
countries worldwide. Children account for 1-5% of diagnosed
COVID-19 cases [1]; although, many infected children may be
asymptomatic and therefore not diagnosed without population
screening. At the time of writing, in India, the number of
virologically confirmed COVID-19 positive cases is 5273 (149
deaths) as per the Ministry of Health and Family Welfare (MOHFW)
[2].
VIROLOGY AND EPIDEMIOLOGY
Coronaviruses are a family of enveloped, single stranded,
zoonotic RNA viruses which can rapidly mutate and recombine,
leading to novel viruses that can spread from animals to humans
[3]. The precise events that led to the emergence of Severe
Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causing
COVID-19 remain unknown. SARS-CoV-2 is transmitted through
inhalation of respiratory droplets of an infected person and
touching surfaces contaminated with the virus. In previous
coronavirus epidemics, children globally accounted for 6.9% of
SARS 2002-3 infections and 2% of Middle East Respiratory
Syndrome (MERS) infections. It appears that SARS-CoV-2 has a
higher transmission capability compared with the closely related
viruses causing SARS 2002-3 and MERS [4]. The true case fatality
rate (CFR) of COVID-19 infection is currently unknown due to
lack of population-scale longitudinal data. Thus, estimates of
CFR currently vary between 0.5-5% [1,5].
PATHOGENESIS
The SARS-CoV-2
virus utilizes Angiotensin Converting Enzyme 2 (ACE2) receptors
as its cell surface receptor, similar to the SARS 2002-3 virus.
ACE2 is expressed in highly byciliated epithelial cells in the
human lungs and this receptor allows the virus to attach to the
cell [6]. The ACE2 receptor is also expressed in the intestines,
potentially accounting for the gastrointestinal symptoms that
commonly occur in the early stage of the illness.
Severe COVID-19 disease is characterized by three phases: the
first being the viral phase; the second being the cytokine
storm; and the third encompassing acute respiratory distress
syndrome (ARDS), impaired cardiac function and death [7]. The
cytokine storm appears to be driven by a dysregulated host
immune response [8] and might contribute to mortality [9]. The
profile of the cytokine storm associated with severe COVID-19
disease is similar to that of secondary hemophagocytic
lymphohistiocytosis (HLH), which is a rare complication of other
viral infections (3.7-4.3%) [8]. Secondary HLH is characterized
by fulminant and fatal hypercytokinemia with multiorgan failure.
In severe infection, lower peripheral lymphocyte counts (CD4 and
CD8 T cells), higher interleukin (IL) levels (IL-6 and IL-10),
decreased interferon-gamma expression in CD4+ T cells and higher
D-dimer and fibrin degradation products (FDP) levels, leading to
increased thrombosis and multiorgan injury has been described.
Moreover, patients with severe infection may also have abnormal
coagulation para-meters, perhaps related to high expression of
ACE2 receptors in vascular endothelial cells.
Transmission
Most infected children are likely to be secondary cases and
acquire the infection after exposure to a COVID-19 positive
adult, although there are no longitudinal data to confirm this
yet. Intra-family transmission may be important [10]. An as yet
unquantified proportion of children with COVID-19 is
asymptomatic and may contribute to transmission. It is unknown
whether COVID-19 is acquired by contact with infected feces
[10,11]. In a report of 10 children admitted for COVID-19 with
positive nasopharyngeal swabs, 8 of 10 children demonstrated
persistently positive real time reverse transcriptase-polymerase
chain reaction (RT-PCR) of rectal swabs after their
nasopharyngeal testing had become negative [12]. It remains
unclear whether the detection of virus by RT-PCR in fecal matter
represents active viral replication or residual viral genomic
material; however, it appears that viral shedding from the
digestive tract might be greater and last longer than that from
the respiratory tract [12].
Why is Covid-19 Milder in Children?
Multiple reports have demonstrated that children and young
adults have a milder form of the disease compared to adults
[13]. Asymptomatic, mild and moderate infections comprise over
90% of all children who have tested positive for COVID-19 with
fewer severe and critical cases (5.9%) compared to adults
(18.5%) [13]. The possible reasons for lower number and milder
infections in children and young adults include lower exposure
to virions, being isolated at home and minimal exposure to
pollution and cigarette smoke contributing to healthier
respiratory tracts. The elderly may be susceptible to severe
COVID-19 disease by their qualitatively different immune
response, encompassed by the terms ‘immunosenescence’ and
‘inflammaging’ [14]. Viral co-infection may be important in
potentially leading to limited replication of the SARS-CoV-2 by
direct virus-to-virus interaction and competition [15].
Additionally, the distribution, maturation and functioning of
viral receptors such as ACE2 may be important in age-dependent
susceptibility to severe COVID-19 [13,16].
Due to smaller number of reported cases in children, it is at
present challenging to delineate the clinical characteristics of
children with severe COVID-19 infection, combined with the lack
of a clear biomarker to indicate severity of infection [17].
Dong, et al. [13], in the largest pediatric review of
2143 children, described that 13% of virologically confirmed
children were asympto-matic. This makes epidemiological
inference problematic since asymptomatic children are less
likely to be tested and may still contribute to transmission. In
addition, a significant proportion of children can also have
co-infections with other viruses, and the detection of
SARS-CoV-2 may therefore be clinically insignificant [11]. It
has been proposed that the outcome for some children may be
worse due to exposure to antenatal smoking and obesity [17].
Another theory that has been postulated is the protective role
of Bacillus Calmette-Guérin (BCG) vaccine in COVID-19. BCG
vaccination has been associated with heterologous immunity to
other pathogens, potentially by a phenomenon called ‘trained
immunity’ involving innate cells such as macrophages, monocytes
and epithelia [18]. Trials are underway to understand if BCG
vaccination may offer protection against COVID-19.
CLINICAL FEATURES
Children of all ages can be infected with COVID-19, with more
cases reported in younger children and infants [13].
Acknowledging the possible reporting biases discussed above,
there is no age or sex preponderance [13] and the median age of
infection is 6.7 years (range-newborn to 15 years) [19]. The
incubation period of COVID-19 in children has been reported as 2
days (range-2 to 10 days) [1]. At the time of diagnosis, 13-15%
of virologically positive children may be asymptomatic [13,19].
The most common symptoms described at onset in children are
fever (50%) and mild cough (38%) [10]. Fever is present in about
40% of children [19]. Other clinical features include sore
throat, rhinorrhea, sneezing, myalgia, fatigue, diarrhea and
vomiting. Children may have more upper respiratory symptoms than
lower respiratory symptoms [13], and appear to recover in 1-2
weeks [20].
Risk Stratification and Severity Classification
In the largest pediatric cohort to date, Dong, et al.
[13] describe suspected and confirmed cases based on symptoms,
laboratory abnormalities, chest imaging, and RT-PCR/genomic
analysis. The severity of COVID-19 was divided into
asymptomatic, mild, moderate, severe and critical. Severe
COVID-19 accounted for 18 (2.5%) of virologically confirmed
cases, and furthermore the definition of severe included
children with only mild hypoxia. Critical COVID-19 was observed
in 3 (0.4%) of virologically confirmed cases, defined by the
presence of ARDS or organ failure. Though data on chronology of
complications and predictors of mortality is available in
adults, there is insufficient data on predictors of mortality in
children.
DIAGNOSTIC TECHNIQUES
The Ministry of Health and Family Welfare (MOHFW) [2] in their
updated guidelines (as of 7 April, 2020) has categorized
patients into three groups – those with mild, moderate and
severe illness, and have designated COVID dedicated facilities
for their treatment.
RT-PCR testing of nose and throat swab for detection of
SARS-CoV-2 nucleic acid has been recommended as the confirmatory
test for COVID-19 [21]. Other alter-native samples for RT-PCR
include bronchoalveolar lavage or endotracheal aspirate. The
Government of India has now advised the use of antibody tests in
patients with symptomatic influenza-like illness (ILI) in 25
districts across the country, or ‘COVID hotspots’ [22]. Based on
the results of the antibody test, confirmatory RT-PCR and
clinical assessment, hospital treatment or home isolation
measures are instituted, with contact tracing measures as per
protocol.
The limited data in children describes relatively lower rates of
lymphopenia and elevated inflammatory markers compared to adults
[1]. Henry, et al. [23] summarized the findings from 12
studies on 66 children and reported normal leucocyte counts
(69.2%), neutropenia (6.0%), neutrophilia (4.6%) and lymphopenia
(3.0%). C-reactive protein (CRP) and procalcitonin were high
only in 13.6% and 10.6% of cases, respectively. Slight elevation
of liver transaminases is common [23]. It is recommended to
monitor the lymphocyte count and CRP as signs for severe
infection, while using procalcitonin levels to detect potential
bacterial co-infection [23].
Chest X-ray findings in children appear to be
non-specific. Children with mild disease should not routinely
need computed tomography (CT) chest imaging in view of the high
radiation exposure [24]. When CT is performed, ground glass
opacities is seen in one third of patients [19]. Peripheral
distribution of lung lesions has been noted, with multilobar
involvement [25]. Consolidation with surrounding halo sign is
considered typical of pediatric patients [26]. However, chest CT
alone cannot accurately diagnose COVID-19 due to similar
radiological presentations with other infections.
Patients admitted with severe infection are known to have
elevated plasma levels of IL-2, IL-7, IL-10, granulocyte colony
stimulating factor (GCSF), interferon-gamma-inducible protein 10
(IP10), monocyte chemoattractant protein 1(MCP1), macrophage
inflam-matory protein 1-alpha (MIP1A) and tumor necrosis factor
(TNF) alpha [9]. In a study comprising of 150 confirmed COVID-19
cases in Wuhan, China, elevated ferritin (mean 1298 ng/mL vs 614
ng/mL; P<0.001) and IL-6 levels (P<0.0001) were
found in survivors compared to non-survivors [7]. These
cytokines are produced by inflammatory macrophages which have
been implicated in the cytokine storm. This is similar to
previous outbreaks of MERS and SARS 2002-3 in terms of having
high proinflammatory cytokines in patients with severe disease
[27].
MANAGEMENT OF PEDIATRIC COVID-19
Upon suspicion of COVID-19 infection, immediate Infection
prevention control (IPC) measures must be instituted. Standard
precautions such as hand hygiene, use of personal protective
equipment (PPE), safe waste management and cleaning and
disinfection of equipment must be followed as per the guidelines
issued by the MOHFW [2].
For the few children who will require admission to a healthcare
facility, the cornerstone of management is supportive therapy
including adequate nutrition and calorie intake, fluid and
electrolyte management and oxygen supplementation. Communication
with parents and alleviating anxiety is an important part of
management. In adults with severe COVID-19, early intubation and
mechanical ventilation with lung protective strategies and prone
positioning has been recommended [20]. Antibiotics may be
indicated if bacterial super-infection is suspected.
There are no randomized clinical trial data to guide treatment
of the very few children that present with life-threatening
COVID-19 including severe pneumonia,
ARDS, sepsis and septic shock. Hence, the World Health
Organization has not recommended any specific treatment for
children until the results of ongoing clinical trials are
available. We strongly believe that clinical trials of all
therapeutic agents for COVID-19 are needed in children as well.
It is important that when such clinical trials are open,
children are treated only in the context of clinical trials and
not outside these. In the absence of data from these trials,
clinicians may be left in the difficult scenario of deciding
whether to pursue treatment with antiviral drugs and
immunomodulatory therapies for children with severe COVID-19. A
relatively new antiviral drug being tested in adults with
COVID-19 is remdesivir, which in combination with chloroquine
has been found to inhibit SARS-CoV-2 growth in vitro
[28]. Interferon alpha-2b and oral lopinavir/ritonavir
together with corticosteroids for complications and intravenous
immunoglobulin for severe cases has been recommended in one
report in China [29]. A HIV test should be performed before
commencing antiviral treatment, in particular
lopinavir/ritonavir.
The MOHFW has allowed off label use of hydoxychloroquine in
combination with azithromycin in adults with severe disease and
requiring intensive care [2]. However, these treatments are not
currently recommended in children below the age of 12 years.
Corticosteroids are not routinely recommended and might
exacerbate COVID-19 associated lung injury [30]. Ivermectin, the
broad spectrum anti-parasitic agent, has in vitro
antiviral action against SARS-CoV-2 [31].
Owing to the cytokine storm syndrome in COVID-19, there may
potentially be a role of immunomodulators in treating patients
with severe infections to ameliorate pulmonary inflammation and
hopefully improve mortality. There is an established role of
anakinra (IL-1 blockade) in survival benefit of patients with
hyperinflammation, without increased adverse events [8]. A
multicenter randomized control trial (RCT) of the IL-6 receptor
blocker, tocilizumab is in progress in China for adults with
COVID-19 pneumonia and raised IL-6 levels (ChiCTR2000029765)
[32]. There may also potentially be a role of janus kinase
inhibitors (JKI), since these drugs block downstream
inflammatory pathways and may alter cellular viral entry [33].
|
Fig.1 Suggested
algorithm for case management of children with COVID-19
symptoms. |
|
Fig. 2 Suggested
algorithm for case management of confirmed COVID-19
(Adapted from the BPAIIG Position Statement: SARS CoV2
Treatment Guidance version 1.2) [37]. |
A suggested management algorithm
based on the limited observational data from adults is depicted
in Figs. 1 and 2. The common drugs used in
COVID-19 are detailed in Table I. It is important
to note that very few children with COVID-19 are likely to need
any specific therapy other than supportive treatment, and the
decision to start antiviral or immunomodulatory treatment should
therefore be made carefully in consultation with experts in
pediatric infectious disease and immunology. Given that severe
COVID-19 appears very rare in children, an important part of
this assessment is ascertaining whether a positive RT-PCR for
SARS-CoV-2 is a clinically important factor in explaining the
child’s condition, or whether more occult pathology may be
responsible.
Table I Medications for Coronavirus Disease 2019 (Covid-19)
Drug |
Indication/Limitation |
Paracetamol |
•Recommended antipyretic (Avoid ibuprofen) |
Oseltamivir |
•To be considered in influenza H1N1 is differential |
Lopinavir /Ritonavir |
•Can be considered if no improvement/severe infection |
|
•Do not co-administer with hydroxychloriquine |
|
•Limited data available on benefit in children |
Remdesivir |
•Used as experimental drug in adults, limited data available on benefit in children. |
Hydroxychloroquine |
•Can be used if no improvment/severe infection in children >12 years |
|
•Do not co-administer with azithromycin |
|
•Limited data available on benefit in children |
Azithromycin |
•Can be considered if no improvment/severe infection |
|
•Limited data available on benefit in children |
Ivermectin |
•Has shown in vitro anti-viral activity |
Immunomodulators |
•Can be considered in suspected hemophagocytic syndrome |
•1L 1 inhibitor (Anakinra) |
Not available in India |
•1L 6 inhibitor (Tocilizumab) |
Limited data available on benefit in children |
For neonatal management of COVID-19
infected mothers, it is recommended to have a separate room
adjacent to the delivery room for neonatal resuscitation or for
resuscitation staff to maintain atleast a 2 meter gap between
the infected mother and newborn [34]. Only essential personnel
should attend the delivery with full PPE, with the mother
following meticulous hand hygiene and wearing a mask. Standard
neonatal resuscitation measures are to be followed and positive
pressure ventilation if needed should be provided by a
self-inflating bag and mask rather than a T-piece resuscitator.
If the baby requires intensive care, a single patient room is
ideal preferably with negative pressure. The baby should be
tested at 24 hours of life and repeat testing should be
performed at 48 hours. Antivirals/hydroxy-chloroquine/steroids
or intravenous immunoglobulin (IVIG)should not be administered
to the newborn. The baby should then be tested every 48-72 hours
until two consecutive negative tests. It is critical that
breastfeeding shouldbe encouraged with the mother wearing a
mask. The baby should be vaccinated prior to discharge from the
hospital.
IMPACT ON IMMUNOSUPPRESSED CHILDREN
Data on children with immunocompromised conditions and
COVID-19 are scarce, but severe disease may be more common in
adults with cancer [35]. Despite concerns that immunocompromised
children may have severe infection analogous to infection with
adenovirus, rhinovirus, influenza, respiratory syncytial virus,
and experience from previous pandemics (such as influenza
H1N1),Antiga,et al. [36] described that children who were
immunocompromised were not at greater risk of severe COVID-19,
probably owing to the fact that a functional host innate immune
response is the main driver for lung damage. In Bergamo, among
200 transplant recipients including 10 inpatients, 100 with
autoimmune liver disease and three undergoing chemotherapy for
hepatoblastoma (inpatients), none had clinical pulmonary
disease, despite the fact that 3 patients tested positive for
SARS-CoV-2, suggesting that the immunocompromised may be
protected by their weaker immune response. No data is available
on severity of COVID-19 infection in children with malnutrition,
rheumatic heart disease or Human Immunodeficiency Virus (HIV)
positive children.
THE FUTURE
Several vaccines against SARS-CoV-2 are in development;
however, it remains unclear when a successful vaccine might be
rolled out. Studies on factors responsible for immune
dysregulation may provide insights into developing vaccines
capable of inducing durable protective immunity and avoiding
vaccine-related adverse events.
This unprecedented pandemic should prompt improved global
surveillance of infectious diseases, as well as cooperation and
communication so that the global society remains interconnected
and limits the spread of this outbreak.
Lastly, we fear the greatest impact on children from COVID-19 is
likely to be delayed presentation of other childhood illnesses
due to fear and ignorance amongst parents/families. This coupled
with the impact of economic uncertainty on those in the low
socio-economic strata, is likely to have a greater adverse
impact on child health in India in these uncertain times.
Contributors:
SB, AVR- Initiated the preparation of the manuscript;NMR:
Substantial contribution to the conception and design of the
work, and prepared and finalized the draft; SB, AVR, AG,
MR-Substantial contributions to the acquisition, analysis, and
interpretation of data for the work, SB, AVR, AG, MR-Revising it
critically for important intellectual content;SB, NMR, AG, MR,
AVR: Final approval of the version to be published, and
agreement to be accountable for all aspects of the work in
ensuring that questions related to the accuracy or integrity of
any part of the work are appropriately investigated and
resolved.
Funding:
None; Competing interests: None stated.
REFERENCES
1. Ludvigsson JF. Systematic review of COVID-19 in children show
milder cases and a better prognosis than adults. Acta Paediatr.
2020 Mar 23. [Epub ahead of print]https://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15270.Accessed
on April 08, 2020.
2. Ministry of Health and
Family Welfare. Available from: https://www.mohfw.gov.in.
Accessed on April 08,2020.
3. Zimmermann P, Curtis N. Coronavirus Infections in Children
Including COVID-19. PIDJ. 2020 Mar 12. [Epub ahead of
print]Available from:
https://journals.lww.com/pidj/Abstract/onlinefirst/Coronavirus_Infections_in_
Children_Including.96251.aspx.Accessed on April 06, 2020.
4. Pedersen SF, Ho Y. SARS-CoV-2/ : A Storm is Raging. JCI. 2020
Mar 27. [Epub ahead of print].Available from:
https://www.jci.org/articles/view/137647/pdf. Accessed on
April 05, 2020.
5. Spychalski P, Blazynska-Spychalska A, Kobiela J. Estimating
case fatality rates of COVID-19.Lancet Infect Dis. 2020 Mar 31.
[Epub ahead of print]Available from:
https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30246-2.pdf.
Accessed on April 04, 2020.
6. Weston S, Frieman MB. COVID-19: Knowns, Unknowns, and
Questions. mSphere. 2020 Mar 18. [Epub ahead of print].
Available from: https://msphere.asm.org/content/msph/5/2/e00203-20.full.pdf.
Accessed on April 07, 2020.
7. Brodin P. Why is COVID-19 so mild in children? Acta Paediatr.
2020 Mar 25. [Epub ahead of print]. Available from:
https://onlinelibrary.wiley.com/doi/epdf/10.1111/apa.15271.
Accessed on April 06, 2020.
8. Mehta P, Mcauley DF, Brown M, Sanchez E, Tattersall RS,
Manson JJ, et al. COVID-19: consider cytokine storm syndromes
and immunosuppression. Lancet. 2020; 395: 1033-4.
9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al.
Clinical features of patients infected with 2019 novel
coronavirus in Wuhan , China. Lancet. 2020; 395:497–506.
10.Jiehao C, Jing X, Daojiong L, Lei X, Zhenghai Q, Yuehua Z,
et al. A case series of children with 2019 novel coronavirus
infection: clinical and epidemiological features. CID. 2020 Feb
28. [Epub ahead of print]. Available from:
https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciaa198/32709823/ciaa198.pdf.
Accessed on April 06, 2020.
11.Cruz A, Zeichner S. COVID-19 in Children: Initial
characterization of the pediatric disease. Pediatrics. 2020 Mar.
[Epub ahead of print]. Available from:
https://pediatrics.aappublications.org/content/pediatrics/early/2020/03/16/peds.2020-0834.1.full-text.pdf.
Accessed on April 06, 2020.
12.Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al.
Characteristics of pediatric SARS-CoV-2 infection and potential
evidence for persistent fecal viral shedding. Nat Med. 2020 Mar
13. Available from:
https://www.nature.com/articles/s41591-020-0817-4.pdf.
Accessed on April 05, 2020. [Epub ahead of print]
13.Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al.
Epidemiological characteristics of 2143 pediatric patients with
2019 coronavirus disease in China. Pediatrics. 2020 Mar.
Available from: https://pediatrics.aappublications.
org/content/pediatrics/early/2020/03/16/peds.2020-0702.1.full-text.pdf.
Accessed on April 04, 2020. [Epub ahead of print]
14. Murray MA, Chotirmall
SH. The impact of immunosenescence on pulmonary disease. Hindawi
[Internet]. 2015 Jun 24. Available from:
http://downloads.hindawi.com/journals/mi/2015/692546.pdf.
Accessed on April 06, 2020.
15. Nickbakhsh S, Mair C, Matthews L, Reeve R, Johnson PCD,
Thorburn F, et al. Virus–virus interactions impact the
population dynamics of influenza and the common cold. PNAS
[Internet]. 2019 Dec 26;116:27142-50. Available
from:https://www.pnas.org/content/pnas/116/52/27142. full.pdf.
Accessed on April 04, 2020.
16. Lee PI, Hu YL, Chen PY, Huang YC, Hsueh PR. Are children
less susceptible to COVID-19? JMII [Internet]. 2020 Feb
25;S1684-1182(20)30039-6. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102573/pdf/main.pdf.
Accessed on April 04, 2020.
17. Sinha IP, Harwood R, Semple MG, Hawcutt DB, Thursfield R,
Narayan O, et al. COVID-19 infection in children. Lancet Respir.
2020 Mar 27. Available from:
https://www.thelancet.com/action/showPdf?pii=S2213-2600%2820%2930152-1.
Accessed on April 05, 2020. [Epub ahead of print]
18. Covián C, Fernández-Fierro A, Retamal-Díaz A, Díaz FE,
Vasquez AE, Lay MK, et al. BCG-induced cross-protection and
development of trained immunity: Implication for vaccine
design.Front Immunol [Internet]. 2019 Nov 29;10:2806. Available
from: https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC6896902/pdf/fimmu-10-02806.pdf.
Accessed on April 04, 2020.
19. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al.
SARS-CoV-2 Infection in children. NEJM. 2020 Mar 18. Available
from:
https://www.nejm.org/doi/pdf/10.1056/NEJMc2005073?articleTools=true.
Accessed on April 05, 2020. [Epub ahead of print]
20. Cao Q, Chen Y, Chen C, Chiu C. SARS-CoV-2 Infection in
children: Transmission dynamics and clinical charateristics. J
Formos Med Assoc. 2020;119:670-673.
21. Revised Guidelines on Clinical Management of COVID - 19
[Internet]. Ministry of Health and Family Welfare. Available
from:
https://www.mohfw.gov.in/pdf/RevisedNationalClinicalManagementGuidelinefor
COVID1931032020.pdf. Accessed April 01, 2020.
22. Advisory to start rapid antibody based blood test for
COVID-19 [Internet]. Indian Council of Medical Research.
Available from:
https://www.mohfw.gov.in/pdf/Advisory&StrategyforUseofRapidAntibodyBasedBloodTest.
pdf. Accessed April 05, 2020.
23. Henry BM, Lippi G, Plebani M. Laboratory abnormalities in
children with novel coronavirus disease 2019. CCLM. 2020 Mar 16.
Available from:
https://www.degruyter.com/downloadpdf/journals/cclm/ahead-of-print/article-10.1515-cclm-2020-0272/article-10.1515-cclm-2020-0272.xml.
Accessed on April 05, 2020. [Epub ahead of print]
24. Kelvin AA, Halperin S. COVID-19 in children: the link in the
transmission chain. Lancet Infect Dis. 2020 Mar 25.
Available from: https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930236-X.
Accessed on April 06, 2020. [Epub ahead of print]
25. Li B, Shen J, Li L, Yu
C. Radiographic and Clinical Features of Children with 2019
Novel Coronavirus (COVID-19) Pneumonia. Indian Pediatr. 2020 Apr
07. Available from:
https://www.indianpediatrics.net/CONVID29.03.2020/RP-00156.pdf
Accessed on April 08, 2020. [Epub ahead of print]
26. Xia W, Shao J, Guo Y, Peng X, Li Z, Hu D. Clinical and CT
features in pediatric patients with COVID-19 infection:
Different points from adults. Pediatric Pulmonology. 2020 Mar 5.
Available from:
https://onlinelibrary.wiley.com/doi/epdf/10.1002/ppul.24718.
Accessed on April 05, 2020. [Epub ahead of print]
27. Mahallawi W, Khabour O, Zhang Q, Makhdoum H, Suliman B.
MERS-CoV infection in humans is associated with a
pro-inflammatory Th1 and Th17 cytokine profile. Cytokine.
2018;104:8-13.
28. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al.
Remdesivir and chloroquine effectively inhibit the recently
emerged novel coronavirus (2019-nCoV) in vitro. Cell Res.
2020;30:269-71.
29. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and
epidemiological features of 36 children with coronavirus disease
2019 (COVID-19) in Zhejiang, China: an observational cohort
study. Lancet Infect Dis. 2020 Mar 25. Available from:
https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930198-5.
Accessed on April 05, 2020. [Epub ahead of print]
30. Russel CD, Millar JE, Baillie JK. Clinical evidence does not
support corticosteroid treatment for 2019-nCoV lung injury.
Lancet. 2020;395:473-5.
31. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The
FDA-approved Drug Ivermectin inhibits the replication of
SARS-CoV-2 invitro. Antiviral Res. 2020 Apr 03. Available from:
https://www.sciencedirect.com/science/article/pii/S0166354220302011/pdfft?md5=bd2a8d1cfbe3680f2d40
5b4a62642a15&pid=1-s2.0-S0166354220302011-main. pdf.
Accessed on April 05, 2020. [Epub ahead of print]
32. Chinese Clinical Trial
Registry. A multicenter, randomized control trial for the
efficacy and safety of tocilizumab in the treatment of new
coronavirus pneumonia (COVID-19). 2020 Feb 13. Available from:
http://www.chictr.org.cn/showprojen.aspx?proj=49409.
Accessed April 05, 2020.
33. Richardson P, Griffin I, Tucker C, Smith D, Oechsle O,
Phelan A, et al. Baricitinib as potential treatment for
2019-nCoV acute respiratory disease. Lancet. 2020;395:E30–E31.
Available from:
https://www.thelancet.com/action/showPdf?pii=S0140-6736%2820%2930304-4.
Accessed on April 05, 2020.
34. Chawla D, Chirla D, Dalwai S, Deorari AK, Ganatra A, Gandhi
A, et al. Perinatal-Neonatal Management of COVID-19
Infection - Guidelines of the Federation of Obstetric and
Gynecological Societies of India (FOGSI), National Neonatology
Forum of India (NNF), and Indian Academy of Pediatrics (IAP).
Indian Pediatr. 2020 Apr 01. Available from:
www.indianpediatrics.net/CONVID29.03. 2020/RECOMM-00154.pdf.
Accessed on April 06, 2020.
35. Landman A, Feetham L,
Stuckey D. Cancer patients in SARS-CoV-2 infection: A nationwide
analysis in China. Lancet Oncol. 2020;21:335–7.
36. Antiga LD. Coronaviruses and immunosuppressed patients. The
facts during the third epidemic. AASLD. 2020 Mar 20. Available
from: https://aasldpubs.
onlinelibrary.wiley.com/doi/epdf/10.1002/lt.25756. Accessed
on April 05, 2020. [Epub ahead of print]
37. British Paediatric Allergy Immunity and Infection Group.
BPAIIG Position Statement: Sars-CoV-2 Treatment Guidance version
1.2. Available from:
https://www.bpaiig.org/news-bpaiig-position-statement-sars-cov-2-treatment-guidance-version-12.
Accessed April 06, 2020.