Though COVID-19 so far appears to be largely sparing children, researchers are cautioning that it is critical to understand how the virus affects kids to model the pandemic accurately, limit the disease’s spread and ensure the youngest patients get the care they need.
The warning comes from Steven L. Zeichner, MD, PhD, the head of UVA Health’s Division of Pediatric Infectious Diseases, and Andrea T. Cruz, MD, MPH, a pediatric emergency medicine physician at Houston’s Baylor College of Medicine.
They have authored a commentary in the journal Pediatrics accompanying a new article that reveals a small percentage of infected children become seriously ill. Those at greatest risk include babies and preschoolers.
“Many infectious diseases affect children differently than adults and understanding those differences can yield important insights,” the commentary authors write. “This will likely be true for COVID-19, just as it was for older infectious diseases.”
Assessing COVID-19 Risks
Zeichner and Cruz note that there are subgroups of children who appear to be at greater risk of COVID-19 complications, particularly those who are younger, immunocompromised or have other pulmonary health problems.
However, the presence of other viral infections in up to two-thirds of childhood coronavirus cases makes it very difficult to assess the true effect of COVID-19 on children, they state. (This figure is based on prior studies of children with coronaviruses detectable in the respiratory tract.)
While much remains unknown, Cruz and Zeichner caution that children, even asymptomatic children, could play a “major role” in disease transmission. For example, they cite a study that found the virus remained in children’s stool for several weeks after diagnosis.
That, combined with other routes of transmission such as nasal secretions, could pose a major challenge for schools, day care centers and the children’s families, they note.
Zeichner and Cruz note that there are subgroups of children who appear to be at greater risk of COVID-19 complications, particularly those who are younger, immunocompromised or have other pulmonary health problems.
“Since many children infected with COVID-19 appear to have have mild symptoms, or even no symptoms at all, it is important to practice all the social distancing, hygiene and other precautions being recommended by public health authorities to minimize transmission from children to others, including family members who may be at greater risk from the infection, such as grandparents or family members with chronic medical conditions,” said Zeichner, who is working on innovative potential COVID-19 vaccines in his lab.
“In addition, studies of the reasons why children are affected differently than adults by the infection may yield insights that can be helpful in understanding the disease and ways to treat or prevent it.”
Zeichner holds appointments in the UVA School of Medicine’s Department of Pediatrics and the Department of Microbiology, Immunology and Cancer Biology. He is part of UVA Children’s Child Health Research Center. Cruz is part of Baylor’s Department of Pediatrics. They are associate editors of the Pediatrics journal.
In addition, Zeichner is an inventor of technology to develop vaccines rapidly that is being patented by UVA.
In the largest study to date, a paper published by the Chinese Center for Disease Control and Prevention (CCDC) analyzed all the cases diagnosed up to 11 February 2020, which came to 44,672 cases. Of these 1.2% were asymptomatic and 80.9% were classed as “mild”. The overall mortality rate was found to be 2.3%.
In an article examining the first 425 infected cases in Wuhan, 56% of the infected were male and the median age was 59 years .
In this early cohort, there were no children under 15 years old. Using this dataset, the group estimated that the R0 (basic reproduction number) of the novel coronavirus was 2.2, that is each infected individual – on average – causes 2.2 new cases of the disease.
The incubation period in this group has been calculated to be 5.2 days on average .
A more recent study, for which researchers reviewed 12 studies of COVID-19, calculated the average R0 to be higher at 3.28, with the authors estimating the likely R0 to lie between 2 and 3.
Interestingly children seem to be relatively unaffected by this virus, or indeed other closely-related coronaviruses. A Chinese study reviewing the first 31,211 cases in mainland China found that only nine children under one year of age were confirmed with COVID-19.
All nine cases were admitted to hospital, and symptoms were mild or absent. None required intensive care or developed severe sequelae.
A later study of the epidemiology by a case series of over 2,143 Chinese children showed there have been critically ill children, and although the numbers are fewer than in the elderly population, infants under 12 months were more likely to have become critically ill than other pediatric age groups .
In children, male gender does not seem to be a risk factor.
COVID-19, when symptomatic, tends to present with respiratory manifestations. However, it is now clear that some individuals, especially young children, remain asymptomatic, whilst others have mild upper respiratory tract symptoms only. Some also experience mild GI or cardiovascular symptoms . However, its full spectrum of clinical effects remains to be determined.
Symptoms and signs are non-specific :
- fever (85-90%)
- cough (65-70%)
- fatigue (35-40%)
- sputum production (30-35%)
- shortness of breath (15-20%)
- myalgia / athralgia (10-15%)
- headaches (10-15%)
- sore throat (10-15%)
- chills (10-12%)
- pleuritic pain
- nausea, vomiting, diarrhea, nasal congestion (<10%)
- palpitations, chest tightness 50
The definitive test for SARS-CoV-2 is the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test and is believed to be highly specific, but with sensitivity reported as low as 60-70% and as high as 95-97% depending on the country.
Thus, false negatives are a real clinical problem and several negative tests might be required in a single case to be confident about excluding the disease.
Therefore, in many cases, CT findings have been used as a surrogate diagnostic test. Indeed, recent work supports the notion that CT is a more sensitive test for the virus than is the confirmatory RT-PCR test. In a cohort of 1,014 patients, with a positive PCR as the diagnostic test, the sensitivity of CT in reaching the same conclusion was 97%.
In those patients in whom RT-PCR was negative – yet the CT chest was positive – clinical records were comprehensively re-reviewed and 48% of these cases were deemed to be “highly likely” to be COVID-19, with a further 33% as “probable”.
On 16 March 2020, an American-Singaporean panel published that CT findings were not part of the diagnostic criteria for COVID-19.
The WHO has published official case definitions for COVID-19 surveillance. These definitions remain under constant review.
The most common ancillary laboratory findings in a study of 138 hospitalized patients were the following :
- increased prothrombin time (PT)
- increased lactate dehydrogenase
Mild elevations of inflammatory markers (CRP and ESR) and D-dimer are also seen.
In a small study of five children that had been admitted to hospital with positive COVID-19 RT-PCR tests and who had CT chest performed, only three children had abnormalities.
The main abnormality was bilateral patchy ground-glass opacities, similar to the appearances in adults, but less florid, and in all three cases the opacities resolved as they clinically recovered.
PATHOGENESIS, DISEASE SEVERITY AND EPIDEMIC SPREAD
Epidemiological studies suggest that SARS-CoV-2 has an intrinsic capacity to cause epidemic spread 41. The current fatality rate for COVID-19 cases is about 3.4%, significantly less than SARS and MERS but potentially higher than those reported for endemic human non-SARS CoV infections 42.
During the first two months of the current outbreak, COVID-19 has spread rapidly throughout China and caused varying degrees of illness 19.
Several studies suggest that antibodies against non-SARS-CoVs are highly prevalent in the general population including in children, suggesting that most individuals have been infected by CoVs and have potentially developed a certain degree of (protective) immune response 43,44.
re is no clear evidence on whether and how prior exposure to a strain of CoV can produce permanent immunity against the strain species or even cross-immunity for other CoV species 43.
Unlike other respiratory diseases that have a quadratic (“U”-shaped) lethality curve (killing infants and elderly, but sparing adults, presumably because adults have a higher chance to be immune against the infection), SARS-CoV-2 has a lethality that continuously rises with age (sparing children but mostly killing elderly).
The severity and the clinical picture could be even related to the activation of exaggerated immune mechanism, causing uncontrolled inflammation as this has been suspected for SARS and MERS 45.
Hence, there is uncertainty on the impact of individual immune responses on the severity of SARS-like CoV infections.
The discrepancy between the severity of cases observed in China and those outside China could be a result of prior exposure community circulation of non-SARS-CoVs and their antigenic epitopes, leading to antibody-dependent enhancement (ADE) of SARS-CoV-2.
ADE can elicit sustained inflammation, lymphopenia, and/or cytokine storm, which have been observed in severe cases and those who die. This might explain observed the geographic discrepancies of severe cases and lower mortality than SARS of MERS 46.
SARS-CoV-1 caused an important outbreak in 2002-2003, but it is currently though to be extinct 32.
This eradication of SARS-CoV-1 has been attributed to successful contention by public action, consisting in quarantining potentially affected persons and isolating affected areas. However, other factors might have played a role in the fall of the SARS epidemic leading to the eventual extinction of the virus.
In particular, it is possibility that only a minority of the population was actually susceptible to develop severe illness (some HLA haplotypes reportedly conferred resistance to SARS-CoV-1, but these studies have not been confirmed or even disproven) 44,47,48,49,50.
The hypothesis that SARS-CoV-1 (or other, antigenically similar CoV-1) have silently infected a significant proportion of the local population, inducing herd immunity needs to be confirmed.
Indeed, immunity against the infection, or also patterns of semi-immunity (capacity of the immune system to avoid severe infection) may be due to cellular rather than humoral immune responses.
Animal models suggest that the efficiency of T lymphocyte-mediated immune responses is pivotal for controlling MERS-CoV and SARS-CoV infections 51,52. Evidence in animals are confirmed by observational studies in humans suggesting that MERS-CoV-specific T-cell responses is a strong predictor of the clinical outcome in patients 53.
Of note, antibodies against MERS-CoV have been detected in a significant fraction of persons exposed to camels and dromedaries without any clinical evidence of prior MERS 54,55,56, suggesting that MERS-CoV can infect individuals in an asymptomatic fashion, yet induce signs of a (protective?) immune response.
ROLES OF HUMORAL AND CELLULAR IMMUNE RESPONSES
There are currently no data on the specific role of either humoral or cellular immunity or innate immunity in patients recovering from COVID-19. Only highly specialized laboratories are able to conduct experiments to investigate immune responses against HLA class-I and class-II-restricted viral epitopes mediated by CD8+ and CD4+ T lymphocytes, respectively, to confirm the conjecture of a cellular (rather than humoral) immunity against SARS-CoV-2. Moreover, the T lymphocytes responsible for clinically relevant antiviral immune responses have high chances to be locally present in, or close to, respiratory epithelia but have comparatively low chances to be detectable in peripheral blood 57,58,59.
It is well possible that the exclusive detection of humoral immunity (antibodies against SARS-CoV-2) leads to an underestimation of the anti-SARS-CoV-2 immune responses. Thus, it is possible that the actual incidence of infections with SARS-CoV-2 is much higher than the observed number of clinically and serologically evident cases of COVID-19.
In fact, a larger epidemic might be smoldering. This silent epidemic, made of mild and paucisymptomatic (usually flu-like) infections, could parallel the evident COVID-19 outbreaks that are detected when patients develop radiological or functional signs of pneumonitis and they are tested for SARS-CoV-2.
This scenario may have two consequences.
First, over the forthcoming months, symptomatic cases could haphazardly occur either as (apparently) sporadic cases or as epidemic clusters among frail subjects (e.g. as nosocomial outbreaks), driven by unrecognized occasional spreaders.
Second, these occasional spreaders might accelerate the induction of immunity at the population level.
By analogy to other CoVs, SARS-CoV-2 might induce a T-lymphocyte-mediated protective immune response. However, patients infected by SARS-CoV-2 that are hospitalized frequently manifest a lymphopenia, suggesting that cellular immune responses may be suppressed 60,61.
In this context, it becomes plausible that, after infection by SARS-CoV-2, a sort of race decides the course of the events. Either a cellular immune response rapidly clears SARS-CoV-2 – in the best-case-scenario without any (or mild) clinical signs of infection – or the virus causes a state of immunosuppression that debilitates and sometimes overwhelms the host’s defense (Fig. 1A).
In this context, the initial dose of the viral inoculum leading to infection may have a decisive impact on all subsequent events (Fig. 1B). A small burden of SARS-CoV-2 should have a higher chance to stimulate a protective immune response than a high one, although additional factors like the fitness of the individual’s immune system and prior exposure to other in part cross-reactive CoVs might influence the outcome of the race between viral replication and T-lymphocyte responses as well.
Hence, it is possible, but remains to be demonstrated, that SARS-CoV-2 transmission from indolent or mildly symptomatic persons to naive individuals generally occurs at a relatively low viral load (lower than if the infection stems from severely affected patients), which then might have higher probabilities to induce immunity instead of severe and sometimes lethal infection (Fig. 1C).
That said, current evidence suggests that the most solid predictors of disease severity after infection with SARS-COV-2 are the patient’s age and the concurrence of specific co-morbidities.
In contrast, there is no proof (yet) that infection by a pauci-symptomatic person would result in a milder clinical course of immunocompetent neo-infected person.
CHALLENGES FOR CONTROL OF THE EPIDEMIC
COVID-19 outbreak poses significant challenges for curtailing global spread and maintaining global health security. Implementation of collective infection control measures (e.g. social isolation, distancing or quarantine of entire communities) may be useful.
Nonetheless, these measures should be implemented in a prudent fashion while considering their cost efficiency (e.g. for controlling small clusters of sporadic transmission). There is a real need to avoid an unmanageable epidemic wave that would saturate the capacity of health services.
It is important to note that collective infection control measures can actually reduce the frequency of infection, though at the price of a prolongation of the epidemic period. Thus, in the absence of an effective vaccine and effective antiviral drugs, all infection control measures should be properly undertaken with the aim of modulating the trajectory of the epidemic so that the impact on global health is minimized and each epidemic wave does not exceed the healthcare system capabilities.
TAKING FORWARD INTERVENTIONS TO CONTROL THE EPIDEMIC
The first pillar for interventions is to preserve the healthcare system. The implementation of infection control measures within hospitals is crucial to protect healthcare workers, maintain adequate work force levels and to prevent hospital outbreaks that eventually foster larger community epidemics.
Second, there is a growing need for providing advice on proper management of COVID-19 patients so that each individual can receive the most appropriate treatment. Currently, most of the SARS-CoV-2 infections need no therapy, and overtreatment of patients without current or future medical needs should be avoided.
Third, trust between people and institutions (at the local, national and international levels) must be maintained or reestablished so that local communities and individual subjects adhere to medical advice, for instance by respecting temporary individual restrictive measure (i.e. fiduciary isolation at home for mild-symptomatic cases of COVID-19).
Fourth, any antagonism between countries and their governments must be carefully avoided. The scientific community is global, by definition and for necessity. There is no individual solution for a globally spreading infection. Antagonism and lack of trust between countries will affect scientific collaboration and will retard or even jeopardize the control of SARS-CoV-2.
Fifth, research on effective prevention or treatment of COVID-19 must be accelerated. Yet unconfirmed reports indicated that inhibitors of SARS-CoV-2 replication including chloroquine are clinical efficient against declared SARS-CoV-2 infection 62,63,64. If these findings are confirmed, chloroquine might be used to prophylactically treat vulnerable individuals (in particular the elderly and patients with existing medical problems) that have a high risk of viral exposure. Chloroquine has been used for decades for the prevention and treatment of malaria with minimal side effects and at a low cost, suggesting the practicability of such a measure.
Sixth, it is essential to control panic and to minimize the potential for social disruption that is typical of any global epidemic event. Again, exaggerated infection control measures may be pernicious as they increase frustration among the population, undermine the economy, and evoke a false feeling of safety.
Despite the fact that SARS-CoV-2 appears much less virulent than SARS-CoV-1 and MERS-CoV, it is associated with significant mortality among susceptible individuals with comorbidities.
Moreover, the hype and scaremongering going viral on mass news and social media, predicting the dawn of a new fatal pandemic, are spurring global hysteria.
Thus, the current COVID-19 epidemic is resulting in a social rather than a viral catastrophe. Whilst the future evolution of this epidemic remains unpredictable, classic public health strategies must follow rational patterns.
The development of the response cannot be standardized as ‘one size fits all’ but should be tailored based on the local evolution of the epidemic and the socio-economic settings involved.
Indeed, the emergence of yet another global epidemic unveils the permanent challenge that infectious diseases represent for humankind and underscores the need for global cooperation and preparedness, even during inter-epidemic periods.
These lists are in alphabetical order:
- general information
- research publications
- government information
- Australia (Department of Health)
- Australia (Smartraveller)
- Canada (Infection Prevention and Control Canada)
- Canada (Government of Canada)
- Europe (European Center for Disease Prevention and Control)
- Israel (Ministry of Health)
- Italy (Dipartimento della Protezione Civile)
- Mexico (Secretaría de Salud)
- New Zealand (Ministry of Health)
- Singapore (Ministry of Health)
- United Kingdom (National Health Service UK)
- United States of America (Centers for Disease Control and Prevention)
19. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, et al Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 doi: 10.1056/NEJMoa2002032. [CrossRef] [Google Scholar]
40. de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016;14(8):523–534. doi: 10.1038/nrmicro.2016.81. [PubMed] [CrossRef] [Google Scholar]
41. Rocklov J, Sjodin H, Wilder-Smith A. COVID-19 outbreak on the Diamond Princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures. J Travel Med. 2020 doi: 10.1093/jtm/taaa030. [CrossRef] [Google Scholar]
42. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 doi: 10.1001/jama.2020.2648. [CrossRef] [Google Scholar]
43. Severance EG, Bossis I, Dickerson FB, Stallings CR, Origoni AE, Sullens A, Yolken RH, Viscidi RP. Development of a nucleocapsid-based human coronavirus immunoassay and estimates of individuals exposed to coronavirus in a U.S. metropolitan population. Clin Vaccine Immunol. 2008;15(12):1805–1810. doi: 10.1128/cvi.00124-08. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Wang SF, Chen KH, Chen M, Li WY, Chen YJ, Tsao CH, Yen MY, Huang JC, Chen YM. Human-leukocyte antigen class I Cw 1502 and class II DR 0301 genotypes are associated with resistance to severe acute respiratory syndrome (SARS) infection. Viral Immunol . 2011;24(5):421–426. doi: 10.1089/vim.2011.0024. [PubMed] [CrossRef] [Google Scholar]
45. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016;38(4):471–482. doi: 10.1007/s00281-016-0558-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Xiong P, Zeng X, Song MS, Jia SW, Zhong MH, Xiao LL, Lan W, Cai C, Wu XW, Gong FL, Wang W. Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: a cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China. Int J Immunogenet. 2008;35(1):69–74. doi: 10.1111/j.1744-313x.2007.00741.x. [PubMed] [CrossRef] [Google Scholar]
49. Ng OW, Chia A, Tan AT, Jadi RS, Leong HN, Bertoletti A, Tan YJ. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection. . Vaccine. 2016;34:2008–2014. doi: 10.1016/j.vaccine.2016.02.063. [PubMed] [CrossRef] [Google Scholar]
50. Yuan FF, Velickovic Z, Ashton LJ, Dyer WB, Geczy AF, Dunckley H, Lynch GW, Sullivan JS. Influence of HLA gene polymorphisms on susceptibility and outcome post infection with the SARS-CoV virus. Virol Sin. 2014;29(2):128–130. doi: 10.1007/s12250-014-3398-x. [PubMed] [CrossRef] [Google Scholar]
51. Zhao J, Zhao J, Mangalam AK, Channappanavar R, Fett C, Meyerholz DK, Agnihothram S, Baric RS, David CS, Perlman S. Airway Memory CD4(+) T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses. Immunity. 2016;44(6):1379–1391. doi: 10.1016/j.immuni.2016.05.006. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Coleman CM, Sisk JM, Halasz G, Zhong J, Beck SE, Matthews KL, Venkataraman T, Rajagopalan S, Kyratsous CA, Frieman MB. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J Virol. 2017;91(1) doi: 10.1128/jvi.01825-16. [CrossRef] [Google Scholar]
53. Zhao J, Alshukairi AN, Baharoon SA, Ahmed WA, Bokhari AA, Nehdi AM, Layqah LA, Alghamdi MG, Al Gethamy MM, Dada AM, Khalid I, Boujelal M, Al Johani SM, et al Recovery from the Middle East respiratory syndrome is associated with antibody and T-cell responses. Sci Immunol. 2017;2(14):eaan5393. doi: 10.1126/sciimmunol.aan5393. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
54. Muller MA, Meyer B, Corman VM, Al-Masri M, Turkestani A, Ritz D, Sieberg A, Aldabbagh S, Bosch BJ, Lattwein E, Alhakeem RF, Assiri AM, Albarrak AM, et al Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect Dis. 2015;15(5):559–564. doi: 10.1016/s1473-3099(15)70090-3. [PubMed] [CrossRef] [Google Scholar]
55. Kayali G, Peiris M. A more detailed picture of the epidemiology of Middle East respiratory syndrome coronavirus. Lancet Infect Dis. 2015;15(5):495–497. doi: 10.1016/s1473-3099(15)70128-3. [PubMed] [CrossRef] [Google Scholar]
56. Al Kahlout RA, Nasrallah GK, Farag EA, Wang L, Lattwein E, Muller MA, El Zowalaty ME, Al Romaihi HE, Graham BS, Al Thani AA, Yassine HM. Comparative Serological Study for the Prevalence of Anti-MERS Coronavirus Antibodies in High- and Low-Risk Groups in Qatar. J Immunol Res. 2019;2019:1386740. doi: 10.1155/2019/1386740. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Woodward Davis AS, Roozen HN, Dufort MJ, DeBerg HA, Delaney MA, Mair F, Erickson JR, Slichter CK, Berkson JD, Klock AM, Mack M, Lwo Y, Ko A, et al The human tissue-resident CCR5(+) T cell compartment maintains protective and functional properties during inflammation. Sci Transl Med. 2019;11(521) doi: 10.1126/scitranslmed.aaw8718. [CrossRef] [Google Scholar]
59. Haddadi S, Vaseghi-Shanjani M, Yao Y, Afkhami S, D’Agostino MR, Zganiacz A, Jeyanathan M, Xing Z. Mucosal-Pull Induction of Lung-Resident Memory CD8 T Cells in Parenteral TB Vaccine-Primed Hosts Requires Cognate Antigens and CD4 T Cells. Front Immunol. 2019;10:2075. doi: 10.3389/fimmu.2019.02075. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, et al Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 doi: 10.1001/jama.2020.1585. [CrossRef] [Google Scholar]
61. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, Akdis CA, Gao YD. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 doi: 10.1111/all.14238. [CrossRef] [Google Scholar]
62. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 doi: 10.1038/s41422-020-0282-0. [CrossRef] [Google Scholar]
63. Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2. Int J Antimicrob Agents. 2020;2020:105923. doi: 10.1016/j.ijantimicag.2020.105923. [CrossRef] [Google Scholar]
64. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 doi: 10.5582/bst.2020.01047. [CrossRef] [Google Scholar]