A View for COVID-19 in Japan

Author: Nobuo Handa

Affiliation: Handa Clinic

Editors: Tetsuya Tanimoto MD., Akihiko Ozaki MD., PhD., Yuki Senoo

Introduction:

My name is Nobuo Handa, MD. I have 40 years of experience in clinical practice, operating my clinic in Japan for over twenty years in a front-line setting for infectious diseases such as the recent swine flu pandemic. I would like to offer my observations and opinion on Japanese policy regarding the novel coronavirus (COVID-19) pandemic.


Japanese Strategy Against COVID-19 Today:

Based on careful observation of the situation regarding the COVID-19 pandemic in both China and Japan, it appears to be challenging to contain COVID-19. Two factors contribute to this difficulty: the presence of asymptomatic healthy carriers and the often-rapid onset of ARDS pneumonia.


On March 29, 2020, the ad hoc committee (later renamed the Experts Meeting on the Novel Corona Virus isease Control/EMNCVC) indicated to the Japanese central government that ensuring delivery of appropriate medical treatment for critically ill patients and finding and containing infectious clusters to prevent the spread of the contagion were necessary to control the COVID-19 pandemic and reduce mortality associated with COVID-19.1


Despite the recommendation of the EMNCVC, the government did not increase the number of real time polymerase chain reaction (RT-PCR) tests conducted in the country. It was reported that this was hindered by manpower limitations and RT-PCR test kit shortages.1 


This strategy seemed to be working well at first, as mortality associated with COVID-19 was extremely low in Japan compared to Western countries.2 However, the case growth rate in Japan was still accelerating more quikly compared to those in early April, in contrast to rates in China, Taiwan, and South Korea. For this reason, the central government declared a national-wide state of emergency on April 16th.


The first Japanese measures against COVID-19 were similar to other countries' lockdown policies. While the Japanese strategy successfully lowered the overall mortality rate, new clusters developed at many hospitals and nursing facilities. Thus, it is necessary to separately build and implement measures against COVID-19 in the short, middle, and long term. Here, I would like to suggest a framework to prevent the spread of COVID-19 and to reduce both mortality and incidence of the disease, which could help the development of a strategy to prevent pandemics in the future.


Short Term Goal: Understanding and Managing the COVID-19 Clinical Course

At the beginning of the spread of an infectious disease, the most crucial clinical issue is how to treat individual critical pneumonia cases. When patients' disease progress to ARDS, the COVID-19 fatality rate is thought to increase to levels similar to that of SARS and MERS. Characteristics of ARDS associated with COVID-19 are bilateral lung damage in the lower airways and damage to interstitial tissues.3,4 This damage is thought to be caused by SARS-CoV-2 and the subsequent cytokine storm.5,6 Therefore, we have to consider treating COVID-19 with a three-pronged strategy: (1) eradicate the SARS-CoV-2 virus, (2) control the cytokine storm, and (3) provide the best supportive care for multiorgan failure.


Most COVID-19 patients present with only mild or no symptoms. However, fever, fatigue, and dry cough may be signs of COVID-19?associated pneumonia, and patients reporting such symptoms need careful observation.


The mechanisms of pneumonia caused by SARS-CoV-2 and other viruses have been shown to be quite different. Orthodox pneumococcus pneumonia or mycoplasma pneumonia are caused by pathogen invasion of the host lung and damage to pulmonary parenchyma. In contrast, SARS-CoV-2 pneumonia causes damage to the whole lung, including to both parenchyma and interstitial tissues, and to other organs.3 Recently researchers have reported SARS-CoV-2 viremia attacks multiple organs, including erythrocyte and vascular epithelium, and damage is possibly caused not only by the virus but also by immune chain reactions.4,7


To provide effective treatment, physicians should take the following three stages of the disease into consideration. In the first stage, the patient typically complains of common flu-like symptoms such as fever, dry cough, loss of taste, and severe fatigue. Patients with such symptoms should be tested using RT-PCR tests and instructed to stay home. According to a recent paper, acetaminophen, erythromycin, azithromycin, and/or carbocisteine can be prescribed for common cold-like symptoms. Although chloroquine and hydrochloroquine have been prescribed for disease, recent preliminary trials reported that they do not have a prophylactic effect against COVID-19.8 Colchicine is traditionally used to treat gout and rheumatic disease, and was recently recognized as an anti-inflammatory agent. A Greek research group showed that patients with severe COVID-19 who received colchicine had significantly improved time to clinical deterioration.9 Although the research paper suggests potential benefits from colchicine against COVID-19 cytokine storm,9 their long-term outcomes are still unknown. Therefore the application of colchicine requires careful assessments and further evidence provided through trials.10


In the second stage of the disease, patients with COVID-19 may experience dyspnea, high fever, and severe fatigue, which could be signs of pulmonary interstitial tissue damage. These patients should be hospitalized and given oxygen supplementation by artificial ventilation. Among numerous agents that have been investigated, remdesivir (anti-Ebola medicine) and dexamethasone are shown to reduce mortality of patients with COVID-19.1 Unfortunately, other agents, including AVIGAN (favipiravir) and hydroxychloroquine have failed to show efficacy against COVID-19.11,12 In the last stage, patients with COVID-19 suffer from multiple organ failure. One study demonstrated that ECMO, extracorporeal membrane oxygenation, may be an effective therapy, but it not been proven through trials.13


Middle Term Goal: Protecting the Medical Community

In Japan, we have witnessed new viral clusters emerging in hospitals, nursing homes, and other medical facilities. We have seen medical personnel become infected in the course of their duties, something that was also observed in China, Europe, and the United States. During the mid-term phase of the pandemic, it is crucial to build a plan that focuses on reducing the risk of infection among medical professionals.


To prevent nosocomial infection, it should be a priority to check all patients and medical staff, whether they have the SARS-CoV-2 virus or not. Antibody serum tests, in addition to PCR tests, should be conducted for all patients and medical care providers.


Here, I would like to provide an example of a testing regime. First, every inpatient should be tested for SARS-CoV-2 upon admission. Testing for medical personnel assigned to infectious disease wards should be conducted weekly. There are several advantages to testing for infectious disease; it can help control the spread of COVID-19 inside the medical community, and we can also confirm the real features of the SARS-CoV-2 virus, including how it spread and immune reactions against this virus.


Long Term Goal: Mapping Viral Mechanisms and Immunological Interactions

It is important to acknowledge we are dealing with a truly novel virus. The virus has newly sequenced genes, there are no proven treatment strategies, and limited information is known about the virus. We have to research the characteristics of COVID-19. A recent study of COVID-19 found patients who are elderly and have underlying health conditions such as diabetes mellitus, hypertension, and/or lung disease are high risk.14 Another observational study conducted in the United States suggested that hypertension and obesity are the 2 greatest risk factors after age.14 In addition, many researchers have demonstrated that the ACE2 receptor plays a key role in SARS-CoV-2 invasion into host cells.7 ACE2 receptors exists in all human organs, not only the lungs, including the vascular epithelium. Thus, overexpression of ACE2 is a key risk factor in SARS-CoV-2.


However, it is still not understood why some young and reasonably healthy people have died from COVID-19 infections.2,8,14 To effectively fight the virus, it is necessary to confirm contributing factors that lead to high affinity for and vulnerability to SARS-CoV-2. Recently, Japanese researchers suggested that BCG vaccination, type of SARS-CoV2 gene, and HLA typing were strongly related to vulnerability to this virus.15


References

1. Oshitani H. Concept of measures against COVID-19. 2020; https://www.jsph.jp/covid/files/gainen.pdf. Accessed October 11, 2020.

2. Ministry of Health Law. Current status of new coronavirus infection and response by the Ministry of Health, Labour and Welfare. 2nd edition. Ministry of Health, Labor, and Welfare; 2020. https://www.mhlw.go.jp/stf/newpage_10887.html.

3. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-422.

4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.

5. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Engl J Med. 2020;382(13):1268-1269.

6. Chen Y, Li L. SARS-CoV-2: virus dynamics and host response. Lancet Infect Dis. 2020;20(5):515-516.

7. Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020;395(10235):1517-1520.

8. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857-e208857.

9. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: The GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136-e2013136.

10. Rabbani AB, Parikh RV, Rafique AM. Colchicine for the treatment of myocardial injury in patients with coronavirus disease 2019 (COVID-19)—an old drug with new life? JAMA Netw Open. 2020;3(6):e2013556-e2013556.

11. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-525.

12. Chen C, Zhang Y, Huang J, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. medRxiv. 2020:2020.2003.2017.20037432.

13. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA. 2020;323(18):1824-1836.

14. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052-2059.

15. Toyoshima Y, Nemoto K, Matsumoto S, Nakamura Y, Kiyotani K. SARS-CoV-2 genomic variations associated with mortality rate of COVID-19. J Hum Genet. 2020;volume(issue):page-page.



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