Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m606 (Published 19 February 2020) Cite this as: BMJ 2020;368:m606Read our latest coverage of the Coronavirus outbreak
Linked Editorial
Covid-19: a puzzle with many missing pieces
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Dear Editor
In view of rapidly spreading coronavirus disease across the world, various public health strategies need to be devised which can be administered to the whole population at a time. Addressing nutritional component in prevention and treatment is the need of the hour.
Zinc is a crucial micronutrient that plays a diverse role in physiological functions as well as in controlling viral infections. Its antiviral action has been proved in vitro infection models through the induction of host viral response. (1, 2). The literature shows that zinc inhibits coronavirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture (4). Moreover, a metanalysis has also demonstrated that zinc in various forms such as lozenges, tablets, etc. has an important role in the common cold due to its antiviral activity. It decreases the duration of nasal discharge, congestion, sore throat, muscle ache at a dose of 80 mg/day taken for less than 2 weeks. (3)
An estimated 17.3% of the world's population is at risk of inadequate zinc intake and in South Asia, it is up to 30% (6,7). However, around 800,000 people die annually due to zinc deficiency, 450,000 of these being children under the age of five according to the World Health Organization (WHO) estimates.(5) As per the Comprehensive National Nutrition Survey also (2016-18), zinc deficiency is reported to be around 21% among the age group 1-4 years (8). Zinc deficiency has serious health consequences in humans especially in children, who are more susceptible to contract infections like malaria, diarrhea.
Furthermore, increasing carbon dioxide levels due to pollution can accelerate zinc deficiency in crops and consequently in humans (9). A study from Harvard university projected 50 million people in India especially the south and northeastern region to become zinc deficient by 2050. As these areas consume large proportion of rice in their diet which is deficient in zinc. Considering all the pieces of evidence, taking zinc supplements and increasing zinc in the diet by eating zinc fortified flour and salt, legumes, seeds, dairy, eggs, whole grains, nuts could be one of the additional public health measures especially in zinc-deficient populations, and it needs to be explored further to deal with the current panic situation.
References
1. Kaushik N, Subramani C, Anang S, Muthumohan R, Shalimar null, Nayak B, et al. Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase. J Virol. 2017 01;91(21).
2. Kar M, Khan NA, Panwar A, Bais SS, Basak S, Goel R, et al. Zinc Chelation Specifically Inhibits Early Stages of Dengue Virus Replication by Activation of NF-κB and Induction of Antiviral Response in Epithelial Cells. Front Immunol [Internet]. 2019 [cited 2020 Mar 23];10. Available from: https://www.frontiersin.org/articles/10.3389/fimmu.2019.02347/full
3. Hemilä H, Chalker E. The effectiveness of high dose zinc acetate lozenges on various common cold symptoms: a meta-analysis. BMC Fam Pract [Internet]. 2015 Feb 25 [cited 2020 Mar 23];16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359576/
4. te Velthuis AJW, van den Worm SHE, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010 Nov 4;6(11):e1001176.
5. Zinc in Health - Zinc.org India [Internet]. [cited 2020 Mar 23]. Available from: http://zinc.org.in/programs-and-activities/zinc-in-health/
6. Maxfield L, Crane JS. Zinc Deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [cited 2020 Mar 23]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK493231/
7. Wessells KR, Brown KH. Estimating the Global Prevalence of Zinc Deficiency: Results Based on Zinc Availability in National Food Supplies and the Prevalence of Stunting. PLOS ONE. 2012 Nov 29;7(11):e50568.
8. https://www.popcouncil.org/uploads/pdfs/2019RH_CNNSreport.pdf
9. Smith MR, DeFries R, Chhatre A, Ghosh-Jerath S, Myers SS. Inadequate Zinc Intake in India: Past, Present, and Future. Food Nutr Bull. 2019 Mar 1;40(1):26–40.
Competing interests: No competing interests
Dear Editor,
Xu and colleagues reported clinical features of patients infected with coronavirus disease 2019 (COVID-19) in Zhejiang province, with treatments including antivirals, antibiotics, or steroids.[1] However, it’s noteworthy that traditional Chinese medicine (TCM) has also been applied widely, and has played substantial roles in management of COVID-19 in China.
Since the ongoing pandemic of COVID-19 that first outbroke in Wuhan, more than 3,100 TCM practitioners across China have been sent to Wuhan, and contributed their joint efforts with doctors of modern Western medicine to control the disease. According to the press conference of the State Council,[2] up to 60107 confirmed cases of COVID-19 in the country have received TCM treatment by February 17, 2020.
The latest version of the Diagnosis and Treatment Protocol of COVID-19 by the National Health Commission has advised to apply TCM in the treatment of COVID-19 patients.[3] TCM prescriptions and patent drugs were recommended based on patients’ symptoms and signs, vary with severity from mild ones to critical conditions. According to the press conference,[2] the therapeutic strategies of combining the merits of both TCM and modern Western medicine for the treatment of COVID-19 patients can effectively relieve symptoms such as fever, cough, sore throat, myalgia and fatigue, shorten the course of disease, reduce the probability of mild infections turning into severe or critical conditions.
The application of TCM in management of infectious diseases dates back thousands of years. Pestilent diseases have been described in details in TCM literatures. The Yellow Emperor’s Internal Classic (about 425-221 BC) described the ancient medical scholars’ understanding of pestilences: During the epidemic, people are generally susceptible, regardless of adults and children, and the symptoms are similar. During the Han dynasty (202 BC-220 AD), Treatise on Febrile Diseases written by an eminent physician Zhongjing Zhang (150-219 AD) is the earliest monograph on the treatment of acute infectious diseases with TCM. Zhang prescribed many formulas for the febrile diseases, such as Mahuang decoction for chill, myalgia, and cough, and Maxingshigan decoction for high fever and dyspnea, which are still popular in clinical use.
Although the TCM theory is obscure and complicated for Western medicine doctors and researchers, several clinical trials have confirmed some herbal formulas may be safe and effective. Chen Wang, member of the Chinese Academy of Sciences, together with his colleagues[4] investigated the efficacy of maxingshigan-yinqiaosan, a traditional herbal formula, in a clinical trial including 410 patients with laboratory-confirmed H1N1 influenza. The multicenter, prospective, randomized, controlled trial was conducted at 11 medical sites in 4 provinces in China during the H1N1 influenza epidemic. The results showed that maxingshigan-yinqiaosan, alone and in combination with Oseltamivir, significantly shorten the course of fever in patients with H1N1 influenza virus infection. Only 2 of 103 patients who have taken maxingshigan-yinqiaosan experienced nausea and vomiting. They suggested that maxingshigan-yinqiaosan may have beneficial immunomodulatory effects for rapid recovery of viral infections, and it could be used as an alternative treatment of H1N1 influenza virus infection.
The underlying mechanisms of TCM in management of infectious diseases have also been investigated. Lianhuaqingwen Capsule (LH-C), another TCM prescription, inhibited the proliferation of a series of influenza viruses in vitro, suppressed virus-induced NF-kB activation, and alleviated virus-induced gene expression of IL-6, IL-8, TNF-α, IP-10, and MCP-1 in a dose-dependent manner, indicating that LH-C regulates the immune response of virus infection.[5] A latest study identified five active natural compounds from Chinese herbal medicine, including Baicalin, Scutellarin, Hesperetin, Nicotianamine, and Glycyrrhizin, which are potential compounds that target the Angiotensin-converting enzyme 2 (ACE2) receptor, and may exert antiviral effects for preventing novel coronavirus infection.[6]
These studies showed TCM remedies may have both antiviral and anti-inflammatory effects. Such properties are particularly important in the treatment of severe cases of COVID-19, because the host inflammatory response is a major cause of lung damage and subsequent mortality.[7] Although TCM has been applied widely to the treatment of COVID-19, by far, to our knowledge, there is still no scientific articles regarding this experience.[1,8,9] The main reason is that herbal formulas contain many compounds, they are tailored to patient's symptoms and environmental factors, and often work in a holistic approach. Given the complexity of TCM, it is very important to conduct high-quality clinical trials and basic researches to determine the exact efficacy and safety profiles, so that we can put the effective agents into large-scale clinical applications to benefit more patients.
Traditional medicines are potential sources of new drug candidates. The antimalarial drug artemisinin that has saved millions of lives, was extracted from traditional Chinese herb sweet wormwood. Irrespective of TCM or modern Western medicine doctors, we share the same goal to help, to care, to relieve, and to cure our patients. When we face the challenges of COVID-19 outbreak, drug-resistant infections, or future public health crises, it could be an option to give a warm embrace to this millennium-old practice. Several effective formulas and compounds originate from TCM, deserve further validation by rigorous clinical trials.
Yichang Yang, Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. yangyichang.ll@163.com
Ting Zhang, Department of Immunology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Competing interests: We have read and understood BMJ policy on declaration of interests and declare that we have no competing interests.
References
1 Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368: m606. DOI: 10.1136/bmj.m606.
2 National Health Commission. Press conference of the joint prevention and control mechanism of the State Council on Feb 17, 2020. http://www.nhc.gov.cn/xcs/fkdt/202002/f12a62d10c2a48c6895cedf2faea6e1f.s... (in Chinese, accessed Feb 20, 2020).
3 National Health Commission. Diagnosis and Treatment Protocol of COVID-19 (Seventh Edition). published March 3, 2020. http://www.nhc.gov.cn/xcs/zhengcwj/202003/46c9294a7dfe4cef80dc7f5912eb19... (in Chinese).
4 Wang C, Cao B, Liu QQ, et al. Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial. Ann Intern Med 2011; 155: 217-25.
5 Ding Y, Zeng L, Li R, et al. The Chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function. BMC Complement Altern Med 2017; 17: 130.
6 Chen H, Du Q. Potential natural compounds for preventing 2019-nCoV infection. Preprints. 2020; 2020010358. https://www.preprints.org/manuscript/202001.0358/v1.
7 Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis 2020; published online Feb 27. DOI: 10.1016/S1473-3099(20)30132-8.
8 Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28. DOI: 10.1056/NEJMoa2002032.
9 Wang FS, Zhang C. What to do next to control the 2019-nCoV epidemic? Lancet 2020; 395: 391-93.
Competing interests: No competing interests
On February 25, China ’s top legislative body passed the “Act on Comprehensively Banning the Trading of Illegal Wildlife, Eliminating the Bad Habits of Eating Wild Animals, and Effectively Protecting People's Health” (hereinafter referred to as the “Act”), which strictly prohibits the trade and consumption of wild animals by law.
The legislation was believed to be a response to an outbreak of “Novel Coronavirus Pneumonia” (NCP) that occurred late last year in China's Hubei region. By 19 p.m. on March 15, the cumulative number of confirmed cases in mainland China was 81,059, with a cumulative death toll of 3,204, and the current mortality rate was 3.95percent.
Although there is still no very conclusive evidence, it is widely believed that the novel coronavirus (named COVID-19 by the WHO) is closely linked to eating wild animals. The COVID-19 virus may have originally come from bats. Chinese scientists have discovered the Rhinolophus yunnanensis whose coronaviruses are very similar to those found in currently-diagnosed patients, with a sequence similarity of up to 96 per cent.
Zhong Nanshan, an academician of the Chinese Academy of Engineering, said: "Scientists are looking for the COVID-19’s intermediate host. The COVID-19 was first found in a bat, but intermediate hosts have not been identified. ".
At present, the majority of confirmed infected in mainland China were from Wuhan, or people who have been to Wuhan before; most of the initial infectors came from a seafood market in Wuhan, which sells a large number of wild animals.
Chinese have no habit of eating bats, from bats that transmit COVID-19 to humans, requiring intermediate hosts. The scholars from the South China Agricultural University have found that the virus strains isolated in pangolins are 99% similar to those in the infected, and considered pangolins to be potential intermediate hosts of the COVID-19. The Chinese traditionally have the habit of eating wild animals. They believe that the taste of wild animals is more delicious and nutritious than farmed animals. Chinese medicine, which has been trusted by many Chinese, treats a large number of animal organs as medicine raw materials, such as tiger bones, rhino horn, ivory, deer antlers, bear bile, etc. For pangolins, Chinese medicine thinks that eating pangolins can make breastfeeding women lactate smoothly, which is based on the fact that the pangolin's hard shell can penetrate hard objects to gain access. According to statistics, China consumes 300,000 pangolins each year.
The Chinese like to eat wild animals, the serious consequences of which already appeared in the 2003 SARS Incident. The outbreak from southern China was believed to be caused by the consumption of civets carrying the SARS coronavirus. The outbreak infected 8,069 people worldwide and killed 774 as a result of the disease.
The scope of the ban on wild animals in the Wildlife Protection Act, which came into force in March 1989, was limited to State-protected wild animals and other protected wild animals without legal sources or quarantine qualification. But if wild animals were artificially domesticated, they can be eaten. This was actually a loophole in the law. Many wild animals can enter the table of Chinese because of this rule, because there is no way to tell whether they are wild or domesticated. The Act closes this loophole, which, on the basis of the Wildlife Protection Act, significantly expands the prohibition of eating wild animals, especially those of terrestrial animals. Only animals included in the nationally determined livestock and poultry catalogs, which generally refer to domestically raised livestock and poultry, such as farmed chickens, ducks, cattle, sheep and pigs, are allowed to eat. This also means that many insects and wild birds Chinese like to eat will no longer be eaten.
There are two legal consequences of violating the Act. If State-protected animals are consumed, criminal liability will be incurred; if other wild animals, administrative liability incurred, such as fines or administrative detention.
The sudden outbreak of the NCP has dealt a heavy blow to China's society and economy, and has had a huge impact on people's daily lives, which has directly led to the enactment of the Act. But can it change the habit of eating wild animals in China for thousands of years? Not only does this require Chinese to be able to strictly abide by the law, but also to truly recognize the harmful consequences of overeating wild animals and only in these ways can they truly consciously change the eating habits of wild animals that has evolved over the years.
Competing interests: No competing interests
Dear Editor
I am writing this letter to outline my concern regarding a still unidentified correlation between the new Covid-19 and patients with history of hypertension. If you allow, I will also describe my personal experience with influenza as I have been treated for essential hypertension for over 5 years. I hope my thoughts and speculations may help raise awareness and support studies on the subject.
Early publications of Covid-19 patients have highlighted the strange and still unknown correlation between the virus and patients with hypertension. An early clinical investigation of 140 hospitalised Covid -19 cases indicates hypertension as a comorbidity with the highest association (42%) in both non-severe (20%) and severe (22%) cases (1) . In another publication from February, from the 41 cases with fatality, hypertension is again the highest comorbidity (53.8%) (2).
The disease progresses from an upper to a lower respiratory tract infection with pneumonia and a particular development in the lung (2).
However it seems that COPD, asthma and other respiratory comorbidities may have little correlation with Covid-19 (1).
As exposed by Vetter (3), these are very early days of the investigation of the pathogenesis of the disease and a number of questions are still to be answered. Further data from other regions might corroborate or challenge the current information.
Conversely, my personal experience with hypertension and influenza had taught me a few lessons. It is well known that drugs for the treatment of essential hypertension such as calcium channel blockers and ACE inhibitors have side-effects. One of the most common is xerostomia. As a dental surgeon and a senior lecturer in oral biology, I have been aware of the connection between xerostomia and anti-hypertension drugs for some time. As a patient, I learned that the the symptoms of xerostomia can extend to when one is recovering from common influenza. I have been treated with an association of a calcium blocker (Lercanidipine) and a ACE inhibitor (Ramipril) for some time with the associated xerostomia as a side-effect.
After one week of typical flu symptom, I was left for over a month with a persistent cough, which couldn’t be treated by other coughing medicines. A visit to my GP (and a few arguments) brought a change of my prescription from Ramipril to Cadesartan (an angiotensin II receptor antagonist). There was a clear improvement on my coughing symptoms, which disappeared a week later. My educated guess is that xerostomia does have an effect on the protective layers of the respiratory tract. However, there is very little research on the specific changes in saliva beyond volumes and patient symptoms.
I would speculate that the connection of the new Covid-19 with the comorbidity hypertension may be related to the use of anti-hypertension drugs and the side effects on the salivary secretion (both serous but most probably mucous). Data from patients with Covid-19 should have the information of prescribed drugs for association studies. I fear to bring with this letter more a problem than a solution but if this is confirmed, it may help others to identify alternative ways to protect patients with comorbidities and the new Covid-19.
My sincere regards
Joao Carlos Miguel
1. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020.
2. Deng SQ, Peng HJ. Characteristics of and Public Health Responses to the Coronavirus Disease 2019 Outbreak in China. J Clin Med. 2020;9(2).
3. Vetter P, Eckerle I, Kaiser L. Covid-19: a puzzle with many missing pieces. Bmj-Brit Med J. 2020;368.
Competing interests: No competing interests
SARS-CoV-2, hypertension and ACE inhibitors
Giovanni Di Guardo, DVM, Dipl. ECVP,
University of Teramo, Faculty of Veterinary Medicine,
Località Piano d’Accio, 64100 - Teramo, Italy
(E-mail address: gdiguardo@unite.it)
Dear Editor,
The interesting article by Dr Xiao-Wei Xu and coauthors (1) follows another nice contribution focused on the clinical features of SARS-CoV-2-infected patients from Wuhan, China2. In the latter work diabetes, hypertension and cardiovascular disease (CVD) were reported to occur as frequent comorbidities in hospitalized patients with CoViD-19 (CoronaVirus Disease 2019) (2), an interstitial pneumonia caused by the newly discovered SARS-CoV-2, the seventh hitherto recognized human coronavirus (3).
Following the SARS epidemic in 2002-2003, in-depth investigations were carried out with the aim of deciphering the receptor(s) allowing viral interaction and entry into human (and animal) cells. Angiotensin-converting enzyme 2 (ACE2) was identified as a crucial factor mediating SARS-CoV spike (S) protein’s interaction with susceptible host cells (4). Noteworthy, an ACE2-dependent mechanism of infection has been recently shown also for SARS-CoV-2, with its receptor-binding motif potentially recognizing ACE2 from different animal species, which could serve both as “intermediate” hosts and as putative models for the comparative study of viral infection’s pathogenesis (5).
Therapeutic protocols based upon ACE inhibitors’ utilization are widely used in the clinical management of patients affected by hypertension and diabetes, both of which are well-known CVD risk factors (6). Within such context, it would be worthwhile to investigate CoViD-19 evolution and outcome in SARS-CoV-2-infected, diabetes, hypertension and/or CVD-affected patients under treatment with ACE inhibitors. Indeed, based upon the clear-cut evidence of an ACE inhibitor-induced upregulation of ACE2 previously shown in murine models (7), this could additionally speed-up viral uptake and host’s pulmonary tissue colonization, should a similar mechanism of ACE2 upregulation take place also in SARS-CoV-2-infected humans.
This information could prove useful, first of all, in the clinical and therapeutic management of CoViD-19-affected patients suffering from hypertension and other CVD risk factors like diabetes. No less importantly, it could also provide insightful clues into host-SARS-CoV-2 interaction dynamics, a crucial prerequisite for the development of safe and efficient antiviral therapies and immunization protocols.
References
1) Xu X-W, Wu X-X, Jiang X-G, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: Retrospective case series. BMJ 2020;368:m606.
2) Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
3) Gorbalenya AE, Baker SC, Baric RS, et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses-a statement of the Coronavirus Study Group. bioRxiv. 2020; published online Feb 11. Doi: 2020.02.07.937862 (preprint).
4) Li WH, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454.
5) Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol 2020; published online Jan 29. Doi: 10.1128/JVI.00127-20.
6) Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998;338:645-652.
7) Huang M-L, Li X, Meng Y, et al. Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. Clin Exp Pharmacol Physiol 2010;37(1):e1-6.
Competing interests: No competing interests
Dear Editor，
This excellent work from Dr. Xu et al provided us the clinical features of patients with novel coronavirus disease (COVID-19) in Zhejiang province. Moreover, several articles have been published on the COVID-19, with The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team having published the largest sample-sized study.[1-5] Based on these data, we can draft some epidemic characteristics of COVID-19 and reassess the steps to be taken next for this international public health emergency.
First, COVID-19 shows a strong transmission potential. As of March 7, 80,813 cases of COVID-19 have been confirmed, with 3,073 deaths in China, 18,989 of which were laboratory-confirmed, and 416 deaths outside of China. The basic reproduction number, R0, of COVID-19 ranges from 2·23 to 4·82.[6] This suggests that each patient might spread the infection to two to five other individuals on average. Apparently, the transmission of COVID-19 is much higher than that of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The screening of potentially infected people has become an emerging critical concern. Ideally, all confirmed cases should test positive for viral nucleic acid by RT-PCR or genetic sequencing. However, current nucleic acid tests have insufficient sensitivity, at about 30–50%.[7] Some suspected cases were not diagnosed until the ninth test. In other words, this could lead to missed diagnoses of some COVID-19 patients. For the highly infective COVID-19, diagnostic methods with low sensitivity are not suitable for screening. Alternatively, chest computed tomography scans found pneumonia in 76·4% of confirmed cases.[8] Hence, clinical diagnoses that highlight typical imaging features should be used earlier for screening.
Second, there are no particularly susceptible populations except children. Regardless of age, sex, living habits, or physical weakness, all adults can potentially be infected with COVID-19.[2] However, it is worth noting that the prevalence rate in children is low; only 0·9% of the confirmed cases were under the age of ten.[2] In fact, from personal communications with colleagues, it has come to our attention that many children in Wuhan caught a cold before the COVID-19 outbreak during November and December 2019. Is this related to the low infection rate among children? Or is the reception of COVID-19 in children’s alveolar epithelial cells different from that of adults’?
Third, the mortality rate in Hubei is higher than that in other areas. As of March 7, the mortality rate in Hubei province is much higher than that in other provinces and other countries (4·0% vs. 0·8% vs 2.2%). This can be attributed to limited medical resources, an overly-strict method of diagnosis, the allowance of many infected patients to stay in communities, and the lack of effective care. Additionally, one could speculate that the toxicity of COVID-19 may gradually decrease in subsequent generations, as it did with SARS and MERS.[9]
Fourth, many asymptomatic infections are emerging. Recently, more and more asymptomatic cases have been confirmed. Strikingly, the asymptomatic infection rate on the Diamond Princess cruise ship is up to 47·8%.[10] This raises a new question: how contagious, if at all, are the asymptomatic patients? Does this characteristic suggest that COVID-19 will not disappear like SARS did in 2003, but will evolve into a seasonal epidemic? These questions must be answered urgently.
Fifth, there are no specific medications for COVID-19 as yet. The hope is that an existing anti-viral medication or a new medication currently in clinical trial such as remdesivir will demonstrate antiviral activity; however, we still need to wait for the clinical trial results. Therefore, evidence-based treatment for COVID-19 is still our standard clinical practice.
Despite preliminary insights into the nature of COVID-19, information is still insufficient. The above issues with COVID-19, such as the diagnostic approach with low sensitivity and the question of how contagious asymptomatic cases are, need to be clarified urgently. Therefore, individual level community screening using a highly sensitive approach and subsequent centralized isolation are crucial measures that need to be taken. Taking the issues mentioned above into account, we need to be alert to the possibility that COVID-19 may eventually become a global and seasonal epidemic.
Reference
1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020.
2. Team TNCPERE. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Chin J Epidemiol 2020; 41(2): 7.
3. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine 2020.
4. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine 2020.
5. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. Bmj 2020; 368: m606.
6. Yang Y, Lu Q, Liu M, et al. Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China. medRxiv 2020: 2020.02.10.20021675.
7. Xiao SY, Wu Y, Liu H. Evolving status of the 2019 novel coronavirus Infection: proposal of conventional serologic assays for disease diagnosis and infection monitoring [Commentary/Review]. Journal of medical virology 2020.
8. Guan W-j, Ni Z-y, Hu Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China. medRxiv 2020: 2020.02.06.20020974.
9. Chowell G, Abdirizak F, Lee S, et al. Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study. BMC medicine 2015; 13: 210.
10. http://mil.news.sina.com.cn/2020-02-18/doc-iimxxstf2541676.shtml. 2020 (accessed February 19th 2020).
Competing interests: No competing interests
Dear Editor:
Importance of understanding the anti-hypertensive treatment patterns in patients with COVID-19
Murthi M, Santos K, Batra M, Haddadi S, Mirsaeidi M
Department of Pulmonary and Critical Care
University of Miami Miller school of medicine, Miami, FL, USA
Angiotensin converting enzyme 2 (ACE2), a type-1 membrane bound glycoprotein, has recently been identified as the receptor for the novel Coronavirus, SARS-COV2 causing COVID-21. ACE2 is present in endothelial and epithelial of various organs including the heart, kidney and testis2. The role of ACE2 in cardiovascular health is well established and it is recognised as the prime converter of angiotensin 2 to angiotensin 1-9. Studies have identified that blockade of angiotensin 2 production by ACE inhibitors(ACEI) results in the upregulation of ACE23.
Reports from China suggest that hypertension was the most common comorbid condition in patients with COVID-19, with a prevalence of 15% in all patients and 23.7% in those with severe disease4. Anti-hypertensive medications prescription patterns in China show that 10.1% of Urban as well as 21.5% of Rural population are treated with ACEI monotherapy and 0.9% of urban and 2.1% of rural use ACEI in combination with other medications for the treatment of hypertension 5.
Theoretically, the elevated level of ACE2 receptors could increase the risk of infection with SARS-COV2 in patients who are treated with ACEI. Thus, it is essential to understand the treatment patterns for hypertension in these patients to analyse whether the use of ACEI is associated with an increased risk of infection.
1. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine 2020 doi: 10.1007/s00134-020-05985-9
2. Riordan JF. Angiotensin-I-converting enzyme and its relatives. Genome Biol 2003;4(8):225-25. doi: 10.1186/gb-2003-4-8-225 [published Online First: 2003/07/25]
3. Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept 2012;2012:256294. doi: 10.1155/2012/256294 [published Online First: 2012/04/27]
4. Guan W-j, Ni Z-y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2002032
5. Wang Z, Chen Z, Zhang L, et al. Status of Hypertension in China. Circulation 2018;137(22):2344-56. doi: doi:10.1161/CIRCULATIONAHA.117.032380
Competing interests: No competing interests
Dear Editor,
One speculation for the lower SARS infectivity in children is that cross‐protective antibodies were elicited in children as a response to one of their childhood vaccines.
A 2007 paper (on mice immunised with various vaccines) states that children's vaccines do not induce cross reactivity against SARS‐CoV
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860633/
However, the above-mentioned paper is affected by several biases.
Therefore, would it be feasible to look for cross-correlations between the RNA and proteic sequences of the NCOV 2019 and the immunogenic epitopes of the vaccines administered to Chinese children? If a correlation does exist, it could be possible to vaccinate the whole sensitive population.
Arturo Tozzi
Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA
tozziarturo@libero.it
Arturo.Tozzi@unt.edu
Gennaro D'Amato
Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High Specialty A. Cardarelli Hospital, Napoli, Italy
Medical School of Specialization in Respiratory Diseases, University on Naples Federico II.
gdamatomail@gmail.com
Competing interests: No competing interests
Dear Editor:
Thanks to the excellent research from Prof. Xu, the clinical features of patients with coronavirus disease 2019 (COVID-19) in Zhejiang outside of Hubei, China, have been reported.[1] Although this retrospective case series presented mild symptoms and a low proportion of severe events, notably, the clinical characteristics of these patients in Zhejiang included complications such as diabetes mellitus (DM).
Since December 2019, a novel infection disease named COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been spreading from Wuhan, China. It has caused a large global outbreak and become a major public concern worldwide. Nowadays, the Chinese Government, health officials and workers have implemented rapid and comprehensive public health emergency interventions to cope with the SARS-CoV-2 outbreak, and more patients infected with SARS-CoV-2 have recovered. However, patients with chronic noninfectious disease such as DM should not be a neglected aspect of care while managing patients with infectious diseases during the COVID-19 outbreak. As one of the most common noninfectious disease, DM is the common endocrine problem that affects hundreds of millions of the population, especially in China. In the era of the outbreak of COVID-19, the concern about the effect of COVID-19 on DM should be noted. Previously, other coronavirus zoonotic influenza infections, the effect of the SARS-CoV and MERS-CoV on the clinical course of DM was mentioned.[2, 3] Additionally, it is noteworthy that the prevalence and severity of SARS-CoV-2 infections in the cases that has DM, as a concomitant disorder is also available in recent reports.[1, 4, 5]
According to the reports by the National Health Commission of the People’s Republic of China, as of Mar 5, 2020, 80 552 people have been confirmed to have a SARS-CoV-2 infection in 31 provinces (including autonomous regions, municipalities directly under the central government) and Xinjiang Production and Construction Corp in mainland China.[6] It is no doubt that the SARS-CoV-2 infection already occurs in people with diabetes. However, there is still no report on this specific issue. We do not yet know the definite interaction between DM and COVID-19. The evidence from fighting SARS showed us that a known history of DM and ambient hyperglycaemia were significantly associated with death and morbidity in patients with SARS infection. Moreover, metabolic control could improve the prognosis of patients with SARS.[7] From the latest Guideline on the Diagnosis and Treatment Scheme for Pneumonitis with Novel Coronavirus Infection-2019 (version 7) by the Chinese government,[8] physicians mainly focus on the field of respiratory system treatment, critical care and other life-support interventions. In addition to the critically ill patients who are being treated in designated hospitals, there are nearly 4,000 COVID-19 patients with mild symptoms or asymptomatic infected in the cabin hospitals. In view of the above mentioned facts, there may be necessary to pay more attention to the blood glucose level of COVID-2019 patients, especially those with diabetes and other complications.
Fever is a common alarming symptom of SARS-CoV-2 infections. Fever caused by virus has been reported to be the precipitant in a case of hyperglycemic crisis.[9] Furthermore, a gastrointestinal problem, such as diarrhea or vomiting, is also recently reported in patients with COVID-2019.[10] Hence, not only high but low blood sugar level can be expected. The extreme fluctuation in metabolic condition can be the serious comorbid which superimpose the serious condition of the patients with infection, thus, maintain blood glucose level stable in outcome of the patients with SARS-CoV-2 infection should be mentioned. However, there is still no information on this issue, and it is needed to perform an investigation to review the current registry database and identify the characteristics of DM among the patients infected with SARS-CoV-2. These data will help us to make clear the unknown relationship. Herein, it is generally noted that a patient with DM and its systemic complications might have a high risk to the infection. These patients may require special care to prevent the development of infection.
Previous reports noted when a person gets an infection, such as Influenza, Cholera, Plague, Ebola, Anthrax or SARS, the blood glucose level changes, and concluded that continuous monitoring of blood glucose level may have a potential role in preventing large outbreaks of these diseases.[11] At the Norwegian Centre for Telemedicine, researchers use the electronic health record system to access blood glucose data and extend their work into Epidemic Disease Detection.[11] This makes it possible for health authorities to take action to control the outbreak and its consequences for all residents of the affected areas even at an early stage such as the incubation period. Future studies are still needed to validate this initial concept.
Generally speaking, SARS-CoV-2 infection is a major public health problem. In order to better prevent and control COVID-19, the relationship between the disease and DM should not be a forgotten issue and needs to be considered.
Reference
1. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606.
2. Yang JK, Feng Y, Yuan MY, et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med. 2006;23(6):623–628.
3. Kulcsar KA, Coleman CM, Beck SE, Frieman MB. Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection. JCI Insight. 2019;4(20):e131774.
4. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected by SARS-CoV-2 in Wuhan, China. Allergy. 2020;10.1111/all.14238. [published online ahead of print, 2020 Feb 19]
5. 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.
6. National Health Commission of the People's Republic of China. Update on epidemic situation of novel coronavirus-infected pneumonia by 24:00 on Feb 26, 2020. http://www.nhc.gov.cn/xcs/yqtb/202003/b59dbcc84ed1498292714975039dcdc9.s... (Mar 5, 2020), Accessed 6th Mar 2020.
7. Chan JC, Zhang Y, Ning G. Diabetes in China: a societal solution for a personal challenge. Lancet Diabetes Endocrinol. 2014;2(12):969-979.
8. Guideline for Diagnosis and Treatment of Pneumonitis Caused by New Coronavirus-2019 (trial version 6). Available at http://www.nhc.gov.cn/xcs/zhengcwj/202003/46c9294a7dfe4cef80dc7f5912eb19... (Mar 4, 2020), Accessed 6th Mar 2020.
9. Edo AE, Okaka E, Ezeani IU. Hyperglycemic crisis precipitated by Lassa fever in a patient with previously undiagnosed type 2 diabetes mellitus. Niger J Clin Pract. 2014;17(5):658-661.
10. Han W, Quan B, Guo Y, et al. The course of clinical diagnosis and treatment of a case infected with coronavirus disease 2019. J Med Virol. 2020;10.1002/jmv.25711. [published online ahead of print, 2020 Feb 19]
11. Arsand E, Walseth OA, Andersson N, et al. Using blood glucose data as an indicator for epidemic disease outbreaks. Stud Health Technol Inform. 2005;116:217–222.
Competing interests: No competing interests
Lessons learned by the SARS-CoV epidemic: Viral modulation of the host's glucose and lipid metabolism
Dear Editor
The recently emerged COVID-19 pandemic has been met with a rapid response from the scientific community, both in generating and disseminating clinical data, and in preclinical data generation. Among the first studies to report clinical data on COVID-19 was a recent publication by Xu et al (1). The authors provide detailed clinical and laboratory data, contributing to a growing body of evidence (2) that will allow researchers to phenotype infection patterns and outcomes. Currently, there are more questions than answers regarding the COVID-19.
In this light, previous knowledge stemming from the 2002-2003 SARS-CoV epidemic should be utilized, on the premises of structural and syndromic similarities between SARS-CoV and SARS-CoV-2 (3),(4).
Meta-analyses on SARS cohorts have indicated that both a history of diabetes and hyperglycemia were independent factors of worse outcomes including more severe respiratory symptoms and death, regardless of medication (5). In another study, SARS-CoV was shown to cause diabetes by ACE2-dependent infection of pancreatic isle cells (6).
Aside from ACE2 dependent entry, lipid metabolism is an important target of single strand RNA viruses, critical for the formation of the viral envelope in subsequent lifecycles (7). Autophagy mediated triglyceride and lipid droplet catabolism is one such mechanism, as identified in DENV (8). Hijacking the host cell's lipid metabolism has been shown to be a critical step in HCoV-22E and MERS - coronavirus latency (9). In SARS-CoV patients, alterations in lipid metabolism have been detected as far as 12 years after the initial infection, and were found to be related to corticosteroid treatment (10).
By contrast, diabetes has arisen as recurring comorbidity in COVID-19 cohorts (11), whereas lipid profiles remain unreported. Currently, no study has reported on the lipid profiles of COVID-19 patients. Given the role of lipids such as cholesterol in SARS virion assembly, preclinical pharmacotherapy / drug repurposing concepts have been developed (12). In this light, it is equally important to phenotype (i) COVID-19 patients receiving both antidiabetic and hypolipidemic agents and related comorbidities, (ii) to determine the de novo development of hyperglycemia / diabetes (iii) the long term follow up of COVID-19 patients, with respect to the future development of metabolic comorbidities.
REFERENCES
1. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368:m606.
2. Zhang X, Cai H, Hu J, et al. Epidemiological, clinical characteristics of cases of SARS-CoV-2 infection with abnormal imaging findings, International Journal of Infectious Diseases 2020; doi: https://doi.org/10.1016/j.ijid.2020.03.040
3. Ceccarelli M, Berretta M, Venanzi rullo E, Nunnari G, Cacopardo B. Differences and similarities between Severe Acute Respiratory Syndrome (SARS)-CoronaVirus (CoV) and SARS-CoV-2. Would a rose by another name smell as sweet?. Eur Rev Med Pharmacol Sci. 2020;24(5):2781-2783.
4. Xu J, Zhao S, Teng T, et al. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses. 2020;12(2)
5. Yang JK, Feng Y, Yuan MY, et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med. 2006;23(6):623-8.
6. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47(3):193-9.
7. Zhang Z, He G, Filipowicz NA, et al. Host Lipids in Positive-Strand RNA Virus Genome Replication. Front Microbiol. 2019;10:286.
8. Heaton NS, Randall G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe. 2010;8(5):422-32.
9. Zhang J, Lan Y, Sanyal S. Modulation of Lipid Droplet Metabolism-A Potential Target for Therapeutic Intervention in Infections. Front Microbiol. 2017;8:2286.
10. Wu Q, Zhou L, Sun X, et al. Altered Lipid Metabolism in Recovered SARS Patients Twelve Years after Infection. Sci Rep. 2017;7(1):9110.
11. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis. 2020; 10.1016/j.ijid.2020.03.017
12. Baglivo M, Baronio M, Natalini G, et al. Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity?. Acta Biomed. 2020;91(1):161-164.
Competing interests: No competing interests