Un po´di storia del COVID-19

JAMANETWORK.Articles and Comments:

COMMENTS:

February 13, 2020
Pathology Studies Necessary to Determine Cause of Death

Giuliano Ramadori, Professor of Medicine | University Clinic, Internal Medicine, Göttingen,Germany

The new coronavirus pandemic originating from Wuhan, China has had a tremendous impact on the Chinese population and all nations around the world. The description of the cases in whom the coronavirus has been isolated and its genome has been sequenced has to be hugely appreciated.The coronavirus is supposed to be the cause of pneumonia in all patients and of the death of > 1100 Chinese patients. However it would be very important to obtain tissue pathology findings of the lung and of the other organs. In fact cofactors such as bacterial coinfection or even or even pollution particles in the patient´s bronchial macrophages may have played a role in inducing respiratory problems which may have led to the death of the patients, and should be investigated. We still do not know whether the new coronavirus is really more dangerous than the
already known human coronavirus strains HKU1, NL63, 229E and 0C43, or the different influenza viruses.

CONFLICT OF INTEREST: None Reported
March 1, 2020
Air Pollution an Important Cofactor to Consider in Pathogenicity Studies

Giuliano Ramadori, Professor of Medicine | University Clinic,Göttingen, Germany
We all know that the Chinese and some inhabitants in northern Italy used to put masks on to avoid inhalation of microparticles before COVID-19 was discovered in Wuhan.The NASA pictures (now published by Spiegel online) of the China region taken by the NASA before and after the beginning of the COVID-epidemic show the impressive changes of the sky color (now blue) (1).Similar pictures of the nothern italian regions and of South Korea or of Iran would also be very informative when thinking about causes of death and antiviral therapies.

Reference

1. https://www.axios.com/coronavirus-nasa-images-china-pollution-clears-7dd8961d-0627-4342-ab0d-029c872ced1e.html

CONFLICT OF INTEREST: None Reported




COMMENT:

February 24, 2020
COVID 19: a global presence and not only a new pathogen?

Giuliano Ramadori, Professor of Medicine | University Clinic, Göttingen, Germany

In the winter season there comes the time of upper and lower respiratory tract infections characterised by cough, dyspnea and eventually fever (influenza-like illness).Some of the patients, especially older people living alone affected by the disease ,may need hospitalization and eventually intensive care. In many of the cases who are hospitalized nasal and/or tracheal fluid are examined for viral or bacterial agents. Only in less than 50% of the cases influenza viruses are considered to be the cause of the disease.In the rest of the cases diagnostic procedure for human coronaviruses is not performed routinely. One of the four different Human Coronaviruses (HuCoV: 229E,NL 63,0C43 and HKU1) can however be found in up to 30% of patients negative for influenza viruses (1). Chinese scientists in Wuhan, who had to deal with an increasing number of acute respiratory tract diseases resembling viral pneumonia, performed deep sequencing analysis from samples taken from the lower respiratory tract and found a „novel“ coronavirus. The sequence of the complete genome was made public. At the same time, however, the notice from Wuhan brought to mind the SARS- and MERS-epidemics. The measures taken by the Chinese- and WHO-authorities are now well known.

Recently about 150 new cases have been identified in northern Italy and health authorities are still looking for case 0 (the source). Is it possible that COVID-19 was already existent in Italy — and not only in Italy but possibly everywhere in the world — and that newly available nucleotide sequence allows now to find the cause of previously undefined influenza-like illness?

REFERENCE

1. Benezit F et al.:Non-influenza respiratory viruses in adult patients admitted with influenza-like illness:a 3- year prospective multicenter study.Infection, 13 february 2020, https://doi.org/10.1007/s15010-019-01388-1).

CONFLICT OF INTEREST: None Reported
COMMENT:

February 29, 2020
Coronavirus is a Known Human Pathogen
Giuliano Ramadori, Professor of Medicine | Univeristy Clinic, Göttingen,Germany

I am grateful to the authors for the comprehensive review of the events of the last three months concerning COVID-19 first described in China.I would like however to add the information that the „new“ virus belongs to a group of viruses which have been endemic in humans for long time (1) and are responsible for a significant number of pneumonia cases as reported by prospective investigations (2) which demonstrate that this testing for coronavirus is not part of the routine search causes of pulmonary disease. Every year we have to deal with mutated influenza viruses, which are considered to be responsible for influenza symptoms even in those persons who were vaccinated against the most common strains. As the first case of the Italian COVID-19-epidemic does not seem to be of Chinese origin, the question arises whether a mutated CoV have been already circulating around the world for a longer time.

References

1.Jonsdottir HR, Dijkman R.Coronaviruses and the human airway:a universal system for virus-host interaction studies.Virological Journal,2016. https://creativecommons.org/licences/by4.0/)
2.Iven M et al. Aetiology of lower respiratory tract infection in adults in primary care: a prospective study in 11 European countries. Clin Microbiol and Infect,2018;24:1158-1163

CONFLICT OF INTEREST: None Reported
COMMENT:
February 25, 2020

Date of Onset of Symptoms in the First Patient And Supposed Source of Infection

Giuliano Ramadori, Professor of Medicine | University Clinic Göttingen Germany

I am grateful for the enormous amount of work done by the authors in reporting as precisely as possible the numbers and characteristics of patients demonstrated (or supposed to have been) infected by a variant of the coronavirus.

In the report, however, I do not find a demonstration concerning the hypothesized „zoonotic spillover“ as the cause of human infection. In public imagination this assumption turns the viral infection into a much stronger threat than it is.

According to Chaolin Huang et al.(1), „the symptom onset date of the first patient identified was Dec. 1,2019.“
Therefore this date should be added to the very important and comprehensive epidemic curve (Figure 1) and to the timeline comparing the SARS and the COVID-19 outbreaks (Figure 2) in this report.

REFERENCE

1. Chaolin Huang et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan,China. The Lancet, January 24, https://doi.org/10.1016/50140-6736(20)30183-5

CONFLICT OF INTEREST: None Reported

1 Comment for this article March 12, 2020

Additional Clinical Expertise for Treatment of Severely Ill ICU Patients Needed

Giuliano Ramadori, Professor of Medicine | University Clinic,Internal Medicine,Göttingen,Germany

The priorities listed for responding to COVID-19 are of general interest and not only for the US Health community.Thank you to the authors for having put together the experiences made by past epidemics and the Chinese experience. I also fully agree with the sentence „Because some proportion of patients will be severely ill and require critical care interventions, specific preparation is needed in ICUs“. As many of the critically ill patients are > 60 years old, they suffer from many „internists'“ (comorbid) conditions — chronic diseases like diabetes, NAFLD, and chronic kidney disease, and many of them also take at least 3 different drugs every day.

For correct treatment of these patients it is not sufficient to try to optimize respiratory function with different technologies like ECMO but it is mandatory to know how to protect other vital organs aside from the lung. In fact it has not yet been demonstrated in any of the past coronavirus epidemics (SARS, MERS) that the virus induces loss of organ function by directly infecting those organs. (1)

Treatment by interdisciplinary medical teams would be the best for those patients.

I also would like to suggest to avoid use of „experimental“ drugs outside of well planned clinical trials in critically ill patients.

REFERENCE

1. Liu J,Zheng X, Tong Q, et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-Cov, and 2019-cCoV. J Med Virol 2020; February 13:1-4.

CONFLICT OF INTEREST: None Reported

JAMANetwork.Comment:

March 24, 2020 COVID 19:

IS COMPARISON WITH CHINA SO IMPORTANT?

Giuliano Ramadori, Professor of Medicine | University clinic ,Internal Medicine,Göttingen,Germany

The Italian patient number one (38 year old) has just been released from the hospital San Matteo. His pregnant wife, who was also infected, was already at home.The patient`s father, however, unfortunately died of COVID-19. We are informed by very transparent Italian journalism. This makes comparison of numbers coming from other countries around the world very difficult.

On the other hand it is important to focus on Italian numbers which mostly come from Lombardy. In some of the areas of Lombardy, the number of deaths are five times higher compared with those of the same period of last year. This in a region with the best health care system in Italy. What went wrong? This is the question politicians will have to answer as soon as the pandemic will be over.

COMMENT:

April 2, 2020

Sporting Event in Lombardy and COVID-19 Viral Transmission Giuliano

Ramadori, Professor of Medicine | University Clinic,Internal Medicine,Göttingen,Germany

The soccer fight Atalanta Bergamo against Valencia which took place in Milan on February 19 may become a milestone in the history of epidemiological studies. About one third of the population of Bergamo attended the match. One can only imagine what happened in Bergamo when the fans went back to Bergamo from Milan after their team had won the match.

On march 16 th the news paper La Repubblica published an article :Spagna,Valencia:“ il 35% di noi positivi dopo aver giocato a Milano“ („35% of us are positive after playing in Milan).

Two days after the match the first (official) COVID 19-positive patient appeared at the Codogno-Hospital because of influenza-like symptoms. He was patient number 1 in Italy while a Chinese couple was treated in Rome since the 28 th of January. At the same time however, a 78 year-old man in Vó Euganeo fell ill on February 20th and died the next day of COVID-19 infection. He was the first person in Italy who died of the COVID-19. The area around Codogno (about 50.000 inhabitants) and the area around Vó were locked down, but not the area around Bergamo (ca 1.3 million people).

The number of new infections became such that the doctors at the university hospital in Bergamo, Papa Giovanni Paolo II, did not have time to decide who  should be treated by mechanical ventilation.This was mainly because the Italian health care system does not have intermediate structures between home doctors and the hospitals.

While in Codogno only symptomatic persons were tested for COVID 19-infection ( all 78 chinese citizens were negative), all the inhabitants  of Vó Euganeo,a town near Padova, 3.500 persons, were tested and asked to stay home. Seventy persons were tested positive at the beginning of the 14-day quarantine and seven of them were still COVID-19 positive when the quarantine was officially terminated. Eight Chinese citizens were negative (1)

As far as I know none of the positive persons became ill (with the exception of the 78 year old man who died first) during the quarantine. The experience of VÒ demonstrates that there are asymptomatic persons who can transmit the virus.It also demonstrates that quarantine may help to avoid the the appearence or worsening of symptoms in infected persons bevfre the virus is eliminated.

Two regions, Lombardy and Veneto, close to each other, each have two different approaches with different epidemiology. As of 01.04.2020 (April 1), the Veneto has tested 112,000 persons and found 9625 COVID-19-positive persons; 1,718 have been hospitalized and 350 are being treated at an ICU. Lombardy has tested 121,000 persons and 44.773 were positive,11927 are hospitalized and 1342 are being treated at the ICU.

The lesson is to test as many persons as possible.If one needs to choose whom to test then it should begin with workers in the different health care structures.

REFERENCE
1.These zu Corona Herkunft. Brachten Chinesen das Virus nach Italien? Tageschau.de.26.03.2020.
www.tagesschau.de › faktenfinder › italien-coronavirus-china-101

CONFLICT OF INTEREST: None Reported

March 14, 2020

Emergency Response of a Western Country to the COVID-19 „Tsunami“

Giuliano Ramadori, Professor of Medicine | University Clinic,Internal Medicine,Göttingen,Germany

This is an impressive report about the challenge the Lombardy Health care system had to face after the outbreak of COVID-19 became clear in an area of Italy with a large Chinese minority. In fact it was supposed that the virus originated from China but the first patient with COVID-19 pneumonia is a young marathon runner of 38 year of age and not a person belonging to the Chinese minority. It is still unclear how he, his wife and his parents became infected.

The number of ICU-patients is impressive. Even more impressive is the velocity of the increase of the number of people who needed ICU care.

It would be more impressive for the countries who are reluctant to consider preventive measures be taken to have the number of patients reported who unfortunately died while being treated at the ICU. How many patients were Chinese?

The relatively  high number of the ICU admissions in the Lombardy compared to the numbers observed in China may be primarily due to the number of ICU-beds available.

I am surprised to read the word „race“ as one of the possible predisposing factors for ICU-admission. Ligi Luca Cavalli Sforza, who died in Belluno in August 2018 was the italian „grandfather of the field of human population genetics“(1) who clearly demonstrated that humans belong to one single race.Therefore „race“ can not be a predisposing factor for ICU-admission in Lombardy besides age and comorbidities.

REFERENCE

1. Henn BM,Quintana-Murci L.:Editorial Overview:The history, geography and adaptation of human genes: A tribute to L.Luca Cavalli-Sforza.Curr Opin Genetics & Developement 2018;53:iii-v CONFLICT OF INTEREST: None Reported READ LESS

March 14, 2020

Mild COVID-19 Cases: Who Might Be Hospitalized And Who Can Be Quarantined?

Arturo Tozzi, Pediatrician | University of North Texas

The escalating number of Italian patients with positive COVID-19 test results causes an unmanageable increase of hospital admissions, including of mild/moderate cases. Indeed, about three fifths of the patients with confirmed SARS-CoV-2 are currently hospitalized in Italy, while the rest are home quarantined. Therefore, it would be useful to grasp who of the patients affected by mild to moderate symptoms require hospital admission instead of household follow-up.

White blood cell counts in SARS-CoV-2-positive but not critically ill patients might be a way to determine who requires hospitalization. Indeed, lower lymphocyte counts have been associated with increased disease severity in COVID-19,compared with survivors (1,2), and Chen et al (3) reported that 35% of non-critical infected patients had only mild lymphocytopenia, suggesting the severity of lymphocyte depletion reflects the severity of COVID -19.

In sum, the proposed approach would lighten the load of the otherwise congested hospitals.

REFERENCES

1) Ruan Q, Yang K, Wang W, Jiang L, Song J. 2020. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020. DOI:10.1007/s00134-020-05991-x.
2) Yang X, Yu Y, Xu J, Shu H, Xia J. 2020. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. https://doi.org/10.1016/S2213-2600(20)30079-5.
3) Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507–13.


Arturo Tozzi
Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA
tozziarturo@libero.it
Arturo.Tozzi@unt.edu CONFLICT OF INTEREST: None Reported READ MORE March 15, 2020

Behavioral factors; clinical COVID-19 exacerbation; prevention and recommendations Stefano Olgiati, PhD (Epidemiology) | University of Bergamo, Bergamo, Italy Dear Fellow Researchers,

a. In the article, Grasselli et al (2020) report: „with predisposing factors such as race, age, and comorbidities“

b. In the Comments, Ramadori (2020) observes that: „… the first patient with COVID-19 pneumonia is a young marathon runner of 38 year of age.“

c. Fragmented health data report that the marathon runner (and other critically or severely ill patients) practiced high performance sports and / or occupational activities during the asymptomatic and /or mild symptomatic period;

d. Zhoukun et al (2020) report that: “ … clinical symptoms and radiological abnormalities are not the essential components of SARS-CoV-2 infection.“ and identified a sample of „…asymptomatic SARS-CoV-2 infected patients with persistent negative CT findings“.

Research Questions:

1. Does behavior (heavy exercise, etc ) of asymptomatic or mildly symptomatic SARS-CoV-2 infected patients exacerbate the severity of COVID-19 outcomes?

2. Should behavioral factors during the asymptomatic or mildly symptomatic period be reported / included among potential COVID-19 predisposing / clinical exacerbating factors?

3. Should public health authorities and primary care physicians produce behavioral recommendations aimed not only at containing / mitigating the spread of COVID-19 but also at preventing a potential clinical exacerbation during incubation, mild infection period and / or quarantine ?


Stefano Olgiati, PhD, FRSM, MSE
stefano.olgiati@unibg.it
s.a.olgiati@gmail.com

REFERENCES
1. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. Published online March 13, 2020. doi:10.1001/jama.2020.4031

2. Ramadori G. Mild COVID-19 Cases: Who Might Be Hospitalized And Who Can Be Quarantined? in Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. Published online March 13, 2020. doi:10.1001/jama.2020.4031

3. Zhoukun Ling et al. Asymptomatic SARS-CoV-2 infected patients with persistent negative CT findings. European Journal of Radiology. Published:March 12, 2020DOI:https://doi.org/10.1016/j.ejrad.2020.108956 CONFLICT OF INTEREST: None Reported READ MORE

March 19, 2020

What about Non Invasive Ventilation in ICU/Sub-Intensive Units

Paolo Bonazza, MD (Internal Medicine) | Karolinska University Hospital Huddinge First of all I send you great thanks for taking the time to share your experiences just a few days after you began to manage the COVID outbreak.

As an internist working in a COVID high-dependency unit (HDU) is important to try to help our critical care colleagues and try to know, since the beginning of the outbreak, indications for, and other experiences with, use of non invasive ventilation.

What do you have to say about non invasive ventilation (NIV)? Both in ICU as well HDU/Sub-intensive units. I read already that the majority of patients with advanced disease require intubation.

Is non invasive ventilation with CPAP/BiPAP an alternative as a first step? Do you have any experience about that, and which modalities and pressure have you used?

And do you have any experience with stepdown care, and NIV treatment after ICU ward? CONFLICT OF INTEREST: None Reported READ MORE

March 20, 2020

What was the required number of ICU beds per 100.000 inhabitants? Ignacio Garcia Doval, MD, MSc Epid, PhD | Complexo Hospitalario Universitario de Vigo. Spain

Thank you very much for this description of an impressive, and frightening, effort.

The results would be more valuable elsewhere, and useful to plan for the emergency, if they were related to the population in the area. What is the source population of these hospitals? What was the required number of ICU beds per 100.000 inhabitants? Could the authors answer? CONFLICT OF INTEREST: None Reported March 23, 2020 ACE2 and COVID-19 ISKANDAR MONEM ISKANDAR BASAL, medstudent | Università di Roma La Sapienza Today is the 23rd of March and it is the second day in which the report of the “Protezione Civile” here in Italy registers a small reduction either in the number of infected persons or the number of deaths. We all hope and intensely pray this trend to continue in the following days.

What is happening in Italy has been actually very unusual and the heroic efforts of the Italian health system to face this tsunami of epidemic is already evident to everybody.

However, many are asking a question. Even the JAMA Editor in his video meeting with Dr. Maurizio Cecconi (one of the authors) asked this question: why this odd distribution of cases? Three regions in particular were hit very severely by COVID-19.

I would like if the authors allow me to share two thoughts relating to this issue:

It is known that the SARS-CoV-2, the cause of  COVID-19 enters cell through ACE2 receptors especially on the endothelium of lung vessels and elsewhere too (1,2).

First: Is it possible that some people have inherited a high density of ACE2 on their cells?

Second: More probably it might be related to polymorphism. Are there some alleles of the ACE2 to which the virus attaches more easily than others which might explain the severity of the disease in some individuals?

REFERENCES

1. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. February 2020. doi:10.1038/s41564-020-0688-y

2. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426(6965):450-454. doi:10.1038/nature02145 CONFLICT OF INTEREST: None Reported READ MORE

Comment

2 Comments for this article
EXPAND ALL
April 22, 2020
Effective Treatments For COVID-19: Supportive Care Before and In the ICU Is Crucial

Giuliano Ramadori, Professor of Medicine | University Clinic,Internal Medicine,Göttingen,Germany

The authors might be congratulated for the scientifically honest and well balanced viewpoint.
I think the policy of the FDA at this moment is well „counterbalanced“ by the seriousness of Dr A.Fauci.
All the world is listening to the press conferences every day to learn about the decision process in the USA which of course influences the behaviour of the people responsible for clinical and political strategies against COVID-19 around the world.

I would like to underline the second conclusive point the authors make that adequate treatment is very important for COVID-19-positive patients staying at home and seeking simple nutritional support, for the patients in the emergency room, and even more for the severe cases in the ICU.

While well-managed structures are needed for treatment of infected patients at home, well prepared „all-round“ doctors are crucial for „optimimization“ of supportive care in the ICU. Postmortem analysis of all organs (1) in patients who died of COVID-19 (but also of influenza) is of clinical importance, not only to understand the pathophysiology of such a new disease as basis for development of new drugs, but also to learn what should be optimized during the stay of the patients in the ICU.This would also contribute to reestablish public confidence in academic medicine.

Reference
1. Barton LM,Duval EJ,Stroberg E et al.: COVID-19 autopsies, Oklahoma,  USA.Am J Clin Pathl 2020:1-9

CONFLICT OF INTEREST: None Reported

COMMENT
April 18, 2020
Race can not be the problem but education may be the solution

Giuliano Ramadori, Professor of Medicine | University Clinic Göttingen,Germany

Dr Yancy mentioned „race“ three times as one of the possible reasons for higher infection and death rate amongst the African American and hispanic minorities in the US. Race cannot be the reason for this situation as African-American and Hispanic people the same race as white people. Education is the most important reason for different epidemiology.

CONFLICT OF INTEREST: None Reported
COMMENT
May 24, 2020
COVID-19
Giuliano Ramadori, Professor of Medicine | University Clinic, Internal Medicine, Göttingen, Germany

Del Rio C and Malani P have spent many efforts to summarize the flood of communication about the most important aspects of the COVID-19-pandemic published in the last five months. By doing that they offer a platform for additional thoughts and discussions. I think it is important to remember how the new coronavirus was „born“. 

A doctor, Ai Fen, the chief of the emergency unity at the Wuhan Central Hospital, had to deal with several patients with pneumonia of unclear origin and had the idea and the opportunity to ask the laboratory of the hospital to test swabs from a patient for SARS-Coronavirus (1). The laboratory had a real-time PCR-kit which could also identify the RNA of several viruses responsible for „atypical pneumonia“ including several betacoronaviruses and SARS-CoV-1 (2).

Human Coronaviruses belonged to a family of now seven components which have a large sequence similarity. With the exclusion of SARS-CoV-1 and MERS the other four HuCoV are responsible for 10-30% of atypical pneumonias every winter. These viruses use the same receptor the new CoV uses to colonize the human upper and lower airways. Antibodies against those viruses are quite common in the sera of many persons (3), and we do not exactly know how COVID-19-specific the antibodies are which we are measuring in the sera of COVID-19 infected patients (4).

Serum level of neutralizing antibodies will also decrease with time and their presence does not mean that they will help to clear the virus and to prevent reinfection.

Under these conditions and considering the not-so-positive past experience with the influenza vaccine, the production of a COVID-19-vaccine represents a true challenge.

As we have recently learned that pulmonary disease without thrombosis of the pulmonary vessels is mainly responsible for the death of elderly COVID-19-patients with several comorbidities, while other organs supposed to be invaded by the virus seem not to be much damaged, efforts should focus on early supportive care and therapy to avoid development of severe respiratory insufficiency.

References

1. Kuo L: Coronavirus:Whuan doctor speaks out against authorities.The Guardian 2020,March 11.
2. Zhu N,Zhang D, Wang W et al.A novel Coronavirus from patients with pneumonia in China,2019 New Engl J Med2020;382:727-733.
3. Gorse GJ,Patel GB, Vitale JN,O`Connor Z.:Prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum.Clin Vaccine Immunol 2010,17(2):1875-1880.
4. Du Z, Zhu F, Guo F et al.Detection of antibodies against SARS-CoV-2 in patients with COVID-19.J Med Virol 2020:1-4

CONFLICT OF INTEREST: None Reported
READ LESS
May 30, 2020
CoVID19: coagulopathy treatment option?

Camilo Colaco, PhD | ImmunoBiology Ltd

This Viewpoint summarized the current status of potential drug therapies, vaccine development and convalescent antibodies as treatment. However, it does not discuss progress in clinical care resulting from the increased scientific understanding of the pathophysiology of SARS-CoV2 infection that has the potential to make the largest improvement in clinical care of CoVID19 patients.

As with earlier coronavirus outbreaks, the current CoVID19 infection has been associated with adult respiratory distress syndrome (ARDS), with worse outcomes in older patients and a systemic inflammation response triggered by a cytokine storm (CS) (1-3). Treatment has thus focussed primarily on oxygen supplementation with mechanical ventilation in more acutely ill patients with therapeutic consideration of anti-virals and immunosuppression (1,2).

However of the three diagnostic criteria that determine hospital admissions of CoVID patients, only acute breathing difficulty and a characteristic lung CT image are consistent with a diagnosis of ARDS. The third, the elevation of blood D-dimer levels, is indicative of some type of coagulation pathophysiology such as disseminated intravascular coaguloapathy (DIC) (3). This suggestion is consistent with a re-evaluation of characteristic CT lung images and autopsy results from patients with CoVID19 which report widespread microthrombi in lung and other tissues and offers an alternate mechanism of disease progression in CoVID19 patients, namely DICS (3).
 
Most importantly, considering DIC instead of ARDS as the primary pathophysiological problem in CoVID19 suggests a pragmatic therapeutic option with the early treatment of patients with mild breathing difficulties using anticoagulants such as LMW heparin (4). This therapeutic approach is strongly supported by a retrospective analysis of the treatment of CoVID19 patients in China which reported better outcomes in patients treated with LMW heparin, as well as a reduction of IL6 and the CS that is thought to induce the ARDs that is the focus of most current clinical therapies (4).

It is thus quite likely that the EARLY treatment of CoVID19 patients with anticoagulants such as LMW heparin could result in better patient outcomes and reduce the mortality risk and concomitant fear elicited by the current global CoVID19 pandemic.

Camilo Colaco
Camilo.colaco@immunobiology.co.uk

References

1. Clinical management of severe acute respiratory infection when COVID-19 is suspected. WHO/2019-nCoV/clinical/2020.4 https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected

2. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395 (10223):507-13. PubMed PMID: 32007143.

3. Oudkerk M et.al. Diagnosis, Prevention, and Treatment of Thromboembolic Complications in COVID-19: Report of the National Institute for Public Health of the Netherlands. Radiology Published Online Apr 23 2020. https://doi.org/10.1148/radiol.2020201629

CONFLICT OF INTEREST: None Reported





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COMMENT
November 24, 2020
COVID-19 vaccine trials:too many white partecipants may be a bias and undermine acceptance?

Giuliano Ramadori, Professor of Medicine | University Clinic, Internal Medicine, Göttingen,Germany

I am thankful to Jennifer Abbasi for the comprehensive update about the actual situation in the field of COVID-19 vaccines (1). I was one of the participants in the first vaccine trial against Hepatits B in 1981 (?) and I still have a measurable titer of „protective“ antibodies against HBs-Antigen. It is in fact very important to underscore the fact that this vaccine, like several others (e.g.polio vaccine), does prevent infection and also life-threatening diseases. I have already had the occasion to mention in a previous comment (2) however that „neutralizing“ antibodies as determined in vitro are not a guarantee of infection prevention as it seems to be the case also for SARS-CoV-2-reinfection (3).The measurement of such antibodies in the actual COVID-19-vaccine-studies should however transmit the hope that the induced antibodies will prevent SARS-CoV-2-infection. This can only be demonstrated by showing real prevention in a large phase III-study. After approval of the vaccine this should be accepted by all components of the society (White, Black, Hispanic, Asian). As it is, however, the participants in ongoing trials are almost exclusively white (4,5), similar to some influenza vaccine trials(6 ).The trials seem to exclude the majority of those people who are mainly hit by the infection and therefore less willing to accept vaccination (7).

LITERATURE
1. AbbasiJ.JAMA 2020;324(12):1125-1127,
2. Ramadori G.JAMA 2020;324(2):131-132
3. Tillet RL et al.Lancet Infect Dis 2020,Oct.12
4. Anderson EJ et al.New Engl J Med 2020 Nov 6
5. Walsh EE et al.New Engl J Med 2020 Oct 14,
6. DiazGranados CA et al.New Engl J Med 2014;371:635-645
7. Knowable MAGAZINE 2020 Oct 11.

CONFLICT OF INTEREST: None Reported

COMMENT:

November 29, 2020

HCoV-2-Infection: early supportive care (pre-hospitalisation period) is crucial to avoid second period of illness.

Giuliano Ramadori, Professor of Medicine | University Clinic, Internal Medicine, Göttingen, Germany.

CONFLICT OF INTEREST: None Reported

Most of the clinical data published so far have been obtained by analysing charts from hospitalized patients with little gain of knowledge concerning the treatment strategy of symptomatic patients during hospitalisation. References 5-7 in this Viewpoint give little information about the early phase of the infection (in the pre-hospitalisation period) which however may lead patients to the emergency room and to hospitalisation with severe consequences.

At this stage supportive care is crucial before starting experimental therapy (2,3).

Dr Tomera above suggests that biochemical and immunological parameters could predict the outcome, but albumin serum level is a very important prognostic marker that is not on his list (4). The publications of the Tomera`s group (5-8) have however seminal value not only because of the possible importance of the administration of a COX-2-inhibitor (9,10) together with the histamine-2- receptor inhibitor famotidine but also and most importantly because of the repeated determination of the creatinine and eGFR which shows improvement during hospitalisation and points toward use of fluid administration to the studied patients as supportive care (2,3). This procedure has not been stressed highly enough in guidelines but may be worth further study as all the severely ill patients in the Tomera`s study could be released from the hospital.

References

1.Datta SD,et al. JAMA 2020,nov.18
2.Ramadori G JAMA,2020;323(4):2464-2466(comment)
3.Ramadori G,JAMA,2020 june 20 (comment)
4.Ramadori G,Hepatoma res.2020,jun 3
5.Tomera K,JAMA 2020; nov 18 (comment)
6.Tomera K,Kittah JTrialSitenews2020,July 31
7.Tomera K,Kittah J,Preprints 2020 August 24
8.Tomera K,Kittah J SSRN 2020,oct 1(revised)
9.Amici C et al.Antiviral Therapy 2006;11:1021-1030
10.Tuveson D et al.TrialSitenews 2020,Jun 7

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