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.
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
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.
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.
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.
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 firstname.lastname@example.org 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“.
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 ?
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?
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
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.
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
L´arrivo delle belle stagioni di primavera ed estate ci riportano alla mente con piu´forza quanto sia importante avere abbastanza acqua dolce adisposizione. Questo anche perche´ in diversi casi in cui l´acqua significava energia essa e´stata sostituita dall`energia elettrica.In altri casi come quello dell ´irrigazione dei campi essa e´scomparsa dalla superficie e ora scorre all´interno di tubature che ne´riducono la dispersione. Si puo´quasi affermare che Il tenna e` rimasto l´ultimo testimone di quanto l´acqua „pulita“ sia importante non solo per la produzione delle fonti principali del nostro nutrimento e del nutrimento dei nostri animali,come cereali,verdure e frutta. Anche se attualmente molta della produzione agricola di un tempo e´stata „smantellata“ e il territorio un tempo agricolo e´stato in parte „cementificato“ dobbiamo ricordarci
che quello che ora ci resta a disposizione deve essere conservato con cura sia che esso sia ancora coltivato o che esso sia stato in parte abbandonato.
A questo proposito c´e´e ci sara´bisogno dell´acqua „pulita“.E`molto importante che ci sia acqua potabile a disposizione al di fuori delle mura domestiche in diversi punti del territorio.
Per turisti che vogliono visitare il nostro territorio,fare una sosta presso una sorgente di acqua potabile rappresenta una occasione di riposo e una fonte di ristoro.
Ogni persona che sia essa adolescente o adulta abbisogna in condizioni normali da 1.5 a 2,5 litri di acqua al giorno.Per molti giovani e´diventato abituale portre con se acqua in bottiglia in quantita´diverse a seconda delle ore da trascorrere fuori di casa e dell`attivita´che si vuole svolgere.
La persona di eta´magari oltre i settanta anni e´cronicamente „disidratata“ e magari sente di meno il senso della sete.
La mancanza acuta di acqua specialmente in queste persone provoca una serie di disturbi come, vertigini,senso di spossatezza, confusione mentale e anche cadute con conseguenze che possono essere gravi e condurre all´ospedalizzazione dove magari la causa principale della caduta non viene neanche presa in considerazione.
Nel caso della attuale pandemia da SARS-CoV-2 (COVID-19) la disidratazione e´la causa principale dei disturbi che ormai tutti conosciamo , che attribuiamo all´azione diretta del virus e che possono condurre all`ospedalizzazione.Qualche volta questo puo´succdere perfino dopo che il virus e´stato eliminato.
Il virus che magari si manifesta all´inizio con un semplece raffreddore e tosse secca provoca spesso non solo perdita del gusto e dell´olfatto ma anche febbre che puo´arrivare a 39-40 gradi e persistere per diversi giorni.La febbre aggrava di molto la disidratazione che porta poi alla sonnolenza,e perfino perdita di coscienza e riduzione acuta dell´apporto di calorie con la dieta.Si mette in moto un circolo vizioso che deve essere interrotto subito appena compaiono i primi sintomi.
Potrebbe essere successa una cosa simile al giocatore danese ERIKSEN.
Infatti l´aritmia cardiaca come causa dell´arresto cardiaco e` una delle possibili cause della caduta dellatleta alla fine del primo tempo della patita.
In questo frangente l´acqua diventa un „farmaco“ salvavita.
Non e´pero´superfluo ricordare che,durante questa fase non bisogna dimenticare la nutrizione. Questo non solo come apporto calorico ma e soprattuto per l´apporto proteico che e´indispensabile per la produzione di importanti proteine del sangue.La piu´
Importante di queste e´l´albumina che trattiene l´acqua nei vasi e e´responsabile (insieme all´acqua) a mantenere la pressione sanguigna che „ci tiene in piedi“.
Der Begriff betrifft den Schutz gegenüber übertragbaren viralen und bakteriellen Erkrankungen und ist im Zusammenhang mit der bisher grössten Pandemie seit 100 Jahren, der Hu-CoV-2-Infektion, ins Spiel gebracht worden (1:“it assumes random mixing which is ridiculous“,2).
Der Begriff „Herdenimmunität“ wurde Anfang des 20ten Jahrhunderts zunächst für Tiere verwendet und dann auf den menschlichen Bereich übertragen (3).
Schon allein deswegen ist der Begriff, in Bezug auf die
Wenn eine Gruppe (Herde) von Tieren gegen eine meist tödliche Infektion geschützt werden soll, wird die Produktion von „schützenden“ Antikörpern bei den Tieren induziert und gleichzeitig aber das Eindringen von Tieren aus nicht geimpften Herden verhindert.
Dies setzt aber voraus, dass es Antikörper gibt, die die
Übertragung der Infektion und den Ausbruch der Krankheit verhindern.
Dies ist z.B. bei der Polio-induzierten schlaffen Lähmung, bei Masern oder aber auch bei der Hepatitis B der Fall (4,5).
Menschen, die solche Infektionen gehabt und Antikörper entwickelt haben, sind gegen eine erneute Infektion geschützt. Diese Beobachtung hat man genutzt, um Impfstoffe zu entwickeln und um Impfprogramme aufzulegen (6).
Man hat aber auch festgestellt, dass die Verbreitung einer Polio-Infektion nur sicher verhindert werden kann, wenn jedes Jahr mehr als 90% der Kinder geimpft wird (7).
Im Fall der Polio-Schluckimpfung wird angenommen, dass die im Impfstoff enthaltenen halb-inaktivierten Polio-Viren durch ihre Ausscheidung im Stuhl an
nicht geimpfte Personen in die unmittelbare Umgebung weitergegeben werden.
Dadurch werden auch diese Personen immunisiert.
Gleichzeitig, folglich, ebenso wird die Wahrscheinlichkeit, dass die Infektion
übertragen werden kann, stark reduziert (5).
Fällt die Zahl der geimpften Personen unter eine gewisse Grenze (60-80%,1) besteht die Gefahr eines Infektionsausbruchs bei den 20-40% der nicht immunisierten Personen.
Als es noch keinen Impfstoff gegen Polio gab, erkrankten jährlich ca.350.000 Kinder weltweit an einer schlaffen Lähmung. Durch die konsequente hohe Impfquote ist die Infektion in sehr vielen Ländern der Welt ausgerottet worden (4).
Dies wäre auf natürlichem Wege nie möglich gewesen.
Selbst wenn alle HuCov-2-Infizierte Personen schützende Antikörper produzieren würden, wäre ein genereller Schutz der Bevölkerung auf „natürlichem Wege“ nicht erreichbar.
Gleich zu Beginn der jetzigen Pandemie haben chinesische und dann deutsche Wissenschaftler (8) festgestellt, dass neutralisierende Antikörper gegen das HuCoV-2-Virus messbar waren, bevor das Virus eliminiert worden und damit die Genesung erfolgt war.
Folglich darf die Tatsache, dass ein Teil dieser Antikörper in der Lage, war die Infizierung von Zellen in der Kulturplatte zu verhindern und deswegen „neutralisierende Antikörper“ genannt wurde, nicht die Schlussfolgerung erlauben, dass eine Immunität durch die Infektion entstehe.
Diese Beobachtung ist schon bei der Infektion durch das Hepatitis C-Virus gemacht worden (9,10). Antikörper gegen das Hepatitis-C waren sowohl bei den Patienten, die das Virus spontan eliminiert als auch bei den Patienten, bei denen das Virus noch vorhanden war, nachweißbar.
Die Induzierung einer humoralen Immunantwort (Produktion von Antikörpern,“Serokonversion“) muss nicht immer Schutz gegen die Infektion durch einen bestimmten Erreger bedeuten, wie es für die verschiedenen Erkältungs-bzw .-Influenzaviren der Fall ist (11,12 ).
Ebenso wichtig zu wissen ist, dass Infektion nicht gleich Krankheit bedeuten muss, wie es klassischerweise für die Hepatits C-Infektion der Fall ist (9).
1.Jones D,Helmreich S:The art of medicine.A history of herd immunity.Lancet 2020;396,September 19.
2.Fine P.Herd Immunity:what is it and how do we reach it?Will weg et there for coronavirus? MVu Medi October 27.2020.
4.The African regional commission fort he certification of poliomielitis eradication:certifying the interruption of wild poliovirus transmission in the WHO African region on th turbulent journey to polio-free world.The Lancet Global Health.2020 Oct;8(10):e 1345-e1351
5.Jilg W: Gründe für eine generelle Impfung gegen Hepatitis B.Dtsch Arztebl 1996;93(47):A-3122-3126
6.Robert Koch Institut.Imfungen A-Z
7.Robert Koch Institut.Impfquoten bei der Schuleingangsuntersuchng in Deutschland 2016.Epidemiologisches Bulletin 2018;6
8.Wölfel R Corman V Guggemos W et al.Virological assesment of hospitalized patients with COVID-2019.Nature;581:465- 2020
9.Wietzke-Braun P,Mähnardt LB,Rosenberger A et al.Spontaneous elimination of Hepatitis C virus infection:A retrospective study on demografic,clinical and serological correlates.World J Gastroenterol 2007;13(31):4224-4229
10.Böttler T,Thimme R:Hepatitis C Virusinfektion.Status der Impfung.Dtsch Aztebl.2017;114(7):15-16
11.Ramadori G:Results may disappoint.Comment to:Viewpoint :monoclonal antibodies for prevention and treatment of COVID-19 by Mary Marovich et al,
12.Chow EJ,Rolfes MA,O´Halloran M et al. Respiratory and Nonrepsiratory diagnoses associated with influenza in hospitalized adults:JAMA Network Open 2020,3(3) e 201323
Del Rio C and Malani P have spent many efforts to summarize the
flood of comunications 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 that 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).
This was the basis for the sequencing work which was quickly performed by the chinese scientists(2).This would not have been routinely possible in many other hospitals in western countries.
As pointed out by Caterine Paules, Hilary Marston and Anthony Fauci(3) in their viewpoint,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 around the world.These viruses use the same receptor(4) the new CoV uses to colonize the human upper and lower airways.This means also that antibodies against those viruses are quite common in the sera of many persons(5) 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 (6).
Serum level of neutralizing antibodies (7) will also decrease with time (8,9) and their presence does not mean that they will help to clear the virus and to prevent reinfection (10,11).
Under these conditions (6) and considering the not so positive past experience performed with the influenza vaccine (12,13) the production of a COVID-19-vaccine represents a true challenge.
As we have recently learned that the pulmonary disease without thrombosis of the pulmonary vessels, is mainly responsible for the death of elderly COVID-19-patients with several comorbidities (14),while other organs supposed to be invaded by the virus(15), seem not to be much damaged, efforts should focus on early supportive care and therapy to avoid development of severe respiratory insufficiency.Autopsy of the patients who died of the disease is still a priority especially in academic centers.
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.Paules CI,Marston HD,Fauci AS.:Coronavirus Infection-More than just the common cold.JAMA2020;January 23:E1-E2.
4.Wu K,Li W,PenG G. Li F.:crystal structure on NL63 respiratory coronavirus receptor-binding domain complexed with ist human receptor.Proc Natl Acad Sci.2009;106(47):19970-19974.
5.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.
6.Eder S,Twohey M,Mandavill A.:Antibody test,seen as key to reopening country,does not yet deliver.The New York Times2020 April 10
7.Wölfel R, Corman VM, Guggemos W et.al.Virological assessment of hospitalized patients with COVID-2019.Nature 2020 April 1.
8.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
9.Lin Q,Zhu L,Ni Z et al.:Duration of serum neutralizing antibodies for SARS-CoV-2:lessons from SARS-CoV infection.J Microbiol,
10Chen D, Xu W Lei Z et al.:Recurrence of positive SARS-CoV-2-RNA in COVID-19:A case.Int J of Infec Dis 2020;93:297-299.
11.Lan L,Xu D, Ye G et al. Positive RT-PCR test results in patients recovered from COVID-19.JAMA 2020;323(15):1502-1503
12Simonsen L, Reichert TA, Viboud C et al.:Inpact of influenza vaccination on seasonal mortality in the US elderly population.Arch Intern Med 2005;165:265-272.
13.Choe EJ Rolfes MA,O`Halloran A et al.Respiratory and non-respiratory Diagnoses associated with influenza in hospitalized Adults:JAMANetwork 2020March 20
14.Horowitz J.:Surviving Covid-19 May not feel like recovery for some.New York Times 2020 May 20
15.Schaller T, Hirschbühl K Burkhardt K et al.Postmortem examination of patients with COVID-19.JAMA 2020,May 21
A part of this article as been published in part as a comment to the vewpoint:Translating Science on COVID-19 to Improve Clinical Care and Support the Public Health Response,published online in the Journal of American Medical Association May 22 2020 by Carlos del Rio,and Preeti Malani
Looking at the number of deaths in northern Italy and listening to the continuous requests for
mechanical ventilation machines (1) and for extracorporal membrane oxigenation (ECMO) devices (2) now the time has come to realize that ICU-admission and intubation of all COVID-19-patients with acute respiratory problems very often is not saving lives. The use of prognostic scores (3) may be used to avoid ICU-admissions. CT-scan of the chest and repetition of this procedure(4), however, is often not helpful and even dangerous as contrast medium is needed which may damage the kidney and augment blood volume. The report published by Arentz et al (5) clearly show that more than 50% of COVID-19 positive patients with severe comorbidities die shortly after ICU-admission, the other 50% continues to need mechanical ventilation.This severely reduces the ICU-capacity. A careful selection of ICU-admissions is necessary (6).
As suggested by Dr Bonazza (7), treatment of patients with severe comorbidities should better be treated with non invasive ventilation (NIV) (6).The questions asked by Dr Olgiati (8) are very appropriate. In fact many people believe that intensive physical exercise can only be healthy. This is not always the case (9), especially when„little“ viral Infections (e.g.common cold) are ongoing.
The answer to the third question is clearly affermative.This is even more approrpiate if we presume that many patients in home quarantene continue to smoke cigarettes.
1.Murthy S, Gomersll ChD, Fowler RA.:Care for critically ill patients with COVID-19.JAMA 2020 March 11
2.McLaren G,Fisher D,Brodie D.:Preparing for the most critically ill patients with COVID-19. The potential role of extracorporal Membrane oxygenation.JAMA 2020,February 19
3.Wujtewicz M et al.: COVID-19-what should anaesthesiologists and intensivists know about is. Anaestheiol Intensive Ther.2020;52:1-8
4.Wang D et al.:Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan,China.JAMA 2020 February 7
5.Arentz M et al.Characteristics and Outcomes of 21 critically ill patients with COVID-19 in Washington state.JAMA 2020 March 19
6.Sun Q,Qiu H,Yang Y.:Lower mortality of COVID-19 by early recognition and intervention:experience from Jiangsu Province. Ann Intensive Care 2020; 10:33
7.Bonazza P.:What about Non Invasive Ventilation in ICU/Sub-Intensive Units . Grasselli G,Pesenti A,Cecconi M :Critical Care Utilization for the COVID-19 Outbreak in Lombardy, ItalyEarly Experience and Forecast During an Emergency Response.JAMA 2020,March 11.
Most of the knowledge we aquired about the target organ(s) of human coronavirus originates from the clinical,radiological and,most importantly, autoptic studies (1-5) on patients who died during the SARS- and MERS- epidemics. Most of the actual informations about SARS-CoV-2(COVID 19) infection in hospitalized persons relys on clinical „surrogate“ findings and on CT-scans of the chest for both,those who were released from the hospital and those who unfortunately died of the disease (6-9). Infact no complete autoptic studies (with one single exception,10 ) have been performed in the more than 4.200 patients who died because of COVID 19.
By putting together the main clinical, radiological and histological data from the SARS-CoV 1 and MERS-epidemic we have a quite clear picture of the sequence of events occurring after the virus reaches first the bronchial and then the alveolar epithelium.
There is the invasion of the resident macrophages and of the epithelial cells by the virus and the recruitment of inflammatory
cells (granulocytes and macrophages) follows the release of pro-inflammatory cytokines and chemokines synthesized by the infected resident macrophages and epithelial cells(11,12) with some similarities to what happens in acute viral hepatitis( 13). The inflammatory cells also cause release of fluid into the alveoli from the capillaries which can be damaged and trhombosised with reduction of functional tissue. The size of the area could be dependent on the viral load reaching the respiratory tract.
The degree of the functional reduction can be proportional to the size of the pulmonary area involved in the process and could be predicted by analysing the CT-scan.
Immunohistological, and electronmicroscopy studies have given indications for the presence and multiplication of virus particles in the inflamed areas of the lung. Similar findings have not been detected in other organs even if viral RNA has been detected in liver samples and in stool-samples in patients showing
mild elevation of serum transaminase levels at a later time after beginning of the disease, of the consequent hospitalisation (14) and transfer into ICU. No hepatic functional reduction has been described in these patients. None of the retrospective clinical publications contained data indicating reduction of hepatic function,e.g. hyperbilirubinemia, or massive increase of transaminase serum level in patients dying from COVID 19.
Intriguing however is the low albumin serum level found not only in the ICU-care patients in two of the publications (6,8 ).Albumin serum level is an indicator for the synthetic capacity of the liver which is on the one hand dependent of sufficient nutritional delivery of proteins and or amino acids to the liver, and on the other hand, on the availability of enough healthy hepatocytes .This can happen in cases of acute hepatitis, when about a third of the hepatocytes dies and serum transminase levels and bilirubin are massively elevated.
No similar data have been found in COVID 19 patients (15).
The same is true for the kidney. No indication has been given for
viral replication in the kidney (2,3). A few autoptic data seem to support the assumption that the kidney might be suffering from massive intravasal fluid reduction (2,16) which can cause tubular necrosis (2 ).This may be due to the intention to reduce cardiac work load in patients with hypoxia due to reduction of functional lung tissue and not by cardiac insufficiency. The complexity of the handling of such patients with additional comorbidities asks for doctors who can deal not only with respiratory insufficiency but also with the protection of other vital organs while the lung needs help to win the fight against the viral infection.
1 Nicholls JM, Poon LLM,Lee KC,et al.:Lung pathology of fatal severe acute respiratory syndrome.Lanct 2003;361:1773-1778
2 Chong PY,Chui P, Ling AE,et al.:Analysis of Death During the severe acute respiratory Syndrome (SARS) Epidemic in Singapore.Arch Pathol Lab Med 2004;128: 195-204
3 Gu J, Gong E,Zhang B,et al.:Multiple organ infection and the pathogenesis of SARS.J Exp Med 2005;202:415-424
4 Nicholls JM,Butany J Poon LM et al. Time course and cellular localisation of SARS-CoV nucleoprotein and RNA in Lungs from fatal cases of SARS.PloS Medicine 2006; 3(2):e27
5 Liu J,Zheng X, Tong Q,et al.: Overlapping and discete aspects oft he pathology and pathogenesis oft he emerging human pathogenic coronaviruses SARS-CoV,MERS-CoV, and 2019-nCoV.J Med Virol 2020 February 13:1-4
6 Huang Ch,Wang Y,Li X et al.:Clinical features of patients infected with 2019 novel coronavirus in Wuhan,China.Lancet 2020;395 February 15
7 Shi H, Han X, Cao Y,et al.:Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan,China: a desciptive study.Lancet Infect Dis 2020;February 24
8 Zhou F, Du R, Fan G,et al.: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan,China: aretrospective cohort study.Lancet 2020;March 9
9 Wang t, Du Z,Zhu F, et al.:Comorbidities and multi-organ injuries in the treatment of COVID-19.Lancet 2020;March 9
10 Zhe X, Wang Y, Zhang J,et al.: Pathological findings of COVID-19 associated with acute respiratory distress syndrome.Lancet Resp Med 2020,February 17.
11 Chien JY,HSUEH PR,Cheng WC et al.:Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome.Respirology 2006;11:715-722
12 Zhou J,Chu H,Li c et al.:Active replication of Middle east respiratory Syndrome Coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages:implications for pathogenesis.J Infec Dis 2014:209:1331-1342
13 Wietzke P, Schott P, Mihm S,et al.:Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection.Liver 1999;19:348-353
14 Chau TN,Lee KC,Yao H, et al.:SARS-Associated Viral Hepatitis caused by a novel coronavirus:report of three cases.Hepatology 2004; 39:302-310.
15Zhang C, Shi L Wang FS.:Liver injury in COVID-19:management and challenges.Lancet Gastroenterol Hepatol 2020 March 4.
16 Ng DL, Al Hosani F, Keating K et al.:Clinicopathological,Immunohistochemical,and ultrastructural findings of a fatal case middle East Respiratory Syndrome coronavirus Infection in the United Arab Emirates,April 2014.Am J Pathol.2016;186:652-658.
Thank the efforts and the generosity of chinese scientists
COVID 19 is now one of seven most common human coronaviruses(HuCoV:229E,NL 63,0C43,HKU1) including SARS and MERS. By using primers derived from the RNA-sequence published by chinese scientists it has become possible to identify the agent causing influenza-like symptoms and advanced pulmonary disease around the world.
The experience of the Diamond Princess cruise ship (1) tells us that 6 patients of 705 infected persons have died.This amounts to less than 1 %.The cause of death, however, has not been determined by autoptic studies.
Furthermore it is not known which investigational drugs have been used in these patients.
In many cases use of investigational drugs, often together with corticosteroids, antibiotics and sedation drugs, not only may be responsible for clinical findings attributed to the virus.
Use of experimental drugs (2) may contribute however to increase the fear of the population and most importantly of the ICU medical and paramedical personnel that prognosis be bad, no matter what measure can be further taken.
This has also negative consequences for psychology of the population and aggravates the fear especially in those areas wehre COVID-positive cases were found.
1.Roköv J, Sjödin H, Wilder-Smith A, COVID-19 outbreak on the Diamond Princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures Journal of Travel Medicine, taaa030, https://doi.org/10.1093/jtm/taaa030Published: 28 February 2020
2.Stebbing J,Phelan A,Griffin I, Tucker C, Oechsele O, Smith D Richardson P.:COVID-19:combining antiviral and anti-inflammatory tretments.Lancet,February 2020
Almost at the same time the Bertelsmann Foundation(05.11.2019) and JAMA(Journal of American Medical Association)Internal Medicine (published online september 9,2019) published data on overuse of the medical system including laboratory testing, radiological testing, medical (over)treatment ( antibiotics in urgent care clinics) and surgical (e.g. thyreoidectomy)interventions.
Both publications came m0re or less to the same conclusions „the findings suggest that many tests are overused,overtreatment is common,and unnecessary care can lead to patient harm“.
Therefore politicians should start a broad information campaign for all workers and employers who pay for health insurance and who sustain the health system.After that they should start to control the system more closely and to reduce expences. May be privatisation of the health care system and adoption of the „american“ DRG-system was not as successful as it was suggested it would be when both were introduced into the european systems more than 15 years ago.In fact now both sides of the atlantic independently from eachother come to the same conclusions:at least one third of the expenses can be avoided and even a better quality of the health care system with less patient harm could be the consequence.
Grote-Westrick,Marion,Münch Inga,Volbracht Eckhardt.Überversorgung schadet den Patienten.BertelsamnnStiftung05.11.2019
Morgan DJ,Dhruva SS, Coon ER,Wright SM, Korenstein D.:2019Update on medical overuse.A Review.JAMAInternal Medicinepublished onlin september 9;E1-7
This is a summary accompanied by some personal comments of a very recent Viewpoint report(Academic medical centers.Too large for their Own Health?) published in JAMA (june 17,2019,E1,E2) by S.Claiborne Johnstone (Dell academic medical school,university of texas,Austin)
1) fully accreditated medical schools(141) in the US not only educate medical students but they mainly „operate clinics and own hospitals“ defined as „Academic Medical Centers“ (AMCs)
It would be interesting to know how the accreditation procedure works.Who decides about the qualification of the teaching personnel and about the scientific quality of the publications? Deans of medical faculties are judged on the basis of the „quality“ of researchers they are able to hire The researchers are judged on the basis of their publications and of their funding.However there is no way to check the quality of the scientific production independent of the scientific journal lobby. More and more researchers within AMCs have not studied medicine.They can not even judge the real impact of their research on medical pathology.
2)56% of the AMCs have annual revenues greater than 500 million dollars.
The crucial question raised by the author is : „have some AMCs grown to large to survive a changing health care system,much less to lead the change required?“
In other words can the AMCs lead the necessary structural(dimension ) reduction by reducing the number of treatments to those really needed?
Or do the economical and occupational constraints dominate the scientific knowledge which seems to suggest that less is more for the comunity?
3)„AMCs generate an estimated 6.3 million jobs and contribute an estimated 562 billion dollars to gross domestic product“
That is to say that each employee contributes with his medical insurance fee to the maintenance of the largest employers in many cities hosting AMCs.
4)„At the same time, academic medicine has contributed to the creation of a suboptimal health system.“
5)„The World Health Organisation ranks the US health care system 37th among countries worldwide,just above Cuba“
6)„and life expectancy has declined in the United States during the last 3 years“.
7)„health care costs in the united states are 25% greater than the second most expensive country and 14-fold greater than Cuba`s“.
That is to say that „scientific progress“ contributes to increased expenses for the health care system but not to prolong life expectancy in a country with the most expensive health care system which, however, ranks just above that of Cuba, still a comunist country. On the contrary,decreasing life expectansy may be also because of an „aggressive“ DRG-based health care system mainly working for profit „.
8) „AMCs are major sources of health care in nearly every US metropolitan area,and costs of care at virtually all AMCs are particularly high“
9)„so there is no denying that they have contributed to the health care system that currentlx exsists“
This is a polite way to express the concept that AMCs,which are supposed to path the way for the rest of the health system by mainly contributing to the medical guidelines, instead of becoming more and more restrictive, are developing toward a growing business branch.This of course influences the consideration given (mostly by the CEOs) to less aggressive and chipper diagnostic and therapeutic procedure in comparison to more aggressive and more expensive tools with a disavantage for the patient. In fact,if the system can not be made responsible for the reduction of life expecatncy,it does not seem to be able to stop this trend.
10)„the shiftng balance of the three major missions of AMCs-education,research, and clinical care-underlies the current challenge“
This is a crucial point. Education and research , existing within the same structure,can not be other than dominated by the economical constraints of clinical care,which forces to rewrite physiology , pathology,diagnostic and therapy toward profit oriented SOPs(standard oerating procedures) combined with ultra short permanence in the clinic.
Internal medicine has become much less important than surgery.
11)„however, the proportion of medical school funding derived from research has declined more recently,with federal grants making an average of 14% of medical schools revenues (Figure),with industry and foundation funding accounting for another 9%.“
12)“ from this perspective,funded research is actually a modest function of medical schools and their associated AMCs.Clinical revenue dearly is the dominating source of revenue at virtually every AMC.“
What we really would like to know is how many AMCs are in private hands,and how much private funding influences non private funding by lobbying work into the review system.How much is the educational system including scientififc society meetings,therapeutic tryials and scientific journals influenced by private interest groups? The continous advertising within the health care system does not make it different,if not even worse than other commercial branches with little possibility of defence for the „consumer“,in this special case, the sick patient.
13)„As greater and greater margins were realized from these faculty clinicians with revenue exceeding costs,more were hired and clinics and hospitals were constructed to support them“
14)“ These trends have accelerated during the last 20 years,with many faculty devoted nearly to clinical care“
At the same time the scientific world is asking itself why is the figure of the physician scientist within the AMCs disappearing ?
15)„Thus many of today`s AMCs are similar to huge tankers loaded with health care services,and research and education are merely passengers“.
The consequence of this developement is much worse.As mentioned above, the chief of administration are the true deus ex machina.They decide about who is going to be hired und who is „disturbing“ the business within the clinical teams. Honest medicine is in the middle of two enemies, the industry and the administrators of the clinical every day life.
15)„there is the crux of the issue :any changes threatening the margins from clinical care will affect the intire mission of an AMC“.
This consideration does not take into account that part of the revenues of the clnical care goes into the pocket of private investors at total disavantage of the fee-payers. This money influences the fate of „honest“ medicine.
16)„Academic medical centers tend to do well in negotiating reimbursement rates from insurers,and they tend to admit patients who require more expensive and invasive interventions.“
This assumption goes back to the time where medical knowledge about tissue damage leading to organ dysfunction was poor and patients with acute or with terminal organ insufficiency made the bulk of the patient population. Conservative medicine has however made giant progresses and many invasive procedures (even oragan transplantation) are much less necessary than it was 20-30 years ago when patient presented with more advanced disease stages.
17) „Thus by necessity,the majority of AMCs are inclined to stay the course of the current health care system.“
18) “ A move to value-based care is more than just risky;it is counter to their best interests unless a clear line of sight to new payment models exists.
In fact so far using the DRG-system no attention was paid to quality of medical treatment as it is not considered by the reimbursement system. For this reason number and quality of the persons involved in treatment was less important than costs.
19)„In the fee-for-service payment system, preventig illness and reducing wasteful diagnostics or unnecessary treatment could reduce the income of AMCs (as well as other medical centers)“.
20)„Although many reports that have described the need to reallocate resources toward prevention,population health, and value-based care come from medical school faculty, the leaders of the AMC clinical enterprise will tend to resist change because it puts the entire institution at risk“.
21)„Faculty can discuss population health and value,but may be stymied from making important progress“.
22)„In this way,academic medicine is not fully aligned wih society´s interest in optimizing health outcomes or in reducing waste.“
23)„To better align with society´s interests,AMCs must reduce their reliance on fee-for -service medicine and the associated pressures to retain market share,raise prices,and increase consumption of health care.“
24)„Instead,they should leverage their expert leaders to develop and coordinate new models of care,focusing on solutions that enhance value„.
25)„If payers are reinbursing for value,the planning and coordination role naturally payed by AMCs could produce revenues that exceed costs.“
26)„Academic medicine could then lead in innovation and coordination of new models of care,being paid for value without necessarily owing all components of the system“.
27)„Academic medical centers should be optimized to enable rapid innovation in health that aligns with society´s interests.“
28)„Getting this alignement right will not be easy,particularly in an industry that has rewarded the traditional fee-for-service model with fairly reliable margins“
29)„Similar to a nimble schooner,an AMC that can alter course quickly and test new waters may be more valuable to society than megatanker,particularly given the narrow straits ahead“.
This would however mean reduction of the number of beds and of the number of employees,which is politically very inconvenient.