SARS-CoV-2-Infection (COVID-19):Clinical Course,viral acute respiratory distress Syndrome (ARDS) and Cause(s) of death.
Prof.Dr. Ramadori Giuliano Pasquale
Unvaccinated but also vaccinated older persons continue to die,after SARS-CoV-nfection, every day, although the infection has been demonstrated to be self-limiting.
Together with local symptoms,such as runny nose and headache, fever is the leading systemic reaction to the local infection.Later,dry cough can also appear.Eight to ten days after the first symptoms, hospitalization may follow, mostly for debilitated patients who may need mechanical ventilation and transfer to the ICU.A significant number of those patients may die during treatment.The most striking macroscopic autopsy finding is a significant weight increase of both congested lungs, as it was observed 100 years ago in victims of the first influenza pandemic,in victims of the asean influenza pandemic 1957 and in SARS-CoV-1 victims 20 years ago.The second most frequent autopsy finding is necrosis of the epithelium of the kidney tubuli as the patognomonic sign of renal fluid insufficiency due to dehydration.Dehydration explains not only the development of respiratory distress, but also appearance of dry cough.Both symptoms cannot be justified by viral damage of the lower respiratory tract as no viral replication has been demonstrated.Death may be due to cardiac failure by hypovolemia.
A sommer story of SARS-CoV-2-Infection after three or four vaccinations in older and frail people.
Domenica 23.07.2022 una sedicenne (3 volte vaccinata con green pass) avvisa mal di gola,mal di testa e innalzamento della temperatura corporea).Il test antigenico per la diagnosi di infezione da SARS-CoV-2 e´positivo.La ragazza si mette in quarantena a casa e tratta i disturbi „influenzali“ con brufen..
per circa 8 giorni. Sara´negativa al test antigenico rapido il 01.08.2022.
Il 24.07.2022, succede la stessa cosa con il suo amico un sedicenne(anche lui vaccinato 3 volte),che accusa gli stessi lievi disturbi e un lieve aumento della temperatura corporea (37,5 C) mentre la temperatura esterna e´di 35 C gioranlieri.Anche lui e´positivo al test antigenico rapido e si mette in quarantena, diventera´negativo il 05.08.22 (senza sintomi).
Il 25.07.2022 la nonna del giovane , 74 anni.in sovrappeso,con asma bronchiale cronica accusa primi lievi sintomi influenzali („naso chiuso“).Il test antigenico rapido per infezione da SARS-CoV-2 e´risultato positivo nel primo pomeriggio del 25.07.2022.Il 26.07.2022 pomeriggio,test antigenico di nuovo positivo.Temperatura corporea 38.C.Suggerimento di iniziare terapia con Tachipirina 1.000 (presunta allergia allaspirina) e con abbondante ingestione di fluidi.Sale la preoccupazione di contagio del marito di anni 77 in trattamento „cronico“ di dialisi bisettimanale con cui condivide l´appartamento di 70 mq.Nel suo caso il primo test antigenico rapido epero´negativo.
Tre ore piu´tardi temperatura corporea della nonna e´di 36 C .
Il 27.07.2022 alle ore 5 del mattino temperatura corporea 38 C,dopo ingestione di tachipirina 1.000. Alle 19.00 dello stesso giorno temperatura corporea 37,5 C, tosse e forte dolore retrosternale.Suggerimento di aumentare la quantita´di liquidi ingerita ma niente terapia antibiotica.
Il 27.07.2022 un giovane di 21 anni ( tre vaccini Moderna),amico della famiglia accusa lievi sintomi alla gola e l´immediato test antigenico risulta positivo mentre il test in farmacia risultera´ripetutamente negativo (sempre presso la stessa farmacia) ; anche lui va`in quarantena,risultera´negativo il 04.08.22 (8 giorni di positivita`)(gli altri 2 giovani risultano essere completamente asintomatici).Due altri amici ventenni tre volte vaccinati rimarranno negativi.
Un amico sessantenne aveva avuto l`infezione con sintomi lievi quattro settimane dopo aver avuto la seconda dose di vaccino mRNA in febbraio 2022 ed e´rimasto questa volta indenne.
La mattina seguente,giovedi 28.07.2022 la „nonna“ non ha piu´ nessuna febbre ma riporta residuo lieve di tosse.Venerdi´29.07.2022 temperatura corporea normale,persistenza di tosse „catarrale“ in ex fumatrice.
Il marito accusa leggero disturbo faringeo,test antigenico rapido positivo.Grossa apprensione per le eventuali conseguenze pratiche per l`esecuzione della prossima dialisi. Suggerimento di stare calmi e bere molto (in soggetto dializzato ma con persistenza di una diuresi di 800-1300 ml`di urina al di) e di prendere acido aceltilsalicilico (400 mg).
Il sabato 29.07.2022 la signora e´diventata asintomatica(„se il COVID e´cosi`´,posso dire che e´come una semplice influenza…io sto` bene.Il problema adesso e´lui“).
Il marito accusa un leggero aumento della faringite in mattinata (raucedine facilmente percepibile durante una conversazione telefonica!) e assume una pasticca di aspirina da 500 milligrammi.
Alle 18.30 persiste la ruacedine come unico sintomo e
assunzione di ulteriori 500 milligrammi di acido acetilsalicilico.Il paziente aveva avuto la quarta dose del vaccino Pfizer/Biontech il 21.04.2022 dopo la terza dose effettuata il 05.10.2021).
Il 30.07,31.07 e 01.08.2022 continuo miglioramaento della raucedine dopo ulteriore assunzione di 500 mg di acido acetilsalicilico (aspirina) e assunzione abbondante di liquidi
con lieve aumento del peso corporeo.Il mattino del 02.08.2022 il paziente viaggia in macchina verso il centro dialisi,viene accolto dal personale fuori dal centro e accompagnato in una stanza apposita per pazienti positivi al SARS-CoV-2. Effettuato trattamento di dialisi (riduzione di peso di 1,5 kg) il paziente torna a casa guidando la macchina senza nessun problema.
Il 04.08.2022 il giovane di 16 anni e´ancora positivo al test rapido come lo sono i nonni mentre il giovane ventunenne e`
finalmente negativo (otto giorni dal primo test positivo).
Il 05.08.22 la nonna risulta negativa (11 giorni dall´inizio die sintomi e dalla positivita´del test antigenico rapido) ma il nonno e´ancora positivo al test rapido (settimo giorno di positivita`). Questa volta la dialisi e´alle ore 14 del pomeriggio (il 04.08 ha preso di nuovo una pasticca di aspirirna 500 mg a causa di un residuo di raucedine).
Il nonno sara´negativo al test antigenico rapido il 06.08.2022
Sommario:
1.Cinque persone di una famiglia 3 giovani e due „fragili“ si sono infettati con il SARS-CoV-2.I giovani (2 sedici anni e uno 20 anni) hanno vuto solo sintomi simili a un lieve raffreddore.
La nonna ha avuto „sindrome influenzale“ con innalzamento della temperatura fino a 38,5 gradi centigradi raffeddore e
lieve tosse.Il nonno ha sviluppato solo raucedine.
2.Il trattamento immediato con assunzione abbondante e continuo di liquidi e con adeguato dosaggio di farmaci antiinfiammatori non-steroidali ha portato alla veloce scomparsa dei sintomi molto simili a quelli di una influenza lieve e al ritorno di una situazione di benessere ne i due individui „fragili“.
Questo non solo ha evitato la progressione dello stato di malessere sia per quanto riguarda le vie respiratorie superiori (naso „pieno“, mal di gola,mal di testa,tosse)
sia per quanto riguarda lo stato generale,niente febbre,niente spossatezza, ne confusione mentale o disturbi gastrointestinali.
3. E´essenziale combattere immediatamente i primi sintomi,quali essi siano ma soprattuto la febbre con semplici farmaci „antiinfluenzali“ in dosi adeguate fino al raggiungimento della scomparsa dei sintomi stessi (Tolleranza zero,hit fast and strong).
In questi periodi ognuno dovrebbe avere a casa una riserva di
farmaci come Tachipirina (pasticche da 1.000), Aspirina (pasticche da 500 o 1.000).Aspirina deve essere presa sempre con un grosso bicchiere di acqua e se possibile non a stomaco vuoto.
In questo modo diventa superfluo un trattamento antivirale che deve rispettare
alcuni limiti concernenti l´interazione di questi con altri farmaci ( )
Essenziale e´la continua assunzione di liquidi (naturalmente
niente alcoolici) .Per evitare conseguenze negative sulla pressione arteriosa potrebbe essere consigliabile ridurre temporaneamente la dose di farmaci antiipertensivi.
1.16 anni femmina;positivita`9 giorni
2.16 anni maschio „ 12 giorni
3.21 anni maschio 8 giorni
4.74 anni femmina 11 giorni
5.77 anni maschio 8 giorni
Tutti sono rimasti in quarantena fino alla negativizzazione del test antigenico rapido.
CONCLUSIONI
a)línfezione da SARS-CoV-2 e`stata „introdotta“ nel gruppo da una 16dicenne.
b)le due persone „fragili“ erano vaccinate e hanno avuto sintomi non distinguibili da una „sfreddatura“ o al massimo „similinfluenzali“.
c) in questi i sintomi sono scomparsi dopo immediato trattamento con farmaci antipiretici/antiinfiammatori in quantita´sufficiente a far scomparire in sintomi in tempi brevi(1-2 giorni).
d) il test antigenico rapido sembra essere affidabile nell´identificare le proteine del coronavirus (diagnosi iniziale) e nel determinarne la scomparsa prima della PCR ,che si negativizza piu´tardi.
e)si dovra´discutere sulla lunghezza della quarantena dopo la indotta scomparsa dei sintomi.
Letteratura:
1.Ciotti M et al.Performance of a rapid antigen test in the diagnosis of SARS-CoV-2 infection.J Med Virol 2021;93:2988-2991.DOI:10.1002/jmv.26830
2.Chu VT et al.Comparison of home antigen testing with RT-PCR and viral culture during the course of SARS-CoV-2 infection.JAMA Intern Med.doi:10.1001/jamainternmed.2022.1827
3.Cosimi LA et al.Duration of symptoms and association with positive home rapid antigen test results after infection with SARS-CoV-2.JAMANetwork =pen2022;5(8):e2225331.DOI:10.1001/jamanetworkopen.2022.25331.
4.10 ways to treat flu symtoms and feel better.https://vicks.com/en-us/treatments/how-to-treat-the-flu/how-to trea
5.Duda K.the difference between cold and flu.verywellhealth.https://www.verywellhealth.com/cold-flu-overview-4014743?print
6.Erlikh IV,et al.Management of Influenza:Am Fam Physician.2010;82(9):1087-1095.
4.Hammond J et al.Oral Nirmatrelvir for high-risk,non-hospitalized adults with Covid-19.N.Engl J Med 2022;386:1392-1408
5.Chamess M et al.Rapid relapse of symptomatic omicron SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir.Research Square.DOI:/10.21203/rs.3rs-1588371/v3
6.Kuehn BM.News from the centers of disease control and prevention.JAMA 2022;328(4):323
8.Ramadori G: Comment Differences Between Bacterial vs Viral Infections With Consequences for Treatment of SARS-CoV-2.JAMA June 8, 2022. doi:10.1001/jama.2022.9925
9.Simieniuk RAC et al.Drug treatments for Covid-19:living systematic review and network meta-analysis.BMJ 202;370m2980.DOI:101136/bmj.m2980
1o Frantzen L et al.COVID-19 vaccination in haemodialysis patients:good things come in threes…Nephrol Dial Transplant (2021) 36:1947-1949.DOI:10.1093/nd/gfab224.
11.Hsu C et al.Seroresponse to third doses of SARS-CoV-2 Vaccine among paients receiving maintenance dialysis.AJKD2022;80(1):151-153
12.Karoui K et al.COVID-19 in dialysis:clinical impact,immune response,prevention,and treatment.Kidney International 2022;101:883-894.DOI:10.1016/j.kint.2022.01.022.
As a person belonging to the so called frail population because of age over 65 and with comorbidities (hypertension and overweight), I underwent triple vaccination with the mRNA-Pfizer-Biontech vaccine (the third dose was administered on 10.11.2021).I could fly and also move around by train (always using a face mask).
It was understandable that a fourth vaccination at the beginning of the spring and of the summer would not make very much sense.However although the offically number of recorded infections was decreasing,everybody knew somebody in the own family and in the „enviroment“,who was affected by the infection although fully vaccinated. Less attention was payed
to wearing face masks especially in crowded interiors such as restaurants.
Three days after a nice dinner with some wine(saturday 11.06.2022),which lasted about three hours with friends a mild but fastidious headhache began to occupy my imagination. I tried to understand the cause.I was feeling a vey mild sore throat when my friend called me to tell me that he was running a fever and that he was found to be SARS-CoV-2-positive.His wife was at first negative with no symptoms.She became later positive and had mild running nose only.
He asked me for therapeutic suggestions although he had alreasdy consulted several doctors. It was strange,“if you have fever you have to take antibiotics“ he was advised.
He also got prescribed vitamin D,C an B and nimesulide (Aulin) as an antiinflammatory drug.
I explained to him that there is no reason to take antibiotics and suggested abundant fluid intake.While discussing with ihm, I realized that I also was developing the full blown picture of a flu.In fact, my nose became closed by increasing intranasal pressure and my headhache became stronger.I started to take aspirin pills (500 mg/each) and to lay down and rested.Always accompained by a 1.5 liter bottle of water.
The SARS-CoV-2 Antigen Rapid Test was clearly positive, while my wife´s was negative.Body temperature was around 37 degree Centigrade.I continued to eat and drink abundantely.
After two days of taking 2gr Aspirin/each, symptoms improved substancially and I stopped to take aspirin on the third day.Symptoms continued to improve on the third day (wihtout Aspirin).On the day 4 in absence of symptoms the rapid antigen test showed a significant decrease of the viral antigen in the nose.My wife`s test continued to be negative.I decided to continue to stay home and to perform a PCR-analysis on next monday.
SARS-CoV-2 Antigen Rapid Test(WITZBIOTECH) clearly positive at the day of symtom´s beginning (14.06.2022)For two days 2 grams/day (13-14.06.2022)
SARS-CoV-2 Antigen rapid test shows a significant reduction of the viral antigen on the second day of recovery from the flu-like symptoms
Rapid antigen Test 15.06.2022The rapid antigen test continued to be positive on the 18.06.22
PCR-analysis of the nasal RNA was positive on the 21.06.22 wit a CT-value of 33 (JAMA Intern Med. Published online April 29, 2022. doi:10.1001/jamainternmed.2022.1827). At the same day IgM anti-spike were not detectable while IgG -antibodies against the RBD of the spike protein were measurable (620,4 Binding Antibodies Unit/ml serum 6Vol:.(1234567890)Scientific Reports | (2022) 12:8679 | https://doi.org/10.1038/s41598-022-1275).The rapid antigen test was still positive on friday 24.06.22
and definitively negative (LUNGENE) on saturday 25.06.22
Montegiorgio (FM),Italy ,saturday ,June 25th
Summary:
1.Infection with SARS-CoV-2 has happened in a 70 -year-old person with comorbidities 8 mounths after the third mRNA-vaccination (Pfizer/Biontech).
2.Flu-like symptoms (headasche,runny nose and mild jount pain) occurred on the third day after infection
3.one day after beginning of the symptoms rapid antigen test was clearly positive
4.immediate beginn of anti-inflammatory therapy with aspirin , 2 grams/day.
5.After two day of therapy accompanied by aboundant drinking (>3 L /day)
symptms had disappeared.
6.Antigen rapid test was still positive as it was the PCR-RNA-test (CT=33)
7.Immunoglobulin M antibodies were not detectable before 10 day after infection and
8 days after apparence of first symptoms.
8.Antigen rapid test was negative 14 days after infection and 11 days after symptoms started.
QUESTIONS:
1.if the first action to take is immediate reduction of symptoms (especially fever,headhasche,joint-pain) may just aspirin be the first choice drug in consideration of the low diffusion and accessibility of antiviral drugs(ANNALS OF MEDICINE 2022, VOL. 54, NO. 1, 516–523 https://doi.org/10.1080/07853890.2022.2034936) ?
2.why does it take so long for IgM to become detectable after 3 vaccinations?
3.were the IgG-antibodies pre-existent before infection?
4.do I need a forth vaccination or does it make sense at all? (see recent publication in JAMA JAMA Intern Med. Published online June 23, 2022. doi:10.1001/jamainternmed.2022.2658 )
SARS-CoV-2 infection of the upper respiratory tract continues to cause hundreds of deaths every day worldwide.Most of the efforts, however, continues to concentrate on avoiding transmission of the virus and on vaccination to prevent infection transmission.Both measures seem not to be enough. What is the clinical consequence of the entry of the virus into the nose? Flu-like symptoms and fever of different lenght at first.In the second phase respiratory distress can develop,which is the most important reason to seek help in the emergency room of an hospital even when the virus titer in the nose has already started to decrease. Laboratory changes such as moderate elevation of serum level of inflammation markers,like C-reactive protein,interleukin-6 and interleukin-8 but not of the classical sign of bacterial infections,increase of granulocyte number, are the characteristics of this viral infection. The main acute-phase mediator Interleukin-6 , responsible for the increase of serum level of the chemokine interleukin-8, mainly produced by the main liver cell,the largest cell of the body the hepatocyte, are considered to be „pro-inflammatory“ mediators.This definition is not appropriate and suggests that therapeutic interventions with the aim to inhibt their production,such as corticosteroids administration should be helpful to cure the acute viral infection.However the opposite is true. Interleukin-6,massively produced at the site of tissue damage,and reaching the liver trough the blood circulation, is one of the main component of the defence apparatus of the body aiming to eliminate the cause of tissue damage and to initiate the repair process by inducing a massive change of protein synthesis in the liver („acute-phase modus“).These proteins are called „positive acute-phase proteins“.Beside coagulation- ,complement- proteins and anti proteases, chemokines like interleukin-8 belong to the different groups of those proteins each with a special task,locally at the site of tissue damage and systemically (e.g.production of granulocytes in the bone marrow) within the defence system.In some cases an acute phase situation can take place within the liver itself when the clearance capacity of the hepatic tissue macrophages is overwhelmed and massive cytokine and chemokine-production is started in the liver.Also in these cases is inhibition of this production not the appropriate therapeutic measure to clear the cause of tissue damage which can even simply be dehydration and hypoxia after the virus being already eliminated.As corticosteroid therapy is sometimes initiated at an early time after infection,suppression of release of acute-phase cytokines by macrophages, may even cause a delay of viral clearance.The same holds true for the attempts to reduce the effect of interleukin-6 by administration of specific antibodies. https://lnkd.in/eGa2SpBe
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.
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 ReportedCOMMENT:
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 ReportedCOMMENT: 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 ?
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
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 ReportedCOMMENT 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
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
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,
JAMA 2020;324(2):131-132
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.
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.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,
Immunol&Infect.2020.
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.
REFERENCES
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.
REFERENCES
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.
