April 30, 2020



This is the second of a series of Covid-19 newsletters from FDIME (Foundation for the Development of Internal Medicine in Europe). The aim of the newsletters is to present qualified answers to the public, specifically on issues in which internists have a saying.
FDIME is a non-profit organizations, which aims to improve medical care for patients in Europe and has several activities promoting medical research and medical education of young European specialists in internal medicine. FDIME supports young internists to attend the European School of Internal Medicine, participate in the European Exchange program and also provide grants for research in Internal Medicine.

You are also invited to pose additional questions, which we can try to answer in one of our next newsletters.

1Question: Are wearing masks and social distancing presently necessary to prevent infections?

Covid-19 is mainly transmitted via droplets produced by coughing, sneezing or even speaking at close range. Maintaining a distance of 1 - 2 meters between people is generally considered as a sufficient safety measure. But distancing is not always possible and wearing a mask (surgical or cloth) when being in public areas or transports or confined environments is a good solution. These measures are still recommended in most European countries at the end of May 2020 particularly in regions with a high number of infected persons. These recommendations are particularly important for elderly persons and all those with a high risk of developing severe complications such as people with cardiac or pulmonary chronic diseases, immunodepression or morbid obesity. There is no reason wearing a mask if you are walking alone or with your family in the countryside. Epidemiologists are monitoring the evolution of Covid-19 new infections and will inform national authorities when these preventive measures are no more necessary.

2Question: The internists and telemedicine in times of Covid-19.

Telemedicine, initially limited to the care of sick people in remote areas or on ships, is more and more widely used to avoid transporting patients. The wide spread of smartphones, tablets and computers equipped with cameras facilitates telediagnostics and even teletreatments. The outbreak of Covid-19 epidemic has provoked a sudden afflux of patients to medical clinics, emergency rooms, hospital wards and Intensive Care Units. Remote care through telemedicine has been an extremely efficient way to avoid displacements, limit contaminations and shorten hospital stays. Patients data can be transmitted electronically. The physician can talk with the patient and interact visually thanks to a camera if necessary. Internists have been widely active in the care of Covid-19 infected patients through telemedicine, in particular for their patients with chronic diseases. In a crisis like the Covid-19 outbreak, hospitals and healthcare professionals are rapidly overwhelmed. Telemedicine allowed retired doctors to be immediately involved working from home in continuity with hospital and primary care doctors. The wide range of expertise of Internists was an advantage in the evaluation and care of patients with complex situations due the different complications of Covid infection itself and their previous medical condition.

3Question: Which organs are affected the most?

It is well-known that the lungs, or more precise the respiratory system, are affected by Covid-19 the most. Especially in critical ill patients there are bilateral infiltrates (Pneumonia), sputum is gathered in infected lung vesicles, which makes breathing difficult. Also pulmonary emboli (in the context of general clotting abnormalities) may occur and worsen the disease. Ultimately Acute Respiratory Distress Syndrome (ARDS) is the result in critically ill patients. In mild cases which are the most frequent higher respiratory symptoms may be seen as in flu or a common cold, including sore throat, fatigue and fever. Possible virus-induced damage of the nerve endings in the nose and the olfactory bulb in the brain cause altered smell and taste. Involvement of the brain may furthermore result in headache, dizziness, confusion, fit or stroke, perhaps caused by overaction of the immune system or bloodclots. Sore eyes or conjunctivitis has been reported Blood clots can arise , and also inflammation of the heart or a heart attaque, resulting in decreased blood circulation in other organs. Gastrointestinal symptoms are rather common, such as diarrhea, nausea, vomiting, anorexia and abdominal pain. This is because there are certain receptors (ACE 2 receptors, specific receptors at the surface of cells which regulate dilatation or contraction of small arteries. The virus uses these receptors as keys to enter and infect human cells) in the intestines at which the virus can act. Also the liver can be attacked by the virus through overreaction of the immune system and after the use of medicaments such as chloroquine. In the kidney there are Angiotensin Conversion Enzyme 2 receptors (see above) too, so the virus is able to damage the kidney. Finally, muscle aches and joint pain and even rapid breakdown of muscles (rhabdomyolysis) have been encountered.

4Question: What will be the expected road ahead now that the peak of the pandemia, at least in Europe, seems to have been passed?

Now that the peak number of infected persons, ICU (Intensive Care Unit) admissions and deceased patients, at least in Europe, might has been passed, it is wise to consider what the key points are for the risk of a new outbreak. Although many research groups all over the world are working hard to develop a vaccin, this probably will take at least 6 months, a year or even longer. Also effective medical treatment is far away. In many European countries a new phase of “open-up” has now begun. This means that, although measures have become less strict, a normal open society is not yet possible. Main restrictions still applicable are social distancing (variable per country 1 – 2 m) and travel restrictions. In busy places, for instance public transport, mouth masks are compulsory. People are still advised to work at home if feasable and sick people should stay home in quarantaine. It is not the expectation that higher temperatures as in summer will extinguish the virus. Auto-immunity of the population could help to prevent a new outbreak, but until now only a very small part of the people has acquired auto-antibodies against the Corona virus matching with auto-immunity. It is also probable that part of the population has acquired antibodies against other corona virus species from previous infection and are totally or partially resistant to Covid-19. As for now the reproduction number R (number of people infected by a single infected person) in most countries is well below 1, which means that one Covid-19 patient does infect less than one other person. If, for instance caused by the alleviated measures, this reproduction number will rise again and more sick patients are expected, all measures will be reinstated and a lock-down might be inevitable. However, before that it will be tried to localize the new hearth, to trace all contacts and then quarantaine those who will test positive. It is obvious that ample testing is crucial here.

5Question: What did we learn about treatment of severe/critical Covid-19?
We do know now that a couple of medicines are not as useful as some people have thought. (Hydro)chloroquine does not work and corticosteroids may increase mortality and length of ICU (Intensive Care Unit) stay and predispose for bacterial infections. On the other hand, in an advanced stage of the disease, the so-called  ARDS (Acute Respiratory Distress Syndrome), corticosteroids might be helpful. Antiviral agents such as the combination lopinavir-ritonavir do not provide benefit. Remdesevir, however, another antiviral agent, shortens recovery time (ICU admission period) with 4 days in hospitalized patients requiring oxygen. Moreover, clinical improvement was seen in about two-thirds of patients. It should be started before mechanical ventilation/intubation. It appears that 5 days treatment is as good as 10 days. It is expected that combination therapy will be more successful, but for now there are no data about that. In severely ill patients thrombo-embolic complications, caused by clotting problems, are observed in a higher frequency than in similar non-Covid-19 patients. Inflammation causes increase of cytokines and subsequent increased production of clotting factors in the liver. In critically ill patients thrombo-embolic complications include mainly pulmonary embolism, but also deep venous thrombosis, strokes, heart attaques etc. Therefore it is debated whether thrombosis prophylaxis therapy should be increased or that therapeutic anticoagulation has to be prescribed. At least it is advised to look for thrombotic complications, especially pulmonary embolism, through CT scanning in case of persisting or aggravating pulmonary symptoms.  Recent research, moreover,  suggests that Covid-19 patients on the ICU have extremely low vitamin K levels. Vitamin K is important in the inhibition of clotting, so a shortage may lead to an increased risk on thrombosis. Two anti-inflammatory drugs, used in rheumatoid arthritis and lupus, tocilizumab and anakinra  decrease the intensity of the cytokine storm leading to severe tissue damage as may be seen in Covid-19 patients (see also earlier). Another possible last-resort measure is the administration of inhaled nitric oxide (NO). This vasodilator and bronchodilator, already in use in pulmonary arterial hypertension, has been used successfully in Covid-19. It might even have an antiviral effect. More controversial still is the administration of convalescent plasma in critically ill patients. The plasma contains neutralizing antibodies, which may induce improvement. Results of small studies, however, are preliminary. Although many uncertainties still exist, we may conclude that we have learned that there are many possible ways to better treat severely ill Covid-19 patients and that their prognosis will improve thanks to improved medical care.
6Question: What is done to accelerate the development of treatments and vaccines?

The development of a new medicine takes in average ten years and costs more than 2 billion US dollars. The process starts with the discovery of a new compound aimed at the cure of a certain condition in the laboratory. Then the potential medicine will be tested for safety on animals. If these previous stages have been successful, the sponsor (usually a pharma company) will ask for authorisations to start clinical development. When a green light is obtained the drug can be tested on humans. The first phase is an administration to 10 to 100 healthy volunteers, mainly to evaluate safety and the absorption and elimination of the drug in the body: this will take at least one year. The following steps will be phases II and III which are basically a succession of Randomised Clinical Trials comparing the outcome of patients treated by the new drug with others receiving an existing treatment or a placebo. Both efficacy and safety are evaluated. This will involve in average of up to 3000 patients and take several years. If the efficacy is confirmed and the side effects moderate and acceptable, the company will present a request to the FDA in the US or the EMA in Europe for a marketing authorisation. This will take at least a year; Then the drug can be manufactured and marketed. Two other important issues will be discussed at the national level: price and conditions for reimbursement by the health insurances.

This long process can be shortened for innovative medicines like in orphan diseases (diseases with no available treatment), life threatening conditions (it has been done for AIDS, cancers, etc) or in crisis like the Covid-19 pandemic.

The classical randomised Clinical Trials may for example be replaced by adaptive trials in which the comparison between the groups is rendered faster. There are also trials which permit to compare several potential treatments in parallel, permitting an important gain of time.

The EMA has put in place a “fast track “development specially for Covid19 treatments and vaccines.  Every step of the process development is accelerated thanks to a collaboration between the sponsor and the EMA. There is a similar plan in the US.  A considerable amount of money has been invested in research by companies or given by governmental national and international organisations.  Scientific and medical journals are giving immediate and free access to papers dedicated to Covid-19: this never happened before.

An existing medicine may be considered as potentially effective after observation of a possible better outcome of patients receiving it. This was the case with hydroxychloroquine (Plaquenil) combined or not with an antibiotic (azithromycin) in Covid-19 infected persons. In this situation there is no need to remake the whole process of drug development to evaluate safety, which should not be different from what is already known. But the efficacy remains to be confirmed by a comparative trial.

What happened during the last months is that under the pressure of the crisis and the lack of alternative many organisations have given a provisory authorisation to hydroxychloroquine. But today, as no evidence of benefit of has been produced and side effects are not uncommon, the authorities are withdrawing their authorisation. It must be noted that the enthusiasm produced by the promotors of treatment by hydroxychloroquine has delayed the realisation of controlled studies because patients were reluctant to accept the risk of receiving a placebo.

Several new antivirals are presently tested, alone or in combination, as well as anti-inflammatory medicines, antibodies or other immunotherapies. Besides, numerous other treatments aimed at treating the numerous complications of the infection are put in clinical research.  There are currently in the world more than one thousand clinical trials dedicated to research on treatments or vaccines against Covid-19.

The Foundation for the Development of Internal Medicine (FDIME),

Daniel Sereni, Ramon Pujol, Ewa Biskup, Jan Willem Elte.

With the help of Imad Hatem, Nica Cappellini, Lorenzo Dagna, Chris Davidson, Runolfur Palsson, Stefan Lindgren, Vereny Briner, Werner Bauer (in random order).