14 days. The quarantine period is set to be so long and strict so that nobody who is infected escapes detection. Could it be made shorter? The German authorities have published two quarantine periods, 8 days for health-care workers (they are described as “relevant” for keeping the health “system” up and running) and two weeks for other people. Surprising.
Daily news bulletins are reporting about the statistics of the disease. At the beginning of May 2020, the worldwide registered number of cases was close to 3 million, and the death toll was close to 200,000 cases.
Disease
Influenza starts with high fever, muscle pain, joint ache, runny nose, headache and rapidly increasing viral loads, virologists call it titer. Therefore, one of the drugs against influenza, Tamiflu, which blocks the enzyme neuraminidase and prevents the virus from leaving an infected cell, has to be taken immediately, on the first day — otherwise the virus titer becomes so high that the dose of the drug is no longer sufficient to stop the virus. A vaccine and the drug are often overestimated as a major advantage of Influenza — but many people do not get a vaccination and the drug has only a small therapeutic window.
Yet, this is different with CoV-2, where we do not have anything.
About 80% of the patients initially have fever. It is a matter of controversy whether this is a useful indicator, as routinely used in Asia but mostly ignored in Europe. The fever can fluctuate, with body temperature even going below normal. Then the result may be a “wrong-negative” one. Other indicators are dry cough, shortness of breath, joint and muscle ache, headache and a sore throat. These symptoms overlap with those of flu, but runny noses and stuffy sinuses are less common. The disease starts as atypical lung disease. Some people start with diarrhea and nausea, which can persist for some time. Recently, loss of taste and smell are sometimes the only early symptoms. Also, blue spots on the toes are regarded as an early indicator of infection, especially in younger people.
After about a week, the patient’s condition can improve or it can deteriorate abruptly, with increased shortness of breath or dyspnea (extreme breathlessness). It is possible that these patients have cleared the first viral attack, but then progresses to a hyperinflammatory condition with life-threatening pulmonary involvement. Immune reactions cause so-called “cytokine storms” and the release of inflammatory cytokines far beyond what is needed for an immune response. Thus, people may die of their hyperreactive immune system, activated by the virus.
The risk factors for this are unknown. However, diagnosis of cytokine storms is possible, by a serum ferritin blood test, and therapy could involve anti-cytokine drugs against interferon-gamma and Interleukin-6 (IL-6). Yet the use of immunosuppressive drugs for a patient fighting a viral infection appears counterintuitive, and may indeed be dangerous and need controls. Such cytokine storms were described as the major cause of death in the Influenza pandemic of 1918. Patients suffering from this may require respirators and treatment in intensive-care wards, sometimes with intubation for long periods. This can be harmful for the lung, among others by mechanical stress or muscle atrophy, and leads to the death of about 25% of patients.
The lung’s “respiratory tree” ends in tiny air sacs, called alveoli, which have been shown to be rich in the ACE-R receptors used by the virus. Normally oxygen crosses the alveoli into the capillaries, but this oxygen transfer is disrupted by both the virus and the immune system fighting against it. Oxygen is then required. Some patients, about 20%, seem to suffer from deterioration of the heart and blood vessels and from heart arrhythmia. Others have high levels of blood clots, which can land in the lungs, blocking arteries and resulting in pulmonary embolism. Pathologists were the first to report about it, they tested corpses, ignoring the risk of getting infected. Thrombosis may be a major cause of death and would have to be treated with anticoagulants. Here the risk-benefit ratio has to be judged because reduced clotting could also result in bleeding. Thus, the blood vessels, rather than the alveoli, may be the problem. The risk factors of patients are surprisingly diverse, comprising high blood pressure, diabetes, obesity, hypertension, cardiovascular diseases, and even the kidney and the brain can be affected. Put simply: patients die of their own immune response against the virus, not primarily of the virus itself!
“Young and middle-aged people barely sick are dying of strokes” was a headline in the Washington Post (April 25, 2020). A related, and surprising, observation was made in a cancer clinic in Hamburg, where COVID-19 was being treated. The cancer patients receiving immune-suppressive drugs showed only weak symptoms, suggesting that low immune responses may be protective. The doctors even wondered whether this might also be the reasons why children do not get sick — because they still have low immune responses (Frankfurter Allgemeine Zeitung (FAZ), May 3, 2020). There are so many unknown mechanisms, and these all require systematic analyses, and not just case reports, even though the latter can give important hints about possible therapies.
This severe final stages of COVID-19 differ from final stages of Influenza, and lead to suffering for the patients and a heavy burden on healthcare workers. This is the reason for keeping the curve of new infections flat by imposing shut-down measures. This has not been a topic for recent Influenza outbreaks. COVID-19 is often compared to the Influenza epidemic of 2018, when in Germany 25,000 people died of Influenza and 300,000 were infected; even so, this did not receive much attention either in the press or with the public. According to the WHO, every year the seasonal influenza epidemic results in an average of 3 to 5 million cases of severe illness and 300,000 to 650,000 respiratory deaths worldwide. This passes by almost unnoticed! The difference is that most Influenza patients recover after a week or two and if not depend less on respirators required by COVID-19 patients.
Severe COVID-19 disease affects mainly the elderly. Among infected persons aged 70 to 80 years, 14% become very sick; these patients often also suffer from comorbidities such as coronary heart disease, diabetes or lung disorders. 6% of these need intensive-care treatment. The average age of patients who died in Italy was about 79 years, and 87% of the fatal casualties were older than 79 years. Another 10% of patents are hospitalized without such severe symptoms, and the remaining 80% — with an average age of 45 years — have much milder symptoms or even none. People of this age range may be important for maintaining the economy. Also, they may or should be the ones, which help to build up the necessary population immunity. Children falling ill much more rarely, and may be less efficient spreaders of the virus than was initially assumed. Very rare cases of a heart disease, Kawaski disease, have been described.
The mortality rate of seasonal Influenza is about 0.1 to 0.2%. The death rate associated with COVID-19 was estimated by the WHO in mid-March 2020 to be 0.7 to 2.9%, depending on location (cities versus rural areas), age, and comorbidity factors. I think an important parameter may be the initial viral dose — which needs to be proven. There is presumably a large number of asymptomatically infected people who go unreported. Possibly, as many as 10 times more people get infected than we at present assume. The initial infection rate of a population is highly relevant for the steepness of the exponential growth curve. The pandemic in Italy and Spain may have started with infection-spreading at football matches, leading to high initial numbers of cases and subsequently a steep increase in infection rates. In contrast Germany was lucky with an identified case zero and immediate actions taken.
History of SARS CoV-2
The first cases of a new atypical lung disease were noticed in November 2019. Some newspapers mention the 17th of November 2019. The ophthalmologist Li Wenliang, in Wuhan, was one of the first to notice a SARS-like disease, and he tried to warn his colleagues. He later passed away at the age of 34. The Chinese government informed the WHO on December 31, 2019, when 41 patients had fallen sick with an atypical pulmonary disease between December 8th and January 1st. No patient had died yet. Patients had fever (90%), dry cough (80%), shortness of breath (20%) and dyspnea (15%). Seven of these patients later died.
Already on January 7th the virus from Wuhan had been sequenced and on January 12th the sequence was published. This took less than a week in Wuhan. One of the best virology institutes in China is located there, the Wuhan Institute of Virology (WIV), with the highest-level