It has been two and a half months since the discovery of the first coronavirus patient in Israel on February 27. During this period the focus has been on counting the sick, the tests and the ventilators, along with the mathematical models, the scenarios and the directives.
Meanwhile, the medical teams have faced the sharp edge: patients afflicted by a pneumonia that sometimes leads to multiple organ failure – and in about half the worst cases to death. These teams had to learn on the job. They scanned scientific studies and drew insights from the medical community both at home and abroad.
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Still, the gaps in the information about COVID-19 left a lot of room for interpretation and each hospital became a research and experimentation center in treating patients. At least 15 different treatment protocols, coming from various places around the world, were adopted and replaced at the hospitals.
The crisis is still far from the summation stage, even as the number of new cases per day in Israel has fallen into the low double-digits. However, in the lull following the first infection wave, the doctors have time to look back.
Above all, every pandemic is a race against time, whether in stopping the spread of the disease or treating individual patients. Many doctors admit that COVID-19 surprised them and that it doesn’t resemble anything they ever encountered.
“At first we thought it was a kind of flu because you see that as with the flu, most people infected get well and recover without complications,” says Dr. Khetam Hussein, head of the Infection Control Service and the coronavirus unit at the Rambam Health Care Campus in Haifa.
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“The clinical picture of the seriously ill also looked similar, or at least we thought so at first. But as you’re treating people, you discover that it has a characteristic very different from the flu.
“At a certain moment the progress of the illness becomes very violent. Within a single day the patient deteriorates and enters a situation of multiple organ failure, which damages the lungs, liver, kidneys and heart.”
Dr. Shaul Lev heads the intensive care unit at Hasharon Hospital of the Rabin Medical Center in Petah Tikva. Hasharon was converted into a facility treating coronavirus patients only. In recent weeks, Lev and his colleagues noticed a pattern of deterioration among the gravely ill, about 3 percent of COVID-19 patients.
“In them, on the eighth or ninth day of the illness, the disease begins a process of lung damage in which there are two elements,” Lev says. “At this point the patients experience an overreaction by their immune system that causes severe bilateral pneumonia.”
Research and science
The urgent need to know as much as possible about the coronavirus and COVID-19 has led doctors to a place they dwell in normal times: the scientific literature. Still, the physicians quickly discovered that it’s hard to rely on the wealth of information that was published quickly.
“One thing that has characterized the coronavirus crisis is the huge amount of scientific garbage that has been disseminated,” Lev says.
For example, many articles that influenced the treatment of the illness were later criticized, in part because of dubious research methods, the absence of suitable control groups and the publication of far-reaching conclusions based on very small groups of patients.
“In the time of the coronavirus, articles have been published that wouldn’t have been published in other times, because of the pressure,” Hussein says. “In normal times researchers have to sweat blood for their articles to be accepted.”
But she believes that the trend will change, with the publication of more in-depth research papers.
Swab tests – polymerase chain reaction tests, or PCR tests – are the main tool for diagnosing COVID-19. But this method suffers two crucial limitations.
First, a PCR test provides a picture of the situation the moment the test is done. Thus a negative result on the day of the test won’t necessarily be valid the following day. The second problem is that reliability is estimated at only around 70 percent.
This triggers dilemmas; for example, when deciding whether to hospitalize a patient with coronavirus symptoms at a coronavirus unit or a general unit.
“We encountered patients with a classical coronavirus clinical picture, sometimes also people who arrived from abroad who came out negative in the swab tests,” says Prof. Dror Mevorach, head of the coronavirus unit and the Rheumatology Research Center at Hadassah Medical Center in Ein Karem, Jerusalem.
As the crisis progressed, the doctors had to find solutions to the unclear science of diagnosing COVID-19. They started doing additional tests, among them antibody (serological) tests as well as bronchoscopy tests, which involves the taking of fluid samples from the lungs.
In addition, at some hospitals such as Hadassah Ein Karem and Sheba Medical Center at Tel Hashomer, units were opened for patients suspected of having COVID-19. They were isolated from both coronavirus patients and other patients.
From the start of the coronavirus outbreak, it was clear that the main manifestation was damage to the respiratory system. In some cases respiratory support has been needed for two weeks or more. In the most severe cases, some patients need so-called extracorporeal membrane oxygenation – ECMO – which buoys the heart and lungs.
“At the start of the outbreak the prevailing method, which came from China and Italy, was that the severely ill patients should be ventilated as quickly as possible,” says Dr. Yonathan Shapira, head of the coronavirus department at Shamir Medical Center.
“Today we realize that this isn’t necessarily right. We’ve also learned that you don’t have to rush into employing invasive ventilation methods. Eventually we began to use less invasive methods, and we had success.”
Prof. Mevorach of Hadassah, too, notes the change in the approach to timing ventilation. “At first we had the impression that it was best to ventilate patients quickly, but now it appears preferable to postpone it as much as possible,” he says, noting that “intubation is violent for the lungs, which could worsen some of the phenomena.”
Mevorach adds that as the crisis proceeded, doctors realized that not all patients were alike. “Today we know that there are at least two subgroups of patients who represent a somewhat different pattern of the illness and need different treatments,” he says.
In the group of severe cases, some have symptoms similar to those suffered by mountain climbers. “The difference is very significant,” he says, noting that in “mountain climber” coronavirus patients ventilation must be done a different way. “Incorrect treatment could worsen the patient’s situation.”
Lev of Hasharon Hospital adds: “We’ve learned that you can manage the ventilated patients, but it’s difficult. This requires many resources and a lot of skill on the part of the team, so the smart thing is to identify the patients who are going to deteriorate and create treatments that will prevent the inflammatory deterioration.”
So far, a number of medications have been used at hospitals for COVID-19, some of them experimental. In fact, sometimes the knowledge and experience has been meager and the doctors have been gambling. Eventually, some drugs have been eagerly adopted and then discarded; treatment changed on the fly.
“The problem is that there wasn’t sufficient data on the efficacy of the medications,” says Prof. Shlomo L. Maayan, an infection control specialist at Barzilai Medical Center in Ashkelon.
“Each medical center had to draw up its own treatment protocol that determines what you do with a patient in medium to grave condition. Right from the very start there were unfounded protocols based on studies that weren’t controlled.
“This is a mistake because without control groups it’s very hard to know whether it was the treatment that helped the patient or the natural progression of the illness in which many patients recover spontaneously. So a doctor gives a medication, the patient recovers and the doctor is convinced that the treatment worked. But this is a bad mistake when it comes to a new disease that there isn’t enough information on.”
Maayan says the difference between the treatments at the various hospitals depends to a large degree on who’s making the decision. “An expert on infectious diseases or intensive care or an internist – each will have a different point of view,” he says.
Thus, for example, many Israeli hospitals began to treat parents with chloroquine – or the more advanced version, hydroxychloroquine – an antiviral intended for malaria whose efficacy hasn’t been proved. Sometimes it was combined with the antibiotic azithromycin, but soon enough it turned out that the combination could cause life-threatening changes to patients’ heartbeats.
“We don’t have a magical treatment for the viral element of the illness,” says Lev of Hasharon Hospital. “Remdesivir looks very promising at the moment in ventilated patients, but we don’t yet know the extent to which it’s successful, and it’s also less available.”
Shapira of Shamir Medical Center adds: “We’ve used hydroxychloroquine and plasma from patients who have recovered, and remdesivir hasn’t reached us.”
Mevorach of Hadassah says: “The American Food and Drug Administration approved remdesivir in a situation of distress. It’s not certain that in an ordinary situation it would have been approved. This is a drug that was originally developed for Ebola. But if I have the drug, I’ll definitely want to give it to a patient.”
To treat the inflammatory element of the illness, many doctors are using the drug Actemra (tocilizumab). “And in extreme cases steroids are also given as a treatment, which is controversial,” Shapira says.
Also noticed in severe cases is excessive clotting, thus blood thinners are usually included. Mevorach says the anticoagulant Clexane (enoxaparin sodium) has become standard treatment for COVID-19.
Children were believed to enjoy a safe haven during most of the crisis; the data showed a low infection rate, or at least asymptomatic infection or very mild symptoms. Some of the evidence supported the hypothesis that children get infected and infect others less than adults do.
But during the past month reports have come in on an illness similar to Kawasaki disease, which was first described in Japan in the 1960s.
“This is an inflammation of the blood vessels that usually appears in children under 5 and is characterized by a rash and involvement of the coronary arteries,” Mevorach says.
“Usually people recover with treatment with aspirin and immunoglobulins and sometimes steroids, but there’s a danger of expansion of the coronary arteries and even death. A number of children with COVID-19 in other countries have died because of those phenomena.”
Last month in various countries, nearly 100 cases were reported of children with the coronavirus who came down with an illness similar to Kawasaki disease; three cases ended in death. In Israel thus far six cases have been reported of children with this illness and COVID-19.
Doctors don’t yet know what causes the disease in children. Mevorach is researching the issue with scientists at Mount Sinai Hospital in New York. ”We’re hoping that there will be findings in the coming months,” he says.