I searched for valid publications in major medical journals as the articles appeared. Initially this was easy, but by mid April, the number of articles became huge and I needed to be selective to what was most relevant. I followed closely the reports from John Hopkins University, but more importantly the Robert Koch Institut as they seemed the most actively involved and had sent researchers to China. Also, I could read the reports in German a day before the English translation became available and would pass any important recommendations to the Coronavirus team at the hospital and to the local public health director. I also tried to listen to the daily podcast from Norddeutsche Rundfunk with Chrstirna Drosten, who is the formost virologist doing research on SARS-CoV-2.

This is clinical evidence gathered on dates listed

The Robert Koch Institut (RKI) is gathering data from all over the world, but especially in Europe and is developing models for spread and for how and when to relax physical distancing restrictions, especially for Germany.

Christian Drosten, also in Berlin, is considered the foremost virologist for SARS-CoV-2 and is working in coordination with the RKI. Both have daily updates which I am following, as well as the reports from Die Welt, BBC Science and any peer reviewed literature that appears online in English or German.

 

Anecdotal reports indicate some success in using steroids on patients with COVID-19 on ventilators. The RKI on a close look at the results cautions against using steroids, unless there is another need for steroids such as adrenal failure or underlying asthma.  At this time, those patients who have been closely followed, especially in Germany do not seem to benefit from steroids, although a multi-center clinical trial is being started in Germany with French collaboration.

 

50% of patients who have needed ventilator support have died, usually from cardiac complications. Once on a ventilator the mean duration for those who survive is 14 days.

 

Hydroxychlorquine is being used in some cases in Spain, with anecdotal success. There are two possible mechanisms of action for hydroxychloroquine and this needs further study to determine the actual clinical usefulness. One mechanism is blocking the serine protesase TMPRSS2 for the S protein (spike protein on the virus that is split by the cellular serine protease that is in mucosal tissue, especially the lung, allowing the virus to attach to the cellular membrane and then inject its RNA into the cell), which would limit the ability of the virus to replicate. There is also a yet to be elucidated mechanism whereby hydroxychloroquine blocks the ability of the viral RNA to highjack the endoplasmic reticulum to replicate the viral RNA). Both of these mechanisms seem to indicate that hydroxychloroquine would be most efficacious early in the infection, or even during the asymptomatic phase. It might therefore be useful as a prophylactic  agent for those exposed and at risk. Renal toxicity is a concern in the most at risk group: elderly diabetics.

 

The serine protease blocking properties seem to be enhanced by Redemsivir. Preliminary studies show the 2 drugs together may inhibit the disease early in the infection, when pulmonary symptoms first appear. The safety of this combination is unknown. (Of course in the US, any use of redemsivir would be limited to registered clinical trials). The possibility of other RNA polymerase inhibitors that are currently being used to treat HIV is being looked into. Redemsivir was successfully used to treat MERS, but did not reduce transmission of the virus.

 

The other mechanism of action for hydroxychloroquine is its anti-inflammatory properties. Whether or not this is the reason it appears to be successful in getting patients with COVID-19 off the ventilator requires more study.

 

Recombinant ACE2 in soluble form is also being studied as an aerosol that could be nebulized into the lungs to competitively bind with the virus and prevent the virus from attaching to the pulmonary ACE2 receptors. This would still need to be used early, before the cytokine cascades overwhelms the lungs to function.

 

The nucleotide sequence in the virus in Spain and Italy is slightly different than that isolated in Germany, all directly descended from several individuals who were in the same ski resort in Austria at the same time and returned, to spread the virus into several major German cities from Munich to Berlin, Hamburg to Cologne. The virus spread most rapidly in Munich and the distancing restrictions were most successful in Berlin, where the spread has slowed to doubling every 7-8 days, while still doubling at 3.5 days in Munich. The clinical significance of the differences in the viral RNA is not yet known and whether it effects virulence or transmission is not yet known.

 

The main therapy that is currently recommended is oxygen and support of any underlying medical condition. Antiviral therapy is recommended only as part of a formal study (a very robust study is being conducted in Stuttgart with hospitalized patients at all levels of disease progression from mild to on a ventilator, but is not yet including nonhospitalized symptomatic patients or presymptomatic positives, so the benefit in early treatment will require further studies.

 

Antibiotics should be used only when bacterial secondary infection or sepsis is detected.

 

Just released guidelines for medical personnel: If exposed to secretions of a cough from an infected patient, the exposed person should be sent home for 2 days and then tested. If positive, that person is on house quarantine for 14 days. If a healthcare provider tests positive for the virus, then in 14 days, if symptom free, they can be retested and return to work after 2 negative tests 24 hours apart. If exposure was not definite, but suspected, that healthcare worker needs to wear a mask for 14 days and have their temperature taken daily. If fever, cough or nasal congestion develops, then be tested.

 

80% of patients with symptoms show lymphopenia. Thrombocytopenia is common, as is elevated LDH and troponin. D-dimer is elevated in 40%. Bilateral pleural effusions are seen on CT scan.

 

Hydroxychloroquine, Lopinavir/Ritonavir, Camostat, Remdesivir are all currently being investigated, but no recommendations for general use at this time. The University of Liverpool is testing interferon.

 

Again today, RKI emphasized not to use steroids for ARDS, but hydrocortisone should be initiated if a patient in shock requires vasopressors for more than an hour.

 

If the patient is on high flow oxygen or BiPap and the ABG shows a pO2 below 200 mm Hg, they should be intubated. (I read this through several times, as it seems aggressive. Perhaps the thinking for this recommendation is that a patient will more likely be able to come off the ventilator sooner, if put on a ventilator sooner. I’m sure they want to shorten the current 14 day average that patients who survive are on a ventilator).  Once on a ventilator, they recommend enough PEEP to keep the pO2 80-150 mm Hg.

 

If pO2 falls below 60 mm Hg, while on a vent, then ECMO should be considered, but first a repeat discussion with the family as to whether or not further support is really indicated and desired.

1 Apr 2020

Looking at data from Italy and analyzing response of human T cells and other immune cells in vitro as well as comparison with SARS- CoV studies from the past and studies involving the other six known human CoV viruses show that steroids block the immune system and facilitate superspreading and massive viral replication. This is not only detrimental to the patient, but can make procedures such as intubation especially dangerous to healthcare workers.

 

This implies that immunocompromised patients can be superspreaders.

 

New estimates of reproductive number (R0) is 3-4.

 

Interferon α2a should have beneficial effects at the initial stage of infection, but would exacerbate inflammation and the cytokine storm later in the infection.

 

SARS-CoV-2 appears to suppress Type I interferon production in the host, allowing rapid viral replication by viral perturbation of the RNA sensor MAVS protein. This has been documented in MERS-CoV.

All coronaviruses use nsp1 to degrade host mRNA transcripts, thus suppressing host interferon response, although homology between nsp1 proteins is different, with alphacoronaviruses being more capable of shutting down host interferon production than betacornoaviruses like SARS-CoV-2.

 

In addition to explaining a mechanism for Interferon having a role in the early phase of the infection, blocking the nsp1 protein might eventually lead to a novel pharmacologic treatment. Alternatively, deleting part of this protein might be a way to develop an attenuated virus for a vaccine.

 

Some CoVs have evolved a phosphodiesterase that blocks signaling in the host cell, so that interferon production ceases. This is also true of some hepatitis viruses and is the primary mechanism how interferon works to treat hepatitis C.

 

The exact mechanism by which SARS-CoV-2 counteracts host interferon signaling and production is not known, but seems less pathogenic than SARS-CoV, but more transmissible between humans.

 

SARS-CoV causes apoptosis in hepatocytes and also the thyroid. This has not been reported in SARS-CoV-2, but clinical data is still being gathered.  Therefore it may be warranted to test the free T4 level of acutely ill patients.

 

Peripheral CD4 and CD8 T cells counts drop very low when COVID-19 becomes severe

 

SARS-CoV-2 not found in amniotic fluid, cord blood or breast milk in study done in UK last month. WHO recommends that infants of mothers positive for the virus should bond, have skin to skin contact and most importantly be breast fed.

 

In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. NEJM 28 Mar. Study did not include mild or severe cases.

 

Baracitinib might have a role in the treatment of COVID-19, because of its ability to inhibit viral replication by AAK1 and GAK—the inhibition and by JAK-STAT signaling inhibition of the interferon system, reduce inflammation and therefore limit the cytokine cascade before a cytokine storm causes ARDS.

 

In younger patients with no history of pulmonary disease, a drop in the pulse ox below 93% is indication of rapid deterioration of pulmonary function. These patients will seem to improve rapidly once on a ventilator, but will decompensate quickly if extubated before at least 7 days and many are advocating 10-14 days of ventilator support. Noninvasive ventilation should be used if possible, but some recommend intubation with only a slight drop in pO2 (below 200 mm Hg if on 100% O2 by mask or high flow O2 via BiPap.

 

The risk of younger patients suddenly relapsing needs to be emphasized. Once respiratory distress starts, the cytokine storm has begun. Initial treatment with fluids and O2 may seem to result in significant improvement, but relapse can occur recently. A previously healthy male in his mid-thirty’s in New Jersey was monitored for several hours in the ED and seemed to respond well to fluids and O2. He was sent home and was noted to be breathing calmly when he fell asleep, but the next morning he was dead.

 

Mechanical ventilation should be with lower tidal volumes (4 to 6 ml/kg predicted body weight, PBW) and lower inspiratory pressures, reaching a plateau pressure (Pplat) < 28 to 30 cm H2O. PEEP must be as high as possible to maintain the driving pressure (Pplat-PEEP) as low as possible (< 14 cmH2O). Moreover, disconnections from the ventilator must be avoided for preventing loss of PEEP and atelectasis. Finally, the use of paralytics is not recommended unless PaO2/FiO2 < 150 mmHg. The prone ventilation for > 12 hours per day, and the use of a conservative fluid management strategy for ARDS patients without tissue hypoperfusion (strong recommendation) are emphasized.

 

Although no antiviral treatments have been approved, several approaches have been proposed such as lopinavir/ritonavir (400/100 mg every 12 hours), chloroquine (500 mg every 12 hours), and hydroxychloroquine (200 mg every 12 hours). Alpha-interferon (e.g., 5 million units by aerosol inhalation twice per day) is also used.  A large study is being conducted in Italy.

 

Once metabolic acidosis develops, it is very hard to correct and is a sign of impending multisystem organ failure.

 

Whether patients with COVID-19 and hypertension who are taking an ACE inhibitor or angiotensin-receptor blocker should switch to another antihypertensive drug remains controversial, and further evidence is required. (Nature 5 Mar 20)

4 Apr 2020

Medical Professionals

8 Apr 2020

Study of patients on ventilator showed that the mean ferritin level of survivors was 614 ng/ml and in those who did not survive 1298.

Early identification of impending cytokine storm may permit earlier intervention, although there is no consensus on what therapies should be initiated at that point, with a great deal of controversy as to whether glucocorticoids should be used, or avoided. Reviewing several studies show that most Chinese authors either advocated its use, or accepted that patients early after intubation were adrenal insufficient and started both mineralocorticoid and glucocorticoid therapy, quickly escalating to high dose glucocorticoids.  Review and further study by WHO physicians from Germany and UK, while in China early in the crisis, felt that glucocorticoid use was associated with greater mortality. Currently German authors advocate against glucocorticoids, although it is widely used in Italy and Spain. The RKI (German equivalent of CDC) strongly recommends against glucocorticoid, except adrenal replacement in patients already adrenally suppressed, or diagnosed with adrenal insufficiency after admission to the ICU. UK studies are now mixed, including articles published in the current issue of Lancet (Vol 395;10229). Of note is a correspondence based on studies by UK physicians in Wuhan:

 

Published Online March 13, 2020 https://doi.org/10.1016/ S0140-6736(20)30628-0: Pts with ARDS were intubated and did best if at least 14 hours per day were prone. Factors indicating pending cytokine storm even prior to intubation were based on the H-score. Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. The H-score[1] was developed in France in 2014 and can be calculated with a risk factor determined at:

                                                http://saintantoine.aphp.fr/score/

sHLH reflects  increased interleukin (IL)-2, IL-7, granulocytecolony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α and is best determined on bone marrow, which was done on a large number of patients managed by the WHO team in China. The score can be calculated without the bone marrow using the above link, but is more accurate with bone marrow aspiration.

 

Corticosteroids are not routinely recommended and might exacerbate COVID-19-associated lung injury (Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020; 395: 473–75), However, in hyperinflammation, immunosuppression is likely to be beneficial. Re-analysis of data from a phase 3 randomised controlled trial of IL-1 blockade (anakinra) in sepsis, showed significant survival benefit in patients with hyperinflammation, without increased adverse events. A multicentre, randomised controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome), has been approved. Janus kinase (JAK) inhibition could affect both inflammation and cellular viral entry in COVID-19. (Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020; 395: e30–31).

 

[1] Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 2014; 66: 2613–20.

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