6 April Importance of biomarkers of severe disease Role of Angiotensin Convalscence and immunity

1. Three papers on the lab/biological parameters of “severe disease”. 

• The first paper by Liu, although only on a limited number of patients is very instructive, as it uses an easily quantifiable parameter to assess the severity of the “acute respiratory distress syndrome (ARDS)”: the Murray score.  See https://www.mdcalc.com/murray-score-acute-lung-injury#evidence .  Fig 3 is very instructive, as it shows that viral load (the LOWER the Ct value, the HIGHER the VL), is directly correlated with the Murray score, some inflammatory parameters (such as CRP and % Neutrophils) and indirectly correlated with lymphocytes and albuminemia.  The NEUT/LY ration(NLR) has also been proposed as a prognostic marker, but I found only associations, no real prospective study in this regard. Fig 4 shows that the higher the Murray score (more serious ARDS),  the lower the albumin and the Lymph, but the higher the Neutrophils, CRP and LDH. No surprise. Fig 6 is interesting, because it shows higher Angiotensin II, related to viral load and oxygen saturation.    
• The paper by Qin is also retrospective, but on a much bigger sample. They provide a clear definition of “severe disease” (p. 7 and Ref 7):
  • 1. Respiratory distress with the respiratory rate over 30 per minute;
  • 2. Oxygen saturation ≤ 93% in the resting state;
  • 3. Arterial blood oxygen partial pressure (PaO2) / oxygen concentration (FiO2) ≤300mmHg.

This paper confirms and extends the findings of Liu with regard to WBC disbalance, T-cell subsets and many inflammatory markers and propose again the NLR as an important marker for severity.

• The most recent stud by Chen, unfortunately again retrospective on a small number further elaborates the previous findings with more immunological data and concludes cytokine storm and lymphopenia, particularly decrease in CD4+T and CD8+T cells counts, as well as suppressed IFN-γ production by CD4+T cells.

One has to realize that the findings in the peripheral blood with regard to WBC subset could be (partially) a “mirror image” of what happens in the lungs, as has been shown in TB for instance: it is possible that lymphocytes are massively recruited to the lungs and are very active there, while they are depleted and hypofunctional in the blood.   

Clearly, there are many disturbed biomarkers in severe cases, some of which have been shown to be quantitatively associated with viral load and pulmonary dysfunction.  The important, as yet unresolved, question is which of these markers besides the obvious clinical and radiological observations, could be used upon admission to predict the prognosis.  In this respect, the viral load as well as “simple” markers such as neutrophil/lymphocyte ratio (NLR) and others (CRP, LDH, ALT, IL-6…) should be studied.      

2. A beneficial effect of inhibitors of ACE2 (ACEIs) and of angiotensin II receptor (ARBs)?

It is a retrospective study on only 42 patients, with similar characteristics that were treated with ACEI/ARB or other antihypertensive drugs.  There is a tendency that the ACEI/ARB group has a more favorable clinical outcome and also a few of the above biological parameters are better.  It is not strong evidence, but it would be in favor of the hypothesis that the renin-angiotensin system could better be blocked, because it may play a role in the hyper-inflammation  

3. Three case reports on measurable viral load in the pharyngeal swabs several days after clinical recovery (1 from Germany, 2 from China).  Just like the excretion of viral RNA in the stools, which can go on for days or weeks, it is unclear whether this phenomenon is associated with infectious virus that could be transmitted. The Euro Surveillance is more systematic, because done on 62 medical staff and the frequency is only 2 (3 %).  In any case, it seems mandatory to keep recovered subjects in quarantine for 2 weeks.

4. Finally, the important and unresolved question to what extent infection induces SARS-CoV-2 antibodies that are protective? Important as potential treatment, but also to understand whether seroconversion in a sufficiently big proportion of the population could lead to the famous “herd immunity”.  To these ends, trials with convalescent plasma (or immunoglobulins) could be very useful. A colleague sent me the following  FDA link and comment

https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds

Although promising, convalescent plasma has not yet been shown to be effective in COVID-19. It is therefore important to determine through clinical trials, before routinely administering convalescent plasma to patients with COVID-19, that it is safe and effective to do so. 

Single Patient Emergency IND: Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the expanding COVID-19 outbreak presents, while clinical trials are being conducted and an expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency Investigational New Drug Application (eINDs) for the individual patient under 21 CFR 312.310.