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A Personal Opinion from Spain: Experience and Insight on COVID-19 Adjuvant Therapy

By Currents Editor posted 03-31-2020 09:53

  

By Alberto Hernandez, MD, PhD, DESA, Director, Anaesthesia & ICU, Grupo Policlinica, Ibiza, Spain; and Peter J. Papadakos, MD, FCCM, FAARC. Director, Critical Care Medicine, Professor Anesthesia, Surgery, Neurology and Neurosurgery, University of Rochester, New York, US. 

Hernandez.jpg
Peter_Papadakos_MD.pngThese days, there are multiple papers emerging daily about COVID-19 management, protocols, guidelines, etc. Many research protocols are in play, but current management of COVID-19 still remains supportive.  

We were intially told the virus would only seriously affect older people; however, in Spain, we are seeing young people — many in their 30s — rapidly deteriorating, requiring rapid intubation, mechanical ventilation and prone positioning to try to stabilize and support them. Why is this happening?  

In our opinión, it’s important to keep two points in mind: 

       1.   In some ways, the
behavior of COVID-19 has similar characteristics to the HIV virus.

HIV is also an enveloped virus. COVID-19 has four small pieces of RNA sequences in its genetic code that are not found in other similar coronaviruses like SARS (severe acute respiratory syndrome). These strands, however, do bear some resemblance to bits of sequence also found in HIV. 

Similar to HIV-1 Gp41, the S2 domain of SARS-CoV spike protein contains HR1 and HR2 sequences, which tend to form a coiled-coil structure. The amino acid sequences of peptides derived from the HR1 and HR2 regions of SARS-CoV spike protein are similar to those from the HIV-1 Gp41 HR1 and HR2 regions. The similarity suggests that these two transmembrane envelope glycoproteins share a common mechanism mediating fusion between the viral and target-cell membranes [1]. Indeed, lopinavir and ritonavir, two drugs to treat HIV in combination, are used in the treatment of COVID-19 by some centers.
 
A key point is lymphopenia is a hallmark of the disease and seems to predict severity of COVID-19 [2,3]. Autopsy series have shown us the severe damage to the lungs and the immune system. Prevention of fibrosis of in the lungs during the early stage of the disease is a fundamental goal in supportive therapy. The influence of COVID-19 on the human body can be summarized as a combination of SARS and AIDS, as it damages both the lungs and immune systems.

2.   Respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality in patients infected by COVID-19. 

People are dying from a massive lung inflammatory response, not from the virus. A massive activation of the cytokine cascade (SIRS) seems to be the main cause of death.
       
I
dentification and early treatment of this cytokine cascade would be key to the reduction of the deaths we are seing around the world. We are seeing that this disease has characteristics of these two known syndromes: 

  • Macrophage activation syndrome, a potentially life-threatening complication characterized among other things by a fatal hypercytokinaemia (cytokines storm) with multiorgan failure.
  • Antiphospholipid syndrome, a disorder of the immune system that causes an increased risk of thombus. D-dimer is elevated in some patients with COVID-19 pneumonia, and other coagulation indicators are abnormal. In this syndrome, thrombocytopenia is also seen in COVID-19 infection. Also, we are seeing microthrombus in patients with COVID-19. 

So, we have two controversial questions:

1.  Should we give high doses of steroids in these patients to stop the cytokines storm?
2.  Should we give anticoagulant doses in patients with high D-Dimer? 

Recently, the Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with COVID-19 [4] were released. The guidelines suggest the use of low-dose corticosteroid therapy for “shock-reversal(weak recommendation, low-quality evidence). The WHO, however, does not recommend either routine use of systemic corticosteroids for the treatment of viral pneumonia outside of clinical trials [5].

So, if we want to stop the cytokines storm, is there another option for treatment if steroids are not agreed upon by major organizations? The answer is yes. We recommend large doses of vitamin C [6].

Vitamin C, has emerged as a relevant therapy due to its potential benefits when administered intravenously. The potential effect of vitamin C in reducing inflammation in the lungs [7] could play a key role in lung injury caused by COVID-19.  

Vitamin C has been shown to increase resistance to infection caused by coronavirus, also modifying the susceptibility to the infection [8]. Vitamin C can also help eliminate alveolar fluid accumulation, a major part of ARDS, by preventing the activation and accumulation of neutrophils and reducing alveolar epithelial water channel damage. 

Some clinical trials have already been registered. Peng Zhiyong, Director of Intensive Care at Zhongnan Hospital of Wuhan University, is one of the investigators [clinical trial identifier: NCT04264533] of a Chinese study. We have developed a protocol for vitamin C administration (see Table 1 below). The potential side effects are minimal, and the benefits could be major. 

Table_1.jpg
In regards to D-Dimer elevation, we strongly recommend a low-molecular-weight heparin in the anticoagulative dose due to the risk of microemboli formation, and, therefore, risk of stroke, myocardial infarct, pulmonary embolism and spleenic infarct. We have also seen some patients die from myocardial infarct and stroke who present positive for COVID-19.  Some autopsy series have shown us high incidence of pulmonary embolism and micro-thrombus in pulmonary circulation. We have been also seeing an excessive CRRT circuit clotting or dialysis catheter malfunction in COVID 19 patients, most likely from their hypercoagulable/SIRS state. Also for our neurocritical care colleagues, we have observed patients who have presented with marked clinical signs of encephalopathy with agitation in our Spanish ICUs. Ongoing evaluation of this syndrome is in play.

References

  1. W. Liu, G.F. Xiao, Y.B. Chen, et al. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet, 363 (2004), pp. 938-947I.
  2. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS­CoV­2 pneumonia in Wuhan, China: a single­ centered, retrospective, observational study. Lancet Respir Med 2020; published online Feb 24. https://doi.org/10.1016/S2213­ 2600(20)30079­5.
  3. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID­19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; published March 3. DOI:10.1007/s00134­020­05991­x.
  4. Alhazzani W, Hylander M, Møller, Arabi Y M et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019(COVID-19). In press and released and on web site SCCM.
  5. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance V 1.2. (World Health Organization, 2020).
  6. Hernandez A, Papadakos PJ, Torres, A et al. Two known therapies could be useful as adjuvant therapy in critical care patients infected by COVID-19 in press Rev Esp Anestsiol Reanim.
  7. Jeong YJ,  Kim  JH,  Kang  JS,  Lee  WJ,  Hwang    Mega-dosevitamin  C  attenuated  lung  inflammation  in  mouse  asthma model. Anatomy and Cell Biology 2010;43:294-302.
  8. Atherton, J. G., Kratzing, C. C. & Fisher, A. (1978). The effect of ascorbic acid on infection of chick-embryo ciliated tracheal organ cultures by coronavirus. Archives of Virology 56, 195–9. 

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