13 March 2021 Episode 117 : The smell of acute and chronic COVID

Sat, 03/13/2021 - 21:08

Dear colleagues,

Today marks the first anniversary of Belgium’s first COVID lockdown. A few days later, I started this series of episodes.  A good opportunity to focus most of this episode on the long term consequences of COVID, which have received various names: “long haulers’, “chronic COVID” and “persistent post-COVID syndrome (PPCS)”. 

  1. But first two nice papers on clinical classification and management of COVID itself
  1. Ep 117-1: The NEJM paper of Ghandi provides a didactic overview of mild-moderate-severe-critical COVID with clear definitions.  I often wonder whether clinicians and researchers follow such definitions in their papers.  Crucial to be able to compare conflicting data on trials in different papers…..

 

  1.  Ep 117-2: A very recent advice by the American College of Emergency Physicians provides a lot of very detailed practical guidelines on diagnosis, prognosis and treatment.  Ready to use at the bedside!

 

  1. Chronic COVID general

 

See/listen to two testimonies (in Dutch) https://www.vrt.be/vrtnws/nl/2021/03/12/1-jaar-na-de-coma-coronapatienten-bruno-en-christophe-blikken-t/

 

  1. Ep 117-3:  A very concise review by Del Rio in JAMA (Nov 2020):
      • Both after mild and severe disease
      • Frequency about a quarter of young adults a third in “middle aged” and almost 50 % in those over 50.
    • Common symptoms: fatigue, dyspnea, joint pain and chest pain
    • Cardiovascular: myocarditis, arrythmias, heart failure
    • Pulmonary: reduced diffusion, weak muscles
    • Neurologic: headache, dizziness, teste and smell, stroke, seizures, mood swings…
    • Emotional: a range of mood disorders from chronic fatigue to depression

 

  1. Ep 117-4: Oronsky in Clinical Reviews in Allergy and Immunology provides more pathophysiological insights of the syndrome as a in which a systemic inflammatory response syndrome or SIRS is predominant, an overwhelming and long-lasting counterbalancing compensatory anti-inflammatory response syndrome (CARS) occurs that leads to postinfectious/posttraumatic immunosuppression
    1. Fibrosis; pulmonary, cardiac and vascular (via transforming growth factor beta or TGF-b?)
      • Pulmonary: Exercised-induce dyspnea and chronic dry cough
      • Pulmonary hypertension and right heart failure
    2. Other cardiac events
      • Overstimulation of renin-angiotensin system with hypokaliema and arrythmias
      • Atherosclerotic plaque rupture with infarction
      • Myocardial damage with hypofunction of left ventricle
    3. Coagulopathy with pulmonary embolism and strokes
    4. The authors speculate about immunomodulatory therapies such as checkpoint inhibitors, TGF-β inhibitors, hematopoietic growth factors

 

  1. Loss of taste and smell (anosmia and ageusia)

 

  1. Ep 117-5: An editorial in Nature of last week by Marshall reminds us that it is very common also in young people and often the only symptom. While the majority regains taste and smell after a few weeks, quite a percentage keeps dysfunction (parosmia) or long-term loss.  But what is the pathophysiology? Theoretically, both damage by direct infection or indirect via inflammation or microvascular lesions at either the olfactory epithelium and/or the olfactory sensory neurons and/or the bulbus olfactorius could be responsible for either temporary or more permanent loss of taste and smell.  As you will see below, published evidence provides some “pieces of the puzzle”, but no final conclusive mechanism.

 

  1. Ep 117-6: Brann in Science Advances of July 2020 argues that the infection of non-neuronal cells may be responsible.  Based on analysis of ACE-2 and TMPRSS2 expression, they propose that 2 “supporting” cell types in the nasal olfactory epithelium may be preferential targets for SARS-CoV-2:
    1. Sustentacular cells: maintenance of water and salt, detoxification etc
    2. Bowman’s gland cells, also with homeostatic function
    3. Horizontal Basal Cells: type of stem cells

 

  1. Ep 117-7: Cazzolla in ACS Chemical Neuroscience  argues that a temporary inflammation in the olfactory epithelium is responsible, based on a close correlation between the levels of IL-6 and the trend of taste and smell dysfunctions. However, there is no control group of patients with no smell/taste disorder and also patients with more permanent loss are not included.

 

  1. Ep 117-8: Lee in NEJM describes microvascular lesions in various brain regions, including the olfactory bulb, but no sign of direct SARS-CoV-2 presence.  However, specific information on whether these patients experienced taste/smell loss is lacking.

 

  1. Ep 117-9: Meinhardt in Nature Neuroscience provides clear-cut evidence of  intact CoV particles together with SARS-CoV-2 RNA in the olfactory mucosa, as well as in neuroanatomical areas receiving olfactory tract projections and also in the brainstem of autopsies.  This may suggest SARS-CoV-2 neuroinvasion occurring via axonal transport. Here again, limited clinical information was available, so that no direct conclusions can be made.

 

  1. Ep 117-10: According to Reiter et al, the recovery is slow: up to two months, but thereafter only 5 % still experienced taste/smell to be absent.

 

  1. Can dogs reliably smell COVID?

 

  1. Ep 117-11: Else in Nature discusses some preliminary results from dogs, trained to smell COVID in either respiratory or sweat samples. At first view, the accuracy approaches that of rapid antigenic tests, but questions are asked about possible confounders.

 

  1. Ep 117-12: Eskandari in BMC Infect Dis reports on a limited series of results with well-identified dogs, which were smelling either throat/pharyngeal secretions  or cloths and face masks from COVID patients and controls. On the respiratory samples, sensitivity was 65 % and specificity 89 %; on the cloths/masks sensitivity was 86% and specificity 93 %.  The sample numbers were well below 100 and there were individual differences between the dogs.

 

  1. Ep 117-13:  Grandjean in PLoS One uses axillary sweat.  The study is very well explained and illustrated. The success rate (correct classification) varied between dogs from 76 to 100 %.

 

  1. Ep 117-14: is the largest published study by Jendry in BMC Infect Dis on over 1000 respiratory samples (saliva or tracheobronchial secretions).  Again, quit some variability was seen between dogs ranging from 70 to almost 100 %; while specificity remained well above 90 %.  There was a correlation between specificity/sensitivity according to the dog.

 

  1. Ep 117-15: Sakr disusses several conditions and confounders
    1. The trainer blindness to the positivity of samples is an important factor
    2. The training samples should be set for a prevalence of positive samples that will reproduce the prevalence in the target population.
    3. Negative and positive samples used to train the dog must be comparable on every point except for the disease marker.
    4. The preparation of the samples when done in different locations or time may lead to false association
    5. Using different samples from different fluids of the same person or from a limited number of persons may lead to false associations

 

Obviously, many conditions to be met  in real life !!!

 

Best wishes,

 

Guido