COVID-19 should be considered a ‘multi-system disease’: Expert

Evelyn Lewin

15/07/2020 1:32:54 PM

newsGP examines a new comprehensive review of the disease’s effect on extrapulmonary systems.

Internal organs x-ray
Extrapulmonary effects of COVID-19 include haematological, cardiovascular, dermatological and renal manifestations.

When COVID-19 first emerged, a primary focus was on its effects on respiratory infection.
Since then, however, evidence has been building regarding its impact on other systems, including the cardiovascular and neurological systems, and how it affects clotting.
The first extensive review of the effects of COVID-19 on extrapulmonary systems has now been published in Nature Medicine.
Lead researcher Dr Aakriti Gupta, a cardiologist from Columbia University Irving Medical Center in New York City, says he was on the ‘frontlines’ of COVID-19 from the beginning.
‘I observed that patients were clotting a lot, they had high blood sugars even if they did not have diabetes, and many were experiencing injury to their hearts and kidneys,’ he said.
Dr Gupta thus realised COVID-19 infection involves far more than the respiratory system.
‘Physicians need to think of COVID-19 as a multi-system disease,’ he said.
‘There’s a lot of news about clotting, but it’s also important to understand that a substantial proportion of these patients suffer kidney, heart, and brain damage, and physicians need to treat those conditions along with the respiratory disease.’
Associate Professor Hassan Vally is an epidemiologist at La Trobe University with a special interest in infectious diseases.
He told newsGP that while he is unsure whether COVID-19 should be defined as a ‘respiratory disease with multi-organ effects’, or whether it should instead be considered a multi-organ disease, he still considers it to be the former.
‘The majority of people do get respiratory symptoms,’ he said.
‘It is a respiratory virus, but it clearly has other effects.’
While Associate Professor Vally says it is well known now that COVID-19 does not solely attack the respiratory system, he was surprised by how extensive its effects can be throughout the body, as detailed in this new review.
‘People are having symptoms that are pretty diverse and clearly this virus is affecting multiple different organs in the body,’ he said.
The cause of these effects on other bodily systems is explored in the new paper. The authors query whether their pathophysiology may relate to the fact that angiotensin converting enzyme 2 (ACE-2), the entry receptor for SARS-CoV-2, is expressed in multiple extrapulmonary tissues.
That means direct viral tissue damage could be a ‘plausible’ mechanism of injury.
The authors theorise that other contributing factors for extrapulmonary manifestations of COVID-19 include endothelial damage, thrombo-inflammation, dysregulation of immune responses, and maladaptation of ACE-2-related pathways.
The new review detailed the following effects of COVID-19 on extrapulmonary systems.
Haematologic manifestations
Patients with COVID-19 may present with several laboratory abnormalities and thromboembolic complications.
Lymphopaenia, leukocytosis (especially neutrophilia) and thrombocytopaenia have all been found to be associated with poorer prognosis.
Meanwhile, elevated D-dimer levels at admission and a longitudinal increase during hospitalisation was linked with worse mortality in COVID-19.
The paper also notes emerging evidence of thrombosis and arterial vascular occlusive events, including acute limb ischemia and stroke in severely affected patients.
Additionally, autopsies of patients who died from COVID-19 have shown high rates of microvascular and macrovascular thromboses, especially in the pulmonary circulation.
Meanwhile, studies found higher rates of thrombotic complications in patients despite use of thromboprophylaxis.
Cardiovascular manifestations
‘The mechanism of heart damage is currently unclear, as the virus has not been frequently isolated from the heart tissue in autopsy cases,’ Dr Gupta said.
However, the review noted that SARS-CoV-2 can cause direct and indirect cardiovascular sequelae, including:

  • myocardial ischaemia and infarction
  • myocardial injury
  • acute coronary syndromes (ACS)
  • cardiomyopathy
  • acute cor pulmonale
  • arrhythmias (including new-onset atrial fibrillation and flutter)
  • cardiogenic shock
  • sudden cardiac death.
While epidemiologist Associate Professor Hassan Vally says it is well known now that COVID-19 does not solely attack the respiratory system, he was surprised by how extensive its effects can be throughout the body.

Renal manifestations
The review noted ‘a substantial proportion’ of patients with severe COVID-19 may show signs of kidney damage.
Acute kidney injury was found to be a frequent complication of COVID-19, and its presence was associated with mortality.
Other effects associated with renal manifestations include:
  • electrolyte abnormalities (such as hyperkalemia, hyponatremia, and hypernatremia)
  • metabolic acidosis
  • haematuria
  • proteinuria.
Gastrointestinal and hepatobiliary manifestations
The authors state the incidence of gastrointestinal manifestations ranges from 12–61% in patients with COVID-19.
They cite a recent meta-analysis of 29 studies, most from China, which noted the pooled prevalence of individual symptoms and included:
  • anorexia in 21%
  • nausea and/or vomiting in 7%
  • diarrhoea in 9%
  • abdominal pain in 3%.
Meanwhile, laboratory markers associated with infection include elevated hepatic transaminases, elevated bilirubin and low serum albumin.
‘Gastrointestinal symptoms may be associated with a longer duration of illness but have not been associated with increased mortality,’ the authors wrote.
Endocrine manifestations
The authors note that a range of endocrine manifestations have been seen in patients without pre-existing endocrine disease.
Patients with diabetes mellitus and/or obesity are at risk of developing more severe COVID-19 illness.
Meanwhile, patients hospitalised with COVID-19 have exhibited a range of abnormalities of glucose metabolism, including:
  • worsened hyperglycemia
  • euglycemic ketosis
  • classic diabetic ketoacidosis.
Neurologic and ophthalmologic manifestations
Non-specific mild neurological symptoms noted in hospitalised patients with COVID-19 include:
  • headache
  • dizziness
  • myalgia
  • fatigue
  • anorexia
  • anosmia (loss of smell)
  • ageusia (loss of taste).
Stroke, confusion or impaired consciousness have also occurred in severe presentations of COVID-19, while acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) has been reported in some patients.
Case reports also describe meningoencephalitis, hemorrhagic posterior reversible encephalopathy syndrome, and acute necrotising encephalopathy.
The paper notes that ocular manifestations – such as conjunctival congestion alone, conjunctivitis, and retinal changes – have also been reported in patients with COVID-19.
Dermatologic manifestations
Cutaneous manifestations of COVID-19 include erythematous rash, urticaria, and chicken pox-like vesicles.
Meanwhile, a study found chilblain-like lesions to be associated with less severe SARS-CoV-2 infection.
The takeaway message
As time goes on and the number of people infected with COVID-19 continues to grow, Associate Professor Vally says clinicians are able to gain a greater understanding of the disease and its effects on the body.
‘We are learning about this disease every day,’ he said.
With current global infection rates now soaring past 13 million cases, Associate Professor Vally believes it is becoming evident that there are patterns in terms of clusters of symptoms and complications associated with infection.
‘So we’re starting to get a good enough sample size to see what’s really going on and to understand this virus,’ he said.
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