COVID-19: Causes

Pathogenesis (disease development)

The disease is caused by SARS-CoV-2 (synonyms: novel coronavirus: 2019-nCoV; NCIP-associated coronavirus, NCIP-CoV; 2019-nCoV (2019-novel coronavirus; 2019 novel coronavirus)). The virus belongs to lineage B of the beta coronaviruses; it is an enveloped (+)ssRNA virus. The mucus-producing goblet cells and ciliated cells in the nasal cavity are likely the first target cells for SARS-CoV-2, with the novel coronavirus using the same cellular receptor as the SARS virus to infect its target cells: It uses the transmembrane enzyme ACE2 (angiotensin converting enzyme 2) as a receptor to enter their host cells. ACE2 is highly expressed in the heart and lungs – as well as in the kidneys, endothelium and gastrointestinal tract. ACE2 expression in the nasal mucosa increases with age and is lowest in under ten-year-olds. This may be one reason for the less frequent occurrence of COVID-19 in the very young. Cardiac myocytes, for example, increase with age the expression of the proteins ACE2 and TMPRSS2, through which the coronavirus SARS-CoV-2 enters the cells.ACE2 levels can be further increased by renin-angiotensin-aldosterone system inhibitors (ACE inhibitors; angiotensin receptor blockers). However, it is considered proven that hypertensive patients taking these drugs do not have a worse prognosis than other people when they develop COVID-19. Meanwhile, drug inhibition of the renin-angiotensin-aldosterone system (RAAS) is shown to have more favorable effects: Number ratio of patients with severe courses to those with milder courses was on average one-third lower in the RAAS-blocker group than in patients not receiving RAAS blockers; this was statistically significant in a subgroup of patients with hypertension. Another factor that appears to facilitate the entry of SARS-CoV-2 into the interior of cells via the known receptor ACE2 is neuropilin-1 (NRP1). NRP1 is found in the mucous membranes of the respiratory tract and nose, which may be of strategic importance in this localization to contribute to the infectious process and spread of SARS-CoV-2. Experiments with cells cultured in the laboratory suggest that NRP1 is able to promote infection “in the company” of ACE2, i.e., NRP1 may represent an ACE2 potentiating factor; however, it is also possible that SARS-CoV-2 can enter cells independently of ACE2 when viral load is high. Natural reservoirs of the pathogen are most likely fruit bats (bats). The intermediate host is not yet known. Infection with SARS-CoV-2 can lead to atypical pneumonia, which has been given the name COVID-19 (Novel coronavirus-infected pneumonia (NCIP)). The SARS-CoV-2 coronavirus damages not only the alveoli in the lungs, but also the endothelia (the cells of the innermost wall layer of blood vessels facing the vascular lumen), causing thrombosis (formation of a blood clot/thrombus) in the small blood vessels. Furthermore, intussusceptive angiogenesis (sprouting of new blood vessels into the surrounding area with invaginations into the vessel lumen; an attempt by the body to divide an already existing blood vessel into two parts) has been demonstrated. The severe courses of COVID-19 are probably caused by immune thrombosis. This is preceded by an exaggerated reaction of the immune system in which neutrophilic granulocytes (belonging to the leukocyte/white blood cell group) expel “nets” of cellular material into the blood plasma. This form of defense is called “neutrophil extracellular traps” (NET). The NET formation actually serves to fight the viruses, but instead the NETs provoke thrombosis/vascular occlusion by a thrombus (blood clot) (= immune thrombosis).

Etiology (Causes)

Biographic causes

  • Genetic burden/disposition-higher ACE2 allele frequency in the “expression-quantitative-trait-locus”(eQTL) variants (variation in mRNA expression levels) in the population in East Asia including China; this is associated with higher tissue expression of viral receptor ACE 2 variants, which may explain higher increased SARS-CoV-2 susceptibility (“susceptibility”).
  • Age – older age and residence in health care facilities.
  • Occupation – medical personnel

Behavioral risk factors

  • Contact with ill persons in the phase of infection.

Disease-related causes

Infectious and parasitic diseases (A00-B99).

  • Infection with the SARS-CoV-2.

Risk groups for infection with the SARS-CoV-2 include:

  • Men – approximately 60% of all patients with COVID-19 are men; for fatal courses, the proportion is 70%.
    • In a cohort of patients with chronic heart failure, men had higher soluble ACE2 receptor concentrations than women
  • Individuals aged 60 years and older
  • People with comorbidities (concomitant diseases).
  • Patients with immunosuppression (suppression of the body’s own defense system).
  • Dialysis patients (due to their multiple comorbidities).
  • Smokers. *

* Due to increased expression of angiotensin-converting enzyme 2 (ACE2) in the respiratory tract, through which SARS-CoV-2 viruses enter cells. According to a meta-analysis of 5 studies, active smokers are not at higher risk for severe courses of COVID-19 * * COPD was the strongest predictive comorbidity for severity of COVID-19 (OR 6.42), followed by cardiovascular disease (OR 4.4) and hypertension (OR 3.7).