The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity

Abstract

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

Figure 1

Hypoxia and lung failure in COVID-19 Conceptual and simplified view of COVID-19 lung pathogenesis. In most patients, hypoxia is the principal and most severe COVID-19 symptom; although still debated, compensatory mechanisms to maintain oxygen delivery such as increased respiratory effort, hypoxic vasoconstriction, and cardiac output are thought to eventually lose efficacy with increasing COVID-19 severity. With a further reduction in functional lung capacity, hypoxia becomes life-threatening and frequently necessitates intensive care support. Mechanisms contributing to COVID-19 severity include increased dead space ventilation secondary to endothelial inflammation and microthrombi, an elevated diffusion barrier secondary to alveolitis and pulmonary oedema, and right-to-left shunt formation secondary to atelectasis, which is related to increased oedema and fibrosis in the long term; these mechanisms collectively reduce gas-exchange capacity. ΔP=change in pleural pressure. ΔV=change in volume. PaO₂=partial pressure of arterial oxygen.

Figure 2

Inflammatory mechanisms, alveolar epithelial and endothelial damage, and coagulopathy in COVID-19 (A) In the early stage of disease, SARS-CoV-2 infects the bronchial epithelial cells as well as type I and type II alveolar pneumocytes and capillary endothelial cells. The serine protease TMPRSS2 promotes viral uptake by cleaving ACE2 and activating the SARS-CoV-2 S-protein. During early infection, viral copy numbers can be high in the lower respiratory tract. Inflammatory signalling molecules are released by infected cells and alveolar macrophages, in addition to recruited T lymphocytes, monocytes, and neutrophils. (B) With disease progression, plasma and tissue kallikreins release vasoactive peptides known as kinins that activate kinin receptors on the lung endothelium, which in turn leads to vascular smooth muscle relaxation and increased vascular permeability. This process is controlled by the ACE2 receptor. Without ACE2 blocking the ligands of kinin receptor B₁, the lungs are prone to vascular leakage, angioedema, and downstream activation of coagulation. Dysregulated proinflammatory cytokine (TNF, IL-1, IL-6) and NO release and signalling contribute to these processes. As a consequence, pulmonary oedema fills the alveolar spaces, followed by hyaline membrane formation, compatible with early-phase acute respiratory distress syndrome. Anomalous coagulation frequently results in the formation of microthrombi and subsequent thrombotic sequelae. ACE2=angiotensin-converting enzyme 2. AT₁ receptor=type 1 angiotensin II receptor. IL=interleukin. NO=nitric oxide. TMPRSS2=transmembrane protease serine 2. TNF=tumour necrosis factor.

Figure 3

Severity-dependent changes in peripheral blood immune cells during COVID-19 COVID-19 is associated with a marked decrease in circulating effector CD4⁺ and CD8⁺ T lymphocytes, leading to an increase in Tregs. In addition to a numerical loss, the high proportion of exhausted and suppressed T cells expressing CTLA-4, PD-1, or TIGIT suggest compromised T-cell immunity. Both CD4⁺ and CD8⁺ T cells show early upregulation of activation markers such as CD38 and HLA-DR concurrent with an altered chemokine receptor pattern (a decrease in CCR6 and CXCR3). Circulating CD4⁺ T cells are skewed towards an IL-2 and IL-17-positive profile. Early in the course of COVID-19, the numbers of B cells and monocytes remain unchanged, whereas mild neutrophilia is frequently observed. Blue area: patients with favourable outcomes have an increased number of circulating dendritic cells and intermediate monocytes that upregulate HLA-DR expression, suggesting recovery of immunocompetence. T-cell numbers recover with an increase in polyfunctional and follicular helper T cells. These changes are accompanied by a humoral antibody response produced by activated and expanded B cells. During recovery, neutrophil numbers normalise. Red area: a more severe disease course is characterised by a decrease in dendritic cells, natural killer cells, and monocytes; monocytes further downregulate HLA-DR expression but upregulate IL-1β, TNF, and ISGs. Although low in number, CD8⁺ T cells in severe COVID-19 show substantial upregulation of their effector molecules, such as granzyme B and perforin. Of note, the numbers of B cells decrease, whereas plasmablasts are increased in the blood; specific antibodies are also produced in patients with severe COVID-19. Profound changes occur among myeloid cells including egress of immature neutrophils and myeloid-derived suppressor cells from the bone marrow, and enhanced formation of NETs. NET formation is likely to be an important contributor to the development of organ and endothelial injury in conjunction with activation of the complement and coagulation cascades. CCR=C-C chemokine receptor. CTLA-4=cytotoxic T-lymphocyte protein 4. CXCR=C-X-C chemokine receptor. HLA-DR=HLA DR isotype. IL=interleukin. ISGs=interferon-stimulated genes. NETs=neutrophil extracellular traps. PD-1=programmed cell death 1. TIGIT=T-cell immunoglobulin and ITIM domain. TNF=tumour necrosis factor. Tregs=regulatory T cells.