Autoinflammatory and autoimmune conditions at the crossroad of COVID-19

Abstract

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.

Keywords: Antiphospholipid syndrome; Autoimmunity; COVID-19; Cytokine storm syndrome; Cytopenia; Guillain-Barré syndrome; Kawasaki disease; SARS-CoV-2; Vaccines.

Fig. 1

Translational overview of COVID-19. Kinetics of IgM and IgG antibodies is shown. The dynamics of SARS-CoV-2 seroconversion is still under study as is the long-term immunity. Positivity of PCR for SARS-CoV-2 could last more than 25 days after the onset of disease. About 80% of patients develop no symptoms or present with a mild/moderate disease. Initially, infection of SARS-CoV-2 through the ACE2 receptor decreases the production of IFN type I and III, with a paradoxical increased secretion of chemokines which stimulate migration of innate immune cells to the lungs. This process takes place in the early stages of the disease. Then, migration of T and B cells, stimulated by chemokines, favors an increase of Th1/Th17 cytokines that perpetuate inflammation. Other cells such as neutrophils are thought to produce NETosis which may help to increase inflammation and produce the release of cryptic antigens leading to autoimmune phenomena. *All these markers are risk factors of progression of disease. Adapted from Ref. [[4], [5], [6], [7], [8]]. ACE2: Angiotensin-converting enzyme 2; ADE: Antibody-dependent enhancement; ARDS: Acute respiratory distress syndrome; ASC: Apoptosis-associated speck-like protein containing a CARD; CCL: Chemokine (C–C motif) ligand; CRP: C reactive protein; CXCL: chemokine (C-X-C motif) ligand; ESR: Erythrocyte sedimentation rate; ICU: Intensive care unit; Ig: Immunoglobulin; IFN: Interferon; IL: Interleukin; IP10: Interferon-inducible protein 10; LDH: lactate dehydrogenase; NAbs: Neutralizing antibodies; NK: Natural killer; PCR: Polymerase chain reaction; PCT: Procalcitonin; RNA: Ribonucleic acid; MIP1α: Macrophage inflammatory protein 1α; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; Th: T helper; TMPRSS2: Transmembrane protease serine 2; TNF: Tumoral necrosis factor.

Fig. 2

Clinical manifestations in the cytokine storm syndrome. This condition is considered as a common end point of different initial insults: infectious, autoimmune/inflammatory, and iatrogenic. Patients with CSS exhibit a plethora of signs and symptoms that compromise several systems. These manifestations resemble those encountered in patients with COVID-19. CSS: Cytokine storm syndrome; CRP: C reactive protein; ESR: Erythrocyte sedimentation rate; PaO2: Partial pressure of oxygen in arterial blood; PaCO2: Partial pressure of carbon dioxide.

Fig. 3

Cytokine network in the cytokine storm syndrome. IFNγ has been recognized as a common mediator of inflammation in CSS, especially in MAS. The production of IFNγ is stimulated by IL-1β, IL-18, and IL-33, which are associated with inflammasome response and play a critical role in inflammation via NK and T cells. IL-6 has been suggested as the central role of CSS. In addition, high levels of IL-10 are thought to be an unsuccessful attempt to compensate inflammation induced by the inflammasome activation. Adapted from Ref. [128]. CSS: Cytokine storm syndrome; IFN: Interferon; IL: Interleukin; MAS: Macrophage activation syndrome; NK: Natural killer; TNF: Tumoral necrosis factor.

Fig. 4

Clinical differences between classic KD (left) and KD associated with SARS-CoV-2 (right). Cardiac involvement is a critical clinical feature in patients with KD or Kawasaki-like conditions associated with SARS-CoV-2, also referred as pediatric inflammatory syndrome temporally related to COVID-19. Adapted from Refs. [[36], [37], [38], [39]].