Extrapulmonary complications mar patients with SARS-CoV-2 infection

Systemic manifestations of SARS-CoV-2 infection vary but are interconnected by shared mechanisms, according to a Singapore study, which has identified two phases of extrapulmonary disease. The first one is an early phase with possible gastrointestinal, ocular, and cutaneous involvement and, second, a late phase characterized by multiorgan dysfunction and clinical deterioration.

“A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome (CRS) in SARS-CoV-2 is needed to identify patients in need of early intervention,” the researchers said.

Medline and Embase databases were searched for studies related to SARS-CoV-2. Meta-analyses, observational studies, case series, and case reports published in English or Chinese between 1 January and 1 May 2020 were included, but reports with only paediatric or obstetric cases were not. A total of 169 articles met the eligibility criteria.

Early manifestations (preceding respiratory symptoms until day 6 of onset) of COVID-19 were as follows: olfactory and gustatory disturbance (self-reported in up to 68 percent and 85 percent of patients, respectively), gastrointestinal symptoms (up to 65.9 percent), and rash (up to 20.4 percent). [Singapore Med J 2021;doi:10.11622/smedj.2021100]

Late manifestations (from day 7 onwards) included hypercytokinaemia, paralleled multiorgan complications including acute cardiac injury (pooled incidence of 17.7 percent in 1,412 patients, mostly with severe disease and 17.4 percent mortality), kidney and liver injury (up to 17 percent and 33 percent, respectively), and thrombocytopaenia (up to 30 percent).

In about 31 percent of patients, hypercoagulability led to venous thromboembolic events. Rare disease presentation and complications included Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis, and spontaneous pneumomediastinum.

“While some manifestations occurred early, including olfactory and gustatory disturbance and gastrointestinal symptoms, late manifestations on day 7–19 were dominated by multiorgan sequelae, mirroring the early ‘viraemic’ and late ‘acute’ phases of disease that were previously described,” the researchers said. [Emerg Microbes Infect 2020;9:727-732]

Multiorgan involvement in SARS-CoV-2 take place through direct cytopathic effect from viral binding to angiotensin-converting enzyme 2 (ACE-2) receptors, endothelial dysfunction and thromboinflammation, and CRS. [Immunity 2020;52:731-733; Lancet 2020;395:497-506; J Thromb Haemost 2020;18:1747-1751]

“Yet, these processes are not separate and exist on a continuum. Viral entry via ACE-2 receptors presages CRS by increasing angiotensin II and activating NF-ĸB and the interleukin (IL)-6 amplifier. IL-1 and IL-6, in turn, promote endotheliopathy and thromboinflammation,” the researchers said. [Immunity 2020;52:731-733; Circulation 2020;142:68-78]

“Biomarkers that identify patients with early endotheliopathy could inform physicians about the patients who are destined to do poorly, but who could still be intervened upon within this narrow window of opportunity,” they added.

The current study had certain limitations. For instance, differences in patient sampling and definitions used for extrapulmonary symptoms in observational studies limited the description of extrapulmonary manifestations and complications of SARS-CoV-2. This resulted in a wide range of incidence of complications reported in this review.

In addition, several manifestations were likely under-reported as patients with SARS-CoV-2 were less likely to receive invasive procedures or radiological investigations. The researchers also failed to examine the validity of observational studies.