COVID-19: Clinical perspectivesMarch 25, 2020
The recent emergence of novel coronavirus (COVID-19) from Wuhan, China has taken quite a few experts by surprise. The family of coronaviridae consists of enveloped, non-segmented, positive-sense RNA viruses distributed in humans and other mammals. Going by the epidemics of two other betacoronaviruses, Middle East Respiratory Syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV), this Covid-19 infection is the tip of an iceberg with potentially more novel zoonotic events to come.
A study of 41 patients who were first reported to have been admitted to the hospital showed that there was a quick increase in mortality and laboratory-confirmed cases (Bin Cao et al. The Lancet. Vol 395,498-506; 2020). This report also found that there are several similarities in the clinical features of MERS-CoV, SARS-CoV and 2019-nCoV. However, COVID-19 patients rarely developed intestinal signs and symptoms (eg, diarrhoea) whereas 20-25% of cases of MERS-CoV and SARS-CoV infected had diarrhoea.
The pathophysiology of the unusually high pathogenicity is not completely understood in the case of MERS-CoV and SARS-CoV. Positive-sense single-stranded RNA viruses (+ssRNA) include dengue (DENV), chikungunya (CHIKV) and Zika virus (ZIKV), which affect millions of people worldwide and have a large impact on public health. The MERS-CoV does not infect large numbers of people like the others mentioned above, but has a high mortality rate of 35%. With the emergence of COVID-19, it becomes imperative to understand the pathogenesis of these viruses to identify proper treatment and prevention methods.
Our innate immune system, the first line of defense against invading viruses, makes use of pathogen-associated molecular patterns (PAMPs), which are conserved microbial structures sensed by pattern recognition receptors (PRRs). The downstream of this signaling system are the interferon (IFNs) molecules, of which type I and III are regarded as the main effectors during antiviral innate response in different cell types, while type II IFNs are mainly in immune cells. There are three types of PRRs which induce the production of type I and III INFs once they sense RNA viruses; toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs).
The human coronavirus has the largest known positive-strand genome (around 30kb). Two-thirds of its genome has two large open reading frames (ORFs) 1a and 1b. ORF1a expression results in two polypeptides (pp1a and pp1ab), which are then processed by two or three virus-encoded proteases into 16 non-structural proteins (nsp). These nsps further help in viral genome replication, sub-genomic RNA synthesis and also evasion of host innate immune response. The other one-third of the genome codes for viral structural proteins like envelope (E), membrane (M), spike (S), nucleocapsid (N) and other accessory proteins. The accessory proteins were also shown to be playing a role in antagonising IFN response. IFNα therapy, in combination with steroids, was shown to be associated with better clinical outcomes in human SARS-CoV infected patients as it improved oxygen saturation levels and reduced lung abnormalities. In MERS-CoV infection, the IFNα therapy, along with ribavirin, improved survival at 14 days after diagnosis, but no benefit was found post 28 days. Even though there is no actual proof of efficacy of IFN treatment alone, there are ongoing clinical trials around using IFNβ1b in combination with lopinavir/ritonavir in MERS patients. Some animal studies in macaques infected with SARS-CoV showed that the pathological disease severity is much lower in young adults on the induction of IFNβ1b. Two other studies did show that peripheral blood mononuclear cells had no detectable or lower levels of IFNs, suggesting that these groups of genes were downregulated by SARS-CoV.
IFNs play a crucial role
Several knockout mice studies also suggest that IFN signaling was important in controlling a coronavirus infection. High levels of pro-inflammatory cytokines like IL-1, IL-6 and IFNγ, and chemokines such as CCL2, CXCL10 and IL-8, were detected in the sera of SARS patients. Most importantly, it was observed that there were higher levels of CXCL10 during the crisis phase of the SARS patient who died, along with downregulation of IFNs. The same was observed in MERS patients. In addition to proteins associated with the pathology of disease, the coronavirus genome also encodes non-coding RNAs (ncRNAs) and their inhibition derived from the N gene was associated with decreased inflammation and reduced gross pathology of lung.
As suggested by Bin Cao et al in their 41-patient cohort study, most patients presented with fever, dry cough, dyspnoea and bilateral ground-glass opacities on chest CT scans. These features of COVID-19 infection have resemblances to SARS-CoV and MERS-CoV infections. It was also noted that patients infected with COVID-19 also had elevated levels of cytokines like IL1B, IFNγ, IP10 and MCP1, potentially eliciting more activated T-helper-1 (Th1) cell responses. In particular, patients admitted to ICU had higher concentrations of GCSF, IP10, MCP1, MIP1A and TNFα than the other patients, suggesting that the cytokine storm was associated with disease severity.
All this data suggests that the emergence of COVID-19 has several molecular signatures which can give us a better handle on the diagnosis and management of coronavirus. Further studies can improve and elucidate COVID-19 infection and pathogenesis.