On 2020-05-26 13:58:13, user Sinai Immunol Review Project wrote:
Main findings<br />
While the growing scientific literature on the immune responses to SARS-CoV-2 infection has highlighted several immunological markers for COVID-19, molecular or cellular determinants of disease severity have not yet been well-described. In this report, Sánchez-Cerrillo et al. profiled myeloid and T cell subsets across mild (G1, n=19; whole blood), severe (G2, n=21; whole blood), and critical COVID-19 cases (G3, n=23; whole blood and paired bronchoscopy samples), and healthy controls (n=22). Clinical parameters, including serum IL-6, procalcitonin (PCT), C-reactive protein (CRP), D-dimer levels, and serum LDH, increased with worsening disease severity.<br />
Using high-dimensional flow cytometry, the authors assessed changes in classical monocytes (C Mo; CD14+CD16-), transitional monocytes (T Mo; CD14+CD16+), and non-classical monocytes (NC Mo; CD14loCD16+), CD14-CD16hiHLA-DR- granulocytes, CD141+ dendritic cells (cDC1), CD1c+ dendritic cells (cDC2), and CD123hi dendritic cells (pDC) in blood and bronchoscopy samples. While almost all myeloid subsets in COVID-19 patients were significantly reduced in the blood circulation compared to healthy controls (with the exception of T Mo), no statistically significant correlations between these myeloid subsets and disease severity were observed. Of note, the overall sparsity of C and T Mo subsets corresponded to high levels of serum IL-6; otherwise, there were no remarkable correlations between the frequencies of the aforementioned subsets and inflammatory markers. Importantly, in the bronchoscopy samples, an unpaired analysis identified an enrichment of granulocytes and inflammatory T and NC Mo. Importantly, a paired analysis of blood and lung samples demonstrated that T, NC, and CD1c+ DCs are significantly enriched in the lung. Collectively, these results reflect a notable recruitment of monocytes to the lung. The authors used CD40 expression as a marker of myeloid activation. While CD40 expression decreased with increasing disease severity, this trend was not significant, and expression was comparable to the cells isolated from healthy controls. Lastly, a survey of markers associated with compromised effector function of T cells isolated from blood and bronchoscopy samples of G3 patients showed that CD38+CXCR5+ T cells are significantly more prevalent in the lungs than in the blood, and differences to healthy controls were significant.
Limitations<br />
Technical<br />
One notable limitation are superinfections as a confounding variable; their effects need to be accounted for with careful multi-variate analysis and should be replicated in larger, multicenter studies. Moreover, flow cytometry markers used in the present study can present a biased view of cell populations, so future studies using higher-dimensional, unbiased techniques may provide a more inclusive view of myeloid heterogeneity in COVID-19 patients with differing severities of disease.
Biological<br />
It is important to note that almost all patients across the different groups had been receiving concurrent therapy, including antivirals, antibiotics, steroids, and immuno-modulators (anti-IL-6); it is unclear when these treatments were administered, relative to the collection of samples. Furthermore, the DC subsets defined in this report comprised significantly small proportions (< 5%) of total CD45+ immune cells isolated from blood and bronchoscopy samples of COVID-19 patients. Lastly, while T cell exhaustion was evaluated based on expression of CD38 and CXCR5, the expression of other, more prominent co-inhibitory receptors, including PD-1 or Tim-3, was not evaluated. Therefore, this report would benefit from a better study of myeloid activation and T cell exhaustion using additional markers that define activation of the myeloid subsets, including an analysis of cytokine production, and markers for T cell exhaustion.
Significance<br />
In summary, this report offers some insight into the profiling of different circulating cell subpopulations across various degrees of COVID-19 severity. However, interpretations of the results should be approached with caution, given the lack of statistical significance and of detailed analyses of important cell groups, including better-defined exhausted T cells. However, thus far, the findings outlined in this report support the notion that monocyte dysfunction, involving a pro-inflammatory state and an overall recruitment from the peripheral blood to disease-afflicted tissues like the lung, characterizes the immune response to COVID-19.
This review was undertaken by Matthew D. Park as part of a project by students, postdocs and faculty at the Immunology Institute of the Icahn school of medicine, Mount Sinai.