Nature - Pathological sequelae of long-haul COVID by Mehandru, Merad, 2022

[Kalliope]

Abstract:

The world continues to contend with successive waves of coronavirus disease 2019 (COVID-19), fueled by the emergence of viral variants.

At the same time, persistent, prolonged and often debilitating sequelae are increasingly recognized in convalescent individuals, named ‘post-COVID-19 syndrome’ or ‘long-haul COVID’.

Clinical symptomatology includes fatigue, malaise, dyspnea, defects in memory and concentration and a variety of neuropsychiatric syndromes as the major manifestations, and several organ systems can be involved.

The underlying pathophysiological mechanisms are poorly understood at present.

This Review details organ-specific sequelae of post-COVID-19 syndromes and examines the underlying pathophysiological mechanisms available so far, elaborating on persistent inflammation, induced autoimmunity and putative viral reservoirs.

Finally, we propose diagnostic strategies to better understand this heterogeneous disorder that continues to afflict millions of people worldwide.

https://www.nature.com/articles/s41590-021-01104-y

 

[Hutan]

The article refers to a study that has good controls - we have a thread on the study here
Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection, 2021, Phetsouphanh et al

A recent study prospectively examined a cohort of 31 individuals with long-haul COVID (based on the presence of one of three major symptoms: dyspnea, fatigue and chest pain), age and gender matched with 31 individuals who had prior COVID infection but lacked long-haul COVID symptoms. In addition, 25 individuals infected with common cold coronaviruses and unexposed healthy individuals (n = 46) served as controls (66).

Patients with long-haul COVID demonstrated persistent increases in the frequency of activated CD14+CD16+ monocytes and plasmacytoid dendritic cells, compared with control individuals 8 months after infection (66). Furthermore, patients with long-haul COVID demonstrated persistent elevation in the levels of type I (IFNβ) and type III (IFNλ1) interferon 8 months post-infection (66). In the study, a combination of IFNβ, pentraxin 3, IFNγ, IFNλ2/3 and IL-6 was associated with long-haul COVID, with an accuracy ranging from 78.5% to 81.6% (66). These analytes have been associated with acute severe disease, suggesting a delayed or defective resolution of inflammation in long-haul COVID individuals.

 

[Hutan]

The diagram in the Nature article provides a good summary of the ground covered:

 

[Hutan]

Viral persistence is one hypothesis discussed, and surely one that could be investigated fairly easily.

To determine whether there might be antigen persistence in the intestine after resolution of clinical illness, we obtained biopsies from the gastrointestinal tract of 14 individuals at an average of 4 months (range 2.8–5.7 months) after initial COVID-19 diagnosis51. SARS-CoV-2 N protein was detected in intestinal enterocytes in 5 out of 14 individuals51. Furthermore, 3 out of the 14 participants produced PCR amplicons that were sequence verified as SARS-CoV-2 (ref. 51). Viral detection in the intestinal epithelium was patchy and sporadic, and none of the patients had symptoms of long COVID. Human body fluids, including bronchoalveolar lavage, sputum, saliva, blood, urine and feces, have also been demonstrated to harbor the virus106.

These data provide proof of principle that SARS-CoV-2 can potentially persist in specific tissues in a manner that would be consistent with the persistence of other nonretroviral RNA viruses107. However, much remains to be determined about SARS-CoV-2 persistence in humans.

They note that they found CoV-2 in the gastrointestinal tract of some individuals at 4 months, although these individuals didn't have Long Covid. It seems plausible that some ongoing host-virus interaction might result in ME/CFS symptoms. There have been suggestions of persistence in fatigue syndromes following Ebola, EBV, rickettsias, other tick borne diseases and more. As the authors suggest, longitudinal measurement of the persistence of viral reservoirs and correlating that with Long Covid symptoms could be very useful.

That the various hypotheses are discussed in Nature seems promising - hopefully it will encourage more research.

 

[Hutan]

Optimal profiling of the immune response before and at different times during the post-COVID syndrome should best help unravel the pathophysiological mechanisms that contribute to the development of the post-COVID syndrome (Fig. 1). Unbiased profiling should include the measurement of systemic and local secreted inflammatory proteins, single-cell RNA profiling of circulating and local immune cells that accumulate at the disease site, as well as detailed ex vivo imaging of diseased organs. Multiplex imaging and spatial transcriptomics analysis of tissue biopsies are also very helpful for measuring the extent of the tissue damage, as well as cellular interactions of immune cells, inflammatory molecules and damaged cells and the potential presence of a viral reservoir.

I like that they noted that immune response profiling has to go beyond the old 'cytokine levels in peripheral blood' analysis. Tissues need to be studied and more detail recorded about the various immune cells.

I also like the recognition in the article that Long Covid is an important problem to solve. The article finishes with some commentary about the NIH PASC initiative.

In February 2021, the National Institutes of Health launched a major initiative known as the PASC initiative to bring together clinicians and researchers to study how to prevent and treat the long-term effects of SARS-CoV-2 infection. One major objective is to collect data from patients who have had COVID-19, both with and without long-term symptoms, and compare them with people who may never have been infected by SARS-CoV-2. The initiative will help to collect large patient cohorts, including children and adults from diverse backgrounds, to ensure that the findings apply to the communities that have been most affected by COVID-19. Here again, it will be important to use cutting-edge technologies to decipher the molecular heterogeneity of post-COVID syndrome and identify precise druggable targets tailored to these defects.