Differential Gene Expression in the Upper Respiratory Tract following Acute COVID-19 Infection in Ambulatory Patients That Develop [LC], 2024, Biondi+

Differential Gene Expression in the Upper Respiratory Tract following Acute COVID-19 Infection in Ambulatory Patients That Develop Long COVID
Biondi, Mia J.; Addo, Mary; Zahoor, Muhammad Atif; Salvant, Elsa; Yip, Paul; Barber, Bethany; Smookler, David; Wasif, Sumaiyah; Gaete, Kayla; Kandel, Christopher; Feld, Jordan J.; Tsui, Hubert; Kozak, Robert A.

BACKGROUND
Post-acute sequelae of COVID-19, or long COVID, is a condition characterized by persistent COVID-19 symptoms. As long COVID is defined by clinical criteria after an elapsed period, an opportunity for early intervention may aid in future prophylactic approaches; however, at present, the pathobiological mechanisms are multifactorial. By analyzing early virally infected upper respiratory tract tissue prior to eventual clinical diagnosis, it may be possible to identify biomarkers of altered immune response to facilitate future studies and interventions.

METHODS
This is a sub-group analysis of samples collected from those with confirmed COVID-19. RNA extraction from nasopharyngeal/mid-turbinate samples, sequencing, and bioinformatic analysis were performed to analyze long COVID and non-long COVID cohorts at day 14 post infection. Differences in mean viral load at various timepoints were analyzed as well as serological data.

RESULTS
We identified 26 upregulated genes in patients experiencing long COVID. Dysregulated pathways including complement and fibrinolysis pathways and IL-7 upregulation. Additionally, genes involved in neurotransmission were dysregulated, and the long COVID group had a significantly higher viral load and slower viral clearance.

CONCLUSIONS
Uncovering early gene pathway abnormalities associated with eventual long COVID diagnosis may aid in early identification. We show that, post acute infection, in situ pathogenic deviations in viral response are associated with patients destined to meet consensus long COVID diagnosis that is entirely dependent on clinical factors. These results identify an important biological temporal window in the natural history of COVID-19 infection and long COVID pathogenesis amenable to testing from standard-of-care upper respiratory tract specimens.

Link | PDF (Pathogens) [Open Access]

 

[12] is Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection (2023, JAMA)

 

GeneCards —

CE2C
KLK4
KRT79
LINC00664
RPS6KA1
YWHAE
NBPF26_1
LIMS4
APCDD1L-DT
SMDT1
ITGA2B
SPPL2C_1
KCNH5
LACRT
LOH12CR2
CPB2
LOC107984156
RPS25_1
SNAP25
SDR9C7
C8G
LINC02389
СРА2
CST4
TMEM78
LCE2B

 

[26] is Carboxypeptidase U CPU, carboxypeptidase B2, activated thrombin‐activatable fibrinolysis inhibitor inhibition stimulates the fibrinolytic rate in different in vitro models (2018, Journal of Thrombosis and Haemostasis)

 

A hope-inducing study, but it was small and the groups weren't well matched
e.g. LC 77% female; controls 50% female

Data on symptoms were collected at day 90 or later:
6/9 of the LC group reported post-exertional malaise (as did 2/18 of the controls)
8/9 of the LC group reported alterations in smell and taste (as did 4/18 of the controls)

 

This is Figure 2a



Genes are the rows, columns are different participants, with the Long Covid participants identified by the red bar at the top (versus black of the controls).

What I want to show you is the variation. Take the gene at the top, NBPF26, really only one participant was expressing that gene differently. YWHAE is mentioned in the text, but at most 6 participants have a higher expression of that gene, and 2 of them are controls.

Advocates often say 'look at all the abnormal results, there is so much evidence of pathology' and might point to a study like this. And, in there somewhere, there may well be the clue, something that really is different. But, there's a lot of noise.

They have grouped the genes together according to the similarity of their expression across the participants (on the left). I would have preferred to see the patients grouped together according to their gene expression.

 

I don't think we can assume that this tells us anything about ME/CFS-like Long Covid. With 8/9 of the Long Covid participants having issues with taste and smell, it might just be indicating that high viral loads in nasal swabs is associated with taste and smell disturbances.

We need more studies like this, but bigger, and with "Long Covid" criteria broken down into subgroups that make sense. We already know that alterations to taste and smell don't seem to have much to do with the ME/CFS-like pattern of symptoms. Persisting cough doesn't seem to either, it probably can be part of a symptom collection to do with easily identifiable lung tissue damage. If controls are reporting PEM, then it is possible that people haven't understood what PEM is.