Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long COVID from controls, 2025, Buonsenso+

Background
Recent proteomic studies have documented that Long COVID in adults is characterized by a pro-inflammatory signature with thromboinflammation. However, if similar events happen also in children with Long COVID has never been investigated.

Methods
We performed an extensive protein analysis of blood plasma from pediatric patients younger than 19 years of age Long COVID and a control group of children with acute COVID-19, MIS-C, and healthy controls resulted similar for sex distribution and age. Children were classified as Long COVID if symptoms persisted for at least 8 weeks since the initial infection, negatively impacted daily life and could not be explained otherwise.

Results
112 children were included in the study, including 34 children fulfilling clinical criteria of Long COVID, 32 acute SARS-CoV-2 infection, 27 MIS-C and 19 healthy controls. Compared with controls, pediatric Long COVID was characterized by higher expression of the proinflammatory and pro-angiogenetic set of chemokines CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. A Machine Learning model based on proteomic profile was able to identify LC with an accuracy of 0.93, specificity of 0.86 and sensitivity of 0.97.

Conclusions
Pediatric Long COVID patients have a well distinct blood protein signature marked by increased ongoing general and endothelial inflammation, similarly as happens in adults.

Link | PDF (Nature Paediatric Research, January 2025)

 

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Reference [39] is to this paper which reported that plasma levels of FGF21 and NT-proBNP were significantly elevated in ME/CFS patients (although no correlation was seen with outcome measures).

 

Fatigue vs non-fatigue subgroup comparison:



FGF21 - primarily secreted by the liver, is a significant regulator of glucose & lipid metabolism and is implicated in modulating insulin sensitivity; also appears to be able to suppress pro-inflammatory cytokines like TNF in certain contexts.

 

Corresponding author has a Substack and a Xitter account with quite a bit of ME/CFS discussion (haven't read through but, looking at the titles, one Substack post even discusses the MEA/Riley issue).

 

@mariovitali liver

 

I skimmed some posts. It seems like he goes beyond the evidence regarding e.g. meds and the immune system.

He also encourages strict rest for severe patients, and movement without PEM for non-severe. Unfortinately, he also talks about gradually increasing the activity level:
https://danilobuonsenso.substack.com/p/long-covid-mecfs-and-movement

To severely ill patients, I do suggest complete rest and pacing. I talk with parents, teachers and so on. Do not push the guy. Let him/her rest. This is key part of the recovery from the crash. Stop saying it’s psychological, it’s inflammation, immunity, bad metabolism, and so on. This patient has to fully rest. Plus, I usually consider a combination of medications, including IVIG, low dose anticoagulation, metformin, ivabradin, antivirals, on a case-by-case scenario

However, there is a large cohort of patients (as I said, I mostly have young patients, children or adolescents) that are ill but not so much to stay bed-bounded the all day. To them, I suggest pacing. Pacing does not means staying at home doing literally nothing. I always say the following: “we need to find for you, and you need to find by yourself, as you can only really discover this, a proper balance between not doing too much, but also not doing nothing. Both will harm you. If you do too much, you crash due to PEM, and you worsen. If you remain bed bounded while you have the potential to tolerate minimal movements, it will harm you as well. It will harm you because you will spend too much time on social media or TV, you will eat trash food more (remember I mostly talk with young patients), you will gain weight, you will loss muscle tones, all things that will make you worsening. So, we need to find a proper balance”.

Usually, in these cases, I suggest my patients not to go to gym, but to have a walk in the nature (eg in plane, not climbing mountains), some minutes a day. If this is tolerated, they can slowly slowly gradually increase. They don’t have to feel a minimal worsening. If they can attend one or two hours of school a day or a week, without crashing, I suggest to do that. It is important to keep some brain activities up, but also to keep social connections.

https://danilobuonsenso.substack.com/p/my-pharmacological-approach-for-long

https://danilobuonsenso.substack.com/p/t-cell-exhaustion-and-mecfs

 

In the absence of any findings with more robust markers I find it hard to be excited by a few chemokines, which are usually pretty uninterpretable. There is no such thing as endothelial inflammation so I am overall sceptical.

 

Regarding the SULT2A1 that @Hutan mentioned. Machine Learning has identified several Sulfotransferases genes as important. Post in 2017


https://twitter.com/user/status/905100352621608960


Also regarding viral persistence and the association of LXR and SULT2B1 : (2023)

https://twitter.com/user/status/1716892855627870282


During a presentation I made to the team of Wenzhong Xiao,the medical concept of human transferases seems to be taking a central role for ME/CFS

 

https://www.eurekalert.org/news-releases/1071370

News Release 24-Jan-2025
Long COVID, Italian scientists discovered the molecular ‘fingerprint’ of the condition in children's blood
Peer-Reviewed Publication

Universita Cattolica del Sacro Cuore


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One day Long Covid in children could be objectively diagnosed with a blood test, thanks to the help of Artificial Intelligence (AI). In fact, a study by the Università Cattolica del Sacro Cuore, Rome campus - Fondazione Policlinico Universitario Agostino Gemelli IRCCS and the Ospedale Pediatrico Bambino Gesù IRCCS, has highlighted the molecular signature of Long Covid in plasma in paediatric age and used an AI tool capable of making the diagnosis based on the results of the blood sample, with 93% accuracy.

The study was published in the journal ‘Pediatric Research’, by Nature Group, and was led by Dr. Danilo Buonsenso, researcher in general and specialist paediatrics at the Faculty of Medicine and Surgery of the Catholic University and paediatrician at the Pediatric Infectious Diseases Operative Unit of the Fondazione Policlinico Gemelli IRCCS, together with Dr. Nicola Cotugno, at the Complex Operative Unit of Clinical Immunology and Vaccinology of the Bambino Gesù IRCCS Paediatric Hospital.

The study involved, among others, Dr. Piero Valentini, researcher in General and Specialist Paediatrics at the Faculty of Medicine and Surgery of the Catholic University and director of the Paediatric Infectious Diseases Operative Unit of the Fondazione Policlinico Gemelli IRCCS, and Dr. Paolo Palma, head of the Complex Operative Unit of Clinical Immunology and Vaccinology of the Bambino Gesù Children's Hospital IRCCS.



BACKGROUND

Long Covid affects on average 0.5% of pediatric patients exposed to SARS-CoV-2. This condition, also known as Post COVID or Post-Acute Sequelae of SARS-CoV-2, is characterized by the persistence of signs and symptoms for at least 8-12 weeks, symptoms not present before the viral infection, with a negative impact on daily life. Long COVID affects patients of almost all age groups, and among pediatric patients those older than 10 years seem to be most affected, regardless of the severity of the initial infection.

In adults, the Long COVID ‘sign’ was found in the blood of adults, but a similar finding in the paediatric population was lacking.



THE STUDY

The experts analyzed the blood of 112 young people aged 0-19 years, of whom 34 had a clinical diagnosis of Long COVID, 32 had the active infection at the time of the study, 27 had Multisystem Inflammatory Syndrome (MIS-C, a severe hyper-inflammatory reaction that almost always requires intensive care) and 19 healthy control peers.

The experts performed an analysis of the blood protein component (proteomics) and saw that, compared to the control groups, the pediatric Long COVID was characterized by a higher presence in plasma of the pro-inflammatory and pro-angiogenic chemokine sets CXCL11, CXCL1, CXCL5, CXCL6, CXCL8, TNFSF11, OSM, STAMBP1a. An artificial intelligence model based on proteomic profiling was able to identify long Covid with an accuracy of 0.93, a specificity of 0.86 and a sensitivity of 0.97.



CONCLUSIONS

Long Covid in pediatric patients also presents a distinct protein signature in plasma, characterized by increased inflammation in general and at the level of blood vessel walls (endothelia), as already seen in adults. The discovery could lead to the development of a simple routine diagnostic test based on a blood sample, allowing timely and complete care of the pediatric patient with Long Covid.

‘The immunological data produced in this study provide the evidence needed to identify therapeutic targets to be tested in efficacy and safety studies in pediatric Long Covid,’ Dr Cotugno of the Bambino Gesù Children's Hospital explains.

‘This work demonstrates incontrovertibly that Long Covid, also in pediatric age, is an organic immune-mediated disease, for which new funding is needed to study the best therapeutic approaches,’ Dr Buonsenso concludes.



Journal
Pediatric Research

Method of Research
Observational study

Subject of Research
People

Article Title
Distinct pro-inflammatory/pro-angiogenetic signatures distinguish children with Long Covid from controls

Article Publication Date
24-Jan-2025

 

Absolutely right , I only wanted to mention that the family of sulfotransferases have been previously identified as a potential research "hotspot"