Preprint Analysis Of Salivary Herpesviruses Reveals Associations Between HHV-6 And Long COVID Severity, 2026, Laxton, Putrino, Iwasaki+

[SNT Gatchaman]

Analysis Of Salivary Herpesviruses Reveals Associations Between HHV-6 And Long COVID Severity

Spoiler: Authors

Claire S Laxton; Alexandra Tabachnikova; Lily Cooke; Kexin Wang; Simone Blaser; Julio Silva; Jamie Wood; Henna Nam; Zhenni Lu; Christine Miller; Gisele Rodrigues; Victoria Fisher; Christian Guirgis; William B Hooper; Alexandra Lee; Mackenzie Doerstling; Bornali Bhattacharjee; Leying Guan; David Putrino; Akiko Iwasaki

BACKGROUND
Reactivation of human herpesviruses (HHVs), particularly EBV, is associated with more severe acute SARS-CoV-2 infections and the development of Long COVID (LC). Observations of higher anti-EBV antibody levels in individuals with LC support the idea that chronic reactivation of HHVs could contribute to LC pathology. HHV shedding in saliva has also been previously associated with saliva hormone levels. This study aims to examine the relationship between salivary shedding of HHV DNA and LC symptoms, as well as cortisol, testosterone, and estradiol levels.

METHODS
We enrolled 45 participants with LC, and 45 age-sex-matched controls. Surveys and validated health questionnaires were used to collect demographics, medical history, and symptom profiles. Saliva was self-collected at waking, 15, 30, and 45 minutes, and 8 and 16 hours after waking, across two consecutive days. Salivary cortisol, testosterone and estradiol were measured, and extracted nucleic acid was tested for EBV, HSV 1/2, HCMV and HHV-6 A/B using multiplex qPCR, plus SARS-CoV-2 and RNaseP using RT-qPCR.

FINDINGS
Detection of salivary EBV and HHV-6 DNA was highest early in the morning. There were no significant differences in salivary cortisol, testosterone, or estradiol, or in EBV or HHV-6 shedding between the LC and control groups. However, salivary HHV-6 DNA levels were positively associated with a greater aggregated LC propensity score, as well as anxiety and depression scores.

INTERPRETATION
The observed correlation between salivary HHV-6 shedding and symptom severity suggests HHV-6 may contribute to post-acute disease, though mechanisms remain unclear. While our study did not identify a relationship between salivary EBV shedding and LC, EBV may still play a role at earlier time points in the disease course, or in compartments not sampled here. These findings highlight the potential importance of HHV-6 in LC pathophysiology and underscore the need for longitudinal, multi-compartment studies of herpesvirus reactivation in LC.

Web | DOI | PDF | Preprint: MedRxiv | Open Access

 

[Murph]

A hint of hhv-6 being involved in severity in long covid? Given we already have reason to think it might be involved it would probably be wrong to totally exclude this study even though its finding is not a blaring foghorn. Not conclusive on its own but another stone to throw on the pile.

There's some other results in here that could hit statistical signifcance with a bigger sample size - assuming they're real - but they'd still have a moderate effect size.

I;d like to have a saliva based test we could really roll out but this isn't it I don't think.

Good to get another confirmation that cortisol is the same between patients and controls.

 

[ChronicallyOverIt]

A hint of hhv-6 being involved in severity in long covid?

they stratify into such a small group then compare against mean controls I don’t think there’s enough power to make that correlation.

Weird to me they enrolled ppl on anti-virals for herpes and possibly included them? Maybe I’m reading that flow chart wrong.

 

[Jonathan Edwards]

If there is no difference between groups a correlation with severity of symptoms is almost certainly a confounder, since symptoms here are so vague. Salivary herpes virus might correlate with not being well generally - like cold sores appearing.

 

[Mij]

I experience repeated reactivations of herpes viruses from triggers such as stress, allergies and hormonal changes. I get them on my lips and my mouth bleeds starting Spring time. I also experience viral vestibular sickness that last for months that can be severe. All my lymphocytes (CD4, CD8 are all way below normal) so not surprised my immune system isn't keeping them in check.

They've been hypothesising persistent and relapsing HHV6 and EBV for decades in pwME/CFS.

 

[duncan]

I spent the first half century of my life believing diagnostics were trustworthy and authoritative and final.

The last two decades has seen the slow unraveling of that belief.

The most recent five years, a desolate realization has breezed over me that, diagnostically speaking, we've been had.

 

[wigglethemouse]

Wasn't the same found by Dr Cliff et al in ME/CFS using digital droplet detection that led to a large well funded follow-up study, both funded by NIH?

 

[Mij]

Could someone explain this saliva sample testing image posted by Prof. Akiko Iwasaki regarding the study?

 

[Utsikt]

Could someone explain this saliva sample testing image posted by Prof. Akiko Iwasaki regarding the study?
View attachment 32476

Left is when the participants collected saliva samples relative to when they woke up. So they did 6 samples on two separate days with most of them within the first hour.

Right says what kind of info they had to write down when collecting the samples.

 

[PageofME]

Really nice to see that Iwasaki together with the group from Mount Sinai has already managed to reproduce Jacqueline Cliff's HHV6 findings from ME/CFS in a Long Covid cohort.

I can't judge this precisely but it looks to me that the Americans have a lot more people and resources for their projects compared to the other herpes leaders in ME/CFS like Cliff, Ariza, and Prusty because it seems that Iwasaki is going at a really good pace.

I already look forward to what they will come up with next to further understand the role of HHV6 in ME. Also, Iwasaki is a chair woman of Roche so as soon as they will have anything substantial the Swiss pharmaceutical company is ready to try to develop blockbuster therapies.

On a personal note I am really looking foward to a cure for this illness and hopefully not spending the rest of my life on high doses of valaciclovir.

 

[PageofME]

I experience repeated reactivations of herpes viruses from triggers such as stress, allergies and hormonal changes. I get them on my lips and my mouth bleeds starting Spring time. I also experience viral vestibular sickness that last for months that can be severe. All my lymphocytes (CD4, CD8 are all way below normal) so not surprised my immune system isn't keeping them in check.

They've been hypothesising persistent and relapsing HHV6 and EBV for decades in pwME/CFS.

Contrary to what many pwME believe, that herpes is a simple problem and that ME is "complex", herpes are not easy to research and it's only in the past twenty years or so that infectological dogma and research technologies have shifted and advanced respectively so that latent virus reactivation moves back to the center of ME research and begins to deserve the attention and investigation that it should have had for a long time.

 

[PageofME]

Weird to me they enrolled ppl on anti-virals for herpes and possibly included them? Maybe I’m reading that flow chart wrong.

I think so too.

they stratify into such a small group then compare against mean controls I don’t think there’s enough power to make that correlation.

Weird to me they enrolled ppl on anti-virals for herpes and possibly included them? Maybe I’m reading that flow chart wrong.

This type of studies are called preliminary studies. They are so small because they want to test whether a hypothesis might make sense at all or not. They don't think that they have revolutionized ME research with these results but they now know that it makes sense to design a more elaborate and more expensive study and this study here will help them get these bigger studies funded.