20 Augustus 2022 Episode 283 COVID and Herpes viridae

Dear colleagues,

Triggered by a clinical “case” on herpes labialis (fever buttons) during a recent COVID reinfection (with BA.5?), I was wondering about the interplay between COVID and Herpesviridae. 

Background:

As we know, Herpes simplex type 1 (HSV-1), Cytomegalovirus (CMV), Epstein Barr virus (EBV) and Varicella Zoster Virus (VZV) are present as chronic asymptomatic infections in a large part of the population.  They are kept in a “latent” state by a healthy immune system (mainly through CD8 T cells).  In many instances of minor immune suppression (e.g. pregnancy, fever), HSV and VZV can “reactivate” (presence of virus in blood and/or tissues) and produce annoying symptoms (limited fever buttons, singles, some “malaise”), while during more pronounced and longstanding immune suppression (metastatic cancer, HIV, transplantation and use of corticosteroids or other immune suppressive drugs) more serious complications can occur.  These can include focal severe syndromes such as HSV or CMV pneumonitis, hepatitis, encephalitis; but also widespread singles; CMV retinitis or even development of (EBV-related) lymphomas. A more generalized “chronic fatigue” without clear localization is also possible.

CMV occupies a special place as it is the most “immunogenic”: to keep the virus latent, strong and prolonged T cell activation is needed, leading to “immune exhaustion” and immune senescence in the long run, potentially even in non-geriatric patients.  

With this background, I screened the literature for evidence of Herpes virus related disease during COVID infection.

Summary of findings and reflections:  

1. HSV reactivation has been shown in association with severe COVID and some HSV syndromes (widespread skin manifestations, hepatitis, pneumonitis, encephalitis) may be associated with increased mortality
2. Severe COVID in general can also be associated with CMV reactivation.  The relation with dexamethasone therapy is controversial.  There is increased mortality in CMV-reactivation, but rather via association with bacterial superinfection and/or mechanical ventilation.   In kidney transplant patients, CMV reactivation may also play a role in mortality
3. Latent CMV infection even in non-geriatric patients, may predispose to symptomatic SARS-CoV-2 infection and hospitalization. This may relate to “immune exhaustion/senescence.
4. Serologic evidence of EBV reactivation has been associated with severe COVID in Wuhan, but also with long COVID.  Long COVID was also positively associated with HIV, but negatively with CMV.
5. Mild, but also severe clinical VZV reactivation has been associated with COVID in a limited number of cases.  There is also some a rare association with COVID vaccination, especially with the first dose of mRNA vaccine.   

As you will see in the summary of the relevant papers and reviews below, the evidence is not really strong, because  most studies are observational, often retrospective and in rather small numbers.  In most cases, no relevant matched controls are considered for comparison. 

Therefore, it is questionable whether there is any specificity in the observed associations or is it rather a consequence of hyper-inflammation, temporary or chronic immune exhaustion and all the conditions associated with ICU (including bacterial superinfection), just like in patients with other life-threatening pneumonias or sepsis.

All the published studies were related to the early waves, none to omicron.

Nevertheless, there may be some benefit of appropriate therapy, including acyclovir (HSV) and ganciclovir (CMV).  

Par 1 HERPES VIRUS TYPE 1 (HSV-1)

Ep 283-1: Antoine Meyer Critical Care Dec 2021  PCR-documented HSV-1 reactivation in a prospective study of 153 hospitalized patients is associated with increased mortality and hospital- or ventilator associated pneumonia (HAP/VAP) between Feb 2020 and Feb 2021 (D614G and Alpha waves)

 Ep 283-2: Sanchez-Belmonte Medicina Clinica April 2022:  In 83 patients with mechanical ventilation for COVID ARDS  HSV-1 PCR positivity in the broncho-alveolar lavage and anapath.  evidence of HSV-1 were associated with increased 30 day mortality.

Ep 283-3: Francescini Microorganisms Sept 2021

Almost one-third of 70 patients with severe/critical SARS-CoV-2 pneumonia experienced HSV-1 re-activation, with 62% of those presenting clinical manifestations: 4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, 1 encephalitis and 2 hepatitis

Factors associated with HSV-1 reactivation: mechanical ventilation, use of steroids (but NOT anti- IL-6)

Ep 283-4: Presenting dermatological manifestations for SARS-CoV-2 infection

Ep 283-4 A:  Anjum Cureus Pakistan 204 SARS-CoV-2 (+) patients presenting to tertiary care hospital:

• 47 patients (24 %) showed specific dermatological manifestations: ecchymosis/purpura in 50% (n=22), maculopapular exanthem in 18% (n=8), livedo reticularis in 16.2% (n=7), ischemia/gangrene in 16.2% (n=7), perniosis in 15.9 % (n=7), vesiculo-bullous rash in 9% (n=4) and urticaria in 4% (n=1). 
• 13 (6.4 %) patients with “non-specific manifestations”: of those only 3 herpes labialis!

Signs of bad prognosis:

• Ischemia/gangrene and urticaria were associated severe disease
• Ischemia/gangrene and vesiculo-bullous rash associated with mortality

Ep 283-4 B: Barman JFMPC India: Three patients with dermatological features resembling (i) varicella zoster, (ii) herpes labialis, and (iii) Steven Johnson Syndrome (SJS) who were subsequently diagnosed with Covid‑19 infection.

Ep 283-4 C: Rodriguez-Cerdeira Biology: 31 cases from 5 countries

Maculopapular rashes (16.10%), urticarial lesions (26.80%), pseudo-chilblains (22.60%), petechiae/purpura (6.50%), distal ischaemia and necrosis (6.50%), livedo racemosa (12.90%), and others (9.70%).

Rash (with or without fever) may be the only early clinical manifestation of COVID-19

Ep 283-5: Giaccobe Infect Dis Ther July 2022 reviews HSV-1 reactivation in critically ill COVID

• Prevalence of HSV-1 reactivation may be as high as 50%, but with large heterogeneity across studies, likely reflecting the different definition, samples and/or cut-offs employed for defining reactivation.

• Clinical implication (bad prognosis) is likely if proven systemic skin manifestation, hepatitis, encephalitis as well as  worsening of respiratory symptoms or anapath evidence of HSV pneumonitis
• Uncertain whether HSV-1 reactivation without clinical HSV manifestation has a prognostic significance

• Therapeutic approaches ranging from prophylaxis to selected antiviral treatment with Acyclovir.  

PAR 2 CYTOMEGALOVIRUS (CMV)

Ep 283-6: Ilenia Gatto Int Care Med 2022 Cytomegalovirus blood reactivation in COVID‑19 critically ill patients

Out of 431 consecutive COVID patients, admitted to ICU Feb 2020-July 2021, 20% showed CMV reactivation, which was associated with higher age, lower platelet counts, more secondary bacterial infections and higher degree of respiratory insufficiency.

Although mortality was higher in the CMV reactivated patients, it was not an independent risk factor ;

while mechanical ventilation and bacterial infections were clearly associated with mortality.

Ep 283-7: Jan-Hendrik Naendrup J Intens Care Med Oct 2021: Reactivation of EBV and CMV in Severe COVID-19—Epiphenomena or Trigger of Hyperinflammation?

A retrospective study on ICU patients with either COVID-19 (n = 117)  or sepsis (n= 126):

• In both groups a similar percentage developed reactivation of EBV (14-16 %) or CMV  (9-13 %)
• A majority of reactivations occurred in the context of steroid- or immune suppressive therapy, again rather similar in COVID and non-COVID patients
• Remarkably: no correlation between viremia and inflammatory lab markers identified.

• Treatment of EBV with rituximab (anti-CD20) did not have a clear effect, but treatment of CMV with ganciclovir seemed beneficial for survival

• Many limitations: retrospective, non-systematic, no matching of control group

Conclusion: Critically ill patients with COVID-19 or sepsis are at high risk for both EBV and CMV reactivations.

Whether viral reactivations are a pathologic cause of hyperinflammation in need of treatment

or epiphenomena related to the severity of COVID-19 or the treatment with systemic corticosteroids remains uncertain

Ep 283-8: Kristina Fuest Multidisc. Resp. Med. 2022: Risk factors for HSV and CMV reactivation in critically ill COVID

All 134 mechanically ventilated COVID March 2020-Jan 2021 in ICU unit: 45 % showed HSV reactivation, 0 % CMV

• Associated with duration of stay in ICU and mechanical ventilation
• NOT associated with dexamethasone or immune suppressive therapy
• No significant difference in mortality between HSV (+) and HSV (-) (57 vs 45 % p = 0.2)

KIDNEY TRANSPLANT RECIPIENTS (KTR)

Ep 283-9: Udomkarnjananun  Sci Rep Nov 2021: Review on mortality risk of COVID-19 in KTR up to Aug 2021

Meta-analysis on 4440 KTR in 13 studies:

• Older age
• Deceased donor graft
• Diabetes
• Cardiovascular disease
• Active cancer
• Pneumonia

Co-infections NOT systematically investigated.

Ep 283-10: Choudhary BMC Nephrology July 2022: Risk factors for COVID mortality in KTR

Matched case-control of 30 KTR who died vs 188 survivors between March 2020 and July 2021:

Oxygen requirement and mechanical ventilation, but also coinfection (with CMV) as well as diarrhea were the most important risk factors for mortality

LATENT CMV (= seropositivity without evidence of reactivation)

Ep 283-11: Aleano J Infect Dis Feb 2022  CMV Latent Infection Associated with Risk of COVID-19- Hospitalization

1. CMV seropositivity associates with risk on SARS-CoV-2 positivity in Penn Medicine Biobank cohort

2. CMV seropositivity associates with risk on hospitalization

Ep 283-12: S Weber PLoS One May 2022 CMV (and HSV) seropositivity risk factor for severe COVID-19                                                                                                               in non-geriatric patients

PAR 3 Epstein-Barr Virus (EBV)

Reminder of serological evidence of initial infection or reactivation of EBV  (VCA = viral capsid antigen)

SEVERE ACUTE COVID

Ep 283-13 : Mei Meng Imm Infl Dis Jan 2022  COVID‐19 associated EBV reactivation and effects of ganciclovir

Retrospective study on 217 COVID patients in Wuhan Jan-March 2020 with EBV and CMV serology

In 55 serological evidence of EBV reactivation (Ab to Early Antigen): associated with higher age, female sex and non-significant risk of mortality (22% in reactivation vs 11 % non-reactivation).

Remarkably: ganciclovir treatment was associated with significantly better survival

Note: CMV reactivation as measured with IgM Ab was not associated with outcome

Cave: no PCR for EBV or CMV was done

LONG COVID

Ep 283-14: Jeffrey Gold Pathogens June 2021: Serological EBV reactivation in long COVID

Association between Early Antigen IgG and Viral Capsid IgM Ab positivity in a small series of 30 patients with long COVID versus 20 controls.  

Ep 283-15: Peluso medRxiv July 2022 Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

In a cohort of 280 adults with prior SARSCoV-2 infection Long COVID (LC) symptoms (fatigue and neurocognitive dysfunction) at a median of 4 months

• Independently associated with  serological evidence of recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen IgG levels, but not with ongoing EBV viremia.
• Evidence of EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12).

Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5).

Serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52)

PAR 4 VARICELLA ZOSTER VIRUS (VZV)

Ep 283-16: Czech Int J Dermatol 2022: Scoping review of VZV reactivation in COVID patients. 

Only 19 articles (of which 16 observational and 3 case reports):

25 patients with VZV associated with COVID, of whom 12 with disseminated location

→ Lack of strong association, but evidence of more severe VZV in COVID

Ep 283-17:  Martinez-Revejo Eur J Int Med 2022  Systematic review on VZV reactivation after SARS-CoV-2 vaccination or infection  (55 papers)

179 cases after vaccination:

• Mostly mRNA (84 %), mostly after 1st dose. 
• Mostly (86.6 %) dermatome singles; but 11.3 % serious (e.g. herpes ophtalmica or post-herpectic neuralgie)  

39 cases associated with COVID disease

Higher percentage of disseminated and serious complication (32 %) than VZV after vaccination  (but still lower than in series of Ep 282-16).

I hope you enjoyed!

Best wishes,

Guido