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Febrile #121: Windpocken with Infektiopod

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Summary

Drs. Till Koch and Annette Hennigs join to discuss their ID podcast Infektiopod and dive into varicella!

Table of Contents

Credits

Host: Sara Dong

Guests: Till Koch, Annette Hennigs

Writing: Till Koch, Annette Hennigs, Sara Dong

Editing, Cover Art: Sara Dong

Produced by Sara Dong with support from the Infectious Diseases Society of America (IDSA)

Our Guests

Dr. Till Koch

Till Koch is an attending in infectious diseases and antibiotic stewardship at Itzehoe, Germany. He divides his time between the inpatient ID ward, consultation service, and antibiotic stewardship efforts in his rural hospital.

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Dr. Annette Hennigs

Annette Hennigs is a Senior Fellow in Infectious Diseases at the University Medical Center Hamburg Eppendorf in Germany. Her daily business is leading the consultation service. Her main focus of interest is cardiovascular infections.

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Culture

Annette has enjoyed going to concerts with her kids, including a recent Taylor Swift show.

Till has been enjoying carpentry and building furniture in his workshop.

Consult Notes

Case Summary

56 yo woman s/p heart transplant who presented with new vesicular rash and is found to have disseminated VZV infection

Key Points

Introducing Infektiopod!

This episode featured a case of VZV reactivation in a heart transplant recipient. Let’s refresh on varicella zoster virus!

  • VZV is herpes virus-3 (HHV-3). Do you remember the other herpesviruses numbered 1 to 8? Check below for a review:
      • HHV-1 = HSV-1
      • HHV-2 = HSV-2
      • HHV-3 = VZV
      • HHV-4 = EBV
      • HHV-5 = CMV
      • HHV-6
      • HHV-7
      • HHV-8
  • Primary infection with VZV is acquired through direct contact with skin lesions or through airborne spread from respiratory droplets —> chickenpox can be asymptomatic or result in clinical varicella infection
  • After infection, VZV establishes lifelong latency in cranial nerve and dorsal root ganglia —> reactivation infection later is known as herpes zoster (HZ) or “shingles”
  • Seroprevalence in adults is around 90%, either through vaccination or natural infection
      • 2-3% of adult SOT candidates are seronegative, while ranges vary in children from 7-50%
      • Adults living in tropical regions show lower seroprevalence rates
  • The lifetime risk of herpes zoster (as reactivation) in previously infected patients is around 20%
      • In SOT recipients, it is around 8-11% in the first four years after transplant (risk factors include older age, heart and lung transplantation)
  • Chickenpox is very contagious: secondary attack ratios of ~85% (range 61-100%) in susceptible household contacts
      • Herpes zoster/shingles is much less infectious compared to varicella (about 1/5th) —> in susceptible people, contact with herpes zoster rash causes varicella, not herpes zoster
  • Individuals infected with VZV are contagious for 24 to up to 48 hours before the typical rash develops → makes it difficult to prevent transmission of VZV to susceptible hosts
  • Key resource for reviewing VZV in solid organ transplant: Pergam SA, Limaye AP; AST Infectious Diseases Community of Practice. Varicella zoster virus in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13622. doi:10.1111/ctr.13622

Comparing primary varicella infection and shingles in transplant recipients

Primary varicella infection

  • Symptoms of varicella in transplant patients is similar to primary varicella symptoms seen in the general population: fever, constitutional symptoms, and a vesicular, pruritic, and widely disseminated rash (primarily trunk and face)
    • The rash is sometimes described as “dew drops on a rose petal”
  • SOT recipients are at greater risk of complications like pneumonia from primary varicella – this is of course rare in adult SOT patients but these complications can be severe

Shingles (VZV reactivation)

  • Reactivation disease can be classic dermatomal shingles but immunosuppressed patients are more likely to develop multi-dermatomal or disseminated zoster (which could mimic primary varicella)
  • Classic shingles presentation is typically rash and acute neuritis.
    • The rash: erythematous papules, typically in a single dermatome or several contiguous dermatomes. “dewdrop on a rose petal”
    • Acute neuritis: Pain is the most common symptom of herpes zoster. Most patients describe a deep “burning,” “throbbing,” or “stabbing”
    • Testing for hyper-esthesia above the rash clinically
    • Itching would make other differentials more likely, point us in other direction
    • Pain can start before, during or after the rash
  • Complications can include ocular, otic, or neurologic disease
    • Postherpetic neuralgia (PHN): in about 15% of patients, usually in >60yrs
    • Herpes zoster ophthalmicus (HZO): potentially sight-threatening condition. prodrome of headache, malaise, and fever. Unilateral pain or hypesthesia in the affected eye, forehead, and top of the head may precede or follow the prodrome
    • Acute retinal necrosis (ARN)
    • Herpes zoster oticus (Ramsay Hunt syndrome): triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal or on the auricle
    • Secondary bacterial infection
    • Aseptic meningitis
    • Encephalitis — Herpes zoster-associated encephalitis
    • Peripheral motor neuropathy (rare)

Disseminated VZV disease in immunocompromised hosts

  • Clinical presentation may include extensive cutaneous involvement (multiple dermatomes, non-contiguous dermatomes, bilateral disease) and/or visceral involvement
  • Generally disseminated VZV disease is going to be limited to immunocompromised patients

Quick note on VZV diagnosis and immunology

  • This will typically be a presumptive clinical diagnosis, although lab confirmation is recommended in immunocompromised hosts
  • Rapid diagnostics like PCR and/or DFA are available → PCR is the method of choice and can use for vesicle fluid like this case, serum/blood, spinal fluid, other tisues
  • A quick note on immunology: serology is valid but immunity is mainly driven through T cells
    • Cellular immune responses play a critical role in controlling VZV latency and limiting its potential to reactivate to cause herpes zoster
    • A decline in cell-mediated immunity has been documented in older individuals and in patients with lymphoproliferative malignancies, both populations that experience high rates of herpes zoster. These epidemiologic observations are supported by in vitro data that demonstrate reduced VZV-specific T-cell frequency in such patients

This episode focused on antivirals and considerations for management of VZV disseminated disease

  • We discussed starting treatment with high dose aciclovir immediately, irrespective of the renal failure
  • We previously referenced the AST ID COP guidelines above, here you can find Table 1 summarizing general recommendations:

This episode discussed antivirals and considerations for management of VZV disseminated disease

  • Reviewing a few of the points from episode:

      • If acyclovir is given intravenously and the speed of infusion is too quick, there will be a sharp spike in plasma levels
        • As aciclovir is primarily excreted unchanged by the kidney but has a poor solubility in urine, high concentrations can exceed the solubility threshold and thus lead to intratubular precipitation and can cause acute tubular necrosis
      • Our experts provided the reminder that not all antivirals are active against all herpesviruses —> and the ones discussed in the episode are mostly active against HHV-1 to -3, so HSV-1/2 and VZV
        • Antiviral substances have a relatively narrow dose range and many are prodrugs
        • All are nucleoside analogs
        • All have a pretty cool mechanism of action: needs to be phosphorylated 3 times
          • 1st Phosphorylation can only occur through a thymidine kinase that is coded for by the Herpes-viruses! So it only gets activated in virus-infected cells.
          • Un-infected cells lack the thymidine kinase that’s encoded by the virus and an activation is much more unlikely.

Now more on the individual drugs:

  • Acyclovir/Aciclovir
      • Prodrug; inhibits DNA polymerase after activation
      • Low oral bioavailability 10%
      • Side effects:
        • Nephrotoxicity: precipitation of relatively insoluble aciclovir crystals in the renal tubules can occur when given IV
        • Neurologic toxicity: rare reports have included agitation, tremors, delirium, hallucinations, and myoclonus
  • Valaciclovir
      • Prodrug to aciclovir (prodrug to the prodrug)
      • Higher bioavailability >50%
      • Side effects similar to aciclovir
  • Famciclovir
      • Also a prodrug that is transformed into penciclovir
  • Brivudine [not available in US]
      • Nucleoside analog that is mono-phosphorylated by a unique VZV-specified enzyme and changed into the triphosphate by cellular enzymes
      • Could be extremely toxic in certain clinical situations when these agents are used.
      • Higher antiviral activity, supposedly faster clearance of symptoms
      • Severe interactions with certain anti-cancer medications, 5-Fluorouracil (5-FU) (used in Colorectal cancer, breast cancer etc.): Brivudine inhibits their degradation
  • Foscarnet is an alternative option in case of allergy or intolerance of aciclovir
      • An anion pyrophosphate
      • Selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases

What do we hope to achieve? What are the goals of treatment?

  • Hasten healing of cutaneous lesions
  • Decrease the duration and severity of acute neuritis
  • Prevent new lesion formation less shedding less onward transmission
  • Unclear if postherpetic neuralgia can be prevented by giving antivirals

What about aciclovir resistance?

  • Resistance is very uncommon
  • Mechanisms include:
    • Mutations in UL36 gene can lead to reduced activity or reduced substrate specificity of viral thymidine kinase
    • Less common are mutations in the DNA polymerase gene (UL37) which can impair aciclovirs binding to the polymerase
  • Risk factors for resistance include: prolonged treatment with acyclovir, severe immunosuppression

VZV vaccination & prevention

Types of vaccines:

 

  • The different vaccine schedules in US and Germany were compared
    • Sara gave overview of US/CDC vaccination recommendations:
      • 2 childhood doses of varicella vaccine at 12-15 months of age and 4-6 years of age
      • 2 doses of RZV for:
        • Adults ≥50 years
          • Whether or not they report a prior episode of herpes zoster; Whether or not they had prior Zostavax
          • They don’t necessarily get screened (via history or serology) for evidence of prior varicella infection
        • Adults ≥19 years who are/will be immunosuppressed
        • Separated doses by 2-6 months
          • if >6 mo since first dose, we just complete dose #2 and do not restart
          • If pt is immunocompromised, we will sometimes give the second dose after 1 month
        • US only has recombinant (Shingrix), no longer have Zostavax (since 2020)
    • Till gave overview of German vaccination recommendations:
      • 2 childhood doses, first at around 11 months of age, then second at 15 months of age
      • Adult RZV recommendations:
        • Adults ≥60 years
        • Adults ≥50 years who are immunocompromised

When should we provide zoster vaccination post-shingles infection?

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to describe the diagnosis, prevention, and management of varicella zoster virus (VZV) infection in a solid organ transplant recipient

Learning Objectives

After listening to this episode, listeners will be able to:

  • Compare and contrast the clinical presentation of primary varicella (”chickenpox”) and reactivation herpes zoster in immunocompromised hosts
  • Describe the available antivirals that target VZV and key side effects
  • Outline the general recommendations for VZV vaccination in adults and children

Disclosures

Our guests (Till Koch and Annette Hennigs) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Koch T., Hennigs, A., Dong, S. “#121: Windpocken with Infektiopod”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/41b1e286-68b4-40f3-b993-e5177ad1ab1f/

Transcript

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