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Hypertrophic herpes simplex virus 2 infection resistant to acyclovir in an immunosuppressed patient

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2 years ago

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An 80-year-old man on ruxolitinib for myelofibrosis was referred to the infectious diseases clinic with a subacute, progressive mass over his left forehead. He also had type 2 diabetes mellitus and dyslipidemia, and was taking rabeprazole, simvastatin and metformin.

Three years before presentation, he developed an erythematous, crusting rash over the outer side of his left ear. He was previously given a diagnosis of otitis externa, but the rash did not improve despite 14 empiric courses of oral antibacterial therapy. A swab from the lesion was sent for herpes simplex virus (HSV) testing by polymerase chain reaction (PCR), which was positive for HSV-2. The patient had no history of oral or genital HSV infection. The rash resolved with a 5-day course of oral valacyclovir (1 g, 3 times daily). Over the following 3 years, the patient had 8 recurrences involving the left side of his face. These were presumed to be episodes of HSV-2 reactivation and each resolved with empiric oral valacyclovir for 7–10 days.

Six months before presentation, the patient developed a small, sessile, sesame seed–shaped lesion over his left forehead. Despite 18 courses of oral valacyclovir and 3 courses of oral famciclovir (500 mg, twice daily), each for 7–14 days, the mass continued to increase in size. A biopsy was performed, and viral culture was positive for HSV-2. Histopathology showed acantholytic keratinocytic cells with viral changes, suggestive of an ulcerative lesion of viral etiology.

When we saw the patient in clinic, he had a fungating, verrucous mass on his left forehead measuring about 12 × 8 cm and extending superiorly to the scalp (Figure 1). The mass was raised and pink, with a well-demarcated border. It had regions of slough and crusting, but was not tender. The mass and associated edema resulted in slight left-sided ptosis. The patient had no other cutaneous lesions on the head and neck. Cranial nerve examination was normal. Laboratory investigations showed leukocytosis and anemia that were caused by his myelofibrosis (leukocyte count 17.1 [normal 4–11] × 109/L and hemoglobin 95 [normal 120–160] g/L). His creatinine was 92 (normal 42–102) μmol/L.

<a href=”https://www.cmaj.ca/content/cmaj/195/13/E479/F1.large.jpg?width=800&height=600&carousel=1″ title=”A large fungating and verrucous lesion on the left forehead of an 80-year-old man, caused by herpes simplex virus 2 infection; the lesion was progressive over a 6-month period.” class=”highwire-fragment fragment-images colorbox-load” rel=”gallery-fragment-images-684742817″ data-figure-caption=”

A large fungating and verrucous lesion on the left forehead of an 80-year-old man, caused by herpes simplex virus 2 infection; the lesion was progressive over a 6-month period.

” data-icon-position data-hide-link-title=”0″>Figure 1:

Figure 1:

A large fungating and verrucous lesion on the left forehead of an 80-year-old man, caused by herpes simplex virus 2 infection; the lesion was progressive over a 6-month period.

Based on the patient’s history, including multiple previous courses of antiviral treatment, our presumptive diagnosis was hypertrophic HSV infection, with concern for resistance to acyclovir and related compounds (valacyclovir and famciclovir), as evidenced by the lack of clinical response. We obtained a swab of the mass for HSV PCR, which was positive for HSV-2. Genotyping was performed at the National Microbiology Laboratory in Winnipeg. Sequence variations in the UL23 thymidine kinase gene were identified, confirming resistance. Testing for HIV was negative.

We treated the patient with intravenous foscarnet (90 mg/kg, daily) in our hospital’s infusion clinic. He received 20 doses in total, with substantial improvement (Figure 2). By the end of therapy, the lesion had flattened and regressed in diameter, with a residual irregularly shaped region of hypopigmented skin. The patient had 2 further recurrences on his left ear 3 and 11 months after his initial treatment. Each responded to foscarnet. Given the resistance to acyclovir and related compounds, no oral antiviral options were available for suppressive therapy. If the patient has additional recurrences, further management strategies will include immune modulation therapy with topical imiquimod.

<a href=”https://www.cmaj.ca/content/cmaj/195/13/E479/F2.large.jpg?width=800&height=600&carousel=1″ title=”Left forehead of an 80-year-old man with herpes simplex virus 2 infection after treatment with intravenous foscarnet, showing flattening and regression of the mass, with areas of postinflammatory hypopigmentation.” class=”highwire-fragment fragment-images colorbox-load” rel=”gallery-fragment-images-684742817″ data-figure-caption=”

Left forehead of an 80-year-old man with herpes simplex virus 2 infection after treatment with intravenous foscarnet, showing flattening and regression of the mass, with areas of postinflammatory hypopigmentation.

” data-icon-position data-hide-link-title=”0″>Figure 2:Figure 2:

Figure 2:

Left forehead of an 80-year-old man with herpes simplex virus 2 infection after treatment with intravenous foscarnet, showing flattening and regression of the mass, with areas of postinflammatory hypopigmentation.

Discussion

Herpes simplex virus 1 and 2 belong to the Herpesviridae family of DNA viruses. Infection with HSV is common; estimated seroprevalences among adults in Ontario are 51.1% for HSV-1 and 9.1% for HSV-2.1 The 2 primary clinical manifestations are oral and genital infection. Classically, HSV-1 is associated with oral infection and HSV-2 with genital infection, but the reverse trend is occurring with greater frequency.2 As with all Herpesviridae, HSV-1 and HSV-2 have the capacity for latency and can reactivate intermittently after primary infection. Primary oral infection can be severe, characterized by painful gingivostomatitis and pharyngitis, with exudative, ulcerative lesions of the oropharynx. Recurrences tend to be mild and are characterized by painful vesicular lesions, classically located at the vermillion border. Similarly, primary genital infection is typically more severe, with bilateral, painful, ulcerative lesions, regional lymphadenopathy and systemic symptoms (such as fever, headache and malaise). Recurrent genital infection is usually less severe, with painful, unilateral, vesicular and ulcerative lesions. Other cutaneous manifestations include herpetic whitlow and herpes gladiatorum, the latter of which occurs in the setting of contact sports.3 Herpes simplex virus 1 and 2 can also cause infection at other sites, such as the anus and perianal skin, particularly among men who have sex with men (MSM).

Mucocutaneous HSV infections are typically diagnosed by HSV PCR of swabs obtained from herpetic lesions. Acyclovir and related compounds are first-line therapies (Table 1).4 Treatment is associated with reduced symptom duration and decreased risk of transmission, and should be started as soon as possible after symptom onset.4 Recurrent episodes are usually self-limited and antiviral therapy may not be required for patients with minimal or mild symptoms. For patients with frequent (i.e., episodes at least every 2 mo or at least 6 times/yr) or severe recurrences, daily suppressive antiviral therapy can be considered and should be re-evaluated annually.4

View this table:

Table 1:

First-line treatment of genital herpes simplex virus infection*

Hypertrophic HSV infection is an atypical and uncommon manifestation of HSV. Described cases have most commonly involved the anogenital structures. In a review of 110 cases, 76.4% were anogenital; lesions of the oropharynx, nose, ears and ocular structures have also been reported.5 The clinical course is chronic and can be disfiguring, and the appearance is often mistaken for cutaneous malignant disease. Hypertrophic HSV infection has predominantly been described among people living with HIV infection. An association with immune reconstitution inflammatory syndrome has been hypothesized, although many cases have been described in patients on stable antiretroviral therapy with long-term virologic suppression.6 Anogenital involvement is most commonly seen among people living with HIV infection and may be related to sexual practices in MSM. Cases have also been seen with other forms of cellular immunodeficiency, such as hematologic malignancy, solid organ transplantation and congenital immune deficiencies (including common variable immunodeficiency secondary to T-cell lymphopenia, congenital T-cell deficiency syndrome and hyperimmunoglobulin E syndrome related to STAT3 sequence variations).5,6

The pathogenesis of hypertrophic HSV infection is poorly understood, although it may reflect chronic viral lytic replication in a host with underlying immune dysfunction.6 Our patient was taking ruxolitinib, a Janus kinase inhibitor, which is used for the treatment of myeloproliferative disorders including myelofibrosis. Increased frequency of Herpesviridae infections have been attributed to ruxolitinib, although these are most commonly varicella zoster virus infections rather than HSV.7 Diagnosis is generally made with biopsy of the lesion for histopathologic examination, HSV PCR or viral culture.5 Previous case reports have suggested that hypertrophic HSV infection is poorly responsive to conventional treatment with antiviral therapy.6 Alternate nonantiviral treatment modalities include surgical resection, topical imiquimod and thalidomide.5

Our patient’s management was complicated by resistance to acyclovir and related compounds via sequence variations in the UL23 thymidine kinase gene. Acyclovir and related compounds are the mainstay of treatment for HSV infections. They exert their effects through termination of viral DNA transcription.8 Upon entry into host cells, these antiviral agents undergo 3 consecutive phosphorylation reactions with conversion to acyclovir triphosphate, the active form.8 The first phosphorylation reaction is by viral thymidine kinase, while the second and third phosphorylation reactions are by host cell enzymes.8 Resistance to these compounds is primarily seen in immunocompromised hosts, such as people living with HIV infection and recipients of solid organ transplants.9 It is most often related to previous substantial exposure to acyclovir and related compounds.9 Our patient was immunocompromised owing to myelofibrosis and treatment with ruxolitinib, and had exposure to multiple courses of antiviral therapy over the previous 3 years, increasing his risk of resistance. Resistance mediated by sequence variations in the UL23 thymidine kinase gene results in absent, low production or altered activity of viral thymidine kinase, thereby preventing the first phosphorylation reaction. Less commonly, variations in the UL30 DNA polymerase gene result in target site alteration.8 In Canada, resistance genotyping is performed by Sanger sequencing at the National Microbiology Laboratory in Winnipeg.10 Alternate antiviral agents that can be used for resistant HSV include foscarnet and cidofovir; we prescribed the former for our patient. Foscarnet and cidofovir are inhibitors of viral DNA polymerase, but unlike acyclovir and related compounds, do not require phosphorylation by viral thymidine kinase. Both agents are administered intravenously and are associated with substantial risk of nephrotoxicity. Patients should be closely monitored for renal impairment and electrolyte disturbances; aggressive hydration and electrolyte replacement may be required.

We report a case of hypertrophic HSV infection in a man with myelofibrosis and substantial previous exposure to antiviral treatment, which was resistant to treatment with acyclovir and related compounds. Hypertrophic HSV infection is uncommon but can be seen in patients who are immunocompromised, most commonly people living with HIV infection. Resistance to antiviral agents should be suspected in patients who do not respond to conventional treatment, especially in patients who are immunocompromised or those with repeated antiviral exposure.

The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca.

Footnotes

  • Competing interests: None declared.

  • This article has been peer reviewed.

  • The authors have obtained patient consent.

  • Contributors: Charlie Tan and Wayne Gold led the conception and design of the work. Charlie Tan wrote the first draft of the manuscript. All authors revised the manuscript critically for important intellectual content, approved the final version to be published and agree to be accountable for all aspects of the work.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

 

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What’s the greatest holiday gift: lips, hair, skin? Give the gift of great skin this holiday season

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1 week ago

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October 31, 2024

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Give the gift of great skin this holiday season

Skinstitut Holiday Gift Kits take the stress out of gifting

Toronto, October 31, 2024 – Beauty gifts are at the top of holiday wish lists this year, and Laser Clinics Canada, a leader in advanced beauty treatments and skincare, is taking the pressure out of seasonal shopping. Today, Laser Clincs Canada announces the arrival of its 2024 Holiday Gift Kits, courtesy of Skinstitut, the exclusive skincare line of Laser Clinics Group.

In time for the busy shopping season, the limited-edition Holiday Gifts Kits are available in Laser Clinics locations in the GTA and Ottawa. Clinics are conveniently located in popular shopping centers, including Hillcrest Mall, Square One, CF Sherway Gardens, Scarborough Town Centre, Rideau Centre, Union Station and CF Markville. These limited-edition Kits are available on a first come, first served basis.

“These kits combine our best-selling products, bundled to address the most relevant skin concerns we’re seeing among our clients,” says Christina Ho, Senior Brand & LAM Manager at Laser Clinics Canada. “With several price points available, the kits offer excellent value and suit a variety of gift-giving needs, from those new to cosmeceuticals to those looking to level up their skincare routine. What’s more, these kits are priced with a savings of up to 33 per cent so gift givers can save during the holiday season.

There are two kits to select from, each designed to address key skin concerns and each with a unique theme — Brightening Basics and Hydration Heroes.

Brightening Basics is a mix of everyday essentials for glowing skin for all skin types. The bundle comes in a sleek pink, reusable case and includes three full-sized products: 200ml gentle cleanser, 50ml Moisture Defence (normal skin) and 30ml1% Hyaluronic Complex Serum. The Brightening Basics kit is available at $129, a saving of 33 per cent.

Hydration Heroes is a mix of hydration essentials and active heroes that cater to a wide variety of clients. A perfect stocking stuffer, this bundle includes four deluxe products: Moisture 15 15 ml Defence for normal skin, 10 ml 1% Hyaluronic Complex Serum, 10 ml Retinol Serum and 50 ml Expert Squalane Cleansing Oil. The kit retails at $59.

In addition to the 2024 Holiday Gifts Kits, gift givers can easily add a Laser Clinic Canada gift card to the mix. Offering flexibility, recipients can choose from a wide range of treatments offered by Laser Clinics Canada, or they can expand their collection of exclusive Skinstitut products.

 

Brightening Basics 2024 Holiday Gift Kit by Skinstitut, available exclusively at Laser Clincs Canada clinics and online at skinstitut.ca.

Hydration Heroes 2024 Holiday Gift Kit by Skinstitut – available exclusively at Laser Clincs Canada clinics and online at skinstitut.ca.
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Here is how to prepare your online accounts for when you die

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2 weeks ago

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October 24, 2024

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LONDON (AP) — Most people have accumulated a pile of data — selfies, emails, videos and more — on their social media and digital accounts over their lifetimes. What happens to it when we die?

It’s wise to draft a will spelling out who inherits your physical assets after you’re gone, but don’t forget to take care of your digital estate too. Friends and family might treasure files and posts you’ve left behind, but they could get lost in digital purgatory after you pass away unless you take some simple steps.

Here’s how you can prepare your digital life for your survivors:

Apple

The iPhone maker lets you nominate a “ legacy contact ” who can access your Apple account’s data after you die. The company says it’s a secure way to give trusted people access to photos, files and messages. To set it up you’ll need an Apple device with a fairly recent operating system — iPhones and iPads need iOS or iPadOS 15.2 and MacBooks needs macOS Monterey 12.1.

For iPhones, go to settings, tap Sign-in & Security and then Legacy Contact. You can name one or more people, and they don’t need an Apple ID or device.

You’ll have to share an access key with your contact. It can be a digital version sent electronically, or you can print a copy or save it as a screenshot or PDF.

Take note that there are some types of files you won’t be able to pass on — including digital rights-protected music, movies and passwords stored in Apple’s password manager. Legacy contacts can only access a deceased user’s account for three years before Apple deletes the account.

Google

Google takes a different approach with its Inactive Account Manager, which allows you to share your data with someone if it notices that you’ve stopped using your account.

When setting it up, you need to decide how long Google should wait — from three to 18 months — before considering your account inactive. Once that time is up, Google can notify up to 10 people.

You can write a message informing them you’ve stopped using the account, and, optionally, include a link to download your data. You can choose what types of data they can access — including emails, photos, calendar entries and YouTube videos.

There’s also an option to automatically delete your account after three months of inactivity, so your contacts will have to download any data before that deadline.

Facebook and Instagram

Some social media platforms can preserve accounts for people who have died so that friends and family can honor their memories.

When users of Facebook or Instagram die, parent company Meta says it can memorialize the account if it gets a “valid request” from a friend or family member. Requests can be submitted through an online form.

The social media company strongly recommends Facebook users add a legacy contact to look after their memorial accounts. Legacy contacts can do things like respond to new friend requests and update pinned posts, but they can’t read private messages or remove or alter previous posts. You can only choose one person, who also has to have a Facebook account.

You can also ask Facebook or Instagram to delete a deceased user’s account if you’re a close family member or an executor. You’ll need to send in documents like a death certificate.

TikTok

The video-sharing platform says that if a user has died, people can submit a request to memorialize the account through the settings menu. Go to the Report a Problem section, then Account and profile, then Manage account, where you can report a deceased user.

Once an account has been memorialized, it will be labeled “Remembering.” No one will be able to log into the account, which prevents anyone from editing the profile or using the account to post new content or send messages.

X

It’s not possible to nominate a legacy contact on Elon Musk’s social media site. But family members or an authorized person can submit a request to deactivate a deceased user’s account.

Passwords

Besides the major online services, you’ll probably have dozens if not hundreds of other digital accounts that your survivors might need to access. You could just write all your login credentials down in a notebook and put it somewhere safe. But making a physical copy presents its own vulnerabilities. What if you lose track of it? What if someone finds it?

Instead, consider a password manager that has an emergency access feature. Password managers are digital vaults that you can use to store all your credentials. Some, like Keeper,Bitwarden and NordPass, allow users to nominate one or more trusted contacts who can access their keys in case of an emergency such as a death.

But there are a few catches: Those contacts also need to use the same password manager and you might have to pay for the service.

___

Is there a tech challenge you need help figuring out? Write to us at onetechtip@ap.org with your questions.

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Pediatric group says doctors should regularly screen kids for reading difficulties

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2 weeks ago

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October 23, 2024

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The Canadian Paediatric Society says doctors should regularly screen children for reading difficulties and dyslexia, calling low literacy a “serious public health concern” that can increase the risk of other problems including anxiety, low self-esteem and behavioural issues, with lifelong consequences.

New guidance issued Wednesday says family doctors, nurses, pediatricians and other medical professionals who care for school-aged kids are in a unique position to help struggling readers access educational and specialty supports, noting that identifying problems early couldhelp kids sooner — when it’s more effective — as well as reveal other possible learning or developmental issues.

The 10 recommendations include regular screening for kids aged four to seven, especially if they belong to groups at higher risk of low literacy, including newcomers to Canada, racialized Canadians and Indigenous Peoples. The society says this can be done in a two-to-three-minute office-based assessment.

Other tips encourage doctors to look for conditions often seen among poor readers such as attention-deficit hyperactivity disorder; to advocate for early literacy training for pediatric and family medicine residents; to liaise with schools on behalf of families seeking help; and to push provincial and territorial education ministries to integrate evidence-based phonics instruction into curriculums, starting in kindergarten.

Dr. Scott McLeod, one of the authors and chair of the society’s mental health and developmental disabilities committee, said a key goal is to catch kids who may be falling through the cracks and to better connect families to resources, including quicker targeted help from schools.

“Collaboration in this area is so key because we need to move away from the silos of: everything educational must exist within the educational portfolio,” McLeod said in an interview from Calgary, where he is a developmental pediatrician at Alberta Children’s Hospital.

“Reading, yes, it’s education, but it’s also health because we know that literacy impacts health. So I think that a statement like this opens the window to say: Yes, parents can come to their health-care provider to get advice, get recommendations, hopefully start a collaboration with school teachers.”

McLeod noted that pediatricians already look for signs of low literacy in young children by way of a commonly used tool known as the Rourke Baby Record, which offers a checklist of key topics, such as nutrition and developmental benchmarks, to cover in a well-child appointment.

But he said questions about reading could be “a standing item” in checkups and he hoped the society’s statement to medical professionals who care for children “enhances their confidence in being a strong advocate for the child” while spurring partnerships with others involved in a child’s life such as teachers and psychologists.

The guidance said pediatricians also play a key role in detecting and monitoring conditions that often coexist with difficulty reading such as attention-deficit hyperactivity disorder, but McLeod noted that getting such specific diagnoses typically involves a referral to a specialist, during which time a child continues to struggle.

He also acknowledged that some schools can be slow to act without a specific diagnosis from a specialist, and even then a child may end up on a wait list for school interventions.

“Evidence-based reading instruction shouldn’t have to wait for some of that access to specialized assessments to occur,” he said.

“My hope is that (by) having an existing statement or document written by the Canadian Paediatric Society … we’re able to skip a few steps or have some of the early interventions present,” he said.

McLeod added that obtaining specific assessments from medical specialists is “definitely beneficial and advantageous” to know where a child is at, “but having that sort of clear, thorough assessment shouldn’t be a barrier to intervention starting.”

McLeod said the society was partly spurred to act by 2022’s “Right to Read Inquiry Report” from the Ontario Human Rights Commission, which made 157 recommendations to address inequities related to reading instruction in that province.

He called the new guidelines “a big reminder” to pediatric providers, family doctors, school teachers and psychologists of the importance of literacy.

“Early identification of reading difficulty can truly change the trajectory of a child’s life.”

This report by The Canadian Press was first published Oct. 23, 2024.

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