The blister beetle and beyond

By Allison Evans, Assistant Managing Editor, July 1, 2024

Molluscum contagiosum (MC), a virus of the Poxviridae family, is a common viral cutaneous infection that primarily affects children, immunocompromised patients, and sexually active adults. With a prevalence between 5.1% and 11.5% in children aged 0 to 16 years, MC is the third most common viral skin infection in children and one of the five most prevalent skin diseases worldwide. Skin lesions present as firm rounded papules, pink or skin-colored, with a shiny and umbilicated surface.

Molluscum produces a variety of substances that block the immune system, said Nanette Silverberg, MD, FAAD, chief of pediatric dermatology for the Mount Sinai Health System. “In the past 40 years, it has become more common. And while it’s not totally known why, it is thought to perhaps relate to the fact that we no longer get smallpox vaccinations.”

“This is an exciting time because for decades we had no FDA-approved treatment options — and within the span of a year, we now have two options — although we’re still waiting for the latest option to become available,” said Deepti Gupta, MD, FAAD, associate professor at Seattle Children’s Hospital.

Pediatric dermatologists discuss the newly approved molluscum contagiosum treatments alongside traditional treatments and highlight approaches and considerations when treating patients with molluscum.

Time to resolution

Molluscum is a self-limiting infection in immunocompetent individuals, although duration is often measured in years. The largest cohort study in 306 children younger than 15 years documented a mean of 13.3 months to resolution without intervention; 30% of the cases persisted at 1.5 years, and 13% persisted at two years.

“For our individuals who have molluscum, we expect them to have disease naturally for one to two years,” Dr. Silverberg noted. “About 50% of people will clear around the one-year mark, 70% by a year and a half, and about 90% by two years out. We really start to see pretty intense clearance in the second year, but not so much in the first year.”

“We see increased lesions in patients who are immunocompromised,” noted Dr. Gupta. “Whether they have an underlying immune deficiency, an inherited immune deficiency, or they’re on immunosuppressive medications or have HIV — these are definitely populations that may have more molluscum lesions.”

For kids with atopic dermatitis, this can mean a lot of itching and spread, Dr. Silverberg explained. This spread can be exacerbated by co-bathing and swimming pools. “About half of kids with molluscum live in households that support co-bathing. It’s certainly something we see in early childhood, particularly with early childhood activities.”

Immunosuppressed patients could also experience complications from eczema and bacterial superinfection, Dr. Gupta noted. “These patients take longer to clear because it takes them longer to mount an immune response,” said Texas dermatologist John Browning, MD, FAAD, MBA, who is board-certified in dermatology, pediatrics, and pediatric dermatology.

“There is a phenomenon called “beginning of the end” (BOTE) sign, which refers to clinical erythema and swelling of an MC skin lesion when the regression phase begins,” Dr. Browning said. This molluscum reaction “is likely due to an immune response toward the MC infection rather than a bacterial superinfection.”

An individual molluscum lesion can get really red, edematous, and can sometimes look infected. But often it’s more of an inflammatory sign that the immune system is starting to recognize the molluscum rather than infection, Dr. Gupta said. “Sometimes these are overtreated for infection or cellulitis, but it’s really a favorable inflammatory response that means that the immune system is starting to recognize these lesions.”

Adults vs. kids

In children, the main affected areas are sites of exposed skin, such as the trunk, extremities, intertriginous regions, genitals, and face. Molluscum does not affect palms and soles, and involvement of oral mucosa is rare.

In adults, lesions are most frequently located on the lower abdomen, thighs, genitals, and perianal area, with most cases being transmitted by sexual contact.

“The peak age is sometime in early childhood, three to four years of age. Then there’s a second smaller peak in school-aged children around age eight. Finally, there is an additional, steady state that occurs, with a little higher commonality, in individuals who are sexually active — so in the adult population with a higher focus from 15 to 26 years of age,” said Dr. Silverberg.

In adolescents and adults, MC could occur either as a sexually transmitted disease or in relation to direct contact, including contact sports. In the 1980s, the number of reported cases of MC increased, apparently associated with the onset of the HIV epidemic. It is estimated that the prevalence of MC in HIV patients is close to 20%. In immunosuppressed patients, there may be extensive lesions located in atypical sites that may be greater than 1 cm in diameter or refractory to treatment.

While physical removal is far from pain-free, Dr. Silverberg agrees that there is a time to consider it for children. “If there is a lesion that is extremely bothersome to a child, we may want to do curettage to try to get the lesion off as quickly as possible.”

Molluscum and atopic dermatitis

“Molluscum is known not just to trigger or flare atopic dermatitis, but it’s also been shown that kids with atopic dermatitis have more lesions,” Dr. Silverberg said. “Ostensibly, more lesions mean more contagion risk, so it may be that it’s spreading partially because we’re running concurrent with the epidemic of atopic dermatitis, which has also worsened over the past 50 years. Studies have found an increased risk of MC in patients with atopic dermatitis, with prevalence rates of AD patients with MC of up to 62%.”

A tendency for cutaneous infections, such as molluscum, is a minor criterion for the diagnosis of atopic dermatitis; it’s part of the Hanifin and Rajka criteria from 1981, Dr. Silverberg explained. “With atopic dermatitis, the skin barrier is weak and because patients are itchy, they may be spreading it. There are also other contributory factors such as an altered immune response,” she said.

“There’s conflicting data about the relationship between atopic dermatitis and molluscum in the literature,” Dr. Gupta explained. “Some studies say that atopic dermatitis is a predisposing factor for molluscum whereas other studies have found no statistically significant association. Atopic dermatitis is a disruption of the skin barrier, and we can definitely see increased risk of bacteria and other viruses that can infiltrate the skin and spread more widely because of that barrier disruption.”

“It’s the same idea for molluscum,” she continued. “When you have a disrupted skin barrier, the virus can infect the skin more easily. I do think there is a relationship between molluscum and atopic dermatitis and patients who have atopic dermatitis may be prone to having more numerous molluscum skin lesions just because their barrier is disrupted.”

Before treating molluscum patients with atopic dermatitis, having and keeping the skin barrier in good shape is important, and then the focus shifts to therapeutics, which often includes use of a topical steroid. “We’re really looking at making sure the eczema is under control first. We use a lot of topical steroids largely because things like topical calcineurin inhibitors may actually promote spread of molluscum,” Dr. Silverberg said.

“There are all kinds of reasons that kids would have more molluscum in the setting of atopic dermatitis,” Dr. Silverberg said. “Why molluscum triggers more atopic dermatitis is not completely clear, but it appears that the cause triggers itching, and because the immune response brings up erythema and inflammation, it may feed into that initial trigger of atopic dermatitis.”

“Molluscum can actually cause a dermatitis in itself,” Dr. Gupta said. “Patients may develop eczematous plaques around one or more lesions, a phenomenon known as ‘molluscum dermatitis,’ which is more frequent in patients with atopic dermatitis.” It is estimated that 9-47% of patients with molluscum develop molluscum dermatitis.

“With this dermatitis, a pruritic rash forms around the molluscum lesions, which will make an individual itch those areas and potentially auto-inoculate,” Dr. Gupta said. “It’s important to treat the dermatitis around the molluscum with emollients and topical steroids to help calm the reaction down, which may not only be bothersome to patients, but can lead to increased spread,” she added.

Treating vs. watch-and-wait

Typically, patients with extensive disease, secondary complications, or aesthetic complaints should be treated. Although, Dr. Browning notes that patients who see a dermatologist with molluscum often fall into these categories already. “They’re usually not satisfied with the ‘watch-and-wait ’ approach offered by a primary practitioner,” he said.

Surveys of U.S. physicians have shown that treatment of MC widely varies. Also, characterizing a condition as benign and self-limiting may compel some physicians toward a “watch-and-wait” approach. However, treatment may be preferred for social and cosmetic reasons or to avoid spreading the infection.

Sometimes, molluscum does get infected, said Dr. Browning, which can cause staph infections. “It’s not just a benign rash that’s just going to go away. It may also leave scarring since it’s a pox virus. There are definitely reasons to treat sooner rather than later, especially if you catch it early.”

Not every child needs to be treated, said Dr. Silverberg. However, many of the children being seen at her office have such extensive disease they must be treated. “They’re walking around with a highly contagious illness, so it becomes important for us to treat those kids.”

“As much as we want to offer people immediate clearance, sometimes it’s okay to do things a little bit more slowly to avoid trauma in children,” she continued. “We sometimes respond to parents’ anxiety and stress, and they may be encouraging us to be very aggressive — and we may want to be a little less aggressive, depending on the situation.”

Some of these newer treatment options are relatively painless, while some of the in-office procedures can be painful and can sometimes require multiple treatments for a disease that is self-limited, Dr. Gupta said. “We have to be cognizant of the stigma that might go along with molluscum for children, particularly in visible areas and dealing with school and daycares. It’s about weighing those options with patients and families and using a shared decision-making model to decide how the patient would like to approach things.”

According to a 2017 Cochrane Review, no single intervention for MC had been shown to be convincingly effective. Since the evidence did not favor any one treatment, natural resolution remained a strong method for dealing with the condition. However, recent phase 3 trial results have shown that two newly FDA-approved drugs may shake up the treatment paradigm.

In terms of treatments, “throughout the years, cryotherapy has proven successful for patients with molluscum, with adults being more tolerant of it,” Dr. Silverberg noted. “Although, cryotherapy can cause pigmentation issues in skin of color patients,” she warned.

“Often, adults would rather have me freeze off the lesions with liquid nitrogen, especially if they have less than a dozen or so molluscum,” said Dr. Browning. “This is a predictable method because we know every lesion that’s treated will be gone. With cantharidin you don’t always get a 100% response rate. Some people don’t blister or don’t have an adequate blister that forms.”

“Adults are also open to having the lesions physically curetted off, whereas I would never curette in a child because it is so painful,” Dr. Browning noted. “Although, I have taken kids to the OR a handful of times to physically remove the lesions, especially when lesions may be causing them a lot of discomfort, such as a lesion on the eyelid.”

New treatments on the block

Cantharidin

Cantharidin 0.7%, which is applied through an applicator device, was approved by the FDA in July 2023. Despite its status as a newly approved treatment for molluscum, the compounded form has been used for decades. “Most of us trained using cantharidin, so even when it wasn’t FDA-approved, it’s been the gold standard of treatment over the past 50 years,” said Dr. Browning.

Cantharidin is derived from a blistering beetle, Dr. Gupta said. “It’s a topical solution approved for children two years of age and older. The FDA recommendation is to use no more than one applicator in a single treatment session, although it can be reapplied every three weeks as needed.”

“It’s a purplish color, which allows you to see where you’ve placed it on the skin,” Dr. Silverberg said. “It comes as a single-use applicator, with usage data for treatment of lesions every four weeks for four treatments,” she added.

The approval is based on positive results from two phase 3 randomized, double-blind, multicenter clinical trials (CAMP-1 and CAMP-2) that evaluated the safety and efficacy compared to placebo in patients two years of age and older diagnosed with molluscum. In both trials, a clinically and statistically significant number of patients treated met the primary endpoint of complete clearance of all treatable molluscum lesions. In CAMP-1, 46% of participants achieved complete clearance of molluscum lesions compared to 18% of participants in the vehicle group; in CAMP-2, 54% of participants treated achieved complete clearance of molluscum lesions compared to 13% of participants in the vehicle group.

While the economics of the treatment must be navigated by individual practices, Dr. Silverberg noted that it is a very user-friendly product with good efficacy. “We’ve always known cantharidin creates blisters, but now we have better control over the product.”

With the cantharidin applicator, there’s a new step involved. “Before, we would see a patient with molluscum and then apply the compounded cantharidin to the lesions. Now, we either have to buy the product ahead of time and have it in the office, or you have to order it and have it shipped to the office, and the patient has to come back to have it applied,” Dr. Browning said.

There’s enough in the applicator to treat numerous molluscum on one patient, and it’s easy to apply, said Dr. Browning. “The applicator looks similar to a super glue dispenser so that it’s easy to get the cantharidin exactly on a single molluscum.”

The beauty of cantharidin, said Dr. Browning, is that it can be applied in the office, and you get a pretty fast response. “You put the cantharidin on and later in the day it blisters, and then the blisters heal over the next few days. A week later the treated molluscum is gone.”

“I think we’re still learning how to transition from the compounded cantharidin to the drug-device to see how it can work for us,” he said.

Berdazimer

A second new treatment option, which was approved in January 2024, but has not yet come to market, is berdazimer 10.3%, a gel that releases nitrous oxide. “It’s currently approved for patients one year of age and older and is expected to be used once daily for up to 12 weeks,” Dr. Gupta said.

Phase 3 trial results showed that after 12 weeks, patients in the berdazimer group, 32.4% achieved complete clearance of MC lesions compared with 19.7% in the vehicle group.

“This is exciting because we will soon have an option that the patient can go home with and apply themselves,” Dr. Browning noted. “It does come in two separate tubes that the patient will need to mix together. Patients really need to be educated about how to apply it and what to expect as the molluscum goes away.”

“Berdazimer is interesting because it has some antiviral properties,” said Dr. Silverberg. “We really have only had compounded cidofovir in the past that has antiviral properties, which we reserve for very severe cases or for people who are treatment resistant. Berdazimer offers an alternative mechanism of action, with the option for combination with other agents.”

Dr. Browning agrees. “You can still treat with cantharidin and then provide them with an at-home treatment. We don’t necessarily want patients having to come back to the office multiple times for molluscum treatment. You want to diagnose, treat, and ideally empower the patient so that they can treat any new lesions that develop.”

Another reason physicians may want to opt for berdazimer gel is if the molluscum is in a sensitive place, such as the face, he added. Since berdazimer isn’t on the market yet, Dr. Browning often treats the face with tretinoin, although he noted that the berdazimer is expected to come to market late this year or even early next year.

Some of the options used for severe molluscum, like liquid cimetidine, have been subject to drug shortages. “We’re really beginning to become more dependent on the products that are released because we’re losing some of our options. And while we have other products like tretinoin, they don’t meet that 50% metric that you get from the FDA-approved molluscum products,” Dr. Silverberg said.

According to Dr. Gupta, the backstep of both therapies is their cost: Are insurance companies going to approve these medications for patients and what will be the out-of-pocket cost for patients? What will this look like for physician offices as far as prior authorizations and ensuring patients are able to access needed treatments?

New treatment paradigms

“The most important thing that we can do is learn how to use these newer products and learn how to help people with wound care so that when people need to use them or when we need to use them for our patients or offer them to our patients, we can give them good anticipatory guidance on what to do at home, so they don’t get alarmed if they see a day of redness that disappears the next day,” Dr. Silverberg said.

“Overall, things are looking bright because once we have FDA-approved products for molluscum, we’ll have the development of published treatment paradigms and better coverage for kids to be treated,” Dr. Silverberg added. “We want to make sure that all our patients get these options and are treated when they need it.”

“We really have to look at each patient individually,” Dr. Silverberg stated. “It’s a patient-centered outcome that we’re looking for because molluscum does eventually go away. We want to make sure it’s not scarring. We want to make sure that they’re not uncomfortable, and then support them in their decisions. If they really feel they want to be clear, and they’re upset with their appearance, we should support those patients and offer them judicious treatment.”

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