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With no clinical trial data yet available for treating severe mpox, the CDC has published an interim report with guidance.

There are many FDA-regulated drugs and biologics stockpiled for smallpox preparedness that can be used to treat severe mpox; however, there are many clinical considerations when using these to help manage strategic decision-making, the CDC report cautioned.

For starters, immunocompromised individuals co-infected with HIV with low CD4 counts in particular, should be considered for treatment with medical countermeasures (MCMs) like tecovirimat (Tpoxx), brincidofovir (Tembexa), cidofovir, trifluridine ophthalmic solution (Viroptic), and vaccinia immune globulin intravenous (VIGIV).

Patients with syphilis, herpes simplex, varicella zoster, or molluscum contagiosum should also be considered, Agam K. Rao, MD, of the CDC's National Center for Emerging and Zoonotic Infectious Diseases, and colleagues wrote in the interim guidance published in .

"Until data from controlled studies are available, these interim clinical considerations facilitate strategic decision-making about the use of MCMs to manage specific severe manifestations of mpox," the group advised.

They compiled the data in the report from 250 U.S. mpox consultations provided by the CDC from May 2022 to January 2023, and from animal model studies, expert input, and reports on MCM use in a range of orthopoxvirus cases.

"As more knowledge was acquired through clinical consultations, many of which involved repeated consultations and regular follow-up, CDC's approach to mpox cases was refined," Rao's group wrote. "CDC recommends clinicians and health departments review these clinical treatment considerations when managing patients with mpox."

Although most people can recover from mpox with treatment for pain control, those with underlying conditions need further support, they wrote.

In the report, each of the drugs and treatments for mpox are described along with indications for drug-drug interactions, previous clinical cases, drug interaction and resistance information, warnings, and information on who may be best suited for each treatment.

For example, extended treatment with tecovirimat might result in drug resistance if not monitored for safety signals and clinical response. The document points out that this antiviral is best taken with a fatty meal. Patients who cannot take oral medications because of gastrointestinal disease may not be able to absorb the medication, so for them, IV tecovirimat should be prioritized.

When giving VIGIV, vaccination with live virus vaccines (such as varicella, measles, mumps, and rubella) should be deferred for 3 months, the report warns. And for patients with ocular mpox involving the cornea, "caution should be exercised ... because of a report of an animal study of vaccinia keratitis in which VIGIV was associated with persistent corneal scarring." Although trifluridine has successfully treated ocular vaccinia virus infections in both animals and humans, more than 4 weeks of treatment "should be avoided because of the risk of corneal epithelial toxicity."

In addition to immunocompromised individuals, those with a history of atopic dermatitis or eczema may also experience uncontrolled viral spread, "possibly as a result of associated defects in the innate or adaptive immune response," Rao and colleagues explained. People who have extensive breaks in the dermal barrier (e.g., from burns, impetigo, varicella zoster virus infections, herpes simplex virus infection, severe acne, severe diaper dermatitis with extensive denuded skin, psoriasis, and Darier disease [keratosis follicularis]) might also be at risk for severe manifestations of uncontrolled viral spread.

For children, adolescents and pregnant persons, MCMs should be used on a case-by-case basis after weighing the potential benefits and harms, the report authors wrote.

Moderately or severely immunocompromised patients, such as those with advanced HIV or those who have had an organ transplant, have developed diffuse and disseminated lesions involving multiple organ systems, "possibly because of persistent viremia or uncontrolled viral growth," Rao and colleagues explained. In these cases, "overwhelming systemic illness has resulted in death."

A recent global case review in The Lancet confirmed that individuals with low CD4 counts are at increased risk for complications and death, such that all deaths were in patients with CD4 counts <200 cells/mm³.

Hemorrhagic disease, confluent or necrotic lesions, severe necrotizing or obstructive lymphadenopathy, obstructive edema, pulmonary nodules, encephalitis, myopericarditis, ocular infections, and sepsis have been reported in patients with severe mpox manifestations. Even if not seen at the first healthcare encounter, immunocompromised individuals are at high risk for these manifestations.

"Optimal immune function is essential to recovery, irrespective of whether multiple MCMs are administered," Rao and colleagues wrote, noting that antiviral MCMs might complement the immune response by reducing replication, maturation, or spread of orthopox virus. "VIGIV might provide some level of passive immunity to certain patients with moderate or severe immunocompromise until a patient's immune system is able to clear the virus. However, earliest optimization of immune function (e.g., by temporarily delaying or decreasing doses of chemotherapy and immunomodulatory therapies and by promptly initiating effective antiretroviral medications [ARVs] for treatment of HIV) is critical to favorable outcomes."

And regardless of immune status, lesions on surfaces such as penile foreskin, urethral meatus, or the vulva put them at increased risk, Rao and colleagues noted. "These might predispose patients to complications such as strictures or edema which could require procedures including urethral catheterization, colostomy, or surgical debridement."

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