Monkeypox outbreak, vaccination, and treatment implications for the dermatologic patient: Review and interim guidance from the Medical Dermatology Society

Abstract

Rapid human-to-human transmission of monkeypox has created a public health emergency requiring prompt, multidisciplinary attention. Dermatologists are at the forefront of diagnosis due to the disease-defining skin lesions. Moreover, patients with pre-existing skin disease and those who are on immunosuppressive medications for skin disease may be at increased risk of severe infection. In this review, a panel of authors with expertise in complex medical dermatology and managing patients on immunosuppression reviews the literature and provides initial guidance for diagnosis and management in dermatology practices. Though there are knowledge gaps due to a lack of controlled studies, we support use of replication-deficit vaccines in all dermatologic patients who meet qualifying risk or exposure criteria. We offer strategies to optimize vaccine efficacy in patients with immunosuppression. We discuss alternative post-exposure treatments and their safety profiles. Finally, we outline supportive care recommendations for cutaneous manifestations of monkeypox. Large scale epidemiologic investigations and clinical trials will ultimately revise and extend our guidance.

Capsule Summary.

• •Monkeypox disease requires prompt, multidisciplinary attention as a public health emergency.
• •We review clinical observations and knowledge gaps in the monkeypox literature, and provide initial guidance for diagnosis and management in standard dermatology practice.

Introduction

Monkeypox, historically a zoonosis endemic to Central and Western Africa, has emerged as a dynamic, multinational outbreak.1, 2, 3, 4, 5, 6, 7, 8 This surge may represent waning immunity to the related smallpox virus, trends of habitat loss and globalization, and/or evolution of the monkeypox virus.^{1 , 9 , 10} Fortunately the case fatality rate remains low (United States: <0.01%, worldwide: <0.05%), reflecting the disease course of the originating Clade IIb strain (overall case fatality rate 3.6%) and differences in health care resources between current and endemic cases.^{2 , 6 ,} 10, 11, 12, 13, 14 Nonetheless, the significant pain associated with monkeypox lesions necessitates prompt diagnosis, treatment, and preventative strategies. Acknowledging the limited data landscape, our expert panel offers guidance to dermatologists on how to provide safe, up-to-date care amidst the monkeypox outbreak. As dermatologists, we can do more than diagnose monkeypox. By informing ourselves, we can risk stratify our patients in the context of their dermatologic diseases and modify treatment plans as needed to balance benefit with safety.

Transmission

As of September 2022, the primary demographic affected—per the handful of larger European case series published—are young to middle-aged men who have sex with men.^{5 ,} 15, 16, 17, 18, 19, 20 Transmission is predominantly human-to-human via skin contact, including sexual contact, as evidenced by increased viral loads in cutaneous lesions (relative to respiratory epithelium or other body fluids) and the distribution of monkeypox lesions.^{18 , 20} Sex with multiple partners is a leading risk factor in the current outbreak.^{2 , 21} Cases without sexual exposures, and in women and children, have been reported.22, 23, 24, 25 Fomite transmission is rare but possible.^{2 , 26} Health care worker cases, including due to needlestick injury, are non-zero but unlikely with standard precautions.^{27 , 28} Rates of asymptomatic transmission and transmission from respiratory secretions or other body fluids remain to be determined.^{2 , 29}

Diagnosis

Unlike prior clinical descriptions of monkeypox, contemporary cases often feature lesions concentrated in anogenital-oral sites, which likely represent sites of inoculation.^{5 , 15 , 17 , 18} A chronologically biphasic course of skin signs, from localized to subsequently disseminated, has also been appreciated.^{16 , 17} Each lesion progresses from macule or papule to vesicle to pustule to scab, such that lesions at a given site are in the same stage of evolution. Lesions have a ‘domed’ or ‘donut’ shaped morphology, with recent reports highlighting the prevalent umbilicated pseudo-pustule.^{7 , 30 , 31} In addition to these classic vesiculopustular lesions, new clinical features include proctitis and tonsilitis.16, 17, 18 Systemic symptoms, including fever, malaise, and lymphadenopathy, are not strictly prodromal and often follow the onset of skin lesions or may be absent.^{2 , 5 , 31}

For testing, synthetic swabs of skin lesions are preferred, and 2 swabs per lesion from 2 to 3 lesions at different sites is recommended.³² Sampling ulcer exudate, vesicle/pustule fluid or crust may all be acceptable.^{32 , 33} Since testing remains centralized at public health department and commercial laboratories, clinicians should consult with their relevant testing site to clarify collection, storage, and shipping specifics.

We recommend dermatologists maintain a broad differential for monkeypox as early lesions can be non-specific and mimic several common sexually transmitted infections.^{2 , 29 , 33} Moreover co-infection with sexually transmitted infections has been demonstrated at high frequency—in addition to the prevalence of HIV, up to 1/3 of monkeypox cases per published series had other lab-confirmed sexually transmitted infections^{5 , 7 , 17 , 18}—and has management relevance. In particular, initiation of and compliance with anti-retroviral therapy (ART) may prevent morbidity and mortality in HIV positive cases.34, 35, 36 Table I outlines our top differential diagnoses and our recommendations for initial co-testing.

Table I.

Differential diagnosis for monkeypox disease and recommended co-testing

Diagnosis	Co-testing
Syphilis (primary, secondary)	Yes, RPR serology
Herpes simplex virus	Yes, HSV-1 and 2 lesional swab for NAAT
Disseminated gonorrhea	Yes, gonorrhea and chlamydia swab for NAAT
Molluscum contagiosum	No
Other poxvirus infection (eg, cowpox)	No
Lymphogranuloma venereum	No
Chancroid	No
Disseminated cryptococcus	Yes, HIV-1/HIV-2 serology

HSV, Herpes simplex virus; NAAT, nucleic acid amplification test; RPR, rapid plasma reagin.

Prevention and treatment

There are no human efficacy studies (either trials or even larger observational cohorts) of monkeypox therapeutics such that choice of agents and dosing strategies for both pre- and postexposure remain inferences at this time.^{4 , 37 , 38} Dermatologists should regularly review the American Academy of Dermatology and Centers for Disease Control and Prevention (CDC) Monkeypox webpages for evolving clinical guidelines.² Preventative counseling presently emphasizes vaccination, contact precautions, and safer sex.^{2 , 6 , 12} Recommendations for safer sex include limiting the number of sexual partners, frequency of one-time sexual encounters, group sex, and use of recreational substances during sex, as well as encouraging barrier protection; emerging survey data suggest that the men who have sex with men community has already adopted strategies to reduce sexual exposures.^{2 , 12 , 39}

For pre- and postexposure prophylaxis (ideally within 4 days after exposure), the JYNNEOS vaccine is favored.^{2 , 40 , 41} As a replication deficient vaccinia virus, it has demonstrated safety in patients with HIV, and is inferred safe for immunocompromised individuals.^{40 ,} 42, 43, 44 JYNNEOS vaccine is administered as a 2 dose subcutaneous injection 4 weeks apart.⁴⁰ To extend availability, the Food and Drug Administration issued an emergency use authorization allowing intradermal injection with one fifth of the vaccine volume at the same administration timepoints for adults at high-risk for monkeypox infection; data from over 500 healthy human subjects support a non-inferior immune response.45, 46, 47 The only contraindication to JYNNEOS vaccine is allergy to a vaccine component (eg, egg proteins). Serious adverse events are rare. Recipients commonly experience mild injection site reactions (especially those with skin barrier defects). Unlike older smallpox vaccines, there is no viral replication at the injection site, which remains non-infectious. Booster doses are recommended every 2 to 10 years based on occupational risk, though this schedule will likely be revised given the current epidemiology.⁴¹ Early data demonstrate breakthrough infections despite postexposure prophylaxis with JYNNEOS.^{12 , 48}

The older ACAM2000 live vaccinia virus with replicating potential is contraindicated in HIV and other states of weakened immunity.^{44 , 49} Given supply issues with JYNNEOS,^{45 , 50} ACAM2000 may be considered for patients at very high-risk of monkeypox exposure without contradictions. Even in such patients, the potential for recombination between monkeypox and vaccinia virus exists, which may drive monkeypox evolution in the setting of breakthrough infections (neither vaccine guarantees immunity, as already observed this outbreak).^{12 , 48 , 51 , 52} Surveillance for cardiac events after the JYNNEOS vaccine will likely remain of interest given the established association of the ACAM2000 vaccine with myopericarditis.⁴⁹

The leading treatment for monkeypox under expanded access for an investigational new drug is tecovirimat (TPOXX), an antiviral that inhibits an envelope wrapping protein in orthopoxviruses.^{2 , 38 , 53} We infer generalizability to monkeypox from efficacy studies in animals, safety studies in largely healthy human subjects, and recent case reports suggesting TPOXX can reduce severity, duration, and respiratory shedding of monkeypox.^{4 , 37 ,} 53, 54, 55 Table II presents a high-level clinical summary of TPOXX use. The primary limitation to TPOXX use is renal clearance of the intravenous formulation (contraindicated when creatinine clearance <30 ml/min). However this formulation is restricted to infectious disease experts in conjunction with public health organizations. There are no identified contraindications to TPOXX capsules. Known drug-drug interactions are minimal and not absolute (Table II); note that the Infectious Diseases Society of America/United States Department of Health and Human Services does not recommend dose modification of any active ART for HIV.^{40 , 42 , 56 , 57} Adverse events are generally mild, including nausea, abdominal pain, headache, fevers/chills, and mild-moderate injection site reaction with the intravenous formulation. Alternate antivirals under consideration include cidofovir and brincidofovir, though both appear limited by side effects such as transaminitis and questionable clinical efficacy in case reports.⁴

Table II.

Summary of tecovirimat (TPOXX) clinical considerations for the dermatologist^∗

Criteria for use	Severe monkeypox disease; risk of progression to severe disease [infection in patients that are immunocompromised, young children/infants (<8 y old), pregnant or breastfeeding, or with impaired skin barriers (eg, exfoliative disease, burns/wounds)]; involvement of cosmetically or functionally sensitive anatomic areas (eg, pharynx, genitalia)
Contraindications	All formulations: allergy to ingredients (active or inactive) in TPOXX; IV formulation: CrCl <30 mL/min
Formulations and dosing†	Oral: 200 mg capsule(s) [quantity determined by weight] for 14 d, capsules to be taken within 30 min of a fatty meal; IV: 200 mg/20 mL glass vials [quantity determined by weight] to be diluted 1:2 with specified dilutants and administered as an infusion (not a bolus)
Drug interactions and monitoring	CLINICALLY SIGNIFICANT INTERACTIONS. Repaglinide (co-administration of TPOXX increases concentration): Monitor blood glucose levels and clinically for signs/symptoms of hypoglycemia; Midazolam (co-administration of TPOXX decreases concentration): Monitor for adequacy of midazolam dose
	NO clinically significant interaction with the following, per existing data: bupropion, flurbiprofen, omeprazole
	NOTE that the HHS/IDSA does not recommend dose adjustments for any active HIV antiretroviral treatments during concurrent TPOXX treatment (even pre- or post-exposure prophylaxis). Initiation of certain antiretrovirals may be delayed.
Adverse events	Oral: [frequent] headache, gastrointestinal upset (nausea, abdominal pain/discomfort, vomiting), [treatment limiting] gastrointestinal upset, fever, severe headache, facial redness/swelling and pruritus, palpable purpura, EKG changes (unspecified); IV: [frequent] infusion site reaction (pain, swelling, erythema, extravasation), headache, [treatment limiting] infusion site reactions (mild-moderate)

CrCl, Creatinine clearance; EKG, electrocardiogram; HHS, United States Department of Health and Human Services; IDSA, Infectious Diseases Society of America; IV, intravenous; TPOXX, tecovirimat.

^∗Adapted from Centers for Disease Control and Prevention guidance on use of TPOXX and the TPOXX US Food and Drug Administration package insert. Latter should be consulted directly for specifics on administration.

^†Recommend collaboration with infectious disease specialist(s) to guide treatment with TPOXX, especially in special populations (pediatric, pregnant/breastfeeding).

Our expert panel recommends TPOXX as first-line treatment for monkeypox infection in any dermatologic patient who meets criteria per CDC guidelines (patients with or at risk for severe disease or complications, including any state of immunosuppression or active exfoliative skin condition).⁵⁸ Dosing is age and weight-based. Nuances regarding vaccination are discussed below. Given such variables in the absence of robust efficacy studies, we recommend collaboration with an infectious disease specialist for all monkeypox patients. Our colleagues can help with shared decision-making about vaccines and therapeutics, access to medication supply, dose determination, and titration of other indicated anti-infective agents such as ART.

Considerations for higher risk dermatologic patients

As dermatologists, however, we must identify which of our patients are at higher risk of complications and/or in need of special guidance during the global monkeypox outbreak. We infer increased susceptibility to or severity of monkeypox infection in immunocompromised patients or those with impaired skin barriers based on historical reports of eczema vaccinatum (generalized, potentially fatal, vesiculopustular rash in patients with atopic dermatitis or other eczematous/exfoliative skin conditions, see Table III )⁵⁹ or progressive vaccinia (slow local viral expansion from the inoculation site in patients with cell-mediated immunodeficiency/immunosuppression) after administration of first-generation smallpox vaccines.^{59 , 60} Even though vaccine-related dissemination has not been reported with the contemporary JYNNEOS vaccine, immunosuppressed and skin barrier deficient patients are still presumed to be at higher risk for morbidity from primary monkeypox infection. Case reports describe complicated or even fatal monkeypox in patients with advanced HIV/AIDS (eg, CD4 count <200 cells/mm³, not on ART) and patients with cancer,34, 35, 36 or disseminated cowpox infections in patients with severe atopic dermatitis (on systemic steroids) or immunosuppressed following solid organ transplant.^{60 , 61}

Table III.

Skin conditions inferred to increase risk for monkeypox infection from cases of accidental transfer or dissemination of vaccinia virus^∗

Atopic dermatitis (± related: hyper-IgE, Netherton, or Wiskott–Aldrich Syndrome)

Contact dermatitis

Darier's disease

Hailey–Hailey disease

Ichthyosis and ichthyosiform disease

Injuries (accidental wounds including burns, surgical wounds, skin grafts)

Pemphigus and pemphigoid disease

Skin infections (varicella, impetigo, secondary syphilis)

^∗Adapted from Table I in (Reed et al⁵⁹).

Nonetheless, we currently lack the data necessary for more clinically robust risk stratification. We await detailed epidemiologic data on dermatologic comorbidities in monkeypox cases, as a correlate to outcomes, before formal interventional studies are completed. Published large observational studies thus far in this monkeypox outbreak also do not feature significantly immunocompromised patients. Though each case series has a high proportion of HIV positive cases (20%-50%), most are extremely well controlled (CD4 counts averaging >500 cells/mm³); HIV status in these studies did not affect disease presentation, and it remains unclear whether co-infection increases monkeypox susceptibility or if confounding by sexual exposures accounts for the association.^{5 , 7 , 15 , 17 , 18} Relative risk remains uncertain despite the established smallpox literature. Most individuals with atopic dermatitis did not experience disseminated vaccinia after smallpox vaccination, indicating unidentified susceptibility factors.⁵⁹

Moreover the types and prevalence of immunosuppression today drastically differ from that in the smallpox era, limiting many comparisons.⁶² We lack data on the impact of different immunosuppressants on monkeypox-related outcomes. As in the COVID-19 literature, we may find that individuals taking immunosuppressants are at risk of severe or prolonged monkeypox disease, but not necessarily at higher risk of contracting monkeypox in the absence of other risk factors.⁶³ Per Medical Dermatology Society guidelines in the COVID-19 pandemic, certain classes of immunosuppression have increased infection risk (eg, high-dose systemic corticosteroids) or risk for more severe disease (eg, rituximab), while others have more potential for drug-drug interactions (eg, cyclosporine may preclude use of IV TPOXX given potential effects on renal clearance).⁶⁴ With the exception of the ACAM2000 vaccine, which poses a clear risk of disseminated disease, no other leading monkeypox therapeutic is absolutely contraindicated in immunosuppression.^{40 , 49 , 53} Moreover, the presence of an alternate non-replicative vaccine (JYNNEOS) essentially eliminates our need to carefully quantify risk by immunosuppressant. In line with the National Psoriasis Foundation, our panel recommends consideration of JYNNEOS vaccination in all exposed dermatologic patients on immunosuppression, with exfoliative dermatologic disease, or other CDC criteria for prophylaxis, if available.^{44 , 58}

Perhaps the greater concern is the ability to mount an effective vaccine response when immunosuppressed. As gathered from influenza vaccination data, seroconversion rates are lowest during the early post-transplant period or during chemotherapy, and with use of calcineurin inhibitors and mycophenolate mofetil in transplant patients or use of tumor necrosis factor-α inhibitor therapy for immune-mediated disease.⁶⁵ Seroconversion may be non-existent during treatment with rituximab, which targets B cells, inducing hypogammaglobulinemia and canceling the humoral mediated vaccine response.64, 65, 66 Potential strategies to maximize seroconversion rates include thoughtful timing of monkeypox vaccines: (1) 4 to 6 months post-transplant or pre-transplant per Infectious Diseases Society of America guidelines for influenza vaccination; (2) before chemotherapy or between cycles; and (3) case-by-case based on type of immunosuppressive therapy.^{65 , 66} For the latter, our panel recommends adapting the American College of Rheumatology guidance for COVID vaccine timing by immunosuppression class (Table IV ).⁶⁷

Table IV.

Preliminary guidance for monkeypox (MPX) vaccination timing in patients on immunosuppression or immunomodulation for dermatologic disease^∗†

Agent	Recommendation
TNFi, IL-6R, IL-1R, IL-17, IL12/23, IL-23, and other cytokine inhibitors	No consensus. Use shared decision-making with patients (eg, continue biologic as scheduled with plan for supplemental booster doses when available)
Cyclophosphamide IV	Time CYC to 1 wk after each MPX vaccine dose as allowed
Rituximab (RXT)	Variable timing if based on CD19 B cell measurement. Otherwise, when initiating RTX, administer the first MPX vaccine dose 4 wk before the first RTX cycle and delay the subsequent RTX cycle 2-4 wk after the second MPX vaccine dose. With maintenance RTX, consider a booster dose 2-4 wk before the next RTX dose.
Other immunosuppressants (eg, JAKi, MMF, MTX)	Hold for 1-2 wk as allowed after each MPX vaccine dose
Acetaminophen, NSAIDs	Hold for 24 h prior to vaccine, no restrictions post vaccine
Hydroxychloroquine, dapsone, IVIG	No modifications needed

CYC, Cyclophosphamide; IL, interleukin; IV, intravenous; IVIG, intravenous immunoglobulin; JAKi, janus kinase inhibitor; MMF, mycophenolate mofetil; MPX, monkeypox; NSAID, non-steroidal anti-inflammatory drug; TNFi, tumor necrosis factor inhibitor.

^∗Adapted from Table III in American College of Rheumatology COVID-19 Vaccine Clinical Guidance Summary.

^†JYNNEOS or other replication deficient MPX vaccine.

Additional research is needed to ascertain the most effective route, dose, and booster strategies for monkeypox vaccination. Dermatologists need to engage immunosuppressed patients in shared decision-making based on the available data, understanding that uncontrolled skin disease and barrier defects themselves confer risk (infection, allergen sensitization, scarring, etc) independent of the monkeypox outbreak.

Supportive care

Dermatologists also play a role in advancing supportive care for monkeypox, to address prominent symptoms including pain, prevent complications (secondary infection or scarring), and maintain infection control.² No protocols have been evaluated in the literature. Our expert panel synthesizes existing recommendations with personal experience to provide the following guidance, aligned with recent American Academy of Dermatology/CDC monkeypox lesion care principles (Table V ).^{2 , 58 , 68 , 69}

Table V.

Supportive care recommendations in human monkeypox

Wound care	Pain control	Scarring
Maintain clean and moist environment	Multimodal non-opioid analgesia: first line	Prevention
Cleanse wound with gentle soap and water daily	Systemic: acetaminophen, NSAIDs (oral, IV; if tolerated)	Optimize wound care and healing
Apply gelling fiber, foam, or ointment (Vaseline, MediHoney) to clean wound before replacing a fixed dressing (eg, Tegaderm, loose gauze dressing secured by medical tape) daily	Topical: lidocaine preparations, cool packs	Avoid secondary skin infection
Avoid secondary skin infection	Severe, refractory pain	Facilitate resolution of dyspigmentation
Advise patient to avoid manipulating lesions/scabs	Consider hospitalization, opioids, and/or palliative care or pain consultation	Sun protection (avoidance, sunscreen) and fading agents (retinoids, hydroquinone)
Treat secondary skin infections	Pain at mucosal sites and mucosal edema	Cosmetics referral
Topical and/or systemic antibiotics only if clinical evidence of infection	Rectal: lidocaine or other topical numbing agent, hydrocortisone 1%, pramoxine	Laser, peels
Incision and drainage if evidence of abscess	Oropharyngeal: magic mouthwash, lidocaine gel, liquid morphine
Note: Consider consultants for wounds in special sites (eye, anal, or genital lesions)	Note: Monitor for ability to maintain oral intake, IV hydration as needed	Note: Screen for psychological sequelae from scarring and refer to mental health services as appropriate

IV, Intravenous; NSAIDs, non-steroidal anti-inflammatory drugs.

Implement gentle wound care (that includes cleansing erosions/ulcers with soap and water, application of gelling fiber, foam, or barrier ointments) to absorb exudate while maintaining a moist healing environment, and covering with a fixed dressing that limits spread through direct contact and deters manipulation of lesions. Advise patients to avoid removing scabs or shaving, and to wash hands after wound care. Daily dressing changes will promote healing and minimize infection risk, though caregivers and close contacts should be trained to handle soiled material and advised not to share clothing, bedding, or other care products given spread via fomites.

Trial topical lidocaine and conservative oral pain relievers for mild, localized pain, and oral antihistamines or non-steroidal topicals for itch. Patients with severe, function-limiting pain may require short-term opioids. Mucosal symptoms can be further addressed with saltwater rinses and other liquid preparations including antiseptic washes or anesthetic gels/solutions. Genital lesions can benefit from topical hemorrhoidal treatments. Sitz baths may provide symptomatic relief but may risk local dissemination.^{70 , 71} Contact allergens should be avoided given potential for sensitization in the context of open wounds and confounding with evolving secondary infection. Advise patients to seek medical attention for rapidly worsening local pain, redness, or purulent discharge suggestive of superinfection. Antibiotic treatment in these circumstances should be guided by culture data, though empiric treatment can be started according to standard guidelines for impetiginized lesions, cellulitis, or abscesses, in the presence or absence of systemic symptoms.

Long term sequelae are largely unknown, but include pitting, scarring, and dyspigmentation, the latter of which may disproportionately affect patients with darker skin tone.³⁵ Sun protection facilitates resolution of dyspigmentation. Providers should ensure appropriate follow up with general and/or cosmetic dermatology for ongoing management.

Precautions

CDC guidelines as of September 2022 recommend use of a gown, gloves, eye protection, and N95 respirators as personal protective equipment when caring for known or suspected monkeypox patients; these patients should be roomed privately but do not require airborne isolation.⁷² All contacted areas and multi-use instruments (eg, dermatoscopes) should be wiped with an Environmental Protection Agency registered wet disinfectant to avoid fomite transmission; recent studies find that monkeypox virus can persist on surfaces for weeks, albeit it is unclear if the virus remains infectious for this duration.^{26 , 72 , 73}

Conclusions and commentary

Monkeypox disease requires many layers of dermatologic care, from diagnosis to healing. Given the nascent evidence base, the Medical Dermatology Society herein provides early guidance to optimize patient care during yet another viral outbreak. We highlight unknowns that limit our ability to risk stratify patients—we do recommend vigilance with exfoliative disease and immunosuppression—and discuss how to stay up-to-date on infection control and testing measures. We recommend TPOXX and JYNNEOS vaccine as first-line agents for treatment and prophylaxis respectively, but encourage partnership with infectious disease specialists while building expertise with monkeypox management and awaiting formal outcomes data. Existing American College of Rheumatology consensus guidelines for COVID vaccine timing per immunosuppressive agent can be adapted to guide monkeypox vaccination in affected populations. Finally, we synthesize the most salient supportive care recommendations for dermatologists. Our guidance will extend upon completion of larger, controlled studies.

Conflicts of interest

Dr Rosenbach is a member of the AAD’s Ad Hoc Task Force for Monkeypox; the views here represent his own and not those of the AAD. Drs Kumar, Chen, Merola, Mostaghimi, Zhou, Fett, Smith, Saavedra, and Noe have no conflicts of interest to declare.