To the Editor: Monkeypox, until recently, was considered a rare zoonotic infection of the sub-Saharan West Africa, associated with contact with infected animals such as squirrels, rats, and primates.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar The monekypox virus belongs to the genus Orthopox of the family Poxviridae, alongside other cutaneous viruses including smallpox and cowpox.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar Whilst occasional cases outside of Central and West Africa have been historically reported, it has been a condition largely ignored by the wider medical community.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar The 2022 monkeypox outbreak has led to an increasing awareness of the condition, and a desire amongst clinicians to know when to clinically suspect the disease. Despite increasing concern regarding reports of human-to-human (including sexual) transmission across more than 40 countries globally,1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar the risk of monkeypox developing into a new global pandemic is less than the situation with SARS-CoV2 (COVID-19) given the obvious cutaneous manifestations of the disease and the lack of presymptomatic contagious spread.3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google ScholarAs dermatologists, we are uniquely skilled to provide expertise in the evaluation of suspected cases of monkeypox through evaluation of cutaneous morphology and clinical exclusion of other differential diagnoses such as varicella and syphilis4Forrestel A.K. Kovarik C.L. Katz KA sexually acquired syphilis: historical aspects, microbiology, epidemiology, and clinical manifestations.J Am Acad Dermatol. 2020; 82: 1-14Google Scholar,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar (Table I). This is particularly prudent given that the global monkeypox outbreak remains an evolving situation, with unresolved questions regarding the relative frequency of droplet transmission,1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar and limited information regarding mortality rates in high-risk groups such as children, the elderly, and the immunocompromised.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google ScholarTable IA comparative table of the disease and clinical characteristics of monkeypox, cowpox, varicella, and secondary syphilis. The varied clinical characteristics of the various stages of the monkeypox associated eruption include the papular eruption on an erythematous (almost morbilliform) base with central umbilication, followed by a painful pustular eruption, and resolving through the development of eschar formation. This is in contrast to the clinical features of other differential diagnoses including cowpox, varicella, and secondary syphilisConditionMonkeypoxCowpoxPrimary varicellaSecondary syphilisCausative agent (Genus)Monkeypox virus (Orthopoxvirus)Cowpox virus (Orthopoxvirus)Varicella zoster virus (Varicellovirus)Treponema pallidum (Treponema)Incubation period5-21 d7 d14-16 d2-8 wk post primary chancreTransmissionDirect contact, droplet, fomites, transplacentalDirect contactDirect contact, droplet, transplacentalDirect contact, transplacentalContagious periodSymptomatic period onlySymptomatic period only2-5 d prior to lesions until 6 d post last cropSymptomatic period onlyMorphologySequential evolution: macules, papules, vesicles, pustules, eschar. (<10 lesions in 64% cases)Solitary or limited 5-20 mm diameter.Sequential evolution: macule, papule, haemorrhagic pustule, eschar.1-3 mm vesicles on an erythematous background. (presence of lesions in various stages)Widespread papulosquamous eruption, mucous patches, alopecia, condyloma lata.LymphadenopathyYes (during prodrome)Yes (with rash)Yes (with rash)Yes (with rash)FeverYesYesYesYes (with chancre and rash)MyalgiaYesYesYesYesLethargyYesYesYesYesComplicationsSecondary bacterial infection, pneumonia, encephalitisDisseminated disease in atopic dermatitis, Darier's diseaseSecondary bacterial infection, respiratory distress syndrome (Adults)Multisystem disease, (cardiac, neurological, ophthalmological etc)Mortality3.6% (West African clade)1%-3%1/100,000-21/100,000 cases per y5%-58% (Untreated) Open table in a new tab A major barrier to clinician education regarding monkeypox, is the current messaging comparing the features of monkeypox to smallpox and primary varicella. Given that it has been over 40 years since the global eradication of smallpox, the number of practicing clinicians who have seen smallpox (as opposed to rare cases of limited variolation) is rapidly declining. Additionally, routine varicella vaccinations have drastically reduced cases of primary varicella,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar making this a rarity to younger dermatologists and trainees. Revisiting the commonalities and differentiating features of these conditions (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/ypy5f6d8r9.1) is important in raising awareness and encouraging accurate clinical diagnosis in cases of suspected monkeypox.Monkeypox virus can be spread through direct contact as well as possibly through droplet transmission.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar The prodromal stage may involve fever, malaise, and lymphadenopathy prior to the development of cutaneous lesions. (Table I, Supplementary Fig 1). Along with cowpox2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar and varicella,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar cutaneous lesions of monkeypox present as erythematous macules, progressing to umbilicated papules, painful vesicles, and pustules, followed by firm indurated eschar during the period of resolution (Supplementary Fig 1).1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar Initial lesions occur at sites of direct contact, however, more disseminated lesions can occur during the course of the illness.The main differentiating features of monkeypox as opposed to other viral infections under consideration, is the monomorphic progression of lesions in distinct anatomical areas. In acral sites, all lesions will progress through papular, pustular, or eschar stages in synchrony, as opposed to primary varicella where various stages of lesion are interspersed1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar and molluscum contagiosum in which morphological progression of lesions will not occur. Monkeypox often presents with less than 10 distinct umbilicated lesions (in 64% cases)2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar which may aid in diagnosis when combined with history and lesion evolution. An additional differentiating feature is the presence of lymphadenopathy in the prodromal stage of the disease. This may be a useful feature for evaluation of close contacts; however, lymphadenopathy is present during the eruptive stages of a number of differential conditions which is why such a feature should not be relied upon in isolation. Secondary syphilis,4Forrestel A.K. Kovarik C.L. Katz KA sexually acquired syphilis: historical aspects, microbiology, epidemiology, and clinical manifestations.J Am Acad Dermatol. 2020; 82: 1-14Google Scholar when rapidly following the initial chancre, may present in a similar fashion to monkeypox and should be a differential diagnosis under consideration.The current monkeypox outbreak is an evolving situation; however, a deeper understanding of the comparative morphological and temporal order of features should allow for a degree of clinical diagnosis to be undertaken by the astute dermatologist. To the Editor: Monkeypox, until recently, was considered a rare zoonotic infection of the sub-Saharan West Africa, associated with contact with infected animals such as squirrels, rats, and primates.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar The monekypox virus belongs to the genus Orthopox of the family Poxviridae, alongside other cutaneous viruses including smallpox and cowpox.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar Whilst occasional cases outside of Central and West Africa have been historically reported, it has been a condition largely ignored by the wider medical community.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar The 2022 monkeypox outbreak has led to an increasing awareness of the condition, and a desire amongst clinicians to know when to clinically suspect the disease. Despite increasing concern regarding reports of human-to-human (including sexual) transmission across more than 40 countries globally,1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar the risk of monkeypox developing into a new global pandemic is less than the situation with SARS-CoV2 (COVID-19) given the obvious cutaneous manifestations of the disease and the lack of presymptomatic contagious spread.3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar As dermatologists, we are uniquely skilled to provide expertise in the evaluation of suspected cases of monkeypox through evaluation of cutaneous morphology and clinical exclusion of other differential diagnoses such as varicella and syphilis4Forrestel A.K. Kovarik C.L. Katz KA sexually acquired syphilis: historical aspects, microbiology, epidemiology, and clinical manifestations.J Am Acad Dermatol. 2020; 82: 1-14Google Scholar,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar (Table I). This is particularly prudent given that the global monkeypox outbreak remains an evolving situation, with unresolved questions regarding the relative frequency of droplet transmission,1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar and limited information regarding mortality rates in high-risk groups such as children, the elderly, and the immunocompromised.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar A major barrier to clinician education regarding monkeypox, is the current messaging comparing the features of monkeypox to smallpox and primary varicella. Given that it has been over 40 years since the global eradication of smallpox, the number of practicing clinicians who have seen smallpox (as opposed to rare cases of limited variolation) is rapidly declining. Additionally, routine varicella vaccinations have drastically reduced cases of primary varicella,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar making this a rarity to younger dermatologists and trainees. Revisiting the commonalities and differentiating features of these conditions (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/ypy5f6d8r9.1) is important in raising awareness and encouraging accurate clinical diagnosis in cases of suspected monkeypox. Monkeypox virus can be spread through direct contact as well as possibly through droplet transmission.1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar The prodromal stage may involve fever, malaise, and lymphadenopathy prior to the development of cutaneous lesions. (Table I, Supplementary Fig 1). Along with cowpox2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar and varicella,5McCrary M.L. Severson J. Tyring S.K. Varicella Zoster virus.J Am Acad Dermatol. 1999; 41: 1-16Google Scholar cutaneous lesions of monkeypox present as erythematous macules, progressing to umbilicated papules, painful vesicles, and pustules, followed by firm indurated eschar during the period of resolution (Supplementary Fig 1).1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar Initial lesions occur at sites of direct contact, however, more disseminated lesions can occur during the course of the illness. The main differentiating features of monkeypox as opposed to other viral infections under consideration, is the monomorphic progression of lesions in distinct anatomical areas. In acral sites, all lesions will progress through papular, pustular, or eschar stages in synchrony, as opposed to primary varicella where various stages of lesion are interspersed1Harris E. What to know about Monkeypox.JAMA. 2022; 327: 2278-2279Google Scholar,3Thornhill J.P. Barkati S. Walmsley S. Rockstroh J. et al.Monkeypox virus infection in humans across 16 countries – April-June 2022.N Eng J Med. 2022; 387: 679-691https://doi.org/10.1056/NEJMoa2207323Google Scholar and molluscum contagiosum in which morphological progression of lesions will not occur. Monkeypox often presents with less than 10 distinct umbilicated lesions (in 64% cases)2Gronemeyer L.L. Baltzer A. Breokaert S. et al.Generalised cowpox virus infection.Lancet. 2017; 390: 1769Google Scholar which may aid in diagnosis when combined with history and lesion evolution. An additional differentiating feature is the presence of lymphadenopathy in the prodromal stage of the disease. This may be a useful feature for evaluation of close contacts; however, lymphadenopathy is present during the eruptive stages of a number of differential conditions which is why such a feature should not be relied upon in isolation. Secondary syphilis,4Forrestel A.K. Kovarik C.L. Katz KA sexually acquired syphilis: historical aspects, microbiology, epidemiology, and clinical manifestations.J Am Acad Dermatol. 2020; 82: 1-14Google Scholar when rapidly following the initial chancre, may present in a similar fashion to monkeypox and should be a differential diagnosis under consideration. The current monkeypox outbreak is an evolving situation; however, a deeper understanding of the comparative morphological and temporal order of features should allow for a degree of clinical diagnosis to be undertaken by the astute dermatologist. JWF has conducted advisory work for Janssen, Boehringer-Ingelheim, Pfizer, Kyowa Kirin, LEO Pharma, Regeneron, Chemocentryx, Abbvie, Azora, Novartis and UCB, participated in trials for Pfizer, UCB, Boehringer-Ingelheim, Eli Lilly, CSL, Azora and received research support from Ortho Dermatologics, Sun Pharma, LEO Pharma, UCB and La Roche Posay.