transmission has been described from primary human cases and secondary cases,53,62,63 and serial transmission across 4 cases has been observed.64 In the current monkeypox outbreak in Nigeria, genomic studies of monkeypox virus isolates from humans60 indicate that the index case was not imported into Nigeria. Thus, the outbreak is considered to be a spillover from multiple sources of introduction into the human population. The zoonotic source(s) of the outbreak are being investigated at present, and it is unclear what, if any, environmental or ecologic changes might have facilitated the sudden re-emergence of monkeypox in Nigeria. Case clustering has been identified within the various states, but no epidemiologic linkages between them have been detected thus far. Three family clusters have been identified, suggesting human-to-human transmission.58–60 In one family the secondary attack rate was 71%. However, most patients had no obvious epidemiologic linkage or person-to-person contact, indicating a probable multiple-source outbreak or, possibly, an endemic disease previously unrecognized. CLINICAL FEATURES The incubation period has been estimated at 5 to 21 days, and duration of symptoms and signs at 2 to 5 weeks. The illness begins with nonspecific symptoms and signs that include fever, chills, headaches, lethargy, asthenia, lymph node swellings, back 6 Petersen et al pain, and myalgia (muscle ache) and begins with a fever before rashes appear. Within 1 to 5 days after the onset of fever, rashes of varying sizes appear, first on the face (Fig. 2), then across the body (Fig. 3), hands (Fig. 4A), and legs and feet (Fig. 4B). The rash undergoes several stages of evolution from macules, papules, vesicles (fluid-filled blisters) (see Fig. 2), and pustules (see Fig. 3B, D), followed by resolution over time with crusts and scabs (Fig. 5), which drop off on recovery. Various stages of the rash may show at the same time (see Figs. 3B and 5). Areas of erythema (see Fig. 2A) and/or skin hyperpigmentation (see Fig. 5) are often seen around discrete lesions. Detached scabs may be considerably smaller than the original lesion. Inflammation of the pharyngeal, conjunctival, and genital mucosae may also be seen. The clinical presentation of monkeypox includes symptoms and lesions that are difficult to distinguish from smallpox.37,60,65,66 Although the clinical manifestations of monkeypox are milder than smallpox, the disease can prove fatal, death rates ranging from 1% to 10%. Mortality is higher among children and young adults and the course is more severe in immunocompromised individuals.67 A range of complications has been reported, such as secondary bacterial infections, respiratory distress, bronchopneumonia, encephalitis, corneal infection with ensuing loss of vision, gastrointestinal Fig. 2. (A–D) Maculo-papular-vesicular-pustular monkeypox skin lesions of varying sizes on the face. (Courtesy of Nigeria Centre for Disease Control, Abuja, Nigeria.) Human Monkeypox 7 Fig. 4. (A, B) Papular-pustular monkeypox skin lesions on the hands, legs, and feet. (Courtesy of Nigeria Centre for Disease Control, Abuja, Nigeria.) Fig. 3. (A–D) Papular-vesicular-pustular monkeypox skin lesions of varying sizes across the body. (Courtesy of Nigeria Centre for Disease Control, Abuja, Nigeria.) 8 Petersen et al involvement, vomiting, and diarrhea with dehydration. Case fatality rates have varied between 1% and 10% in outbreaks, deaths occurring mostly among young adults and children. Particularly those with immunosuppression are at risk of severe disease. Lymphadenopathy is seen in up to 90% of patients and appears to be a clinical feature distinguishing human monkeypox from smallpox. Previous smallpox vaccination confers some cross-protection against monkeypox and modifies the clinical picture toward a milder disease. Between 1980 and 1990, the clinical presentation of human monkeypox seems to have changed: primary human cases have increasingly been seen among those never vaccinated against smallpox. Compared with those vaccinated, the clinical picture described for the unvaccinated was more severe, with more vigorous and pleomorphic rashes and higher mortality.62,66,68–70 The primary differential diagnosis is severe chickenpox with lesions in palms and soles.7,65 The lesions in chickenpox are more superficial and occur in clusters of the same stage, with denser manifestations on the trunk than on the face and extremities. Because of the nonspecific nature of the symptoms and signs of monkeypox, a wide variety of differential diagnoses should be considered, ranging from chickenpox, molluscum contagiosum, measles, rickettsial infections, bacterial skin infections (such as those caused by Staphylococcus aureus), anthrax, scabies, syphilis, and drug reactions to other noninfectious causes of rash. A clinical sign differentiating monkeypox from smallpox and chickenpox is the presence of enlarged lymph nodes, particularly submental, submandibular, cervical, and inguinal nodes.71 SMALLPOX VACCINATION, MONKEYPOX PREVALENCE, AND CHANGING CLINICAL PRESENTATIONS In 1980, the Global Commission for the Certification of Smallpox Eradication (GCCSE) continued to designate monkeypox as a public health threat, recommending that the epidemiologic, ecologic, and surveillance program on monkeypox be