Among the poxviruses causing disease in humans, the following are the most clinically important: variola/vaccinia, molluscum contagiosum, orf and paravaccinia, and monkeypox.
Smallpox (variola) was a highly contagious disease associated with high mortality and disabling sequelae. Its manifestations include severe headache, acute onset of fever, prostration and a rash characterized by uniform progression from macules to papules to firm, deep-seated vesicles or pustules. The synchronous progression in smallpox readily differentiates lesions from those of varicella (see also Chapter 6).
Complications of smallpox include bacterial superinfections (cellulitis and pneumonia), encephalitis, and keratitis with corneal ulcerations (risk factor for blindness). Effective vaccination led to its global elimination by 1979 and routine vaccination stopped in 1985. Recommendations to destroy remaining samples of this virus have not been acted upon thus far, and significant concern exists for potential misuse of these repositories in military or terrorist activities.
Smallpox should be considered, in concordance with the CDC Smallpox Response Plan (https://www.cdc.gov/smallpox/bioterrorism-response-planning/community/index.html), in any patient with fever and a characteristic rash for which other etiologies—such as herpes infections (eczema herpeticum may be differentiated from suspect smallpox by appropriate serologic stains and clinical appearance), erythema multiforme, drug reactions, or other infections—are unlikely. One hundred fifteen cases of vaccine-related vaccinia infection resulting from contact with a smallpox vaccinee in the United States between 2003 and 2011 (including sexual transmission) were reported. Two cases of vaccinia infection after contact with oral rabies animal baits (which uses the vaccinia vector) are reported. An outbreak of at least 11 cases in Brazil was associated with poor milking practices at the time of a large bovine vaccinia outbreak and with infection in dogs, raising the question whether other animal species may be a source of transmission. Patients with suspected infection should be placed in airborne and contact isolation and the official agency contacted (CDC Poxvirus and Rabies Branch help desk may be reached at 404-639-4129 and the Director’s Emergency Operation Center at 770-488-7100). The national stockpile in the United States currently contains three smallpox vaccines: ACAM2000 (the only licensed vaccine) and two investigational vaccines, Aventis Pasteur Smallpox Vaccine and Imvamune. Imvamune is a replication deficient vaccine designed for immunocompromised persons and others for whom ACAM2000 is contraindicated. Contraindications to vaccination include immunosuppression, eczema or other dermatitis in the vaccinee or household contacts, allergy to any component of the vaccine, infants younger than 1 year, and pregnant or breastfeeding women. Imvamune is administered in two doses 4 weeks apart. In recipients with atopic dermatitis, more skin adverse events were experienced but few were severe, and evidence for immunoprotection was similar to that reported in healthy recipients. A modified vaccinia Ankara smallpox vaccine was evaluated in phase 3 clinical trials and found to be safe and immunogenic (NCT01913353).
It is unnecessary for anyone not handling the smallpox vaccine to be vaccinated. Israeli studies suggest about 4% of their population show contraindications to vaccination. Inoculation of the vaccine in inappropriate sites (eg, eyes) is unfortunately common. Asymptomatic vaccinia viremia can be detected up to 21 days post vaccination, and no blood donation should occur during this interval.
Cidofovir may be considered for treatment of poxviral conditions and intravenous human vaccinia immunoglobulin may be useful for vaccinia infection. Its lipid-conjugated prodrug, brincidofovir, is also being developed as a possible less toxic therapy (NCT01143181). Tecovirimat, a drug that inhibits p37 (a protein that is highly conserved in orthopoxviruses) and thereby prevents the formation of enveloped virions, is currently in development to use as a treatment for smallpox (NCT02080767). In the event of smallpox exposure, vaccine may be used to prevent or modulate infection.
A needle-stick injury case of vaccinia virus infection reported in 2019 from California was treated with the p37 inhibitor tecovirimat and vaccinia immune globulin intravenous (VIGIV) and resolution of a necrotic finger lesion was prolonged (94 days).
Guidelines regarding smallpox vaccination are available at https://www.cdc.gov/smallpox/vaccine-basics/index.html.
Molluscum contagiosum is caused by a molluscipox virus that may be transmitted sexually or by other close contact. It may occur also in an extensive form in children with genetic defects in dendritic and T-cell migration (the DOCK8 [dedicator of cytokinesis] deficiency). The disease is manifested by pearly, raised, umbilicated skin nodules sparing the palms and soles. Keratoconjunctivitis can occur. Most ocular lesions are typical umbilicated dome-shaped lesions, but a variety of atypical ocular lesions are reported often in immunocompetent patients, more often in females and young adults (mean age 19). Other atypical presentations are atypical facial lesions in a patient with Crohn disease and intracranial infection, the latter detected in CSF of a girl with headaches.
There may be an association with atopic dermatitis or eczema. Marked and persistent lesions in AIDS patients respond readily to combination ART. Treatment options include destructive therapies (curettage, cryotherapy, cantharidin, 10–15% hydrogen peroxide, and keratolytics, among others), immunomodulators (imiquimod, cimetidine, and Candida antigen), and antiviral agents (topical cidofovir is effective anecdotally in refractory cases; brincidofovir is approved for the treatment of Ebola but is still off-label for molluscum contagiosum, where it shows some efficacy). No treatment is uniformly effective, and multiple courses of therapy are often needed. One meta-analysis recommends natural resolution of lesions if normal immunity can be restored. Cryptococcal skin lesions can mimic molluscum contagiosum.
Orf (contagious pustular dermatitis, or ecthyma contagiosa) and paravaccinia (milker’s nodules) are occupational diseases acquired by contact with sheep/goats and cattle, respectively. Household meat processing and animal slaughter have been implicated as risk factors. A new poxvirus akin to parapoxviruses was reported in 2015 in two patients from rural Tennessee and Missouri (the latter had also traveled to Tanzania). Orf is a common infection in sheep, goats, and deer. Thus, it is found worldwide, and farmers, veterinarians, and hunters are considered high-risk populations. A nosocomial outbreak occurred in 2012 in Turkey in a burn unit. Five cases in France were due to sheep exposures during the Muslim Feast of the Sacrifice (Eid al-Adha). It progresses through six clinically distinct dermatologic stages and lesions usually heal in 3–6 weeks without scarring. The use of nonporous gloves for persons handling animals is recommended, especially if the persons are immunosuppressed. Molecular tests are used to confirm clinical diagnosis. Although there is no specific treatment, Orf anecdotally responds to imiquimod. A live vaccine is available for animals, and the orfvirus, which has immunomodulatory properties, is increasingly used as a vector and as an oncolytic agent in human vaccine trials.
First identified in 1970, monkeypox is enzootic in the rain forests of equatorial Africa and presents in humans as a syndrome similar to smallpox. The incubation period is about 13 days (range, 6–28 in a recent Central African Republic outbreak) and limited person-to-person spread occurs. African mortality rates vary from 3% to 11% depending on the immune status of the patient. Secondary attack rates appear to be about 10%. Since 2017, confirmed cases of monkeypox have occurred in Cameroon, Central African Republic, Côte d’Ivoiure, Democratic Republic of the Congo, Republic of the Congo, Gabon, Liberia, Nigeria (where cases occurred after a 40-year hiatus), Sierra Leone, and South Sudan. Risk factors identified from the Democratic Republic of Congo include being bitten by rodents, working as a hunter, and being male over 18 years of age. The first community-acquired outbreak of monkeypox in the United States occurred in 2003 in Wisconsin and other states of the upper Midwest. The source appeared to be imported Gambian giant rats via consequent exposure of prairie dogs. Other susceptible animals include nonhuman primates, rabbits, and rodents. The giant pouched rat is a particular reservoir for disease in Central Africa.
Confusion with smallpox and varicella occurs; however, both lymphadenopathy (seen in up to 90% of unvaccinated persons) and a febrile prodrome are prominent features in monkeypox infection. The monkeypox rash is distinguished by its deep-seated and well-circumscribed nature, lesions at the same stage of development (unlike varicella but like smallpox), and its centrifugal progression (including palms and soles). Suspected cases should be placed on standard, contact, and droplet precautions; local and state public health officials and the CDC should be notified for assistance with confirmation of the diagnosis (by electron microscopy, viral culture, ELISA, PCR, and a GeneXpert assay referred to as MPX/OPX [monkeypox/orthopox]). There are no standard or optimized guidelines for the clinical management of monkeypox. Cidofovir is effective in vitro against monkeypox, and its less toxic prodrug brincidofovir may be useful as well (NCT01143181). Vaccinia immune globulin can be used in selected cases. Tecovirimat is being developed for the treatment of both smallpox and monkeypox (NCT02080767). Its administration requires an investigational new drug application. More information on treatment can be found at http://www.cdc.gov/ncidod/monkeypox/treatmentguidelines.htm.
Other general precautions that should be taken are avoidance of contact with rodents from endemic areas (whose illness is manifested by alopecia, rash, and ocular or nasal discharge), appropriate care and isolation of humans exposed to such animals within the prior 3 weeks, and veterinary examination and investigation of suspect animals through health departments. Vaccinia immunization is effective against monkeypox and is recommended for those involved in the investigation of the outbreak and for health care workers caring for those infected with monkeypox if no contraindication exists (outlined above). Postexposure vaccination is also advised for documented contacts of infected persons or animals. US federal agencies prohibit the importation of African rodents.
Two cases of a novel orthopoxvirus were identified in the country of Georgia in 2013 with a third diagnosed serologically from 2010. All cases had animal contact, two had cattle contact, and serologic data showed possible associations with rodents and shrews as well as cattle. None had been vaccinated for smallpox (routine smallpox vaccinations ceased before their births). Another novel orthopoxvirus was identified in a patient who had undergone kidney transplantation in North America in 2015. The seroprevalence to orthopoxvirsues is high in veterinary workers and those with cat exposures.
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