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Monkeypox (hMPXV Infection): A Practical Review

Published:December 07, 2022DOI:https://doi.org/10.1016/j.amjmed.2022.10.023
Monkeypox (hMPXV Infection): A Practical Review
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      Abstract

      Monkeypox, a neglected disease previously confined to Africa, is causing a worldwide outbreak affecting predominantly males who have sex with males, especially those who are infected with HIV. The clinical presentation during the current outbreak differs from endemic cases. Treatment with tecovirimat and other antivirals is available. Immunization may be used as preexposure and postexposure prophylaxis.
      Clinical Significance
      • •
        Monkeypox (hMPXV) infection is causing a pandemic (beyond its usual confinement in Africa).
      • •
        Transmission is via skin-to-skin contact, predominantly during sexual encounters.
      • •
        Males who have sex with males, especially those who are infected with HIV are most commonly affected.
      • •
        Pandemic cases have shorter incubation period, lesser number of lesions, and more circumscribed location of the lesions.
      • •
        Treatment is supportive, but specific antivirals are available.
      • •
        Vaccinations can be used for preexposure and postexposure prophylaxis.
      Monkeypox, previously considered an exotic disease confined to Africa, is causing a worldwide outbreak with cases reported predominantly among males who have sex with males. This article provides a practical review of the disease.
      In accordance with the recommendation by numerous scientists to avoid using discriminatory and misleading terminology, we use hMPXV to refer to the virus.
      • Happi C
      • Adetifa I
      • Mbala P
      • et al.
      Urgent need for a non-discriminatory and non-stigmatizing nomenclature for monkeypox virus.
      PLoS Biol. 2022; 20e3001769

      The Organism

      hMPXV belongs to the family Poxviridae and the subfamily Cordopoxvirinae (poxviruses of vertebrates). Several genera of Cordopoxvirinae affect humans (as seen in Table 1), one of which is hMPXV.
      • Regnery RL.
      Poxviruses and the passive quest for novel hosts.
      Curr Top Microbiol Immunol. 2007; 315: 345-361
      hMPXV is a large (400 nm × 250 nm) brick-shaped virus containing double-stranded DNA. The poxviridae family has 90% genomic sequence homology among its members. Figure 1 describes the replication cycle of hMPXV (extrapolated from the vaccinia virus, used to manufacture smallpox vaccine) cycle.
      • Greseth MD
      • Traktman P.
      The life cycle of the vaccinia virus genome.
      Annu Rev Virol. 2022; 9: 239-259
      Table 1Poxviridae Genuses Affecting Humans
      GenusSpeciesHosts Other Than Humans
      Moluscipox virusMolluscum contagiosum virusDogs, birds, kangaroos, equids, primates
      OrthopoxvirusCowpox virusAlpacas, cats and large felids, cattle, elephants, mongooses, okapis, rhinoceros, rodents
      Monkeypox virus (hMPXV)Squirrels, monkeys, great apes
      Vaccinia virus (virus in smallpox vaccine)Buffalo, cattle, swine, rabbits
      Variola virus (smallpox virus)None
      ParapoxvirusBovine popular stomatitis virusCattle
      Orf virusSheep, goats
      Pseudocowpox virusCattle
      YatapoxvirusYabapox virusMonkeys
      Tanapox virusMonkeys
      Figure 1
      Figure 1VACV is a large, enveloped, brick-shaped DNA virus that exists in three infectious forms: the intracellular mature virus (IMV), the intracellular triple-enveloped virus (IEV). and the extracellular double-enveloped virus (EEV).
      1. To enter the cell, the EEV has an entry fusion complex (EFC) on the inner envelope. The outer envelope has proteins that interact with laminin and with the glycosaminoglycans (chondroitin sulfate and heparan sulfate, which facilitate interaction with other proteins, such as beta integrin or MARCO. They in turn allow disarming the outer envelope allowing entry of the virion.
      2. The viral core that enters the cytoplasm contains the viral DNA as well as DNA-dependent RNA polymerase that allows for synthesis of RNA without the intervention of the cell nucleus.
      3. The host cell ribosomes translate early and late genes from the viral mRNA. The early genes codify proteins that counteract host immune defenses and stimulate the replication of viral DNA. The late genes codify for proteins required for viral assembly.
      4. Viral DNA and core proteins are assembled to become the IMV.
      5. Between 5% and 10% IMV are wrapped by a Golgi cisterna or late endosome (LE) becoming 3-membrane wrapped virions (IEV). The F13L gene of the vaccinia virus encodes the membrane protein p37, which is pivotal in the fusion of the IMV membranes with the Golgi or LE. Tecovirimat binds specifically to the homologous F13L proteins (p37 and others), preventing the formation of IEV.
      6. IEV surfs the actin filaments until the outermost membrane of the virion fuses with the extracellular membrane, releasing the two-membrane EEV into the extracellular.
      Since its discovery, hMPXV has been phylogenetically distinguished into 2 clades: the Central African or Congo Basin (Clade 1) and the West African (Clade 2). The pandemic virus isolated in 2022 is phylogenetically close to clade 2; however, there were enough differences to call it clade 3. In August 2022, a group of World Health Organization (WHO) experts established a new nomenclature: clade 1 became clade I, clade 2 became clade IIa, and clade 3 (the current circulating hMPXV) became clade IIb.

      World Health Organization. Monkeypox: experts give virus variants new names. Available at: https://www.who.int/news/item/12-08-2022-monkeypox–experts-give-virus-variants-new-names. Accessed on October 18, 2022.

      The phylogenetic evolution of hMPXV has been attributed to apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) enzymes. These deaminases convert cytidine to thymidine and guanosine to adenine. Although useful to modify foreign nucleic acid by inactivating its replication and transcription, APOBEC could accidentally render the viruses better fit to immune evasion or induce resistance to antiviral drugs.
      • Chen Y
      • Li M
      • Fan H.
      The monkeypox outbreak in 2022: adaptive evolution associated with APOBEC3 may account for.
      Signal Transduct Target Ther. 2022; 7: 323

      Epidemiology

      hMPXV was discovered in 1958 during a smallpox-like outbreak in macaque monkeys at a Danish research center, hence, the “monkeypox” name; however, the animal reservoir is unknown. Small rodents harbor the virus in Africa.
      • Di Giulio DB
      • Eckburg PB.
      Human monkeypox: an emerging zoonosis.
      Lancet Infect Dis. 2004; 4: 15-25
      The first human case, resembling smallpox, was reported in 1970 in the Democratic Republic of Congo. Human disease is different according to the clade involved:
      • -
        Clade 1 hMPXV was reported in the Congo Basin: Cameroon, Congo, the Central African Republic, and Democratic Republic of Congo. Human-to-human transmission occurs. In those not vaccinated against smallpox, the fatality rate was 11% (and 15% in those younger than 4 years of age).
        • Kmiec D
        • Kirchhoff F.
        Monkeypox: a new threat?.
        Int J Mol Sci. 2022; 23: 7866
      • -
        Clade 2 infection was reported in West Africa (Sierra Leone, Liberia, Ivory Coast, Ghana, and Nigeria). All cases were associated with contact with arboreal and nonarboreal rodents. Mortality was low.
        • Likos AM
        • Sammons SA
        • Olson VA
        • et al.
        A tale of two clades: monkeypox viruses.
        J Gen Virol. 2005; 86 (Pt): 2661-2672
      From the 1970s to the present, almost 30,000 cases of hMPXV infection, with a few hundred deaths, have been reported in the Congo Basin. In the 1980s, the source of infection was contact with animals (72%), and in the 1990s, contact with humans explained 78% of cases. Until the 1990s, 100% of deaths occurred in children younger than 10 years of age, and later, this group explained only 35% of the deaths. This change may be explained in part by weaning of the cross-protection provided by previous smallpox vaccination.
      • Bunge EM
      • Hoet B
      • Chen L
      • et al.
      The changing epidemiology of human monkeypox-A potential threat? A systematic review.
      PLoS Negl Trop Dis. 2022; 16e0010141
      Sporadic cases have been reported outside Africa, but in 2003 there was an outbreak of 47 cases of hMPXV infection in the US. These were acquired by contact with prairie dogs, which in turn became infected by being housed with rodents imported from Ghana. There were no fatalities, and no person-to-person transmission was documented. Genetic sequence analysis confirmed the isolates belonged to clade 2.
      • Likos AM
      • Sammons SA
      • Olson VA
      • et al.
      A tale of two clades: monkeypox viruses.
      J Gen Virol. 2005; 86 (Pt): 2661-2672
      Between 2017 and 2020 an outbreak of hMPXV infection was described in Nigeria, with similar modes of transmission as seen in the current epidemic. The surge of the disease was attributed to population growth and loss of smallpox immunity, but the international community paid little attention.
      • Nguyen PY
      • Ajisegiri WS
      • Costantino V
      • Chughtai AA
      • MacIntyre CR.
      Reemergence of human monkeypox and declining population immunity in the context of urbanization, Nigeria, 2017-2020.
      Emerg Infect Dis. 2021; 27: 1007-1014
      In May 2022, an unusual outbreak of hMPXV infection was initially reported in the UK. Subsequently multiple cases appeared throughout the world. On July 23, WHO declared a Public Health Emergency of International Concern. As of October, more than 70,000 cases were reported worldwide, the majority in the United States. The outbreak affects disproportionately males who have sex with males, including many of those infected with HIV.

      World Health Organization. 2022 monkeypox outbreak: global trends. Available at: https://worldhealthorg.shinyapps.io/mpx_global/. Accessed October 18, 2022.

      The epidemiological differences between the epidemic and the endemic forms of the disease are discussed in Table 2.
      Table 2Epidemiological Differences Between Endemic and Epidemic hMPXV Infection
      Epidemiological CharacteristicEndemic InfectionCurrent Epidemic Infection
      Geographic locationRainforest of West and Central AfricaWorldwide
      Areas affectedSmall rural villagesLarge urban areas
      Clade causing infectionI, IIaIIb
      Age of infectedYounger than 15 years of ageSexually active age
      ComorbiditiesNot reportedSexually transmitted infections, including HIV
      HIV coinfection occurs in up to 40% of cases in the US
      TransmissionContact with animals (due to deforestation, hunting, migration) followed by secondary human-to-human transmissionMainly human-to-human transmission during sexual contact
      MortalityHigh (between 3% and 10 % depending on the clade)Very rare
      Transmission of hMPXV from animals to humans occurs through direct contact with infected blood, bodily fluids, or mucosal or cutaneous lesions. Transmission from humans to humans occurs by contact with skin lesions or respiratory secretions, or by indirect contact with fomites. Airborne transmission has not been documented. In the current outbreak, the main means of transmission is close contact during sexual activity;

      Angelo KM, Smith T, Camprubí-Ferrer D, et al. Epidemiological and clinical characteristics of patients with monkeypox in the GeoSentinel Network: a cross-sectional study [e-pub ahead of print]. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(22)00651-x, Accessed October 18, 2022.

      (however hMPXV is not considered a sexually transmitted infection because sexual activity is not the only means of transmission). In a survey of 45 infected patients, 98% identified themselves as homosexual or bisexual, 74% were HIV negative (out of which 91% were receiving HIV preexposure prophylaxis), 26% were HIV positive and were receiving appropriate treatment. A total of 64% had attended group sex events, 75% had new sexual partners, and 83% got dates via social apps.
      • Vivancos R
      • Anderson C
      • Blomquist P
      • et al.
      Community transmission of monkeypox in the United Kingdom, April to May 2022.
      Euro Surveill. 2022; 272200422

      Clinical Manifestations

      The clinical presentation of hMPXV infection in endemic countries differs from the manifestations seen during the current outbreak.

      Angelo KM, Smith T, Camprubí-Ferrer D, et al. Epidemiological and clinical characteristics of patients with monkeypox in the GeoSentinel Network: a cross-sectional study [e-pub ahead of print]. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(22)00651-x, Accessed October 18, 2022.

      ,
      • Philpott D
      • Hughes CM
      • Alroy KA
      • et al.
      Epidemiologic and clinical characteristics of monkeypox cases - United States, May 17-July 22, 2022.
      MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022
      ,
      • Petersen E
      • Kantele A
      • Koopmans M
      • et al.
      Human monkeypox: epidemiologic and clinical characteristics, diagnosis, and prevention.
      Infect Dis Clin North Am. 2019; 33: 1027-1043
      In its classical presentation, hMPXV infection had an incubation period of 7-17 days. The disease started with fever, fatigue, and headache. Prominent maxillary, cervical, or inguinal lymphadenopathy preceding or concomitant with the rash was characteristic. The lymph nodes were described as firm and painful. The rash started in the face and disseminated centrifugally to the rest of the body. There were usually hundreds or thousands of lesions that progressed through 5 phases: macular, papular, vesicular, pustular, and desquamative. During the papular stage a typical central umbilication appeared. The lesions were in the same stage of progression at any given time (a helpful characteristic in differentiating the condition from chickenpox). The rate of complications was high (between 40% and 70%, depending on the smallpox vaccination status) and included dehydration, diarrhea, bronchopneumonia, ocular infections, and encephalitis. The mortality was high, particularly in children (up to 11%).
      • Philpott D
      • Hughes CM
      • Alroy KA
      • et al.
      Epidemiologic and clinical characteristics of monkeypox cases - United States, May 17-July 22, 2022.
      MMWR Morb Mortal Wkly Rep. 2022; 71: 1018-1022
      Table 3 summarizes the contrasting clinical characteristics during the current outbreak: the incubation period is shorter, the number of lesions lesser, and the localization predominantly around the area of inoculation. Intense anal pain and mucosal compromise is common in the current epidemic.

      Angelo KM, Smith T, Camprubí-Ferrer D, et al. Epidemiological and clinical characteristics of patients with monkeypox in the GeoSentinel Network: a cross-sectional study [e-pub ahead of print]. Lancet Infect Dis. https://doi.org/10.1016/S1473-3099(22)00651-x, Accessed October 18, 2022.

      Table 3Clinical Characteristics of Endemic and Current Epidemic hMPXV Infection
      Clinical CharacteristicEndemic InfectionCurrent Epidemic Infection
      Incubation period (Guzzetta, 2022)7-17 days6-11 days
      Prodromal symptomsFever, fatigue, and headache frequently presentFever, fatigue, and headache occasionally present
      LymphadenopathyProminent and painfulMay or may not be present
      Number of lesionsHundreds to thousandsTen or less lesions, including solitary lesions
      Rash distributionGlobalLocalized, around site of inoculation
      Stage of lesionsUsually, all lesions are at the same stage of evolutionLesions may be at different stages of evolution
      Disease without rashNot reportedRectal, pharyngeal, or mucosal lesions without rash have been reported
      ComplicationsDehydration, diarrhea, bronchopneumonia, ocular infections, and encephalitisAnal pain, cellulitis, urinary signs, ocular infections, abscess, lymphangitis, and paronychia
      Figure 2 shows cutaneous lesions of hMPXV infection.
      Figure 2
      Figure 2(A) A baby with “endemic” monkeypox virus in Africa. (B) A male with hMPXV infection following “fisting” (insertion of the hand into the rectum or vagina of someone as a means of sexual stimulation). (C) A female with hMPXV infection after performing cunnilingus and anilingus. Oral lesions not shown.
      Other conditions can resemble hMPXV infection and should be considered in the differential diagnosis: smallpox, chickenpox, molluscum contagiosum, other poxvirus infections, rickettsial pox, and secondary syphilis.

      Hussain A, Kaler J, Lau G, et al. Clinical conundrums: differentiating monkeypox from similarly presenting infections. Cureus. 2022;14(10):e29929.

      Diagnosis

      Confirmation of the diagnosis during the current outbreak requires obtaining samples from the skin or mucosal lesions for nucleic acid amplification.
      Health care personnel should wear gowns, gloves, eye protection, and N-95 respirators while collecting samples. Samples should be obtained using sterile polyester or Dacron swabs (but not cotton) from the surface of the lesions or the exudate. Unroofing of lesions is not recommended, given risk of dissemination. Ideally two swabs from each site involved should be obtained. Testing from multiple sites improves sensitivity and reduces false-negative results. The swab should be transported in viral transport media. The sample should be labeled appropriately, and if not sent immediately, it can be refrigerated (2°C-8°C) or frozen (−10°C or lower) until processed.

      Centers for Disease Control and Prevention. Guidelines for collecting and handling specimens for monkeypox testing. Available at:https://www.cdc.gov/poxvirus/monkeypox/clinicians/prep-collection-specimens.html. Accessed October 22, 2022.

      The Centers for Disease Control and Protection (CDC; via local public health departments) and several commercial laboratories (Aegis Science, Labcorp, Mayo Clinic Laboratories, Quest Diagnostics, and Sonic Healthcare) can process samples for polymerase chain reaction (PCR) testing, the preferred method of nucleic acid amplification. Some tests can identify hMPXV specifically, but others only recognize poxviruses in general. PCR tests are highly sensitive, are able to detect as little as 10 viral genomes, and are highly specific.
      • Jiang Z
      • Sun J
      • Zhang L
      • et al.
      Laboratory diagnostics for monkeypox: An overview of sensitivities from various published tests.
      Travel Med Infect Dis. 2022; 49102425
      ,
      • Gong Q
      • Wang C
      • Chuai X
      • Chiu S.
      Monkeypox virus: a re-emergent threat to humans.
      Virol Sin. 2022; 37: 477-482
      There are tests other than PCR (summarized in Table 4) that could be used for diagnosis of hMPXV, but they do not provide fast enough results to be clinically relevant.
      • Gong Q
      • Wang C
      • Chuai X
      • Chiu S.
      Monkeypox virus: a re-emergent threat to humans.
      Virol Sin. 2022; 37: 477-482
      Table 4Tests to Identify hMPXV (Other Than PCR)
      TestComments
      Restriction length fragment polymorphismDetects nucleic acid material but requires viral culture and is time consuming
      ELISA for detection of IgM and IgG in serumMay be false positive due to cross reactivity with other poxviruses
      Antibodies may appear several days after starting of clinical disease
      Testing of acute and convalescent titers may be necessary
      Electron microscopyOther poxviruses may look morphologically similar
      Sample preparation is complicated, and procedure is expensive
      Immunochemistry and immunofluorescenceRequires biopsy and is not specific for monkeypox
      Viral culturesTime-consuming test
      ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; IgM = immunoglobulin M; PCR = polymerase chain reaction.
      Testing for gonococcus/chlamydia, syphilis, and HIV is pertinent in cases of hMPXV infections as they can coexist.

      Treatment

      Supportive Therapy

      Most cases in the current epidemic are mild and do not require hospitalization. Supportive care is the standard (Table 5). Numerous recommendations are backed by experience in low-resource settings.
      • Reynolds MG
      • McCollum AM
      • Nguete B
      • Shongo Lushima R
      • Petersen BW
      Improving the care and treatment of monkeypox patients in low-resource settings: applying evidence from contemporary biomedical and smallpox biodefense research.
      Viruses. 2017; 9: 380
      Other recommendations are more specific for the current outbreak; for example, rectal pain can be excruciating and may require hospitalization.
      Table 5Supportive Care in Monkeypox Infection
      Type of CareRecommendations
      Systemic careAppropriate oral or intravenous hydration and adequate nutrition may accelerate recovery
      Pain controlAntipyretics and analgesics may improve comfort
      Short-term use of gabapentin and opioids may be indicated after taking into consideration comorbidities and potential medication interactions
      Oropharyngeal pain can be treated with saltwater rinses, chlorhexidine mouthwash, topical viscous lidocaine, or prescription analgesic mouthwash (containing an antihistaminic and a topical anesthetic)
      Rectal pain can be treated with stool softeners (to prevent painful defecation), warm sitz baths, and topical lidocaine
      Genital pain can be treated with topical lidocaine; the use of topical steroids is controversial
      Skin careFrequent cleansing of the skin may prevent overimposed bacterial infections
      Judicious application of occlusive dressings in areas with dense rash or in the face, may promote healing and prevent scarring
      Keeping short nails, wearing mittens, and administering antihistamines may control pruritus and prevent further skin damage
      Incision and drainage of abscess and use of antibiotics is indicated in overimposed bacterial infections
      Ocular careTopical lubricants and antibiotics (prophylactically or therapeutically) may prevent progression of ocular damage (ranging from conjunctivitis to corneal ulcerations)
      Topical trifluridine has been used in ocular vaccinia and may be effective in monkeypox

      Antivirals

      Use of systemic antivirals is only recommended in selected patients as summarized in Table 6. Topical trifluridine has been used in orthopoxvirus-associated corneal lesions, but there is no experience in hMPXV cases.
      Table 6Indications for Antiviral Therapy in Monkeypox
      Treatment IndicationsCategories
      Individuals at risk of complicationsCertain femalesPregnant females, lactating females
      Patients with certain skin disordersAtopic dermatitis, other exfoliative skin conditions
      Pediatric patientsEspecially younger than 8 years
      Immunosuppressed patientsHIV infection, hematological malignancies, solid organ transplant, hematopoietic transplant, use of immunosuppressant agents
      Individuals already having complicationsDisease affecting areas that constitute a special hazardOcular and oral mucosa, genitalia and anus
      Severe diseaseMonkeypox causing encephalitis or sepsis
      Comorbidities and complicationsAssociated bronchopneumonia, gastroenteritis, overimposed skin bacterial infection, other comorbidities
      Tecovirimat (known also as ST-246 or TPOXX) is the antiviral of choice. This agent prevents the final maturation and release of virions by inhibiting the viral protein VP37. Tecovirimat was approved for the treatment of smallpox in adults and children weighing > 3 kg based in the “Animal Rule.”
      • Chan-Tack KM
      • Harrington PR
      • Choi SY
      • et al.
      Assessing a drug for an eradicated human disease: US Food and Drug Administration review of tecovirimat for the treatment of smallpox.
      Lancet Infect Dis. 2019; 19: e221-e224https://doi.org/10.1016/S1473-3099(18)30788-6
      As smallpox was eradicated from Earth and studies were not feasible, the Food and Drug Administration (FDA) allowed the approval based on efficacy in animal models (survival in nonhuman primates infected with monkeypox virus and rabbits infected with rabbitpox virus) and safety in human volunteers. Unfortunately, the few reports of human disease treated with the drug have not provided conclusive evidence of efficacy.
      • Carvalho T.
      The unknown efficacy of tecovirimat against monkeypox.
      Nat Med. 2022; 28: 2224-2225
      Ongoing clinical trials are testing the efficacy and safety of tecovirimat in human infection in Congo and the US.
      • Lane HC
      • Fauci AS.
      Monkeypox - past as prologue.
      N Engl J Med. 2022; 387: 749-750
      Tecovirimat is available in the US via selected local public health departments. Alternatively the CDC Emergency Operations Center can be contacted directly at 770-488-7100 for consultation. The CDC has established an expanded access for this Investigational New Drug (EA-IND). In practical terms, tecovirimat can be used immediately on receipt and required forms for the CDC institutional review board, such as informed consent, patient's intake form, and report of adverse events can be submitted after the vaccination has been administered.

      Centers for Disease Control and Prevention. Guidance for tecovirimat use. Available at: https://www.cdc.gov/poxvirus/monkeypox/clinicians/Tecovirimat.html. Accessed October 20, 2022.

      Tecovirimat capsules should be taken 30 minutes after a full meal with moderate to high fat content. If the patient is unable to swallow capsules, the capsule content can be mixed with water and administer as liquid. Alternatively, tecovirimat is available intravenously. Tecovirimat dosing is based on weight (Table 7). Treatment is administered for 14 days but can be shorter or longer (but not to exceed 90 days) depending on the patient's clinical condition. Tecovirimat has not been studied in pregnant or lactating mothers, the benefits may outweigh potential risks of use.

      Food and Drug Administration. TPOXX (Tecovirimat) label. Available at: https://www.cdc.gov/poxvirus/monkeypox/clinicians/Tecovirimat.html. Accessed October 20, 2022.

      Table 7Formulations and Dosing of Tecovirimat in Adults
      FormulationWeightDosing
      Oral (200 mg capsules)88 to < 244 lb600 mg orally every 12 hours
      > 244 lbs600 mg orally every 8 hours
      Intravenous (10 mg/mL) (Should be diluted in twice as much 0.9 normal saline or 5% dextrose in water)77 to < 244 lb200 mg IV every 12 hours (infusion should last 6 hours)
      264 lb300 mg IV every 12 hours (infusion should last 6 hours)
      IV = intravenously.
      Tecovirimat is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. It may cause increased repaglinide levels (causing hypoglycemia) and decreased midazolam levels. Tecovirimat should not be used concomitantly with carbotegravir/rilpivirine. It may also interact with doravirine, rilpivirine, and maraviroc, but the effects are mild and dose adjustments may not be required. Tecovirimat has a low barrier to resistance and change in the VP37 protein may decrease the efficacy of the drug.
      • O'Shea J
      • Filardo TD
      • Morris SB
      • Weiser J
      • Petersen B
      • Brooks JT.
      Interim guidance for prevention and treatment of monkeypox in persons with HIV infection - United States, August 2022.
      MMWR Morb Mortal Wkly Rep. 2022; 71: 1023-1028
      Intravenous tecorivimat is contraindicated if the creatinine clearance is < 30 mL/min.

      Food and Drug Administration. TPOXX (Tecovirimat) label. Available at: https://www.cdc.gov/poxvirus/monkeypox/clinicians/Tecovirimat.html. Accessed October 20, 2022.

      Cidofovir is a viral DNA polymerase inhibitor approved for the treatment of cytomegalovirus-induced retinitis in patients infected with HIV. Cidofovir has in-vitro and in-vivo activity against hMPXV, but clinical data in humans is lacking.
      • Delaune D
      • Iseni F.
      Drug development against smallpox: present and future.
      Antimicrob Agents Chemother. 2020; 64 (e01683-19)
      Although available commercially and via IND from the CDC, it is not the medication of choice during this outbreak.
      Brincidofovir (Tembexa) is a lipid conjugate of cidofovir also approved by the FDA for treatment of smallpox based in the “Animal Rule.” The medication is not commercially available but can be accessed via IND from the manufacturer by inquiring at [email protected] Brincidofovir is available in liquid formulation and in tablets. The dosage is 200 mg weekly for 2 weeks. Treatment duration longer than 2 weeks has been associated with excessive mortality (in patients infected with cytomegalovirus). Brincidofovir can cause diarrhea and other gastrointestinal side effects and requires monitoring of liver enzymes. The medication is potentially teratogenic and should not be used in pregnancy.

      Food and Drug Administration. Tembexa label. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214460s000,214461s000lbl.pdf. Accessed October 20, 2022.

      Vaccinia immunoglobulin (VIG) was administered in the past intramuscularly, but in 2005 an intravenous formulation was approved. This formulation allows administration of higher doses without causing pain. VIG has been approved for the treatment of vaccinia vaccination complications (specially eczema vaccinatum). VIG has efficacy in multiple orthopoxvirus animal models, but information on human hMPXV infection is lacking. VIG can be obtained via IND from the CDC. VIG should be administered at a dose of 6000 U/kg, but doses of up to 24,000 U/kg have been administered to healthy volunteers. VIG is contraindicated in cases of preexistent anaphylaxis or hypersensitivity. Like with any blood-derived product transfusion side effects may occur. VIG can interfere with the efficacy of live vaccines. VIG niche in the treatment of hMPXV may be as adjuvant along with use of other antiviral agents in severe cases.
      • Titanji BK
      • Tegomoh B
      • Nematollahi S
      • Konomos M
      • Kulkarni PA.
      Monkeypox: a contemporary review for healthcare professionals.
      Open Forum Infect Dis. 2022; 9: ofac310

      Prevention

      Infection Control at Home

      Measures of infection control at home include isolation; containment and use of personal protective equipment; and hygiene, cleaning, and disinfection (Table 8).

      Centers for Disease Control and Prevention. Isolation and infection control at home. Available at: https://www.cdc.gov/poxvirus/monkeypox/clinicians/infection-control-home.html. Accessed October 20, 2022.

      Table 8Infection Control Measures at Home
      MeasureActivity
      Isolation
      • Remain on separate room or space
      • Avoid close contact with other people or pets
      • Avoid sharing household items or utensils
      • Use a separate bathroom if possible
      Containment and use of personal protective equipment
      • Cover lesions with clothes or dressings
      • Change own dressings if possible
      • Wear a well-fitting mask
      • Cover household surfaces that cannot be laundered with covers or blankets
      • Noninfected household members should wear gloves and well-fitted mask at minimum if helping the sick
      Hygiene, cleaning, and disinfection
      • Wash hands with soap and water or alcohol-based rub frequently
      • Use an EPA-approved disinfectant on hard surfaces
      • Contain soiled laundry until washed in a regular washing machine
      • Dispose waste appropriately
      EPA = Environmental Protection Agency.

      Infection Control in the Hospital

      If a patient with hMPXV infection is admitted to the hospital, infection prevention should be contacted immediately. Patients should be placed in a single-person room with private bathroom and the door should be kept closed. There is no need for a negative pressure room unless intubation or procedures that produce aerosols are required. Lesions should be covered with dressings or clothes. Patients should remain in isolation and with limited visitation until all skin lesions have crusted and a healthy layer of skin forms underneath the crust.

      Centers for Disease Control and Prevention. Infection prevention and control of monkeypox in healthcare settings. Available at:https://www.cdc.gov/poxvirus/monkeypox/clinicians/infection-control-healthcare.html. Accessed October 20, 2022.

      Health care personnel should wash hands with soap and water or use waterless antiseptic agents frequently. When entering a patient's room, health care staff should wear gowns, gloves, eye protection, and a N-95 respirator. Cleaning and disinfection of the room and handling of soiled laundry should be done using standard procedure.

      Centers for Disease Control and Prevention. Infection prevention and control of monkeypox in healthcare settings. Available at:https://www.cdc.gov/poxvirus/monkeypox/clinicians/infection-control-healthcare.html. Accessed October 20, 2022.

      Medical waste from patients in the current outbreak (clade IIB) should be managed as a Category A infectious substance (“an infectious substance capable of causing permanent disability or life-threatening disease”). Curiously medical waste from patients infected with clade I is considered Category B (not capable of causing such damage).

      US Department of Transportation. Planning guidance for handling category A solid waste. Available at:https://www.phmsa.dot.gov/transporting-infectious-substances/planning-guidance-handling-category-solid-waste. Accessed October 20, 2022.

      In case of death, remains should be handled using contact, droplet, and airborne precautions. If an autopsy is performed, appropriate measures to prevent percutaneous injury are indicated. Samples should be taken from tissues demonstrating gross pathology. After the procedure, nonreusable items should be handled as medical waste and reusable equipment and surfaces should be cleaned or disinfected according to standard protocols.

      Centers for Disease Control and Prevention. Autopsy and handling of human remains of patients with monkeypox. Available at: https://www.cdc.gov/poxvirus/monkeypox/clinicians/autopsy.html. Accessed October 20, 2022.

      Vaccines

      Smallpox vaccines can be used for prevention of hMPXV infection. Table 9 describes characteristics of smallpox vaccines; however, the remainder of this section only discusses vaccines currently used in the US for prevention of hMPXV infection.
      Table 9Characteristics of Vaccines Approved for Smallpox (and hMPXV)
      TypeGeneration (Examples)Comments
      Attenuated live virus replication-competent vaccinesFirst generation (Dryvax, Wetvax)Used in initial eradication of smallpox; may be held in national reserves but do not meet current safety and manufacturing standards and are not recommended at this time
      Second generation (ACAM2000)Contraindicated in immunosuppressed patients, pregnancy, atopic dermatitis, and others; risk of adverse events (eczema vaccinatum, generalized vaccinia, fatal progressive vaccinia); requires multiple percutaneous punctures with a bifurcated needle
      Attenuated live virus replication-deficient vaccinesThird generation (Jynneos)Uses more attenuated strain (Modified Vaccinia Ankara Bavarian Nordic strain or MVA-BN); administered subcutaneously with regular needle; fewer contraindications and fewer adverse events than lesser generations
      The US National Monkeypox Vaccination Strategy has made available 2 preventative vaccines: JYNNEOS and ACAM2000. The vaccines can be obtained via local public health authorities.

      Centers for Disease Control and Prevention. Monkeypox vaccination. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/overview.html#components. Accessed October 22, 2022.

      JYNNEOS, manufactured by Bavarian Nordic, is the preferred vaccination. This is a further attenuated Modified Vaccinia Ankara (MVA) strain grown in chicken embryos that cannot reproduce in mammal cells but confers immunity to smallpox. JYNNEOS has several advantages over ACAM2000: higher geometric mean titers and seroconversion rates; no cutaneous reactions (so called “take”) that cause a draining lesion with risk of autoinoculation; less risk of myopericarditis; and possibility to be used in immunosuppressed patients and people with eczema. JYNNEOS was licensed based on animal and clinical studies showing a comparable immune response to ACAM2000.
      • Rao AK
      • Petersen BW
      • Whitehill F
      • et al.
      Use of JYNNEOS (smallpox and monkeypox vaccine, live, nonreplicating) for preexposure vaccination of persons at risk for occupational exposure to orthopoxviruses: recommendations of the advisory committee on immunization practices - United States, 2022.
      MMWR Morb Mortal Wkly Rep. 2022; 71: 734-742
      To administer JYNNEOS, the provider is required to sign an agreement with the US Department of Health and Human Services to collect demographic and vaccine related information (product, dose number, lot, etc.) and to report serious adverse events.

      Centers for Disease Control and Prevention. JYNNEOS vaccine. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html. Accessed October 22, 2022.

      The vaccine is administered in two doses (28 days apart) at 0.5 mL subcutaneously. Alternatively (to spare vaccine) 0.1 mL can be administered intradermally at the same interval.

      Food and Drug Administration. Monkeypox update: FDA authorizes emergency use of JYNNEOS vaccine to increase vaccine supply. Available at:https://www.fda.gov/news-events/press-announcements/monkeypox-update-fda-authorizes-emergency-use-jynneos-vaccine-increase-vaccine-supply. Accessed October 22, 2022.

      Contraindications to the vaccine include history of anaphylaxis or severe allergic reaction to a previous dose of JYNNEOS, egg or chicken protein, gentamicin, or ciprofloxacin.

      Centers for Disease Control and Prevention. JYNNEOS vaccine. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html. Accessed October 22, 2022.

      ACAM2000 is a smallpox vaccine derived from a clone of Dryvax (the original vaccine used for eradication of smallpox) approved in 2015 for prevention of orthopoxviruses in laboratory and health care personnel at risk for occupational exposure. The vaccine is available (but not frequently used) via EA-IND. It requires a single dose, but it has several disadvantages including percutaneous administration using a bifurcated needle, more side effects (self-inoculation, myocarditis, pericarditis), and more contraindications (anaphylaxis to previous dose of ACAM2000 or excipients, immunosuppression, pregnancy, breastfeeding, prominent cardiac risk factors, eczema and other exfoliative skin conditions, cheloids, ocular infection treated with steroids, previous history of monkeypox) than JYNNEOS. Details about its administration can be found on the CDC website.

      Centers for Disease Control and Prevention. ACAM2000 vaccine. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/acam2000-vaccine.html. Accessed October 22, 2022.

      Preexposure Prophylaxis

      Vaccination before exposure is recommended in 2 groups:

      Centers for Disease Control and Prevention. Monkeypox vaccination. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/overview.html#components. Accessed October 22, 2022.

      • •
        Certain laboratory and health care workers who can be exposed to orthopoxviruses (a particular group at risk may be proctologists, especially those working with patients infected with HIV).
      • •
        Those with sexual risk in previous 6 months: Males who have sex with males who developed a sexually transmitted infections; people who engage in sex with commercial sex workers, or group sex, or participate in large sexual events in risky geographic areas; partners of people with risk factors.
      Transmission risk among health care workers is possible but, in nonendemic areas, rare, with only 1 case identified in a review between 2000 and 2022.
      • Zachary KC
      • Shenoy ES.
      Monkeypox transmission following exposure in healthcare facilities in nonendemic settings: low risk but limited literature.
      Infect Control Hosp Epidemiol. 2022; 43: 920-924https://doi.org/10.1017/ice.2022.152
      It must be noted that in certain geographic areas, such as New York, vaccine eligibility has expanded, and anyone who considers themselves to be at risk for hMPVX infection through sex or other intimate contact can receive the vaccine.

      New York State Department of Health. State Department of Health expands monkeypox vaccine eligibility to include anyone at risk of exposure. Available at: https://health.ny.gov/press/releases/2022/2022-09-14_monkeypox_vaccine_eligibility.htm. Accessed October 20, 2022.

      Postexposure Prophylaxis

      Vaccination after known exposure to hMPXV is indicated in those identified by the local public health authorities. In addition, expanded postexposure prophylaxis may be offered to those with a sex partner diagnosed with monkeypox within the last 14 days, or to those with sexual risk as described in the preexposure prophylaxis section.

      Centers for Disease Control and Prevention. Monkeypox vaccination. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/overview.html#components. Accessed October 22, 2022.

      ,

      New York State Department of Health. State Department of Health expands monkeypox vaccine eligibility to include anyone at risk of exposure. Available at: https://health.ny.gov/press/releases/2022/2022-09-14_monkeypox_vaccine_eligibility.htm. Accessed October 20, 2022.

      Vaccination is recommended within 4 days of the exposure for maximum efficacy. Vaccination between 4 and 14 days after contact provides lesser protection. Vaccination beyond 14 days may be even less effective but must be considered in immunosuppressed patients.

      Centers for Disease Control and Prevention. JYNNEOS vaccine. Available at: https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/jynneos-vaccine.html. Accessed October 22, 2022.

      VIG could be considered for postexposure prophylactics in those patients with severe T cell immunodeficiency who may be unable to mount an appropriate immune response with vaccination.
      • Gong Q
      • Wang C
      • Chuai X
      • Chiu S.
      Monkeypox virus: a re-emergent threat to humans.
      Virol Sin. 2022; 37: 477-482

      One Health

      Bushmeat hunting for human consumption and international demand of exotic pets may have fueled the emergence of monkeypox. One Health promotes alternatives to bushmeat, public awareness campaigns, education on hygienic handling of wild animals, routine vaccination of people at risk, and abolition of exotic pet trade. Although unlikely to curtail the current outbreak, it may help in preventing other zoonoses.
      • Reynolds MG
      • Doty JB
      • McCollum AM
      • Olson VA
      • Nakazawa Y.
      Monkeypox re-emergence in Africa: a call to expand the concept and practice of One Health.
      Expert Rev Anti Infect Ther. 2019; 17: 129-139

      Misinformation

      Physicians and health care workers play an important role in preventing misinformation and stigmatization because it has occurred in other pandemics.
      • Ennab F
      • Nawaz FA
      • Narain K
      • et al.
      Monkeypox Outbreaks in 2022: Battling Another "Pandemic" of Misinformation.
      Int J Public Health. 2022; 671605149

      Acknowledgments

      The authors would like to thank Isabella Madariaga for her graphic art and editorial services, and Dr Jeffrey Panozzo for sharing a picture

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      Article info

      Publication history

      Published online: December 07, 2022

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Funding: None.

      Conflicts of Interest: None.

      Authorship: All authors had access to the data and a role in writing this manuscript.

      Identification

      DOI: https://doi.org/10.1016/j.amjmed.2022.10.023

      Copyright

      © 2022 Elsevier Inc. All rights reserved.

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