MICROBIOLOGY

  • DNA virus and member of the orthopoxvirus genus of the Poxviridae family, monkeypox is similar to smallpox (variola virus), smallpox vaccine (vaccinia virus), and cowpox virus.
    • Two clades are described:
      • West African clade causes a mild illness with limited human-to-human transmission and low mortality (~1-3%).
      • Central African/Congo Basin clade, higher reported human-to-human transmission and mortality (up to 10%).
      • 2022 global outbreak appears to have sufficient genomic differences to be considered a third clade (and milder disease)
  • Although named monkeypox, the animal reservoir is believed to be African rodents but has not been fully defined.
    • WHO has indicated a desire to rename the human infection.

CLINICAL

  • Previously, an uncommon zoonotic disease spread between infected animals, humans, and contaminated materials.
    • First isolated in 1958, with the first human case in 1970; most human cases are seen in Central and West Africa.
      • Cases in the U.S. are predominantly imported or due to contact with animals.
      • Progressively more cases have been described annually in Africa (DRC and West Africa) since the 1970s.
    • Resembles smallpox, but milder and less transmissible.
    • A large number of cases (> 450) since 2017 in Nigeria can be traced as the basis to the current WHO global health emergency.
  • Outbreaks in the U.S.
    • 2003: 71 confirmed or suspected cases.
      • The first U.S. outbreak was traced to the importation of Gambian giant rats, squirrels, and dormice that spread to prairie dogs sold as pets.[12]
        • 18 hospitalized, no deaths.
    • Current (as of 7/31/22): >22,000 cases worldwide, in U.S. >5,000.
      • WHO declared a public health emergency.
        • In the U.S., most states report cases.
      • Spread within social networks implicated, reported in men who have sex with men (MSM), bisexual; few reports in women or children.[13]
      • No deaths have been reported as of this writing; it appears milder than disease acquired in Africa.
  • Transmission
    • The virus may be acquired through contact, including intact skin and mucous membranes. Most human infections are believed to be respiratory droplet-acquired.
      • Animal-to-human transmission is seen following an infected animal bite or scratch, butchering bush meat, direct contact with body fluids or lesions, or contaminated materials.
      • Acquisition by human-to-human is believed to be predominantly large respiratory droplets among African cases, although they may also be sexually transmitted or through social networks.
        • As a large pox virus, not believed to be aerosolizable but can be spread by droplets.
        • The virus enters the body via broken skin, respiratory tract or mucous membranes.
        • Household and nosocomial transmission described
        • Fomite transmission occurs via contaminated clothing or bed sheets.
      • From acquisition to first symptoms may range 5-21 days but average 1-2 weeks.
  • Symptoms: note that some get a rash first, then symptoms; others experience only a rash.
    • Initial viral prodrome
      • Fever, chills, headache, myalgia, back pain, fatigue
        • Occasionally sore throat with lesions on the tongue and oral mucosa
    • Rash phase, typically 1 to 3 days after symptom onset.
      • Viral exanthem, flat/red, becomes nodular, umbilicated, and pox-like with fluid/pus before crusting.
        • Lesions, described as painful, appear in the same stage of development on a single site of the body.
        • Lymphadenopathy often accompanies this phase.
      • For example, in Africa, the rash often begins on the face [Fig 1], then spreads [FIg 2], including the palms [Fig 3].
        • Skin lesions do not develop in all infected people.
      • 2022 outbreak: nodular, pustular, pox-like, and may have eschar, [Fig 4] and [Fig 5]
        • Consider oral, genital and anal (proctitis, too) lesions potentially due to monkeypox.
          • The rash may appear as pustules, blisters or pimples that may be pruritic or painful.
          • Rash onset and evolution are not synchronous; lesions may range in several stages.
        • Fever, headache, myalgia, fatigue
        • Lymphadenopathy
        • Respiratory symptoms include dry cough, sore throat and nasal congestion.
    • Illness resolves within 4 weeks.
    • Mortality ranges from 1 to 10% in reported series from Africa; the 2022 outbreak appears to be milder though capable of severe illness, especially in immunocompromised.
      • Most deaths occur in children or people with HIV.
      • Risk factors for severe illness appear to be fever ≥ 38.3ºC and > 100 skin lesions.
  • Differential diagnosis: varicella zoster (primary infection, aka chickenpox), other pox infections (cowpox, orf), smallpox.
  • Diagnosis:
    • Clinical suspicion necessary; contact local/state health department for assistance in diagnosis.
    • Real-time PCR of skin lesion material
      • Obtain multiple samples, dry collection, and do not add or store in viral or universal transport media.
        • CDC specimen and handling directions link. Accessed 7/14/22 at: https://www.cdc.gov/laboratory/specimen-submission/
        • Some academic medical centers have established orthopox virus molecular tests (that need confirmation for monkeypox specifically).
        • Commercial labs in the U.S. now offer orthopox testing.
    • Serology is perhaps helpful if specimens are not present.
      • CDC specimen and handling directions link.
    • CDC 2022 Case Definition
      • Suspect, probable, and confirmed
      • Confirmed requires demonstration of viral DNA by PCR or NGS of a clinical specimen or isolation of the virus in culture.
    • CDC recommends that clinicians collect two specimens for each patient, each from multiple lesions, preferably from different locations on the body and from lesions with differing appearances. The CDC Monkeypox virus testing algorithm includes NVO testing, and if results are positive for Orthopoxvirus, further characterization testing at CDC. A subset of specimens was characterized at CDC by a Monkeypox virus-specific real-time PCR assay and genetic sequencing.

SITES OF INFECTION

Oral: oral ulceration(s) or pharyngitis.

Ocular: may threaten vision

Cutaneous: macular or papular lesions evolve into nodules and then vesicles or pustules (pox lesions) before crusting. Lesions often start on the face, mouth, genitals or anus. It may remain limited in a regional area and spread over the body, including palms and soles.

LN: lymphadenopathy

Pulmonary: pneumonitis, particularly in severe cases

Proctitis: may be severe; a frequent reason for hospital admission

TREATMENT

General

  • There are no approved treatments for monkeypox.
  • CDC recommends approaching it as similar to smallpox, as a consideration for those with severe disease (CNS, hemorrhagic, requiring hospitalization) or those at high-risk (immunocompromised, children < 8 yrs, pregnant/breastfeeding women, or experiencing complications).
    • State and territorial health authorities can direct their requests for medical countermeasures for the treatment of monkeypox to the CDC Emergency Operations Center (770-488-7100).
      • CDC interim guidance treatment recommendations (when accessed, last updated 6/22/22)
        • Consider treatment if:
          • Severe disease
          • People at high risk
            • Immunocompromised condition
              • Advanced HIV not on ART, common high-risk group. European reports state that 30-51% of cases with known HIV.
                • Specific guidance from CDC for this group.
            • Children ≤ 8 yrs
            • Hx of atopic dermatitis, exfoliative skin conditions
            • Complicated infected (secondary bacterial infection, gastroenteritis, bronchopneumonia or concurrent disease or comorbidities)
            • Accidental inoculation into the eye, genitals or anus
              • Author note: uncertain how this might be different than customary acquisition in 2022 outbreak; however, could represent lab accident issue, large inoculum or if eyeball, unknown consequence.
    • Antivirals (see smallpox module for details): important note that there is limited data on these drugs’ use in monkeypox and no convincing evidence of effectiveness.
      • Tecovirimat (TPOXX): oral or IV drug, FDA-approved for smallpox treatment in adults and children ≥ 13 kg.
        • CDC has Expanded Access Investigational New Drug (EA-IND) protocol.
      • Brincidofovir: oral drug, FDA-approved on June 4, 2021, for smallpox in all ages, including neonates. CDC developing EA-IND.
        • CDC developing EA-IND to facilitate use for monkeypox.
        • Often causes a brisk elevation in LFTs, prompting discontinuance.
      • Cidofovir: injectable, has in vitro activity but no human data.
    • Vaccinia immune globulin (VIVIG)
      • Potentially has cross-reactivity, unknown if effective for monkeypox.
      • Licensed for treatment of complications or aberrant infections due to vaccinia vaccination
      • CDC holds EA-IND allows the use of VIG in an orthopoxvirus outbreak, which would include monkeypox.

Prevention

  • People with suspected or confirmed monkeypox should be monitored for 21d after the last exposure.
    • If symptoms develop, they should self-isolate and contact their PCP and local health department.
    • CDC monitoring recommendations.
  • Prevention of exposure:
    • Avoid direct or intimate contact with people with monkeypox who have active rashes
    • WHO has suggested limiting sexual partners.
    • Avoid contact with objects used by people with monkeypox, including bed linens, towels, and clothing.
    • Avoid respiratory secretions and close contact without PPE in people with monkeypox.
  • General measures if suspected or confirmed monkeypox:
    • Isolate infected patients from others.
    • Hand hygiene after contact with infected animals or humans.
      • Use soap and water or an alcohol-based sanitizer.
    • Avoid contact with animals that could harbor the virus (including animals that are sick or found dead in areas where monkeypox occurs).
    • Avoid direct contact with any potentially contaminated materials.
      • CDC notes that the monkeypox virus can be killed using a standard washing machine with warm water and detergent.
    • Use appropriate personal protective equipment (PPE) for patient care (gown, gloves, respirator, and eye protection).
    • CDC Infection Prevention and Control of Monkeypox for healthcare settings; for those sent home, CDC isolation recommendations vary depending on the home situation and if people at high-risk present (young children, immunocompromised).
  • Vaccines: smallpox vaccines have been given to some monkeypox patients or their contacts.[12]
    • Pre-exposure prophylaxis in the U.S. is offered to at-risk groups, including MSM and people with HIV.
      • Immunization is the only currently offered PrEP strategy.
      • The release of vaccines from the U.S. stockpile means more should be available to states for distribution in August 2022.
    • Administer within 4 days of exposure (post-exposure prophylaxis (PEP).
      • If administered on days 4-14 post-contact, it may not prevent infection but could lessen the severity if acquired.
    • U.S. Federal Government distributes vaccines to state health departments based on state case numbers. Targeted risk groups are currently MSM and bisexuals at risk for exposure.
    • FDA has approved JYNNEOSTM (MVA-BN in 2019, also known as Imvamune or Imvanex in the UK, an attenuated live virus vaccine that is non-replicating for the prevention of monkeypox; ACIP recommends pre-exposure prophylaxis (PrEP) for occupational exposures).
      • Limited supply as of mid-July 2022, expected to expand through summer 2022 with 4M doses ordered by HHS.
      • It appears to have fewer side effects than the smallpox vaccine/vaccinia.
      • 100% protective in macaques for PEP. Favorable, but limited experience in ring (close contact) PEP in Europe.
    • Smallpox vaccine
      • ACAM2000 (live attenuated): more adverse reactions than JYNNEOS.
      • 85% vaccine efficacy when used in Africa to prevent monkeypox.
      • A far larger supply in the U.S. stockpile but aging status may mean lower potency.

Selected Drug Comments

Drug

Recommendation

Brincidofovir

FDA-approved oral drug available in tablets or suspension for smallpox in ages neonates and above. Three patients received the drug for monkeypox in a UK case series, though uncertain if it helped in their good outcome[1]. In this series, none of the 3 completed the course due to rising LFTs.

Cidofovir

The U.S. maintains a Strategic National Stockpile for use in the case of smallpox. The drug has in vitro activity; however, monkeypox has no human data.

Tecovirimat

FDA-approved for smallpox. Case report of use in monkeypox (1 patient[1]), cowpox, and complicated vaccinia infections. Uncertain if helpful in monkeypox.

VIVIG

Vaccinia immune globulin (IV) is controlled by the CDC, primarily for the use of complications of vaccinia vaccination, including EZ, progressive vaccinia, and generalized vaccinia. Unknown how effective its use would be in monkeypox.

FOLLOW UP

  • Patients are thought to be non-infectious upon crusting of lesions; however, viral kinetics in monkeypox is not fully described.
  • Sterile abscesses, bacterial superinfection, and bacteremia are seen.
  • Isolation practices for confirmed monkeypox.
    • Isolate at home or another location for the duration of illness.
    • Isolation ceases when all symptoms have resolved, including all skin lesions have healed with a fresh layer of skin (not just crusted).
      • Duration ranges from 2-4 weeks.
    • While with rash, cover all parts of the skin with clothing, gloves or bandages.
    • Wear a tight-fitting mask, even if there is no fever or respiratory symptoms.
    • Do not share items with others, avoid close contact, and use alcohol-based sanitizer or soap/water to wash hands.

OTHER INFORMATION

  • An increase in monkeypox cases has been ascribed to the successful eradication of smallpox and the cessation of vaccinia immunization programs.
  • There are insufficient data to make particular recommendations for the treatment of monkeypox.
  • U.S. and UK offering vaccines to risk groups.

Basis for recommendation

  1. Adler H, Gould S, Hine P, et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis. 2022.  [PMID:35623380]

    Comment: The current state-of-the-art review and clinical experience regarding management. Oral antivirals were used (brincidofovir and tecovirimat) but had an uncertain effect in this small patient series. Patients had a surprisingly long period of PCR detection of viral DNA.

  2. 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(22):734-742.  [PMID:35653347]

    Comment: The ACIP recommended use of this replication-deficient live Vaccinia virus vaccine for people at risk of orthopox infection from potential occupational exposures. On November 3, 2021, ACIP voted to recommend JYNNEOS preexposure prophylaxis as an alternative to ACAM2000 for certain persons at risk for orthopoxviruses.

References

  1. Luong Nguyen LB, Ghosn J, Durier C, et al. A prospective national cohort evaluating ring MVA vaccination as post-exposure prophylaxis for monkeypox. Nat Med. 2022.  [PMID:35831633]

    Comment: The authors note in this letter that recent cases in Nigeria (3552) with only one reported fatality, far less than the 1-10% range reported in earlier years. Modified Vaccinia Ankara–Bavarian Nordic (MVA-BN) is a third-generation live vaccine that is non-replicating and reports predominantly African and European experience with PEP, which appears effective.

  2. Orviz E, Negredo A, Ayerdi O, et al. Monkeypox outbreak in Madrid (Spain): clinical and virological aspects. J Infect. 2022.  [PMID:35830908]

    Comment: Spain has the most reported cases; this experience from Madrid from May to June 2022 is reported for 48 men. The mean age was 35 years, and 87.5% were MSM; lesions appeared in the area where they had sexual intercourse (genital or anal). Sequencing found the isolates consistent with the western African clade, specifically the Nigerian outbreak of 2017-18 that had low mortality.

  3. Kwok KO, Wei WI, Tang A, et al. Estimation of local transmissibility in the early phase of monkeypox epidemic in 2022. Clin Microbiol Infect. 2022.  [PMID:35817231]

    Comment: No doubt an imperfect estimate based on early data suggests that in UK, Portugal and Spain, the Ro ranged between 1.3 to 2.1.

  4. Aden TA, Blevins P, York SW, et al. Rapid Diagnostic Testing for Response to the Monkeypox Outbreak - Laboratory Response Network, United States, May 17-June 30, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(28):904-907.  [PMID:35834423]

    Comment: During the first month and a half of the US monkeypox outbreak, the CDC evaluated 2009 specimens from their external lab network on suspicion of monkeypox. The CDC found that 36% were positive for non-variola Orthopoxvirus. Of those sequenced to date, all were from the West African clade, similar to findings from patients in Spain and the UK.

  5. Russo AT, Grosenbach DW, Chinsangaram J, et al. An overview of tecovirimat for smallpox treatment and expanded anti-orthopoxvirus applications. Expert Rev Anti Infect Ther. 2021;19(3):331-344.  [PMID:32882158]

    Comment: This oral drug has broad activity against many known orthopox viruses.

  6. Hutson CL, Kondas AV, Mauldin MR, et al. Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model. mSphere. 2021;6(1).  [PMID:33536322]

    Comment: Animal model of monkeypox, however, authors state that dosing selection may have impacted results.

  7. Petersen E, Kantele A, Koopmans M, et al. Human Monkeypox: Epidemiologic and Clinical Characteristics, Diagnosis, and Prevention. Infect Dis Clin North Am. 2019;33(4):1027-1043.  [PMID:30981594]

    Comment: Authors have organized clinical data and impressions from outbreaks of monkeypox in Africa and the UK. Increase in monkeypox cases has been ascribed to the successful eradication of smallpox and the cessation of vaccinia immunization programs.

  8. Huhn GD, Bauer AM, Yorita K, et al. Clinical characteristics of human monkeypox, and risk factors for severe disease. Clin Infect Dis. 2005;41(12):1742-51.  [PMID:16288398]

    Comment: Risk factors for severe disease appeared to be two: fever ≥ 38.3°C and > 100 lesions.

  9. Learned LA, Reynolds MG, Wassa DW, et al. Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003. Am J Trop Med Hyg. 2005;73(2):428-34.  [PMID:16103616]

    Comment: Six cases among those in this pediatric outbreak had an extended chain of transmission among humans. Authors aptly noted the potential for more concerning and widespread transmission among humans in future if cases are not contained early in an outbreak.

  10. Centers for Disease Control and Prevention (CDC). Update: multistate outbreak of monkeypox--Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(27):642-6.  [PMID:12855947]

    Comment: Report describes 71 cases, 35 lab-confirmed and 36 suspected cases, with majority exposed to prairie dogs. Use of smallpox vaccine included pre-exposure administration to 3 veterinarians, 2 lab workers, and 2 healthcare workers and post-exposure to 23 individuals. All 35 confirmed cases traced back to prairie dogs housed, at an Illinois animal distributor, with Gambian giant rats and dormice that originated from Ghana.
    Rating: Important

  11. WHO Emergency Seasonal Updates. Monkeypox: public health advice for gay, bisexual and other men who have sex with men. 22 May 2022. Accessed 8/1/22 at: https://www.who.int/publications/m/item/monkeypox-public-health-advice-for...

    Comment: Public health advisory reports association of monkeypox outbreak and transmission among communities of gay, bisexual, and men who have sex with men. Sexual health providers and primary care providers of MSM may recognize cases early and reduce risk of outbreak by isolating and testing indivuduals for monkeypox virus.
    Rating: Important

  12. Zhanwei Du, Zengyang Shao, Yuan Bai, Lin Wang, Jose L Herrera-Diestra, Spencer J. Fox, Zeynep Ertem, Eric H. Y. Lau, Benjamin J. Cowling. Reproduction number of monkeypox in the early stage of the 2022 multi-country outbreak. https://www.medrxiv.org/content/10.1101/2022.07.26.22278042v1posted 7/26/22 (accessed 8/1/22)

    Comment:
    Using data as of 7/22/22, this group estimates an Ro of 1.29 (95% CI, 1.26-1.33).


  13. Kelly Charniga, View ORCID ProfileNina B. Masters, Rachel B. Slayton, Lucas Gosdin, Faisal S. Minhaj, David Philpott, Dallas Smith, Shannon Gearhart, Francisco Alvarado-Ramy, Clive Brown, Michelle A. Waltenburg, Christine M. Hughes, Yoshinori Nakazawa. Estimating the incubation period of monkeypox virus during the 2022 multi-national outbreak. https://www.medrxiv.org/content/10.1101/2022.06.22.22276713v1 posted 6/23/22; (accessed 8/1/22)

    Comment:

    CDC data using pooled US patients from 18 cases reported from the Netherlands in late May. The mean onset from exposure to the first symptom was 7.6 days, and the 95th percentile was 17.1 days. Therefore 21d of monitoring appears to be in keeping with current recommendations.

Media

Monkeypox

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Pox lesions on a child from a 1997 outbreak in the DRC.

Source:

CDC/ Brian W.J. Mahy, BSc, MA, PhD, ScD, DSc

Monkeypox

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A child with numerous lesions on the face, from a 1997 outbreak in DRC.

Source: World Health Organization (WHO)/ Brian W.J. Mahy, BSc, MA, PhD, ScD, DSc

Monkeypox palms

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Palms with maculopapular skin lesions appearing similar to smallpox but due to monkeypox (from 1997 DRC outbreak).

Source: CDC/ Brian W.J. Mahy, BSc, MA, PhD, ScD, DSc

Monkeypox lesions 2022

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UK Health Security Agency

Monkeypox lesions

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Source: NHS England High Consequence Infectious Diseases Network

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Last updated: August 1, 2022