Mpox

Peer reviewer: A/Prof Mike Cadogan

OVERVIEW

• Mpox is a zoonotic infection characterized by a flu-like prodrome followed by a rash resembling chickenpox
• The 2022 Mpox outbreak was the first significant outbreak resulting from human-to-human transmission outside of Africa
• The CDC developed case definitions during the 2022 Mpox outbreak
• WHO Director-General declared the mpox outbreak in the Congo and other African countries a public health emergency of international concern in August 2024.
• Mpox was formerly known by the misnomer Monkeypox.

CAUSE

Mpox virus (MPV) (Alakunle et al, 2020)

• belongs to the Orthopoxvirus genus (also includes cowpox and smallpox)
• contains linear double-stranded DNA within lipoprotein envelope
• ovoid or brick-shaped and 200-250 nm in length
• Two clades (strains) are endemic to the Congo/ Central Africa (more virulent) and West Africa (less virulent), causing sporadic outbreaks averaging a few thousand cases per year in these regions

PATHOPHYSIOLOGY

Transmission (Beer and Rao, 2019; Alakunle et al, 2020)

• contact with fomites through broken skin, mucous membranes, or the respiratory tract
  • Direct, e.g. skin-to-skin, including during sexual activity
  • Indirect, e.g. contact with linen and bedding
• Respiratory droplets (airborne transmission)
• Maternal-fetal transmission during pregnancy
• Potential sexual transmission as virus isolated from seminal fluid, however transmission during sexual activity probably mostly results from direct contact
• In endemic areas most transmission is animal-to-human from contact with infected animal carcasses, meat, and blood

Animal reservoir (Parker and Buller, 2013; Alakunle et al, 2020)

• Rodents such as Gambian giant pouched rats, rope squirrels, and dormice
• Pet prairie dogs were important intermediate hosts in the 2003 outbreak in the USA (47 human cases)

Incubation period (Alakunle et al, 2020)

• 4-21 days

Complications (Beer and Rao, 2019; McCollum and Damon, 2014)

• Dehydration (vomiting and diarrhea)
• Pneumonitis
• Keratitis (potentially sight-threatening)
• Sepsis and disseminated rash are more common in immunocompromised
• Deep abscesses (including retropharyngeal abscess)
• Reactive depression and psychosocial distress is common (e.g. stigma, pain, and disfiguring lesions)
• Encephalitis is rare
• Scarring
• Miscarriage if pregnant

CLINICAL MANIFESTATIONS 

(McCollum and Damon, 2014; Girometti et al, 2022; Adler et al, 2022; Tarín-Vicente et al, 2022; Thornhill et al, 2022)

History 

• “Flu-like” prodrome for the first 5 days, including:
  • Fever and chills
  • Headache
  • Malaise
  • Myalgia
  • Respiratory symptoms (e.g. sore throat, nasal congestion, or cough)
  • Lymphadenopathy (>50%)
    • key feature, as not typically seen in influenza or chickenpox
    • may develop before or during the rash
    • Typically maxillary, cervical, or inguinal (1-4 cm)
• Rash
  • may develop without “flu-like” prodrome
  • lasts an average of 10 days
  • 2-5mm diameter pleomorphic lesions that synchronously progress through 4 stages before scabbing over and desquamation:
    • Macular (1-2 days),
    • Papular (1-2 days),
    • Vesicular (1-2 days),
    • Pustular (5-7 days) (filled with opaque fluid; initially firm then become umbilicated), to
    • Scabs (7-14 days)
  • Lesions have a centrifugal distribution
    • typically predominate on the face (including the eyes and oropharynx) but may develop on the hands and feet (both dorsal and ventral surfaces; subungual lesions may occur)
    • the torso is relatively spared but can be affected
    • Initial lesions may occur in the mouth, including on the tongue, and may not be visible on the skin or may only be present in the perineal/genital area
    • Number of lesions may range from 1 to >1000; many patients have <10 at presentation
  • Genital and peri-genital lesions were common features of the 2022 outbreak, including proctitis (e.g. purulent or bloody stools, rectal pain, or rectal bleeding)
  • Lesions are usually painful and pruritic (itchy)
• Exposure history
  • Men who have sex with men (MSM)
  • oral or anal receptive sex (risk factors for tonsilitis and proctitis respectively)
  • Travel history – Travel to an endemic area (Congo/ Central Africa and West Africa)
  • Animal contact – rodents
  • Age <50 years (born since discontinuation of routine smallpox vaccination)

Examination (McCollum and Damon, 2014)

• Fever
• Lymphadenopathy
• Rash on skin – see Dermnet for Mpox images – and/or mucous membranes (early oropharyngeal lesions may resemble pharyngitis; anoscopy may be required)

DIFFERENTIAL DIAGNOSIS

• Chickenpox (similar rash but does not usually occur on feet and lacks lymphadenopathy)
• Smallpox
• Cowpox
• Impetigo
• Infected scabies
• Syphilis (lesions on hands and feet)
• Herpes simplex virus
• Hand-foot-mouth disease (children)
• Gonococcal infection (e.g. pharyngitis, proctitis; may also have rash) and other STIs with symptoms of proctitis and skin lesions (e.g. chancroid, lymphogranuloma venereum, granuloma inguinale)
• Influenza and other flu-like illness (prior to development of rash)

INVESTIGATIONS

Laboratory (McCollum and Damon, 2014)

• Viral swab PCR
  • Deroofed skin lesions
  • Respiratory swabs
  • Blood (may be negative as virus may only transiently be in blood)
  • Urine
  • Rectal
• Serology
  • orthopoxvirus IgG (prior exposure) and IgM (recent exposure) immunofluorescence assay
  • Antibodies usually detectable once rash appears
  • Less sensitive than PCR
• Other diagnostic tests may be considered in specific settings:
  • Viral culture
  • Electron microscopy
  • Immunohistochemistry
  • Rapid antigen tests
• Consider baseline bloods (e.g. if risk of severe disease) and repeat if clinical deterioration
• STI screen if appropriate based on risk factors (STIs may coexist with Mpox)

Imaging

• CT – lymphadenopathy, secondary infection (e.g. pneumonia)
• MRI brain – if encephalitis suspected

MANAGEMENT

Address life/limb/sight threats:

• pharyngeal/ tracheal lesions causing airway compromise are rare 
• Secondary sepsis, requiring resuscitation, may occur in immunocompromised patients
• Keratitis may be sight-threatening

Specific management

• Antivirals
  • Consider for severe cases or cases at risk of severe disease such as:
    • Immunocompromised
    • Children <8yo
    • history or presence of atopic dermatitis, persons with other active exfoliative skin conditions
    • Pregnancy or breastfeeding
    • Complications (e.g. secondary infection, dehydration)
    • Complicated locations (e.g. eyes, mouth, airway, anus, genitals)
  • studies of clinical effectiveness in humans are currently lacking
  • Options include (Adler et al, 2022):
    • Tecovirimat 600mg bd po for 14d (Tpoxx)
      • An antiviral agent that acts inhibitor of the orthopoxvirus VP37 envelope wrapping protein
    • Brincidofovir 200mg po on days 1, 8, and 15 (3 doses) (Tembexa)
      • Prodrug of cidofovir, with activity against dsDNA viruses

Seek and treat complications

• Secondary infections (e.g. pneumonia)
• Corneal lesions
• Disseminated rash
• Severe pain (may be neuropathic)

Supportive care and monitoring

• Multimodal analgesia (pain may be severe especially if perineal/rectal lesions)
  • Pracetamol, NSAIDs
  • Opioids and additional measures (e.g. ketamine; lignocaine gel) may be required for severe or refractory cases
• Psychosocial support

Disposition

• May require hospital admission if:
  • Severe pain
  • Secondary complications
  • Significant comorbidities
  • Social reasons
• Referrals:
  • ICU if risk of critical illness
  • Anaesthesia/ENT if risk of airway compromise
  • Neurology if suspected encephalitis
  • Ophthalmology if keratitis

PROGNOSIS

• 1-10% mortality in endemic regions (Beer and Rao, 2019)
  • 3% in Nigeria (West Africa clade)
  • Up to 10% in Congo (Central Africa clade)
  • Primarily infants and immunocompromised (HIV/AIDS)
• <10% of patients in the UK 2022 outbreak require hospital admission (Girometti et al, 2022)
• Patients with well controlled HIV receiving antiretroviral therapy do not appear to have more severe disease when infected with Mpox
• Duration of illness is usually 2-4 weeks

PREVENTION

Mpox is a notifiable disease in many jurisdictions

Isolation

• CDC infection control recommendations:
  • isolation precautions for Mpox maintained until all lesions have crusted, those crusts have separated, and a fresh layer of healthy skin has formed underneath
  • patients should be in a single isolated room (no special air handling required)
  • 21 days for close contacts

Personal protective equipment (CDC infection control)

• Contact and airborne precautions required
• PPE: gown, gloves, googles, N95 mask

Other measures

• Education of the public
• Case contact tracing

Vaccination (McCollum and Damon, 2014)

• Cross-protection from the smallpox vaccine (85% effective against MPV), which was discontinued in the 1970s after the eradication of smallpox
• Revaccination after 3 years is recommended
• Different smallpox/ Mpox vaccines (CDC recommendations) include:
  • JYNNEOS is a two-dose live virus vaccine that uses non-replicating modified vaccinia Ankara (MVA); which does not produce skin lesions
  • ACAM2000 is a live Vaccinia virus preparation that is inoculated into the skin; produces skin lesions and may be transmissible to others

Pre-exposure prophylaxis (PrEP) (CDC infection control)

• Vaccination considered for certain clinical and laboratory staff at high risk of exposure

Post-exposure prophylaxis (PEP) (CDC infection control)

• Modified vaccinia Ankara vaccination is indicated within 4 days of exposure, although it can be considered up to a maximum of 14 days
• Potential role for antivirals (application in progress for Tecovirimat)
• Vaccinia Immune Globulin Intravenous (VIGIV) can be considered for exposed patients with T cell dysfunction who have a contraindication to smallpox vaccination

OTHER INFORMATION

Discovery (Parker and Buller, 2013)

• First identified in monkeys in a Danish laboratory in 1958
• First identified in humans in the Congo in 1970
• First identified in the USA in 2002

Potential reasons for the emergency of Mpox in 2022 include:

• Declining Smallpox immunity
• Environmental degradation and closer contact with reservoir animal species
• Return of global travel following the coronavirus pandemic
• Outbreaks may have arisen from crowded public events in Spain and Belgium

Pearls and pitfalls

• May coexist with HIV, syphilis, HSV, or other STIs – so test any suspected lesions
• Disease is not restricted to patients with a history of MSM
• Take a detailed sexual history (including oral and.or anal receptive sex) and travel history
• Consider assessing HIV status and for presence of STIs
• Patients may present with 1 single skin lesion or with no rash but a flu-like illness

References and Links

FOAM and web resources

• CDC – Mpox
• Dermnet – Mpox
• Morgenstern, J. Monkeypox, First10EM, May 19, 2022. Available at:
  https://doi.org/10.51684/FIRS.128007
• Radiopaedia – Mpox
• St Emlyns – Monkeypox has arrived. Is the panic justified? (2018)
• World Health Organisation – Mpox

Journal articles

• Adler H, Gould S, Hine P, et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK [published correction appears in Lancet Infect Dis. 2022 Jul;22(7):e177]. Lancet Infect Dis. 2022;22(8):1153-1162. doi:10.1016/S1473-3099(22)00228-6 [article]
• Alakunle E, Moens U, Nchinda G, Okeke MI. Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution. Viruses. 2020;12(11):1257. Published 2020 Nov 5. doi:10.3390/v12111257 [article]
• Basgoz N, Brown CM, Smole SC, et al. Case 24-2022: A 31-Year-Old Man with Perianal and Penile Ulcers, Rectal Pain, and Rash. N Engl J Med. 2022;387(6):547-556. doi:10.1056/NEJMcpc2201244 [article]
• Beer EM, Rao VB. A systematic review of the epidemiology of human monkeypox outbreaks and implications for outbreak strategy. PLoS Negl Trop Dis. 2019;13(10):e0007791. Published 2019 Oct 16. doi:10.1371/journal.pntd.0007791 [article]
• Cohen J. Global outbreak puts spotlight on neglected virus. Science. 2022;376(6597):1032-1033. doi:10.1126/science.add2701 [article]
• Girometti N, Byrne R, Bracchi M, et al. Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis [published online ahead of print, 2022 Jul 1]. Lancet Infect Dis. 2022;S1473-3099(22)00411-X. doi:10.1016/S1473-3099(22)00411-X [article]
• McCollum AM, Damon IK. Human monkeypox [published correction appears in Clin Infect Dis. 2014 Jun;58(12):1792]. Clin Infect Dis. 2014;58(2):260-267. doi:10.1093/cid/cit703 [article]
• Parker S, Buller RM. A review of experimental and natural infections of animals with monkeypox virus between 1958 and 2012. Future Virol. 2013 Feb 1;8(2):129-157. doi: 10.2217/fvl.12.130. PMID: 23626656; PMCID: PMC3635111. [article]
• Patrocinio-Jesus R, Peruzzu F. Monkeypox Genital Lesions. N Engl J Med. 2022;387(1):66. doi:10.1056/NEJMicm2206893 [article]
• Sherwat A, Brooks JT, Birnkrant D, Kim P. Tecovirimat and the Treatment of Monkeypox – Past, Present, and Future Considerations [published online ahead of print, 2022 Aug 3]. N Engl J Med. 2022;10.1056/NEJMp2210125. doi:10.1056/NEJMp2210125 [article]
• Tarín-Vicente EJ, Alemany A, Agud-Dios M, et al. Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study [published online ahead of print, 2022 Aug 8]. Lancet. 2022;S0140-6736(22)01436-2. doi:10.1016/S0140-6736(22)01436-2 [article]
• Thornhill JP, Barkati S, Walmsley S, et al. Monkeypox Virus Infection in Humans across 16 Countries – April-June 2022 [published online ahead of print, 2022 Jul 21]. N Engl J Med. 2022;10.1056/NEJMoa2207323. doi:10.1056/NEJMoa2207323 [article]
• The Lancet Infectious Diseases. Monkeypox: a neglected old foe. Lancet Infect Dis. 2022;22(7):913. doi:10.1016/S1473-3099(22)00377-2 [article]