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Human Monkeypox Disease

Open AccessPublished:August 10, 2022DOI:https://doi.org/10.1016/j.clindermatol.2022.08.009

      Abstract

      There has been an alarming rise in human monkeypox cases during these past few months in countries where the disease is not endemic. The recent COVID-19 pandemic and the connection of the monkeypox virus with the smallpox-causing Variola virus makes it highly likely to be a candidate for another human health emergency. The transmission mode is predominantly via sexual contact, especially among men who have sex with men (MSM) – anogenital lesions are the most typical presentation. Although it is a disease with a self-limiting course, some patients require admission for severe anorectal pain, pharyngitis, eye lesions, kidney injury, myocarditis, or soft tissue superinfections. Antiviral therapy has been advocated, of which tecovirimat is promising in patients with co-morbidities. Vaccines will be the mainstay for the present and future control of the disease.

      Introduction

      When the world is grappling with the mutant SARS-CoV-19, the multicontinental emergence of hitherto endemic monkeypox in human beings is of concern. This is important, considering the virus is related to the ominous, often fatal variola virus. Since the global eradication of smallpox and the subsequent cessation of its vaccination program in 1970, the cross-immunity against monkeypox has been slowly waning in the world community. The new generation is devoid of this vital protection. In this scenario, any change in the behavior and virulence of the monkeypox virus may increase its infectivity and lethal potential. A high degree of suspicion in its prompt diagnosis, isolation of the patient, a thorough screening of the contacts, and other preventive measures are urgent needs. Additional measures, including its effective specific therapy and vaccine development, are significant in preventing the poxvirus disease.

      Epidemiology

      Since the discovery of the monkeypox virus and its isolation from Cynomolgus monkeys in Copenhagen in 1958, this poxvirus infection has remained a zoonosis1, being chiefly confined to African countries. The first human infection due to the monkeypox virus was recorded in a child in the Democratic Republic of Congo in 1970. Soon, it was followed by other sporadic cases from Liberia, Nigeria, and Sierra Leone2-5. Since then, human monkeypox infection was occasionally reported in African countries for the next few decades [Figure 1-7] [Table 1]. Unfortunately, there are an alarming number of human monkeypox cases now reported from non-African.
      Figure 1:
      Figure 17-year-old girl with monkeypox from Equateur Region, Zaire. Front view, during day 8 of rash
      Figure 3:
      Figure 3The old scar on the arm is not due to vaccination. (Courtesy Breman, J. G., Kalisa-Ruti, Steniowski, M. V., Zanotto, E., Gromyko, A. I., & Arita, I. (1980). Human monkeypox, 1970-79. Bulletin of the World Health Organization,1970-1979; 58: 165–182)5
      Figure 4:
      Figure 4Heavy concentration of lesions on the hands, inguinal lymphadenopathy, and pustules on genitalia. (Courtesy Breman, J. G., Kalisa-Ruti, Steniowski, M. V., Zanotto, E., Gromyko, A. I., & Arita, I. (1980). Human monkeypox, 1970-79. Bulletin of the World Health Organization, 1970-1979;58: 165–182)5
      Figure 5:
      Figure 5Swollen lower face and neck due to cervical and submandibular lymphadenopathy. (Courtesy Breman, J. G., Kalisa-Ruti, Steniowski, M. V., Zanotto, E., Gromyko, A. I., & Arita, I. (1980). Human monkeypox,. Bulletin of the World Health Organization, 1970-1979; 58: 165–182)5
      Figure 6:
      Figure 6Lesions on lips, tongue, and eyelids
      Figure 7:
      Figure 7Same patient, 16 months after the initial illness. Hyperpigmentation of lesions with shallow pitting scars, most prominent over the bridge of the nose. (Courtesy Breman, J. G., Kalisa-Ruti, Steniowski, M. V., Zanotto, E., Gromyko, A. I., & Arita, I. Human monkeypox, 1970-79. Bulletin of the World Health Organization, 1980:58: 165–182)5
      Table 1Laboratory confirmed human monkeypox cases6
      YearDurationNumber of cases
      1970 – 200030 years< 1000
      2000 – 200910 years> 10,000
      2010 – 201910 years> 8000
      2020 – April 20222 years 4 months10,545
      May 2022 – July 20223 months> 16000
      The first outbreak of human monkeypox was reported in the Democratic Republic of Congo in 2003, followed by the South Sudan in 20058. Then there was a lull in human monkeypox infections. Similarly, in Nigeria, several cases were reported from 2017 onwards, after the first reported case thirty-nine years ago9. Outside of Africa, the mid-west states of the United States of America recorded 47 cases in 2003, when Gambian pouch rats were imported as exotic pets from Ghana10. Soon after, isolated cases from the United Kingdom, Israel, and Singapore were reported11.
      Beginning on May 7, 2022, a sudden emergence of human monkeypox was reported from 31 countries outside the normal monkeypox endemic cases and has increased exponentially to date12. On June 22, 2022, the World Health Network (WHN) declared the current monkeypox outbreak a pandemic after confirming 3,417 monkeypox cases across 58 countries and rapidly expanding across multiple continents13.
      A significant feature of these patients indicates that they are chiefly men who have sex with men (MSM) and live in urban areas14. Fortunately, the mortality rates are low, permitting ample time for research about the recent behavior of this endemic zoonotic disease.

      The agent

      The Monkeypox virus (MPV) is a large (200-250 nanometers), brick-shaped, linear double-stranded DNA virus enveloped with lipoproteins and belonging to the Orthopoxvirus genus of the Poxviridae family. This genus has over ten member species that are genetically and antigenically related [Table 2].
      Table 2Poxvirus group members15
      SpeciesInfection
      Variola major (Smallpox)
      Variola minor
      Vaccinia
      Variola-vaccinia virusesCowpox
      Monkeypox
      Rabbitpox
      Buffalopox
      Milker's nodules
      Orf-like virusesContagious pustular dermatitis (Orf)
      Bovine papular stomatitis
      Canarypox
      Avian poxvirusesFowlpox
      Pigeonpox
      Turkeypox
      Rabbit myxoma
      Myxoma-fibroma virusesRabbit fibroma
      Squirrel fibroma
      Hare fibroma
      UnclassifiedMolluscum contagiosum
      Entomopox
      The immunity against one species cross-protects against all other species of this genus. MPV is divided into two genetically distinct clades [Table 3]. The human MPV infections outside Africa have been caused by the West African clade, as confirmed by PCR and genetic sequencing17.
      Table 3Strains of Monkeypox virus15,16
      StrainsVirulenceHuman case fatality
      The Congo Basin cladeHigh10.6%
      (Central African)
      The West African cladeLow3.6%
      Transmission is via contact with infected animals, their body fluids, lesion materials, and respiratory droplets. Human-to-human transmission can occur through prolonged close contact. Sexual transmission among humans is another possibility, as the current outbreak chiefly involves MSM. The risk factors include non-smallpox vaccinated patients, people with co-morbidities including HIV, and occupational workers dealing with infected animals or humans18.

      Clinical features

      After an incubation period ranging from 7-21 days (mean – 13 days), the human monkeypox infection exhibits a brief prodromal stage, followed by a characteristic eruption. Prodromal features include fever, malaise, and lymphadenopathy. The dermatitis is monomorphic, being in the same stage of development, starting with macules, then papules, vesicles, and finally pustules6,19-22 [Figure 8]. In a week or so, the pustules crust and peel off23 [Figure 9] [Table 4]. The Congo Basic clade is associated with a more severe illness and a higher mortality rate than the West African clade, especially if there is a co-morbidity, including HIV9. he recent human MPV infection outbreak has been observed across 16 countries outside the endemic African region. 27 There have been several clinical digressions from the conventional infection, including a single genital lesion presentation and a significant rectal/mucosal affliction [Table 5]. Out of 528 total patients, 70 required hospital admission – 21 for management for severe anorectal pain, 18 for soft tissue superinfection, 13 for infection control purposes, 5 for severe pharyngitis, and two for eye lesions, kidney injury, and myocarditis. No death was reported. A July 20, 2022 communication of the Centre for Infectious Disease Research and Policy (CIDRAP) has recorded five deaths in African nations amongst 14,000 worldwide cases of recent human MPV infection28.
      Figure 8:
      Figure 8A – Oral lesions (right tonsil) visible already at the patient's first presentation; B-D – Both patients developed 10–12 initially vesicular, later pustular skin lesions distributed over the entire body. Many of these lesions were umbilicated, and all were at the same general stage of development. The typical septate structure of pox lesions became apparent upon opening the lesions. (Courtesy Noe, S., Zange, S., Seilmaier, M., Antwerpen, M. H., Fenzl, T., Schneider, J., Spinner, C. D., Bugert, J. J., Wendtner, C. M., & Wölfel, R. (2022). Clinical and virological features of first human monkeypox cases in Germany. Infection, 1–6. Advance online publication. https://doi.org/10.1007/s15010-022-01874-z)22
      Figure 9:
      Figure 9Photographs of the penile ulcer and the skin lesions. Non-tender ulcer on the dorsum of the penile shaft, measuring 7 mm in diameter with central umbilication. Erythematous, maculopapular lesions appeared on the upper back and proceeded down the body. The red-colored line indicates the period of fever (≥37.5°C). (Courtesy Jang, Y. R., Lee, M., Shin, H., Kim, J. W., Choi, M. M., Kim, Y. M., Lee, M. J., Kim, J., Na, H. K., & Kim, J. Y. The First Case of Monkeypox in the Republic of Korea. J Korean Med Sci, 2022; 37(27), e224. https://doi.org/10.3346/jkms.2022.37.e224)23
      Table 4Natural history of human monkeypox6,9,24-26
      StageInfectivityClinical featuresDuration
      Incubation periodNon-infectiousAsymptomatic7-21 days
      (Mean – 13 days)
      • Fever
      • Lymphadenopathy –
      ProdromeInfectiousPeriauricular, cervical,1-3 days
      Axillary, and inguinal.
      • Myalgia
      • Fatigue
      • Mucosal lesions in the
      mouth (First to appear)
      • Monomorphic
      dermatitis on the face, extremities,
      palms and
      Exanthematous rashInfectioussoles, possibly involving2-4 weeks
      the genitalia, especially in
      MSM
      • Dermatitis progresses from
      macule → papule →
      vesicle → pustule →
      Crusts → desquamation.
      • Bacterial
      superinfection
      Secondary• Sepsis
      Infectious• Bronchopneumonia2-6 weeks
      complications
      • Encephalitis
      • Keratitis
      • Gastroenteritis
      • Hypo/hyperpigmented
      atrophic scars
      • Alopecia
      SequelaeNon-infectious• Hypertrophic scarring> 6 weeks
      • Contracture/
      deformities in facial
      muscles.
      Table 5Salient characteristics of the current human MPV outbreak (n = 528)27
      ParameterFeatures
      SexExclusively men (Men = 527, trans/non-binary = 1)
      Sex orientationHomosexual = 509 (96%), heterosexual = 9 (2%), bisexual = 10 (2%)
      HIV statusHIV positive = 218 (41%)
      Concomitant STIPresent in 109 (29%) patients among 377 (screened)
      Suspected route ofSexual close contact = 504 (95%), non-sexual close contact = 4 (1%),
      transmissionhousehold/unknown = 20 (4%)
      Dermatitis = 500 (95%), fever = 330 (62%), lymphadenopathy = 295 (56%),
      Clinical featureslethargy = 216 (41%), myalgia = 165 (31%), headache = 145 (27%),
      pharyngitis = 113 (21%), anorectal pain/proctitis = 75 (14%)
      Site of skin lesionsAnogenital region = 383 (73%), trunk and extremities = 292 (55%), face =
      134 (25%), palm and soles = 51 (10%)
      Characters of skinDermatitis (vesicular = 291, macular = 19) = 310 (62%), single ulcer = 54
      lesions (n = 500)(11%), multiple ulcers = 95 (19%)
      Mucosal lesionsOnly anogenital regions = 148 (68%), only oropharyngeal regrion = 50
      (23%), both anogenital and oropharyngeal regions= 16 (7%), nasal/eyes = 3
      (n = 217)
      (1%)
      Site of positive viralAnogenital region/skin = 512 (97%), nose/throat swab = 138 (26%),
      PCRblood = 35 (7%), semen = 29 (5%), urine = 14 (3%)
      Transmission in children can occur through feeding, holding, cuddling, and fomites, as well as from toys29,30. The recent monkeypox affliction of two children in the USA is concerning. Both have received antiviral therapy, recommended by the CDC, as children under eight years are considered at a higher risk30,31.

      Diagnosis

      Monkeypox infection can be confirmed through using PCR for monkeypox DNA from the patient's specimen. Orthopoxviruses in the specimen can be visualized using electron microscopy; viral culture isolation can also be undertaken. Immunohistochemical staining for Orthopox viral antigens, serum studies for anti-Orthopoxvirus IgM (for recent infection), and anti-Orthopoxvirus IgG (for prior exposure/vaccination) are other important laboratory studies32.
      The differential diagnoses include chickenpox, measles, secondary syphilis, hand-foot-mouth disease, and infectious mononucleosis. Genital human monkeypox can be confused with chancroid, donovanosis, and other non-venereal genital ulcers24,32.

      Management

      There is no specific clinically-proven therapy for monkeypox disease. Tecovirimat (S.T.- and Brincidofovir are the two antiviral preparations approved by the U.S. Food and Drug Administration (FDA) for smallpox. Their use in human monkeypox has insufficient data but suggests that Tecovirimat is more effective than Brincidofovir33.
      The preventive measures include isolation of the patient, keeping lesions covered, proper, and disposing of infectious materials with appropriate precautions. Contact tracing and monitoring for a reasonable duration will assist in controlling the spread of the disease25,33.
      A concerted two-decade effort of the United States government to develop antivirals and next-generation vaccines against smallpox resulted in two FDA-approved antivirals and two next-generation vaccines.
      The first next-generation smallpox vaccine called ACAM-2000 is similar to the discontinued Dryvax vaccine, known to generate long-lasting immunity34,35 and provides 85% protection against human monkeypox36.
      The second next-generation smallpox vaccine is MVA-BN (JYNNEOS in the U.S.), manufactured with the Modified Vaccinia Ankara strain and administered by two subcutaneous injections, four weeks apart37. While the former vaccine is contraindicated in pregnancy, atopic dermatitis, and various immune deficiencies, the latter displayed no serious adverse events and no risk of inadvertent inoculation and auto-inoculation6,18,37. Thhe MVA-BN vaccine is approved in the United States for use against both smallpox and monkeypox. Tt still requires clinical trials for human efficacy37.
      Among 528 human monkeypox patients in one report, .27, 23 (5%) were given antiviral therapy or vaccinia immune globulin with a favorable response. Tecovirimat (TPOXX or ST246) inhibits the spread of the virus by inhibiting the viral envelope protein VP37, thus blocking the final steps in the viral maturation and its release from infected cells.
      The CDC-held Emergency Access Investigational New Protocol allows the use of Tecovirimat for non-variola orthopoxvirus infections such as monkeypox. The protocol also includes an allowance for opening an oral capsule and mixing its content with liquid or soft food for pediatric patients weighing less than 13 kgs. Cidofovir and Brincidofovir work by inhibiting viral DNA polymerase, the latter being more effective in controlling MPV infection38.

      Conclusions

      During the last two years, scientists, healthcare personnel, and world authorities have coordinated, promptly combating, and curtailing any future epidemic or pandemic. Our preventive strategy can save allay apprehensions, anxiety, morbidity, mortality, and resources.. Instead of an alarm, a rational scientific approach can help halt the spread from infected areas to other non-infected safe zones.

      Authors' contributions

      Both authors contributed equally to the manuscript.

      Funding Acknowledgments

      None

      Ethics committee approval

      Not required.Table 6
      Table 6Management of human monkeypox disease38-41
      ModeInterventions
      By prior immunization with available smallpox vaccines
      Prevention1.JYNNEOS™ (MVA-BN, IMAVAMUNE, IMVANEX)
      2.ACAM 2000®
      3.Newer APSV (Avantis Pasteur Smallpox Vaccine)
      1.Pre-exposure: Vaccinating select people at risk for occupational
      Prophylaxisexposure.
      2.Post-exposure: Vaccination within four days of exposure to the virus to
      prevent or minimize the development of the disease.
      1.Tecovirimat: (Oral or intravenous) Adults 600 mg, twice daily;
      children 13-25 kg 200 mg, twice daily; children 25-40 kg, 400 mg
      Twice daily. The duration of treatment is 14 days.
      2.Brincidofovir: (Oral suspension) Adults (>48 kg) 200 mg, once
      weekly for two doses; children (>10 kg) 4mg/kg, once weekly for 2
      Antiviral therapyDoses.
      3.Cidofovir: (Intravenous) 5mg/kg, once weekly for two weeks,
      followed by 5mg/kg, once every other week.
      4.Vaccinia immune globulins (Intravenous): 6000U/kg as soon as
      Symptoms appear. Repeat dose required based on response to
      Treatment and severity of symptoms.

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      Conflict of interest

      No conflict of interest between authors.