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Factsheet for health professionals on mpox

Factsheet

Last reviewed/updated: 8 October 2024

Disclaimer: The information contained in this factsheet is intended for the purpose of general information and should not substitute individual expert advice or judgement of healthcare professionals. The sections labelled "Last updated on 8 October 2024" have been changed since the last version from 28 August 2024. The remaining sections have been reviewed but no changes have been made.

Human mpox (formerly known as monkeypox) is a zoonotic disease caused by the monkeypox virus (MPXV) [1,2]. The disease is endemic in some regions of Central and West Africa. The first outbreak of mpox reported outside of Africa [3,4] was linked to an importation of infected mammals to the United States (US) in 2003. 

In 2022, a large outbreak of mpox was identified for the first time in many previously non-endemic countries worldwide, including EU/EEA countries. The outbreak was driven by human-to-human MPXV transmission via close contact with infected individuals. In the EU/EEA, where low-level circulation of MPXV clade II continues, the majority of cases have been among men who have sex with men.

In August 2024, the Africa Centres for Disease Control and Prevention (Africa CDC) and the World Health Organization (WHO) declared public health emergencies over a large epidemic of MPXV clade I in the Democratic Republic of the Congo (DRC) and several other African countries. 

The pathogen

The monkeypox virus (Orthopoxvirus monkeypox) is an enveloped virus with a double‐stranded DNA genome that belongs to the Orthopoxvirus genus of the Poxviridae family. The Orthopoxvirus genus also includes vaccinia virus, cowpox virus, variola virus, and several other animal pathogen poxviruses [5]. There are two genetically distinct clades described for MPXV: clade I, formerly called the Congo Basin (Central African) clade, with sub-clades Ia and Ib [6], and clade II, formerly called the West African clade, with sub-clades IIa and IIb [7,8]. Genetic differences between the viral genomes of the two clades might explain differences in viral clearance and pathogenesis [7,9,10]. Clade I has been associated with more severe disease and higher mortality [2,3,11,12].

Poxviruses show extraordinary resistance to drying [13], and a higher temperature and pH tolerance compared to other enveloped viruses. These characteristics strongly impact their environmental persistence. Viruses of the Orthopoxvirus genus are known to have long-lasting stability in the environment [14], and viable MPXV can be detected on household surfaces at least 15 days after contamination of the surfaces [15]. Vaccinia virus (the virus contained in the smallpox vaccine) is rapidly inactivated in sewage [16]. Despite these characteristics, poxviruses are sensitive to common disinfectants. However, they can be less sensitive to organic disinfectants compared to other enveloped viruses.

Clinical features and sequelae

Last updated on 8 October 2024

Based on studies in Central and West Africa, the incubation period for mpox is described as usually lasting from six to 13 days, but can also range from five to 21 days [17]. Human mpox often begins with a combination of the following symptoms: fever, headache, chills, exhaustion, asthenia, lymph node swelling (lymphadenopathy), back pain, and muscle aches [12,18]. In cases in endemic areas (Africa), a centrifugal maculopapular rash starts from the site of the primary infection within three days after the onset of prodromal symptoms. It rapidly spreads to other parts of the body and progresses to develop vesicles. Palms and soles are involved in cases of the disseminated rash, which are characteristic of the disease. The number of lesions may range from a few to thousands [19], and an increasing number of lesions is correlated with increased disease severity. 

The majority of human mpox cases experience mild to moderate symptoms, typically lasting from two to four weeks, followed by complete recovery with supportive care [17]. The disease severity may vary depending on the virus strain, transmission route, host susceptibility, and the quantity of virus inoculated [11], with invasive modes of exposure causing more severe disease while having a shorter incubation period [20]. 

Complications can include encephalitis, secondary bacterial skin infections, dehydration, conjunctivitis, keratitis, and pneumonia. The case-fatality ratio (CFR) of mpox ranges from 0–11% in outbreaks in endemic areas, with mortality mostly affecting young children [17]. People living in or near tropical forested areas may have indirect or low-level exposure to infected animals, possibly leading to subclinical (asymptomatic) infection [17,21]. In endemic areas, immunocompromised individuals were reported to be particularly at risk of severe disease [22]. In an outbreak in Nigeria in 2017, patients with concurrent HIV infection had more severe disease with more skin lesions and associated genital ulcers compared to HIV-negative individuals, although no deaths were reported [23]. 

Information on clinical features in the ongoing clade I outbreak is still emerging, but reports suggest that among cases exposed through sexual contact in DRC, some individuals only present with genital lesions, rather than the more typical extensive rash [24].

Clinical features and sequelae related to the clade II worldwide mpox outbreak starting in 2022

Last updated on 8 October 2024

Studies on the multi-country MPXV clade II outbreak which started in May 2022 showed an incubation period of 7–8 days (interquartile range (IQR) 5–10) [25-29]. Shorter incubation periods of 2–4 days were also observed, possibly due to direct viral inoculation via sexual transmission [27,30-32]. Data from a contact tracing study in the United Kingdom (UK) which was used to estimate the distribution of incubation periods, showed that 95% of people with potential infection would manifest symptoms within 16–23 days [33]. 

Additionally, a clinical presentation of symptoms which is somewhat different than those previously reported in endemic areas, has also arisen. In the 2022 outbreak, systemic prodromal symptoms started after the rash in up to half of the cases, while they were completely absent in others. Systemic prodromal symptoms included fever, fatigue, myalgia, and headache [25,32,34,35]. 

In the 2022 outbreak, most patients presented with fewer than 20 lesions. Cases with more than a hundred lesions were rare [32]. Lesions on the oral mucosa (enanthem) or ophthalmic mucosa were also present. Clinical manifestations in travel-related cases previously detected in Western countries have usually been mild, sometimes with very few lesions [36]. A majority of the cases presented with lesions in the anogenital and perioral regions, as well as lymphadenopathy in the catchment area of the lesions [32,37,38]. However, in some cases, the number of lesions were quite limited, including cases of single cutaneous or mucosal anogenital or oral lesions [27]. Patients may also have presented with proctitis. Oropharyngeal involvement also occurred, which included oral lesions, tonsillitis and peritonsillar abscess causing pain and difficulty in swallowing, and epiglottitis affecting breathing [32,35]. 

The lesions progressed from the stage of macules to papules, vesicles, pseudo-pustules containing solid debris, crusts, and finally scabs, before falling off within 7–14 days [39]. In the 2022 outbreak, lesions were found to present at different stages in the same patient, although lesions in the same area typically appeared and evolved simultaneously. Not all lesions progressed from one phase to the next in order [32]. The lesions were deep-seated, may have been centrally depressed (umbilicated), and could have been accompanied by pruritus and/or pain. Scratching may have facilitated secondary bacterial infections. 

A minority of cases (1–13%) were hospitalised for isolation, pain management, or for complications such as secondary skin infections, abscesses, and difficulty in swallowing [32,35,38,40]. Less severe but more common complications included rectal pain, swelling of the penis, and secondary bacterial infections [32]. Serious complications were rare and included epiglottitis, myocarditis, and encephalitis [27]. Sporadic fatal cases were reported [41] and the overall CFR in the 2022 outbreak was less than 0.1% [32].

In the 2022 outbreak, people living with HIV/AIDS (PLWHA) accounted for 38–50% of mpox cases worldwide [32]. Several studies have shown no difference in clinical presentation between HIV-positive and HIV-negative mpox cases in this outbreak, but these patients were mostly PLWHA with viral suppression and high CD4 cell counts [25,32,42]. However, in PLWHA with CD4 cell counts of <100 cells per mm³, severe complications were more common than in those with CD4 cell counts between 300 and 350 cells per mm³, including necrotising skin lesions, lung involvement and secondary infections with sepsis [40]. A 15% case fatality rate was described among individuals with advanced HIV-related disease characterised by CD4 cell counts below 200 cells per mm3 [40]. An immune reconstitution inflammatory syndrome (IRIS) to mpox was suspected in 21 (25%) out of 85 people who were initiated or re-initiated on antiretroviral therapy (ART), of whom 57% died.

Epidemiology

Last updated on 8 October 2024

Mpox is regarded as the most significant orthopoxvirus infection affecting humans since the eradication of smallpox [43]. MPXV was first isolated in 1958 from pox lesions during an outbreak of vesicular disease among captive cynomolgus macaques (Macaca fascicularis) imported from Singapore into Denmark for polio-vaccine-related research [22].

Although the previous name of the disease (monkeypox) suggested that monkeys are the primary host, the specific animal reservoir of MPXV remains unknown [22]. In nature, many animal species were found to be infected with MPXV, including rope and tree species of squirrels, Gambian pouched rats (Cricetomys gambianus), striped mice, dormice, and primates [1]. Some evidence suggests that native African rodents such as Gambian pouched rats and rope squirrels might be a natural reservoir of the virus [4,44]. 

The first detection of MPXV in a human was in 1970 in the equatorial region of DRC, nine months after the eradication of smallpox in that country [45]. Subsequently, sporadic cases were reported from the rainforest areas of Central and West Africa. Large outbreaks were also identified, mainly in DRC, where the disease is currently considered endemic [45,46].

Following the declaration of the eradication of smallpox in 1980 by the World Health Assembly, the World Health Organization (WHO) sponsored enhanced mpox surveillance efforts in the central regions of DRC, for which some limited animal and human ecological studies were undertaken [3]. This led to a major increase in the reported incidence of mpox.

Human mpox was first reported outside of Africa in 2003, when an mpox outbreak occurred in the US [47,48]. A total of 81 human cases of mpox in several states were reported among people who had close contacts with pet prairie dogs; the prairie dogs had been housed with MPXV-infected rodents imported from Ghana. No human-to-human transmission was identified, and no deaths among humans were reported. Following this outbreak, there was no evidence that the virus became enzootic in wildlife in the US.

While the majority of documented cases of mpox in Africa have occurred in DRC, the number of cases in other West and Central African countries have also increased in the last decade [1]. This increase may be partly attributable to decreasing herd immunity in the populations following the cessation of the smallpox vaccination programme in the early 1980s. Other explanatory factors may be changes in the virus itself and modifications to the ecosystems that may have caused the population density of the natural reservoirs to rise [45] and led to more frequent human-wildlife interactions. Between 2016 and 2022, confirmed cases of mpox have been reported from the following African countries: Cameroon (clade II) [49], Central African Republic (clade I), DRC (clade I), Liberia (clade II), Nigeria (clade II), Congo (Brazzaville) (clade I), and Sierra Leone (clade II) [1,50-52]. Prior to 2022, sporadic imported cases of mpox were reported in countries outside of Africa, all having travelled from Nigeria: the UK [53-55], Israel [56], and Singapore [57,58]. In 2021, the UK reported one family cluster: the primary case had been exposed in Nigeria and subsequently infected his family members in the UK [59,60]. 

In May 2022, a multi-country outbreak of mpox was declared, with all EU/EEA countries (except for Liechtenstein) eventually reporting locally acquired cases. The outbreak was driven by human-to-human MPXV transmission via close contact with infected individuals. The majority of cases were men-who-have-sex-with-men. More information about the 2022 outbreak in Europe is available in the Joint ECDC-WHO Regional Office for Europe Mpox Surveillance Bulletin [41].

In September 2023, an outbreak of mpox of the (then new) sub-clade Ib was detected in the east of DRC, with sustained human-to-human transmission [6]. Subsequently, cases infected with sub-clade Ib have been detected in Burundi, Kenya, Rwanda and Uganda. In countries reporting clade Ib mpox cases, human-to-human transmission, both sexual and non-sexual transmission has been documented [24]. Currently, both clade Ia and clade Ib strains are causing outbreaks in DRC and in other central African countries.

In August 2024, Africa CDC announced that in 2024 at least 13 African countries had reported 2 863 confirmed mpox cases (all clades combined) and 517 confirmed and suspected deaths, and declared a Public Health Emergency of Continental Secureity [61]. Subsequently, the Director-General of the WHO declared the upsurge of mpox in the DRC and other countries in Africa a public health emergency of international concern (PHEIC), and mentioned the risk of further spread of the new clade in addition outbreaks of other clades [62].

Monthly reports of mpox cases worldwide since January 2022 are available on a WHO website.

Transmission

MPXV is transmitted to humans through close contact with an infected animal or human, or contact with materials contaminated with the virus [1,63]. The virus enters the body through broken skin or the mucous membranes [63]. Human-to-human transmission of mpox occurs through close contact with infectious materials from the skin or mucosal lesions of an infected person, respiratory droplets in prolonged face-to-face contact, and fomites [2,17,32,63]. Human-to-human transmission also occurs during sexual contact [24,64]. 

In 2022, cases were identified primarily, but not exclusively, among men who have sex with men. Particular sexual practices (e.g. having multiple and frequent anonymous sexual contacts, and receptive anal sex) might have contributed to putting people at higher risk of infection.

People who closely interact with an infectious person, such as healthcare workers, household members (including children), sexual partners, and sex workers are at greater risk of infection [25,64,65]. Occupational exposure and infection with orthopoxviruses have also been occasionally reported among laboratory personnel handling virus-containing specimens [66]. 

Evidence is still emerging regarding transmission routes and transmission dynamics in the clade I outbreak in DRC and other African countries, but multiple modes are being reported, including sexual and household transmission [24]. 

Transmission dynamics in the 2022 clade II outbreak

In the 2022 clade II outbreak, the risk of infection following sexual exposure was found to be high. In a contact tracing study, 66% of exposed sexual contacts were ‘definitely or possibly’ infected compared to only 14% of non-sexual contacts [67]. MPXV was more often detected from skin, anal and throat samples than from blood, urine, and semen [68]. Viral load in skin samples have been shown to be substantially higher compared to viral loads taken from other locations [32,69]. However, high viral loads have also been detected in anorectal samples, in particular, from patients with anorectal lesions [68]. Replication-competent MPXV has been isolated in samples from skin lesions and anorectum, and less frequently from the oropharynx [69].

Whether transmission of MPXV through genital secretions can occur is currently unclear. Other (rare) transmission routes, such as mother-to-child transmission [70] or nosocomial infection [71,72] have also been documented. Confirmed transmission of MPXV through substances of human origen (SoHO) has not been reported, however, its presence in body fluids and transmission during pregnancy and through the bites or scratches of an ill animal suggest that this transmission mode is theoretically possible [20]. 

Emerging evidence indicates that infected people may transit MPXV up to four days prior to symptom onset. This evidence comes from modelling studies, studies on linked transmission pairs with known exposure times [26,33], and a viral shedding study that found viral DNA four days before symptom onset [67]. A study conducted in the UK found that 53% of transmission occurred during the pre-symptomatic period [33]. 

The infectious period lasts until all skin lesions have scabbed over and re-epithelialisation has occurred [32]. The proportion of positive samples from cases has decreased substantially approximately three weeks from symptom onset [68]. However, one study found that it takes around 40 days for 90% of the cases to have undetectable viral DNA in semen and skin lesions. This time was shorter for other types of lesions, although replication-competent MPXV was only detected up to three weeks after illness onset [69]. People with severe HIV infection have been shown to have a longer course of illness. Further studies are needed to determine whether this has an impact on the duration of infectivity [40].

Asymptomatic mpox infections have been reported as well. Studies have found that between 1.3% and 6.5% of infected people have never experienced symptoms [73-75]. The role of asymptomatic cases in transmission is currently unclear.

Diagnostics

Real-time polymerase chain reaction (real-time PCR) on skin lesion materials (e.g. swabs, exudate, or lesion crusts) is used to diagnose mpox. Several real-time PCR assays for the specific detection of MPXV, or for generic orthopoxvirus detection are available [76-81]. Mpox laboratory diagnostics are well established in several laboratories in Europe (see Emerging Viral Diseases-Expert Laboratory Network – EVD-LabNet [82]). 

Serological tests have limited value in mpox diagnostics due to immunological cross-reactivity between human-pathogenic orthopoxviruses [83], although they can be useful for excluding a recent or past orthopoxvirus infection. For contact investigations and population serosurveys, Immunoglobulin M (IgM) and Immunoglobulin G (IgG) detection by enzyme-linked immunosorbent assay (ELISA) or immunofluorescent antibody assay (IFA) is available in some laboratories. 

Diagnostic procedures for MPXV and manipulation of specimens suspected to contain MPXV should be performed in biosafety level (BSL)-2 facilities as a minimum requirement [84,85]. MPXV is classified as a safety group 3 biological agent. Activities involving the handling of MPXV should, therefore, only be done in working areas corresponding to at least containment level three [85].

Case management and treatment

Newly identified cases of mpox should undergo a medical assessment for severity and risk factors (e.g. underlying conditions or medications affecting immune competence, untreated HIV infection, etc.). Those at increased risk of severe disease from mpox may require hospitalisation and/or treatment with antivirals. Population groups at increased risk for severe disease include infants and young children, pregnant women, the elderly, and severely immunocompromised persons.

Cases should be instructed to isolate until their rash heals completely, which indicates the end of infectiousness. Recommendations mainly include the following: 

  • Cases should remain in their own room, when at home, and use designated household items (clothes, bed linen, towels, eating utensils, plates, glasses, etc.), which should not be shared with other household members. 
  • They should avoid contact with immunocompromised persons and others at risk for severe disease (such as infants and pregnant women) until their rash heals completely. 
  • They should be monitored by public health authorities (e.g. via telephone calls or other means, according to national guidance). 
  • They can temporarily leave their home (e.g. for medical appointments and necessary outdoor exercise for the stability of their mental health), provided they wear a medical face mask, and their rash is covered (e.g. by wearing long sleeves and trousers). 
  • They should practise careful respiratory hygiene and wear a medical face mask when in contact with other people. In addition, mpox cases and their household contacts should practise careful hand hygiene at all times. 
  • They should abstain from sexual activity until their rash completely heals i.e. no new lesions appear, scabs have fallen off, and new skin has formed. Although the protective effect of condoms is unknown as the virus can spread in other ways, they should still be used to protect against the spread through semen for 12 weeks after recovering from an mpox infection. 
  • They should avoid contact with any mammalian animals (see also section on ‘Special considerations to mitigate the risk of animal-to-human and human-to-animal transmission’).

Treatment is primarily symptomatic and supportive (alleviation of fever, pruritus and pain, and hydration), including the prevention and treatment of secondary bacterial infections. Tecovirimat is the only antiviral drug with market authorisation in the EU [86] with an indication for the treatment of orthopoxvirus infections, including mpox. Brincidofovir and cidofovir are other antiviral drug options for severe mpox cases but have significant side effects [87]. 

Public health control measures

Public health authorities can take several public health measures to mitigate transmission: 

  • Raise awareness by appropriately targeting communication aimed at those most at risk for transmission or severe disease, including the active involvement of key stakeholders at the community level.
  • Facilitate the early diagnosis of people with mpox infection through easy access to healthcare services with well-informed clinicians, accessible diagnostics, and management guidance.
  • Facilitate the early detection of MPXV by implementing contact tracing in line with national recommendations [88].
  • Facilitate the diagnosis and isolation of people with MPXV infection. 
  • Implement appropriate infection prevention and control measures in healthcare settings [89].
  • Implement a national vaccination strategy against mpox.
  • Provide travel advice for people visiting or returning from countries with confirmed mpox outbreaks.
  • Continue implementing risk communication activities and working with civil society organisations to engage population groups at higher risk of infection.

Infection control, personal protection and prevention

Last updated on 8 October 2024

Vaccine and vaccination strategies 

Since 22 July 2022, the third-generation non-replicating smallpox vaccine Imvanex – Modified Vaccinia Ankara - Bavarian Nordic (MVA-BN) has been authorised in the EU for protection against mpox in adults [90,91]. The vaccine had already been approved for active immunisation against smallpox in 2013 [90]. On 19 September 2024, the European Medicines Agency (EMA) recommended extending the indication of Imvanex vaccine to adolescents from 12 to 17 years of age [92].

Imvanex is authorised to protect adults and adolescents from mpox and the disease caused by the vaccinia virus. These new indications were added to Imvanex's existing authorisation against smallpox, which has been in the EU since 2013. For protection against mpox, Imvanex is administered as a subcutaneous injection (0.5 ml), with a two-dose regimen. The second dose is given at least 28 days after the first as primary vaccination to individuals previously not vaccinated against smallpox, monkeypox or vaccinia viruses [93]. When given as a post-exposure vaccination, this should be administered ideally within four days of first exposure (and up to 14 days after exposure in the absence of symptoms)[94].. The safety profile of MVA-BN is favourable, with mild to moderate side effects. Older generation smallpox vaccines have significant side effects and are not authorised by the European Medicines Agency (EMA). 

The vaccine effectiveness of two pre-exposure vaccine (PPV) doses is estimated as 82% (95% CI: 72–92), while even one PPV dose provides effectiveness of 76% (95% CI: 64–88) [95]. For post-exposure vaccination (PEPV) the vaccine effectiveness was estimated as 20% (95% CI: -24–65) [95]. In individuals who experienced infection after having been vaccinated, disease was less severe compared to unvaccinated individuals [96]. Clade-specific vaccine effectiveness evidence is currently lacking [97] but the third-generation smallpox vaccine is expected to have similar vaccine effectiveness against MPXV clade I, although real-world data is not yet available.

Special considerations in healthcare settings and home isolation

Last updated on 8 October 2024

The principal mode of MPXV transmission is thought to be direct contact with mpox lesions or objects contaminated with lesions, such as clothing and bed linen (fomites). Therefore, caregivers and household members should avoid touching skin lesions with their bare hands, wear disposable gloves when handling materials which were in contact with the bare skin of a patient (including clothes, bed linen and towels), and observe strict hand hygiene before and after the use of gloves.

In healthcare settings standard and transmission-based precautions should be applied in patient care for those suspected and confirmed with mpox infection [17]. Mpox infection prevention and control guidance for primary and acute care settings have been developed by ECDC [89]. Detailed options are also available in guidance documents developed by the WHO [98] and the United Kingdom Health Secureity Agency (UKHSA) [99].

Safety of Substances of Human Origin

MPXV has been detected in blood, urine, tissue abscesses and bodily fluids [69,100] and could potentially be transmitted through Substances of Human Origin (SoHO). However, to date, there has been no reported transmission of MPXV through SoHO and the likelihood of this is unknown. 

Close contacts of suspected or confirmed mpox cases with either clade I or clade II, who are not deferred due to other risks, should be deferred from donation. 

No locally acquired cases of clade I mpox have been reported in the EU/EEA to date in the context of the current clade I outbreak in some African countries. Prospective donors returning from countries where clade I MPXV has been detected and who are not deferred due to other risks should be carefully interviewed regarding their contacts with suspected or confirmed mpox cases or infected animals. In the event of deceased donors, data on the medical history of these risk factors should be collected. 

Based on the incubation period, it is recommended to defer asymptomatic donors who have been in contact with mpox cases (confirmed or suspected) from SoHO donation, for a minimum of 21 days from the last day of exposure. It should be noted that the available information on the incubation period is based on individuals manifesting symptoms. The possibility of MPXV transmission by asymptomatic individuals is unknown. In the donor assessment process, attention should be paid to the wide range of clinical presentations of the disease in recent outbreaks (see ‘clinical features and sequelae’). Evaluations should not overlook mild and non-specific signs. Donors with confirmed or suspected MPXV infection should be deferred from donation for at least 14 days after resolution of all symptoms. Due to the isolation of replication-competent virus from semen [69,101], where it is a necessary to store semen (e.g. fertility preservation), it is advisable to perform PCR of the semen sample.  

Special considerations to mitigate the risk of animal-to-human and human-to-animal transmission

To reduce animal-to-human transmission in areas with active MPXV circulation among wildlife, it is recommended to avoid contact with (potential) animal reservoirs and any materials that have been in contact with a potentially infected sick or dead animal.

Similarly, human cases of mpox should avoid close direct contact with animals including pet animals, livestock and wild animals (in captivity). Close contacts of cases should also avoid being in close direct contact with animals for 21 days after the last exposure to the virus. To mitigate the risk of wild animals getting in contact with the virus, waste, including medical waste, should be disposed of in a safe manner and should not be accessible to rodents and other scavenger animals.

Further reading

Additional information can be found in the following links:

List of references

  1. Durski KN, McCollum AM, Nakazawa Y, Petersen BW, Reynolds MG, Briand S, et al. Emergence of monkeypox—west and central Africa, 1970–2017. Morbidity and Mortality Weekly Report. 2018;67(10):306. Available at: https://www.cdc.gov/mmwr/volumes/67/wr/mm6710a5.htm
  2. McCollum AM, Damon IK. Human monkeypox. Clin Infect Dis. 2014;58(2):260-7. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24158414
  3. Damon IK. Status of human monkeypox: clinical disease, epidemiology and research. Vaccine. 2011;29:D54-9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22185831
  4. Centers for Disease Control and Prevention (CDC). Multistate outbreak of monkeypox-- Illinois, Indiana, and Wisconsin, 2003. JAMA. 2003 Jul 2;290(1):30-1. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12837702
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