Monkeypox: an epidemiologic and clinical comparison of African and US disease.
ABSTRACT Monkeypox is a double-stranded DNA virus and a member of the genus Orthopoxvirus. Human monkeypox was first identified in the Democratic Republic of the Congo (formerly Zaire) in 1970. The first outbreak in the western hemisphere occurred in the spring of 2003. Important epidemiologic and clinical differences exist between human monkeypox in the United States and in Africa, including sex distribution, case fatality, morphology of skin lesions, and associated lymphadenopathy. These divergent clinical presentations could be caused by mode of transmission (skin inoculation vs ingestion), the skin color of affected patients, the training backgrounds of those who saw and documented disease outbreaks, the virulence of monkeypox strains involved, nutritional status, access to advanced medical care, and the prevalence of prior smallpox vaccinations.
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ABSTRACT: The actuality in clinical dermatology is, to our opinion, dominated by the emergent or reemergent infections (arboviruses, poxviruses, mycobacteria, leishmania, staphylococcus, papillomaviruses, bedbugs…) and their involvement in certain diseases (atopia, psoriasis), tumours or syndromes with dermatologic signs (IRIS). The cutaneous adverse side effects of the targeted chemotherapies and biotherapies are consequently better surrounded. Some rare new anatomoclinical entities are identified but «classics» (Lipschütz ulcer, pityriasis rosea, deep dissecting hematoma, puffy hand syndrome, disseminata alopecia areata) are rediscovered and better represented thanks to help, sometimes, by new techniques.Annales de Dermatologie et de Vénéréologie 12/2009; 136. · 0.60 Impact Factor
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ABSTRACT: The 2003 monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog is susceptible to MPXV infection and that the ensuing rash illness is similar to human systemic orthopoxvirus (OPXV) infection, including a 7-to 9-day incubation period and, likely, in some cases a respiratory route of infection; these features distinguish this model from others. The need for safe and efficacious vaccines for OPVX in areas where it is endemic or epidemic is important to protect an increasingly OPXV-naïve population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. None of the smallpox vaccines caused illness in this model, and all vaccinated animals showed anti-OPXV antibody responses and neutralizing antibody. We tested vaccine efficacy by challenging the animals with 10 5 or 10 6 PFU Congo Basin MPXV 30 days postvaccination and evaluating morbidity and mortality. Our results demonstrated that vaccination with either Dryvax or Acambis2000 protected the animals from death with no rash illness. Vaccination with IMVAMUNE also protected the animals from death, albeit with (modified) rash illness. Based on the results of this study, we believe prairie dogs offer a novel and potentially useful small animal model for the safety and efficacy testing of smallpox vaccines in pre-and postexposure vaccine testing, which is important for public health planning. Although smallpox has been eradicated (5), orthopoxviruses (OPXVs), such as variola virus (VARV) (6, 32), monkeypox virus (MPXV) (3, 10, 57), vaccinia virus (VACV) (4, 76), and others (53, 68, 77), are a continuing public health concern (61, 67). Due to cellular and humoral protective effects (7, 15, 16, 46, 73), the traditional live VACV-based smallpox vaccines provide cross-protection against multiple OPXV threats (48). Unfortunately, the cessation of routine vaccination (37) has left much of the global population fully susceptible to OPXV infections (34), and the adverse effects of first-and second-generation vaccines (78) coupled with increases in the global immunocompromised population (59) underline the need for continued development and testing of safer smallpox vaccines (30). Testing of smallpox vaccines requires the development of relevant animal models. Current smallpox vaccine testing ani-mal models include ectromelia virus (ECTV) infection of mice (75), VACV infection of mice (63), rabbitpox virus (RPXV) and VACV infection of rabbits (1, 18), VARV and MPXV infection of nonhuman primates (NHP) (13, 19, 21, 25, 26, 31), and others (65, 74). Limitations of current models include abbreviated disease incubation periods and/or differences fromJournal of Virology 01/2011; 85(15):7683-7698. · 5.08 Impact Factor
Monkeypox: An epidemiologic and clinical
comparison of African and US disease
Tanya A. Sale, MD,aJohn W. Melski, MD,band Erik J. Stratman, MDb
Saint Paul, Minnesota, and Marshfield, Wisconsin
Monkeypox is a double-stranded DNA virus and a member of the genus Orthopoxvirus. Human
monkeypox was first identified in the Democratic Republic of the Congo (formerly Zaire) in 1970. The
first outbreak in the western hemisphere occurred in the spring of 2003. Important epidemiologic and
clinical differences exist between human monkeypox in the United States and in Africa, including sex
distribution, case fatality, morphology of skin lesions, and associated lymphadenopathy. These divergent
clinical presentations could be caused by mode of transmission (skin inoculation vs ingestion), the skin
color of affected patients, the training backgrounds of those who saw and documented disease outbreaks,
the virulence of monkeypox strains involved, nutritional status, access to advanced medical care, and the
prevalence of prior smallpox vaccinations. ( J Am Acad Dermatol 2006;55:478-81.)
‘‘OUT OF AFRICA, THERE IS ALWAYS SOMETHING NEW’’1
(‘‘Ex Africa semper aliquid novum’’)
rus.2Monkeypox, a double-stranded DNA virus, is a
member of the genus Orthopoxvirus that is known to
cause human disease, along with variola virus, vac-
cinia virus, and cowpox virus. Much attention was
initially paid to human monkeypox in Africa because
the World Health Organization’s smallpox eradica-
tion program. More recent attention was given to
human monkeypox because of an outbreak in the
midwestern United States, the first such detected
outbreak in the western hemisphere.3
Monkeypox virus was first identified as the causal
agent of a pox infection in captive cynomolgus
monkeys (Macaca fascicularis) in Copenhagen,
Denmark, in 1959.4Eight more outbreaks occurred
during the next 10 years in the United States and the
Netherlands among groups of captive monkeys
imported from Malaysia, India, and the Philippines.5
Although monkeypox virus was recovered from
he genera of poxviruses known to affect
human beings include Orthopoxvirus, Para-
poxvirus, Yatapoxvirus, and Molluscipoxvi-
captive primates originally collected from these
Asian areas, there is no virologic, serologic, or
epidemiologic evidence that the virus occurs natu-
rally anywhere outside of Africa.6Although the
definitive natural reservoir is still unknown, studies
point to rope squirrels of the African genus, Funis-
ciurus. Primates, rabbits, and several rodent species
are also vulnerable to infection.
Human monkeypox was first identified in the
Democratic Republic of the Congo (formerly Zaire)
in 1970 in a 9-month-old infant initially believed
to have smallpox.7Human disease in central and
western Africa is acquired primarily through direct
animal-to-human contact. It is also transmitted from
human-to-human by respiratory droplets or body
INTO THE NEW WORLD
Documented human monkeypox arrived in the
United States in May 2003, occurring in a 3-year-old
girl from central Wisconsin. Trace-back investiga-
tions have implicated a shipment of 800 small
animals from Ghana to Texas as the probable means
of penetration of monkeypox virus into the United
States. A sick Gambian giant-pouched rat (Cricet-
omys gambianus) from this shipment was subse-
quently sold to an Illinois animal vendor where it
was kept in close proximity to prairie dogs (a native
North American rodent [Cynomys species]). Prairie
dogs that became infected were sold to a second
animal distributor, and eventually to two pet shops
and at a pet swap meet in northern Wisconsin.
Additional animals from the Texas shipment, includ-
ing dormice and rope squirrels, tested positive for
monkeypox virus.9As of July 2003, 72 cases of
From the Departments of Dermatology at Aspen Medical Group,
Saint Paul,aand Marshfield Clinic.b
Funding sources: None.
Conflicts of interest: None identified.
Reprint requests: John W. Melski, MD, Department of Dermatol-
ogy, Marshfield Clinic, 1000 N Oak Ave, Marshfield, WI 54449.
ª 2006 by the American Academy of Dermatology, Inc.
human monkeypox were under investigation in
Illinois, Indiana, Kansas, Missouri, Ohio, and Wis-
consin with 37 cases confirmed through laboratory
The Centers for Disease Control and Prevention
and the Food and Drug Administration issued a joint
order on June 2003 prohibiting importation of any
African rodent, andthesale, transport,orrelease into
the wild of prairie dogs, tree squirrels, sun squirrels,
rope squirrels, dormice, Gambian giant-pouched
rats, brush-tailed porcupines, or striped mice. The
joint order was replaced by an interim final rule
on November 4, 2003, that maintained the previous
bans on importation, sale, transport, or release into
Notable clinical differences exist between human
monkeypox in the United States and in Africa. More
than 80% of cases of human monkeypox in Africa
occur in children younger than 10 years. It is mainly
a disease of rural populations, with 90% of those
infected inhabiting villages of less than 1000 per-
sons.12Most patients are male. African monkeypox
most commonly develops through contact with
infected small mammals obtained for food, sport,
or other reasons (72%). Spread by human-to-human
contact occurs not infrequently (28%).13The sec-
ondary attack rate is 3.3% to 10% among all suscep-
tible contacts, significantly lower than smallpox’s
rate of 25% to 40% among unvaccinated individ-
uals.14Vaccination with vaccinia virus provides ap-
proximately 85% protection against monkeypox,15
although possibly less after many decades.16An
increased incidence of human monkeypox was
seen in Africa from 1996 to 1999, probably because
of termination of vaccinia vaccination after smallpox
eradication. No evidence for increased transmissibil-
ity or relation to HIV infection was found.17Case
fatality ranges from 10% to 17%.13,18,19
All human cases in the United States had direct
contactwith infected exotic orwild mammalianpets,
and human-to-human transmission could not be
confirmed. The sex ratio was approximately equal.
The vast majority of patients had light skin. Of
patients described in the initial outbreak, 33% had
been previously vaccinated against smallpox during
the era of compulsory vaccination. No case fatalities
occurred.20Antiviral treatment with cidofovir or a
related compound is more effective than smallpox
vaccination in preventing mortality in experimental
monkeypox virus infection of cynomolgus mon-
keys.21None of the patients in the United States
received these agents. Among the 9 patients hospi-
talized for longer than 48 hours, 5 were defined as
severely ill including one 6-year-old child who
required mechanical ventilation for encephalitis.22
Adequate nutrition and supportive measures such as
hydration and antibiotics may have prevented mor-
tality in patients who were severely ill.
Human monkeypox in Africa has been well
described since its initial presentation in 1970. After
an incubation period of 7 to 17 days (mean 12 days),
a prodrome of fever, headache, backache, and
fatigue begins. This lasts for 2 to 4 days, followed
by the development of skin lesions. Severity of
disease ranges from mild to severe. Marked lym-
phadenopathy occurs in the majority of patients with
submandibular, postauricular, cervical, and inguinal
lymphadenopathy most commonly involved.19In
African cases, this feature was an important clinical
clue that a patient was presenting with monkeypox,
as compared with smallpox, which does not have
such obvious lymphadenopathy.13
period of 4 to 24 days (mean 14.5 days)3followed by
rash, fever, chills, lymphadenopathy, headache, sore
throat, myalgias, sweats, cough, nausea, vomiting,
nasal congestion, back pain, mouth sores, blephari-
tis, conjunctivitis, and gastrointestinal symptoms to
varying degrees.3,19,22Lymphadenopathy was re-
ported in 71% of 34 confirmed cases,22but seemed
less prominent than the marked nodal involvement
reported in Africa.
The most significant clinical difference between
monkeypox in Africa and the United States is the
lesions. Cutaneous eruptions and morphologies de-
scribed in African monkeypox are much more pre-
dictable. Lesions evolve as a group from macules
to papules to pustules that umbilicate, dessicate, and
desquamate during a period of 14 to 21 days, often
leaving residual varioliform scarring.19Lesions mea-
suring approximately 0.5 cm concentrate acrally and
may involve mucous membranes, palms, soles, and
genitals.18The centrifugally clustered rash and pro-
nounced lymphadenopathy help to distinguish the
disease from smallpox infection. Palms and soles are
involved in numerous cases.18Inoculation lesions
are not well described. In Africa, 13% of cases had
less than 25 lesions, 38% had 25 to 100 lesions, and
49% had more than 100 lesions.18
In the outbreak in the United States, lesion mor-
phology varied significantly from person to person
and was even quite varied within a single family
exposed to the same infectious source.23Infected
prairie dogs had clinical manifestations similar to
those exposed to monkeypox experimentally by
intranasalroute, namelylethargy,anorexia, vesicular
lesions on the lips and tongue, and mucopurulent
J AM ACAD DERMATOL
VOLUME 55, NUMBER 3
Sale, Melski, and Stratman479
nasal discharge.24In general the portal of entry to
human beings was not known with certainty.
However, several cases, including the index child,
developed what appeared to be primary inoculation
lesions surrounding bites or scratches before consti-
tutional symptoms and widespread skin lesions. The
index patient’s prairie dog bite sites progressed from
a red erosion to a white vesicle, then to an umbili-
cated pustule with a central hemorrhagic crust and
satellite lesions. The index child’s mother initially
developed white vesicles surrounding a scratch from
her pet cat on the back of her hand. Both mother and
child quickly developed disseminated lesions with a
haphazard distribution suggestive of hematogenous
spread. These lesions, and those reported on other
individuals, evolved from firm papules to vesicles to
pustules, some with prominent erythematous flares.
The erythematous flares noted on disseminated
lesions were, in some cases, quite striking and had
not been previously reported with African cases.
Inoculation lesions present on the hands of both the
index patient and her mother developed large hem-
orrhagic crusts before healing. Healing with prom-
inent hemorrhagic crusts is also distinctive of the US
cases and may correlate with a lack of complement
inhibition by West African strain.25Resolution of
lesions occurred after sloughing of these crusts. Most
lesions left no scarring. Some lesions left minimal
residual scarring, although scarring noted with the
index family could be attributed solely to punch
biopsy site scarring.3Centrifugal distribution was
seen in only 48% of cases with involvement of palms
in 28% and soles in 9%.22Cases described in the
United States reported more than 25 lesions in 53%
and more than 100 lesions in only 20% of patients.22
The divergent clinical presentations of monkey-
pox in Africa and the United States could have
several explanations. Cases in the United States
were largely described by dermatologists who typ-
ically have an expanded descriptive nomenclature
when examining skin lesions compared with other
physician specialists. Differences might also be
explained by the skin color of affected patients.
Erythematous flares are more easily observed on
lighter skin than darker skin, which could explain
why flares were observed in the predominantly
white patients in the United States and not in the
predominantly black patients in Africa. The African
male propensity may be related to increased contact
through male-dominated hunting, killing, and skin-
ning activities,26whereas US contact through pets
would not be sex-specific.
It is also known through genomic sequencing that
monkeypox strains belong to one of two clades
(homologous groups). Monkeypox from the United
States was from the less virulent West African clade
rather than the more virulent Central African clade
endemic in the Congo Basin.25,27This may be
responsible for the milder course of infection and
lower mortality witnessed here. In addition, many or
most African cases are likely to include ingestion of
infected meat,28whereas the US cases were trans-
mitted solely through dermal contact. This may help
accountfor thereducedseverity, earlierdetection,or
both in US cases. Outbreaks in Africa have also been
shown to involve coinfections with varicella-zoster
virus (an unrelated herpesvirus) during concomitant
outbreaks of monkeypox and chickenpox.19
Finally, morbidity may have been reduced by
partial herd immunity to monkeypox as a result of
for civilians and military personnel between 1990
and 2002.29Previously unreported cases of monkey-
pox have been identified serologically in individuals
at 13, 29, and 48 years after smallpox vaccination.16
During the spring of 2003 the virus was imported
into the United States by the exotic pet trade. The
clinical course of human monkeypox in the United
States was found to differ in a number of ways from
that which had been described in Africa. This could
be the result of a number of variables, including
mode of transmission, who is describing the lesions,
of virus responsible for the disease, and the preva-
lence of prior smallpox vaccinations.
This will not likely be the last time that a relatively
remote disease, such as monkeypox, presents in the
United States in a less than classic fashion. Although
a ban was subsequently placed on the importation
and transportation of African rodents,30the current
world movement of human beings and cargoassures
that new infectious agents will continue to journey
around the globe with increasing velocity.
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