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Clinical Characteristics of Human Monkeypox, and Risk Factors for Severe Disease

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Human monkeypox is an emerging smallpox-like illness that was identified for the first time in the United States during an outbreak in 2003. Knowledge of the clinical manifestations of monkeypox in adults is limited, and clinical laboratory findings have been unknown. Demographic information; medical history; smallpox vaccination status; signs, symptoms, and duration of illness, and laboratory results (hematologic and serum chemistry findings) were extracted from medical records of patients with a confirmed case of monkeypox in the United States. Two-way comparisons were conducted between pediatric and adult patients and between patients with and patients without previous smallpox vaccination. Bivariate and multivariate analyses of risk factors for severe disease (fever [temperature, > or =38.3 degrees C] and the presence of rash [> or =100 lesions]), activity and duration of hospitalization, and abnormal clinical laboratory findings were performed. Of 34 patients with a confirmed case of monkeypox, 5 (15%) were defined as severely ill, and 9 (26%) were hospitalized for >48 h; no patients died. Previous smallpox vaccination was not associated with disease severity or hospitalization. Pediatric patients (age, < or =18 years) were more likely to be hospitalized in an intensive care unit. Nausea and/or vomiting and mouth sores were independently associated with a hospitalization duration of >48 h and with having > or =3 laboratory tests with abnormal results. Monkeypox can cause a severe clinical illness, with systemic signs and symptoms and abnormal clinical laboratory findings. In the appropriate epidemiologic context, monkeypox should be included in the differential diagnosis for patients with unusual vesiculopustular exanthems, mucosal lesions, gastrointestinal symptoms, and abnormal hematologic or hepatic laboratory findings. Clinicians evaluating a rash illness consistent with possible orthopoxvirus infection should alert public health officials and consider further evaluation.
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1742 CID 2005:41 (15 December) Huhn et al.
MAJOR ARTICLE
Clinical Characteristics of Human Monkeypox,
and Risk Factors for Severe Disease
Gregory D. Huhn,
1,a
Audrey M. Bauer,
3
Krista Yorita,
2
Mary Beth Graham,
4
James Sejvar,
2
Anna Likos,
2
Inger K. Damon,
2
Mary G. Reynolds,
2
and Matthew J. Kuehnert
2
1
Epidemic Intelligence Service, Division of Applied Public Health Training, Epidemiology Program Office, and
2
Division of Viral and Rickettsial
Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia;
3
School of Public Health,
University of Illinois–Chicago, Chicago; and
4
Infectious Diseases Division, Medical College of Wisconsin, Milwaukee
Background. Human monkeypox is an emerging smallpox-like illness that was identified for the first time in
the United States during an outbreak in 2003. Knowledge of the clinical manifestations of monkeypox in adults
is limited, and clinical laboratory findings have been unknown.
Methods. Demographic information; medical history; smallpox vaccination status; signs, symptoms, and du-
ration of illness, and laboratory results (hematologic and serum chemistry findings) were extracted from medical
records of patients with a confirmed case of monkeypox in the United States. Two-way comparisons were conducted
between pediatric and adult patients and between patients with and patients without previous smallpox vaccination.
Bivariate and multivariate analyses of risk factors for severe disease (fever [temperature, 38.3C] and the presence
of rash [100 lesions]), activity and duration of hospitalization, and abnormal clinical laboratory findings were
performed.
Results. Of 34 patients with a confirmed case of monkeypox, 5 (15%) were defined as severely ill, and 9 (26%)
were hospitalized for
148 h; no patients died. Previous smallpox vaccination was not associated with disease severity
or hospitalization. Pediatric patients (age, 18 years) were more likely to be hospitalized in an intensive care unit.
Nausea and/or vomiting and mouth sores were independently associated with a hospitalization duration of
148
h and with having 3 laboratory tests with abnormal results.
Conclusion. Monkeypox can cause a severe clinical illness, with systemic signs and symptoms and abnormal
clinical laboratory findings. In the appropriate epidemiologic context, monkeypox should be included in the
differential diagnosis for patients with unusual vesiculopustular exanthems, mucosal lesions, gastrointestinal symp-
toms, and abnormal hematologic or hepatic laboratory findings. Clinicians evaluating a rash illness consistent with
possible orthopoxvirus infection should alert public health officials and consider further evaluation.
Monkeypox is a smallpox-like illness caused by infection
with a zoonotic orthopoxvirus. Human infections were
first described in central Africa in 1970 [1–3]. The disease
is endemic in the Congo basin countries of Africa and,
possibly, west Africa as well; the majority of human cases
have been detected in the Congo basin countries [4–8].
Received 6 May 2005; accepted 11 August 2005; electronically published 11
November 2005.
The findings and conclusions in this article are those of the authors and do
not necessarily represent the views of the funding agency.
Presented in part: 43rd Annual Meeting of the Infectious Diseases Society of
America, San Francisco, CA, 8 October 2005 (poster 930).
a
Present affiliation: ACCESS Community Health Network, Chicago, Illinois.
Reprints or correspondence: Dr. Matthew J. Kuehnert, Div. of Viral and Rickettsial
Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., Mailstop
A30, Atlanta, GA 30329-4018 (mgk8@cdc.gov).
Clinical Infectious Diseases 2005;41:1742–51
2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4112-0009$15.00
Comprehensive clinical information has been difficult to
ascertain during these outbreaks, because cases were fre-
quently identified retrospectively, access to medical care
was often limited in remote villages, and civil unrest had
curtailed several epidemiologic investigations [7, 9].
Knowledge of the clinical manifestations and temporal
progression of human monkeypox in adults is limited,
and most laboratory markers of systemic viral illness are
not well defined [9–12].
In 2003, the first reported outbreak of human mon-
keypox in the Western Hemisphere occurred in the
midwestern United States [13–16]. Infection was linked
to direct contact with pet prairie dogs (Cynomys spe-
cies) that became ill after being housed with various
imported rodents shipped from Ghana [13, 14]. On 4
June 2003, health alerts distributed by the Wisconsin
Department of Public Health and the Illinois Depart-
ment of Public Health requested reporting of suspect
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Clinical Characteristics of Monkeypox CID 2005:41 (15 December) 1743
Table 1. Demographic information for 34 patients with con-
firmed monkeypox infection, United States, 2003
Characteristic
No. (%)
of patients
Sex
Male 18 (52.9)
Female 16 (47.1)
Age
118 years 24 (70.6)
State of residence
Wisconsin 18 (52.9)
Illinois 9 (26.5)
Indiana 7 (20.6)
Ethnicity
White 29 (85.3)
Black 1 (2.9)
Unknown 4 (11.8)
Exposure setting
Home 19 (55.9)
Work 2 (5.9)
Pet store 4 (11.8)
Veterinarian’s office 9 (26.5)
Previous smallpox vaccination (age range)
Yes (33–47 years) 7 (20.6)
No (6–31 years) 24 (70.6)
Unknown (28–35 years) 3 (8.8)
Underlying medical condition
a
8 (23)
NOTE. There were 37 total confirmed monkeypox cases during the 2003
US outbreak (J. Cono, Centers for Disease Control and Prevention, personal
communication)
a
Includes hepatitis C, hepatitis (unspecified type), asthma, hydrocephaly,
pregnancy, lupus nephritis, receipt of a bone marrow transplant, and
hemophilia.
cases of unusual rash illness, in response to a cluster of 6 pa-
tients with rash and fever symptoms following exposure to ill
prairie dogs. A total of 37 patients were confirmed to be infected
with monkeypox across the midwestern United States [15]. The
evaluation of patient illness in health care settings, such as
physicians’ offices, emergency departments, and hospitals, al-
lowed health officials to collect a wide range of clinical data
on monkeypox-associated illness that were unavailable previ-
ously [17]. We examined clinical and laboratory characteristics
of confirmed cases of human monkeypox infection in adults
and children in the United States in 2003 to assess risk factors
for severe disease and hospitalization.
METHODS
Patients suspected of having monkeypox virus infection were
identified through clinical reports and active and passive sur-
veillance by state and local public health departments [13–16].
Specimens collected from individuals with rash lesions were
examined at the Centers for Disease Control and Prevention
(CDC; Atlanta, GA) for evidence of monkeypox virus. Cases
were confirmed on the basis of specimen testing by viral culture,
PCR for monkeypox virus and orthopoxvirus, electron mi-
croscopy, and/or immunohistochemical analysis.
Data pertaining to demographic information, medical his-
tory, smallpox vaccination status, signs, symptoms, duration of
illness, and laboratory values (i.e., hematologic and serum
chemistry findings) were reviewed and extracted from patient
medical records by the authors with a standardized data ex-
traction tool. Onset of illness was defined as the date a case
patient reported onset of signs or symptoms (including fever,
rash, sweats, chills, lymphadenopathy, headache, stiff neck, red
eyes, runny nose, sore throat, cough, wheezing, shortness of
breath, chest pain, nausea and/or vomiting, abdominal pain,
myalgia, back pain, joint pain, confusion, and conjunctivitis).
Rash burden was determined using the following parameters
established by the World Health Organization: benign, 5–25
lesions; moderate, 26–100 lesions; grave, 101–250 lesions; and
plus grave,
1250 lesions. Data were entered using Microsoft
Access (Microsoft) and were analyzed using SAS, version 8.01
for Windows (SAS Institute). Signs and symptoms were ana-
lyzed as categorical variables, and syndromes were established
for common complexes of initial signs and symptoms of illness
associated with individual case patients. Hypoxemia was de-
fined as an oxygen saturation of 95% in room air.
The first recorded laboratory values, the maximally deviated
laboratory values, and the last recorded laboratory values dur-
ing illness were selected for analysis. Clinical laboratory mea-
surements were analyzed as continuous and dichotomous var-
iables for deviation from normal values derived from published
laboratory reference intervals and values for adult patients and
pediatric patients (age, 18 years). The median number of
days from onset of illness for all patients who had clinical
laboratory measurements collected was chosen to define early
versus late time points in the duration of illness. Abnormal or
atypical laboratory measurements were defined as laboratory
values greater than the reference range, except for platelet
count, blood urea nitrogen concentration, and albumin, so-
dium, potassium, and calcium levels, which were designated as
abnormal if values were less than the reference range. Abnormal
hematocrit values greater than or less than the reference range
were analyzed separately according to sex. Transaminase levels
were considered to be elevated if either aspartate aminotrans-
ferase or alanine aminotransferase values were greater the ref-
erence range. Six routine clinical laboratory measurements as-
sociated with viral illness (leukocytosis, lymphocytosis,
thrombocytopenia, elevated transaminase levels, elevated al-
kaline phosphatase level, and hypoalbuminemia) were chosen
for analysis. A cut point, defined as a majority of laboratory
measurements (i.e., 3) that were in the abnormal range, was
established to yield the greatest number of patients with values
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1744 CID 2005:41 (15 December) Huhn et al.
Figure 1. Signs and symptoms for 34 patients with confirmed monkeypox, United States, 2003
greater than and/or less than the cut point. Patients with hos-
pitalization durations of
148 h satisfied all inpatient admission
criteria. Admission to the intensive care unit was also evaluated.
Severe illness was defined as a temperature of 38.3C and
a rash comprised of 100 lesions at any point during illness.
Patients whose rash lesions were not quantified or patients who
reported fever without at least 1 recorded temperature mea-
surement were excluded from analysis of illness severity. Bi-
variate analysis was performed to assess risk factors for each
of the following conditions: severe illness, hospitalization
148
h, and 3 abnormal laboratory values. Two-way comparisons
were also conducted between pediatric and adult patients and
between patients with and patients without reported previous
smallpox vaccination. Continuous variables were compared us-
ing a 2-sided t test. Categorical variables were compared using
Fisher’s exact test. Laboratory values were compared using
Mann-Whitney U tests. For multivariate analysis, stepwise lo-
gistic regression was used to calculate ORs for all categorical
variables that had P values
!.2 on bivariate analysis. The a of
statistical significance was set at
!.05.
RESULTS
Medical records from 34 (92%) of 37 patients with confirmed
cases of monkeypox were available for review. Among these 34
cases, 27 (79%) of 34 had quantitative information on fever
and rash. A majority of infections (19 cases [56%]) occurred
after exposure due to either scratch by, bite by, petting of, or
other contact with a monkeypox-infected animal in the home
environment. For 29 case patients, the estimated incubation
period between the time from initial animal exposure to the
onset of illness was 12 days (interquartile range, 11–18 days).
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Clinical Characteristics of Monkeypox CID 2005:41 (15 December) 1745
Table 2. Initial concomitant signs and symptoms at the time of
disease presentation to a health care professional for 34 patients
with confirmed monkeypox infection, United States, 2003
Signs and symptoms
No. (%)
of patients
Rash and fever 26 (76)
Rash, fever, and adenopathy 19 (56)
Rash, fever, and chills 18 (53)
Rash, fever, adenopathy, and chills 12 (35)
Rash, fever, adenopathy, chills, and headache 9 (26)
Rash, fever, adenopathy, chills, headache, and
sore throat 7 (21)
Table 3. Interval between onset of fever or rash to onset of later prominent signs and symptoms in US patients with monkeypox, by
disease severity and age.
Interval measured, by
initial fever or rash and
later sign or symptom
All cases
(n p 34)
Severe
disease cases
(n p 5)
Nonsevere
disease cases
(n p 22)
Pediatric
cases
a
(n p 10)
Adult
cases
(n p 24)
Interval
b
No. of
patients Interval
b
No. of
patients Interval
b
No. of
patients Interval
b
No. of
patients Interval
b
No. of
patients
Initial fever
To rash 2 (0–12) 23 0 (0–2) 5 2 (0–5) 12 1 (0–4) 8 2 (0–12) 15
To nausea and vomiting 1 (0–9) 11 0 (0–4) 3 1 (0–9) 6 2.5 (0–7) 4 0 (0–9) 7
To shortness of breath 5 (0–9) 5 5 2 0 1 5 (0–5) 3 6.5 (4–9) 2
To cough 0 (0–8) 13 0 (0–2) 3 0 (0–8) 8 0 3 0 (0–8)
To seizures 5 1 5 1 0 0 5 1 0 0
To confusion 2.5 (0–5) 2 5 1 0 1 5 1 0 1
To mouth sores 4 (2–7) 6 4 2 3.5 (2–7) 4 3.5 (2–4) 4 5.5 (4–7) 2
Initial rash
To nausea and vomiting 1 (0–14) 8 0 (0–2) 3 7 (0–14) 4 6 (0–14) 4 0 (0–4) 4
To shortness of breath 3 (0–4) 4 3 2 0 1 3 (0–3) 3 4 1
To cough 0 (0–9) 12 0 (0–2) 3 0 (0–9) 7 0 (0–9) 4 0 (0–3) 8
To seizures 3 1 3 1 0 0 3 1 0 0
To confusion 3 1 3 1 0 0 3 1 0 0
To mouth sores 4 (1–11) 6 3 (2–4) 2 7 (1–11) 4 6 (1–11) 4 4 2
NOTE. Cases in which signs or symptoms occurred before fever or rash were excluded.
a
Age, 18 years.
b
Expressed as median no. of days (range).
The median age of patients was 26 years (range, 6–47 years),
and 71% were aged
118 years. A total of 18 patients (53%)
were male. Seven patients (21%; median age, 39 years [range,
33–47 years]) reported known previous smallpox vaccination
or had recognized smallpox scars. Eight patients (24%) reported
an underlying medical condition, including hepatitis C, hep-
atitis (unspecified type), asthma, hydrocephaly, pregnancy, lu-
pus nephritis, receipt of a bone marrow transplant, and he-
mophilia (table 1). For all available case patient records,
findings of the most recent hematologic and chemistry labo-
ratory analyses before diagnosis of monkeypox infection were
normal.
Predominant signs and symptoms of illness included rash
(97% of case patients), fever (85%), chills (71%), adenopathy
(71%), headache (65%), and myalgias (56%) (figure 1). A ma-
jority of patients reported to their health care professional that
rash, fever, chills, and adenopathy constituted the initial syn-
drome at the time of illness presentation (table 2). The median
duration of fever was 8 days (range, 2–13 days), and the median
duration of rash was 12 days (range, 7–24 days). The median
number of days from onset of fever to onset of rash was 2 days
(range, 0–12 days). The number of days from onset of fever
or rash to other prominent signs and symptoms are listed in
table 3. Rash characteristics are listed in table 4 and figure 2.
A majority of patients (68%) had lesions that were mono-
morphic, and 48% of patients had lesions that were distributed
centrifugally. Twenty-five percent of patients reported ulcerated
or necrotic lesions, and 2 patients noted hemorrhagic pustules.
Laboratory measurements collected for 21 patients with con-
firmed cases are listed in table 5. There was no statistically
significant difference between laboratory findings for blood
specimens collected from patients in the early stage of illness
versus blood specimens collected from patients during the late
stage of illness (median time of sampling, 6 days after illness
onset; ). Patients had multiple abnormal laboratory
P p .09–1.0
findings, including elevated transaminase levels (50% of pa-
tients), low blood urea nitrogen level (61%), hypoalbuminemia
(50%), leukocytosis (45%), and thrombocytopenia (35%). The
median interval between the onset of illness to observation of
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1746 CID 2005:41 (15 December) Huhn et al.
Table 4. Characteristics of rash at the time of examination for
US patients with monkeypox.
Rash characteristic
Proportion (%)
of patients
Development
Monomorphic 21/31 (67.7)
Pleomorphic 9/31 (29.0)
No rash 1/31 (3.2)
Distribution
Localized 8/31 (25.8)
Generalized
Centrifugal 15/31 (48.4)
Centripetal 1/31 (3.23)
Even distribution 7/31 (22.6)
Site(s)
Arms and/or hands 26/32 (81.3)
Legs and/or feet 21/32 (65.6)
Head and/or neck 20/32 (62.5)
Chest and/or abdomen 18/32 (56.2)
Back 15/32 (46.9)
Palms 9/32 (28.1)
Groin and/or buttocks 3/32 (9.4)
Soles 3/32 (9.4)
Mucosa (including ocular) 2/32 (6.3)
Severity,
a
maximum no. of lesions
Benign, 5–25 14/30 (46.7)
Moderate, 26–100 10/30 (33.3)
Grave, 101–250 2/30 (6.7)
Plus grave,
1250 4/30 (13.3)
NOTE. Data are no. of patients with the characteristic/no. evaluated (%).
Characteristics were estimated at the height of rash burden. Multiple lesion
types may have been present on a patient at the time of examination.
a
Determined on the basis of World Health Organization criteria.
Figure 2. Characteristics of monkeypox rash lesions at the time of
examination, United States, 2003.
the most severe abnormal laboratory finding ranged from 3 to
12 days (table 6).
Five patients were defined as being severely ill, and 9 patients
were hospitalized as inpatients. Among the severely ill patients
hospitalized as inpatients, one was a 6-year old girl who un-
derwent intubation and mechanical ventilation for encephalitis,
and one was a 10-year girl with tracheal airway compromise
secondary to a large retropharyngeal abscess and cervical
lymphadenopathy (figure 3) [20, 21]. Both patients were hos-
pitalized in the intensive care unit. One patient with an un-
derlying comorbidity (hepatitis C) experienced severe disease
and was hospitalized as an inpatient. The patient recovered
without significant sequelae. Among the adults with compli-
cations of infection, one received a diagnosis of bacterial su-
perinfection (unknown microorganism), and one had keratitis
and corneal ulceration, which ultimately resulted in a corneal
replacement [22]. None of these patients had a preexisting
medical condition. No patients died.
Comparison of outcomes for pediatric patients and adult
patients revealed that pediatric patients were significantly more
likely to be admitted to the intensive care unit, although they
were not significantly more likely to develop severe illness.
There was no difference in illness severity or inpatient hospi-
talization in patients with a reported history of smallpox vac-
cination (table 7). On bivariate analysis, hospitalization for
148
h and presence of dysphagia and hypoxemia were significantly
associated with severe disease. Patients with mouth sores who
reported dysphagia also had an increased risk of severe disease
(table 8). However, on multivariate analysis, there were no
significant risk factors associated with severe illness (table 9).
On bivariate analysis, patients with fever (temperature,
38.3C), rash comprised of
1100 lesions, adenopathy, mouth
sores, dysphagia (with mouth sores), and nausea and vomiting
were more likely to be hospitalized as inpatients. Wisconsin
residents and patients exposed to a monkeypox virus–infected
pet in the home environment were also more frequently hos-
pitalized as inpatients (table 8). On multivariate analysis, nausea
and vomiting were independently associated with a hospitali-
zation duration of
148 h (table 9).
Among patients for whom data on laboratory measurements
were available, 6 (30%) had a majority of laboratory values
(e.g., 3) that were abnormal. On bivariate and multivariate
analysis, patients with mouth sores were significantly associated
with having a majority of laboratory values that were abnormal
(tables 8 and 9).
DISCUSSION
The clinical presentation of human monkeypox, described pri-
marily in children and adolescents identified in central and
west Africa, has been characterized as a viral prodrome of fever,
chills, headache, myalgias, and back pain lasting 1–3 days, fol-
lowed by a maculopapular exanthema eruption. The rash is
predominantly monomorphic in a centrifugal distribution, pro-
gresses to vesicular and pustular stages, and crusts during a 2–
3-week period [8, 9]. The disease course is often milder than
that of smallpox. In contrast to smallpox, pronounced lymph-
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Clinical Characteristics of Monkeypox CID 2005:41 (15 December) 1747
Table 5. Timing and magnitude of laboratory findings for US patients with monkeypox.
Laboratory parameter
Normal
adult range
All patients
Patients with early results
of laboratory tests
Patients with late results
of laboratory tests
P
a
No.
evaluated
Median value
(range)
No.
evaluated
Median value
(range)
No.
evaluated
Median value
(range)
WBC count, cells/mm
3
4000–9000 20 7150 (3900–26,800) 11 6200 (3900–17,900) 8 8670 (4780–26,800) .22
Lymphocytes, % 19 26 (14–47) 11 24 (14–44) 7 36 (18–47) .10
Hematocrit, % 39–49
b
and
35–45
c
20 41 (34.3–52) 11 41 (36–50) 8 42 (35.4–52) .93
Platelet count,
10
9
platelets/L 150–400 20 183 (90–369) 11 154 (126–237) 8 216 (90–369) .09
Sodium level, mmol/L 136–145 19 138 (133–143) 9 137 (135–141) 9 138 (133–141) 1.0
Potassium level, mmol/L 3.5–5.0 19 3.8 (3.2–4.2) 9 3.8 (3.4–4.1) 9 3.9 (3.2–4.2) .90
Blood urea nitrogen
level, mg/dL 10–20 18 9.5 (4–15) 8 9.5 (6–12) 9 10 (4–15) .85
Creatinine level, mg/dL
!1.5 18 0.8 (0.4–1.1) 9 0.9 (0.1–1.1) 8 0.8 (0.4–0.9) .31
Calcium level, mmol/L 9.0–10.5 18 9.3 (8.3–10.3) 9 9.3 (8.9–9.9) 8 9.4 (8.3–10.3) .74
Total bilirubin level, mg/dL 0.3–1.0 17 0.4 (0.1–1.3) 8 0.4 (0.1–0.6) 8 0.5 (0.2–1.3) .35
AST level, U/L 0–35 16 27.5 (17–95) 8 26 (20–95) 7 38 (17–67) .82
ALT level, U/L 0–35 17 35 (11–186) 8 30 (11–186) 8 45 (15–90) .39
ALP level, U/L 40–140 17 94 (30–209) 8 87 (63–145) 8 103 (30–209) .39
Albumin level, mg/dL 3.5–5.5 16 3.7 (1.1–4.2) 8 3.8 (3.5–4.2) 7 3.7 (1.1–4.0) .34
NOTE. Early results of laboratory tests were available !6 days after illness onset, and late results were available 6 days after illness onset. ALP, alkaline
phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
a
Comparison of median values of early vs. late results of laboratory tests.
b
For men.
c
For women.
adenopathy is a distinctive hallmark of monkeypox. The clinical
signs and symptoms observed during the outbreak in the
United States illustrate a similar pattern, although the median
duration of rash was slightly shorter, and back pain was not a
frequent complaint. The orthopoxvirus involved in the US out-
break was identified as a west African variant [16], whereas
most previous clinical descriptions involved persons, mainly
children, who were presumably infected with central African
variants of the virus. Also, in contrast to African epidemics,
the majority of reported cases in the United States were in
adults. These features could account for some of the observed
differences in clinical description between patients in the
United States and patients in Africa.
In smallpox, hematologic abnormalities of lymphocytosis
and thrombocytopenia have been observed early in severe con-
fluent forms of infection [23–25]. Information on general clin-
ical chemistry findings in smallpox infection is lacking in the
published literature. We describe the first comprehensive as-
sessment of clinical laboratory findings in systemic orthopox-
virus infection. Our data demonstrate that leukocytosis, ele-
vated transaminase levels, low blood urea nitrogen level, and
hypoalbuminemia were common features during illness, and
lymphocytosis and thrombocytopenia were seen in more than
one-third of evaluable patients.
In contrast to monkeypox outbreaks in Africa that affected
a disproportionate number of children, none of whom had
smallpox vaccine-derived immunity, a majority of cases in the
United States occurred in adults, nearly one-third of whom had
received the smallpox vaccine before 1972. We observed no
significant differences in serious clinical conditions or com-
plications between vaccinated and unvaccinated individuals.
However, pediatric patients were hospitalized in intensive care
units at significantly higher rates than adults, which may in-
dicate more severe illness or reflect a difference in standard of
care. The most critically ill patients in this outbreak were 2
young school-aged children with complications that included
encephalopathy and retropharyngeal abscess.
Previous research on smallpox has examined probable phys-
iologic factors influencing morbidity and mortality. Patients
with hemorrhagic smallpox, the most lethal form of smallpox,
undergo disseminated intravascular coagulation with throm-
bocytopenia [25, 26]. In this study, only 2 US patients with
monkeypox were noted to have had hemorrhagic pustular le-
sions, and thrombocytopenia was generally mild. No patients
were described as having disseminated intravascular coagula-
tion. In patients who have smallpox associated with confluent
lesions, copious amounts of fluid accumulate subcutaneously
during the vesicular and pustular stages, with weeping of this
fluid during the crusting stage. Massive intravascular volume
depletion may occur during these stages, frequently leading to
shock [27]. In our analysis of monkeypox cases in the United
States, hospitalization of patients with mucosal and gastroin-
testinal clinical symptoms, in addition to low blood urea ni-
trogen levels and hypoalbuminemia, may have indicated a neg-
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1748 CID 2005:41 (15 December) Huhn et al.
Table 6. Timing and magnitude of abnormal laboratory findings for US patients with monkeypox.
Laboratory parameter
Normal
adult range
No. (%) of
patients with
abnormal laboratory
findings
Median value (range)
of most severe
abnormal finding
a
Median no. of
days (range) from
illness onset to
most severe
abnormal finding
WBC count, cells/mm
3
4000–9000 9 (45) 11,000 (9130–26,800) 7 (4–13)
Lymphocytes, % 7 (37) 47 (38–57) 6 (2–14)
Hematocrit, % 39–49
b
and
35–45
c
8 (40)
d
33 (30.7–36) and
51 (50–52)
12 (8–14) and
7 (3–11)
Platelet count, 10
9
platelets/L 150–400 7 (35) 130 (90–143) 3 (2–11)
Sodium level, mmol/L 136–145 3 (16) 133 (133–135) 5 (2–12)
Potassium, mmol/L 3.5–5.0 3 (16) 3.4 (3.2–3.4) 5 (4–6)
Blood urea nitrogen level, mg/dL 10–20 11 (61) 6 (2–9) 9 (5–13)
Creatinine, mg/dL
!1.5 1 2.5 10
Calcium, mmol/L 9.0–10.5 4 (22) 8.7 (8.3–8.9) 6 (5–6)
Total bilirubin level, mg/dL 0.3–1.0 1 (6) 1.3 12
AST level, U/L 0–35 8 (50) 66 (43–95) 6 (3–14)
ALT level, U/L 0–35 10 (59) 66 (42–186) 6 (3–14)
ALP level, U/L 40–140 1 (6) 184
e
Albumin level, mg/dL 3.5–5.5 8 (50) 3.1 (1.1–3.4) 12 (8–14)
NOTE. Pediatric reference ranges are defined as follows, in accordance with criteria published elsewhere [18, 19]: platelet count:
platelets/L; lymphocyte percentage: 2%–8% (4 years of age), 1.5%–7% (5–6 years of age), 1.5%–6.8% (7–8 years of age),
9
150–350 10
1.5%–6.5% (9–10 years of age), 1.2%–5.2% (11–16 years of age), and 1.0%–4.8% (17–21 years of age); WBC count: 5–15.5 cells/mm
3
(2–6 years of age) and 4.5–13.5 cells/mm
3
(7–18 years of age); hematocrit percentage: 34%–37% (2–6 years of age), 35%–40% (7–12
years of age), 36%–43% (boys 13–18 years of age), and 37%–41% (girls 13–18 years of age); alkaline phosphatase (ALP) level: 100–300
U/L (2–10 years of age), 50–375 U/L (boys 11–18 years of age), and 30–300 U/L (girls 11–18 years of age). Reference ranges for albumin,
alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, sodium, potassium, and calcium levels are the same
as those for adults. No reference range for the blood urea nitrogen level was specified for pediatric patients.
a
Abnormal laboratory values for the lymphocyte percentage and the AST, ALT, and creatinine levels were all greater than the reference
range, whereas abnormal laboratory values for platelet count and the sodium, potassium, blood urea nitrogen, calcium, and albumin levels
were all less than the reference range.
b
For males.
c
For females.
d
Two patients had a hematocrit that was less than the reference range, and 6 had a hematocrit that was greater than the reference range.
e
No date was listed in the medical record for the single adult with an elevated ALP level.
ative protein or improper nutritional balance and the need for
volume repletion secondary to gastrointestinal losses. Gastro-
intestinal fluid losses and hypoalbuminemia are consistent with
the movement of fluids from intravascular to extravascular fluid
compartments that occurs in systemic infection [28]. These
findings, in addition to patients with mouth sores for whom
numerous abnormal clinical laboratory findings were observed,
suggest that human monkeypox may also cause systemic com-
plications beyond apparent integument and mucosal surface
compromise. In experimentally induced infection with aero-
solized monkeypox virus in monkeys, lymphatogenous spread
of monkeypox virus from viremia affects disseminated lymph
nodes and the thymus, spleen, skin, oral mucosa, gastrointes-
tinal tract, and reproductive system [29]. Further study is
needed to evaluate the pathophysiology of human monkeypox.
Our study had several limitations. Because this was a ret-
rospective study and patients were not evaluated in accordance
with a uniform protocol, we could not measure temporal trends
between progression of signs and symptoms of illness and evo-
lution of clinical laboratory values; patients visited health care
professionals at different points in their illness, and collection
of laboratory specimens and choice of test were at the discretion
of the clinician. Also, because there were no deaths in the
outbreak, severity of illness was defined by the acuity and bur-
den of fever and rash, rather than by an adverse clinical out-
come. This definition may not have been the most accurate
index of illness severity. Results of analysis of the severity of
illness also may have been affected by the exclusion of 7 patients
(21%) who had no recorded temperature or number of rash
lesions in the medical records. There were no clinical laboratory
test results for 13 patients (38%), none of whom were classified
with severe disease or were hospitalized for
148 h. The aggregate
laboratory values in our analysis may reflect selection bias to-
wards patients with more-severe manifestations of illness.
Lastly, the small sample size led to decreased precision in the
risk factor analyses.
In Africa, mortality due to monkeypox infection has ranged
from 1.5% to 17% and occurs overwhelmingly in children, a
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Clinical Characteristics of Monkeypox CID 2005:41 (15 December) 1749
Figure 3. Physical ((left) and radiographic (right) characteristics of monkeypox infection for a girl aged 10 years with a retropharyngeal abscess,
tracheal impingement, and cervical lymphadenopathy, United States, 2003.
Table 7. Comparison of basic recorded indicators of monkeypox illness severity for adults and children and for patients with
and patients without a history of smallpox vaccination.
Indicator of potential
illness severity
Proportion (%) of
pediatric patients
a
Proportion (%) of
adult patients P
b
Proportion (%) of
patients with
prior vaccination
Proportion (%) of
patients without
prior vaccination P
b
Fever
Temperature of 38.3C 7/10 (70) 11/18 (61) .70 4/5 (80) 12/21 (57) .62
Duration of 7 days 3/7 (43) 7/11 (64) .63 3/5 (60) 6/12 (50) 1.00
Rash comprised of
1100 lesions 3/9 (33) 3/22 (14) .32 1/6 (17) 5/22 (23) 1.00
Cervical lymphadenopathy 6/10 (60) 13/24 (54) 1.00 3/7 (43) 14/24 (58) .67
Hospitalized for
148 h 4/9 (44) 6/22 (27) .42 2/7 (29) 6/22 (27) 1.00
Admitted to ICU 5/10 (50) 2/23 (9) .02 1/7 (14) 5/24 (21) 1.00
NOTE. Data are no. of patients with the indicator/no. evaluated (%). ICU, intensive care unit.
a
Age, 18 years.
b
By the 2-sided Fisher’s exact test.
regrettable consequence most likely due to inaccessible medical
care [30]. One-fifth of pediatric patients in the US outbreak
developed serious complications that could have resulted in
death if intensive medical intervention was not available. The
identification of risk factors and abnormal laboratory findings
described in our analysis may help clinicians determine the
need for hospitalization in future possible outbreaks, should
monkeypox reemerge in the United States [16].
The most common diagnostic challenge that confronted in-
vestigators during monkeypox outbreaks in Africa was distin-
guishing monkeypox vesicular rash eruptions from those of
chickenpox [31]. In the largest reported outbreaks, which oc-
curred in the Democratic Republic of Congo during 1996–1998
and in 2001, interpretation of clinical data specific to mon-
keypox disease was restricted by potential case misclassification,
owing to significant cocirculation of varicella virus in affected
communities, and by the small fraction of cases confirmed by
diagnostic laboratory analysis [7, 8]. Chickenpox has a shorter
and milder prodrome and clinical course, lymphadenopathy is
infrequent, lesions usually evolve pleomorphically in a centrip-
etal distribution, and death is extremely rare [31, 32]. The
additional descriptions presented here may assist in more
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1750 CID 2005:41 (15 December) Huhn et al.
Table 8. Bivariate analysis of characteristics associated with severe illness outcomes for
monkeypox, as defined by intensity of rash and fever, duration of hospitalization, or number
of abnormal laboratory findings.
Characteristic
Index of illness severity (no. of patients with severe outcomes)
Intense rash
and fever
a
(n p 5)
Hospitalized
for
148 h
(n p 9)
3 of 6 laboratory
tests (50%) with
abnormal results
(n p 6)
RR (95% CI) P
b
RR (95% CI) P
b
RR (95% CI) P
b
Hospitalized for 148 h Undefined .01 NA NA 4.4 (0.6–32.8) .14
Hypoxemia Undefined .03 Undefined .29 1.9 (0.4–9.2) .50
Dysphagia
c
Undefined .03 2.7 (0.9–7.4) .19 1.2 (0.2–7.0) 1.0
Wisconsin resident 0.5 (0.1–2.7) .63 0.2 (0.1–0.9) .04 0.5 (0.1–2.0) .36
Home exposure 2.7 (0.4–21.4) .62 6.6 (0.9–46.5) .02 3.6 (0.5–26.8) .18
Fever (temperature of
38.3C) NA NA Undefined .02 Undefined .52
Rash (
1100 lesions) NA NA 3.7 (1.5–9.0) .03 2.8 (0.8–9.6) .26
Adenopathy 1.7 (0.2–12.8) 1.00 Undefined .03 1.2 (0.2–7.5) 1.00
Nausea and vomiting 3.0 (0.6–14.7) .30 6.4 (1.6–25.5) !.01 1.1 (0.3–4.3) 1.00
Mouth sores
c
5.0 (0.9–20.6) .09 4.3 (1.6–11.8) .01 6.4 (1.6–25.1) .01
NOTE. Statistically significant data are in bold face. Risk ratios (RRs) are indicated as undefined if the value
could not be computed because at least 1 patient was not associated with 1 of the 4 possible “character states”
(i.e., presence of characteristic with severe outcome, presence of characteristic without severe outcome, ab-
sence of characteristic with severe outcome, and absence of characteristic without severe outcome). In each
instance in which the RR was undefined but the P value for the 2-sided Fisher’s exact test was .05, either
all patients with severe illness had the character state in question or all patients with the given character state
had severe outcomes. No other individual signs and symptoms, laboratory parameters, sex, and vaccination
status were statistically significant indicators of severe disease outcome. NA, not applicable.
a
Defined as 1100 lesions and a temperature of 38.3C.
b
By the 2-sided Fisher’s exact test.
c
The presence of mouth sores with dysphagia was a significant indicator of severe illness and hospitalization,
with RRs of 9.5 (95% CI, 1.2–72.3) and 4.9 (95% CI, 1.6–15.4), respectively.
Table 9. Multivariate analysis of signs and symptoms independently associated
with severe illness outcomes for monkeypox, as defined by intensity of rash and
fever, duration of hospitalization, and number of abnormal laboratory findings.
Outcome Sign or symptom OR (95% CI) P
Intense rash and fever None
a
……
Hospitalized for
148 h Nausea and/or vomiting 15.8 (2.3–106.2) .005
3 abnormal laboratory findings Mouth sores 28.0 (2.00–394.3) .01
a
No sign or symptom was statistically association with this outcome.
clearly defining the symptom profile of monkeypox and dif-
ferentiating it from other childhood exanthems, including
varicella.
Monkeypox virus, along with variola virus, is on the select
list of biological agents determined to have the potential to
pose a severe threat to human health [33]. Recent surveillance
and health care preparedness initiatives in the United States
have promoted increased awareness of atypical febrile rash syn-
dromes possibly caused by agents of bioterrorism [34, 35].
Given our findings, unusual exanthems or mucosal lesions,
particularly in association with lymphadenopathy, gastrointes-
tinal symptoms (e.g., nausea and/or vomiting), and hemato-
logic or hepatic laboratory abnormalities, should prompt in-
clusion of monkeypox in the differential diagnosis within the
appropriate epidemiologic context. Clinicians evaluating a rash
illness consistent with orthopoxvirus as a possible cause should
alert public health officials and consider urgent evaluation in
accordance with recommended algorithms [36].
Acknowledgments
We wish to thank Dr. Mark S. Dworkin, Dr. Connie Austin, Dr. Craig
Conover, Dr. Jeffrey Davis, Dr. Robert Teclaw, Dr. Michael Anderson, Dr.
Scott Homan, Dr. Chris Croasdale, Dr. Dennis O’Connor, and Dr. Kurt
Reed, as well as Linda Roful.
at University of Portland on May 20, 2011cid.oxfordjournals.orgDownloaded from
Clinical Characteristics of Monkeypox CID 2005:41 (15 December) 1751
Financial support. The Centers for Disease Control and Prevention
provided routine funding for the study design, collection, analysis, and
interpretation of data; the writing of the report; and decision to submit
the manuscript for publication.
Potential conflicts of interest. All authors: no conflicts.
References
1. Marennikova SS, Seluhina EM, Mal’ceva NN, Cimiskjan KL, Macevic
GR. Isolation and properties of the causal agent of a new variola-like
disease (monkeypox) in man. Bull World Health Organ 1972; 46:599–611.
2. Arita I, Jezek Z, Khodakevich L, Ruti K. Human monkeypox: a newly
emerged orthopoxvirus zoonosis in the tropical rain forests of Africa.
Am J Trop Med Hyg 1985; 34:781–9.
3. Jezek Z, Fenner F. Human monkeypox. In: Melnick JL, ed. Monographs
in virology. Vol. 17. Basel, Switzerland: Karger, 1988.
4. Landyi ID, Ziegler P, Kima A. A human infectioun caused by mon-
keypox virus in Basankusu Territory, Democratic Republic of the
Congo (DRC). Bull World Health Organ 1972; 46:593–7.
5. Jezek Z, Grab B, Paluku DM, Szczeniowski MV. Human monkeypox:
disease pattern, incidence and attack rates in a rural area of northern
Zaire. Trop Geogr Med 1988; 40:73–83.
6. Mukinda VBK, Mwema G, Kilundu M, et al. Re-emergence of human
monkeypox in Zaire in 1996. Lancet 1997; 349:1449–50.
7. Hutin YJF, Williams RJ, Malfait P, et al. Outbreak of human mon-
keypox, Democratic Republic of Congo, 1996–1997. Emerg Infect Dis
2001; 7:434–8.
8. Meyer H, Perrichot M, Stemmler M, et al. Outbreaks of disease sus-
pected of being due to human monkeypox virus infection in the Dem-
ocratic Republic of Congo in 2001. J Clin Microbiol 2002; 40:2919–21.
9. Jezek Z, Szczeniowski M, Paluku KM, Mutombo M. Human mon-
keypox: clinical features of 282 patients. J Infect Dis 1987; 156:293–8.
10. Breman JG, Nakano JH, Coffi E, Godfrey H, Gautun JC. Human pox-
virus disease after smallpox eradication. Am J Trop Med Hyg 1977;
26:273–81.
11. Breman JG, Ruti K, Szczeniowski MV, Zanotto E, Gromyko AI, Arita I.
Human monkeypox, 1970–79. Bull World Health Organ 1980; 58:165–82.
12. Jezek Z, Gromyko AI, Szczeniowski MV. Human monkeypox. J Hyg
Epidemiol Microbiol Immunol 1983; 27:13–28.
13. Centers for Disease Control and Prevention. Multistate outbreak of
monkeypox—Illinois, Indiana, and Wisconsin, 2003. MMWR Morb
Mortal Wkly Rep 2003; 52:537–40.
14. Centers for Disease Control and Prevention. Update: multistate out-
break of monkeypox—Illinois, Indiana, Kansas, Missouri, Ohio, and
Wisconsin, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:561–4.
15. Centers for Disease Control and Prevention. Update: multistate out-
break of monkeypox—Illinois, Indiana, Kansas, Missouri, Ohio, and
Wisconsin, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:642–6.
16. Reed KD, Melski JW, Graham MB, et al. The detection of monkeypox
in humans in the western hemisphere. N Engl J Med 2004; 350:342–50.
17. Huhn GD, Chase R, Dworkin MS. The detection of monkeypox in
humans in the Western hemisphere. N Engl J Med 2004; 350:1790–1.
18. Inoue S. Leukocytosis. 24 January 2002. Available at: http://
www.emedicine.com/ped/topic1303.htm. Accessed 18 October 2005.
19. Greene MG. The Harriet Lane handbook: a manual for pediatric house
officers. 12th ed. St. Louis, MO: Mosby Year Book, 1991.
20. Sejvar J J, Chowdary Y, Schomogyi M, et al. Human monkeypox in-
fection: a family cluster in the midwestern United States. J Infect Dis
2004; 190:1833–40.
21. Anderson MG, Frenkel LD, Homann S, Guffey J. A case of severe
monkeypx virus disease in an American child: emerging infections and
changing professional values. Pediatr Infect Dis 2003; 22:1093–6.
22. Croasdale CR, Wise JP, Holland EJ. Human monkeypox ocular infec-
tion: first Western Hemisphere case report [abstract]. 2003 Federated
Scientific Session of the Cornea Sociey and Eye Bank Association of
America (Anaheim, CA). Anaheim, CA: 2003 Federated Scientific Ses-
sion of the Cornea Sociey and Eye Bank Association of America, 2003:
17–8.
23. Ikeda K. The blood in purpuric smallpox, clinical review of fourty-
eight cases. JAMA 1925; 84:1807–13.
24. Haviland JW. Purpura variolosa; its manifestations in skin and blood.
YaleJBiolMed1952; 24:518–24.
25. McKenzie PJ, Githens JH, Harwood ME, Roberts JF, Rao AR, Kempe
CH. Haemorrhagic smallpox. 2. Specific bleeding and coagulation stud-
ies. Bull World Health Organ 1965; 33:773–82.
26. Roberts JF, Coffee G, Creel SM, et al. Bull World Health Organ 1965;33:
607–13.
27. Koplan JP, Foster SO. Smallpox: clinical types, causes of death, and
treatment. J Infect Dis 1979; 140:440–1.
28. Bone RC. The pathogenesis of sepsis. Ann Intern Med 1991; 115:
457–69.
29. Zaucha GM, Jahrling PB, Geisbert TW, Swearengen JR, Hensley L. The
pathology of experimental aerosolized monkeypox virus infection in cy-
nomolgus monkeys (Macaca fascicularis). Lab Invest 2001; 81:1581–600.
30. Heymann DL, Szczeniowski M, Esteves K. Re-emergence of monkey-
pox in Africa: a review of the past six years. Br Med Bull 1998; 54:
693–702.
31. Jezek Z, Szczeniowski MV, Paluku KM, Mutombo M, Grab B. Human
monkeypox: confusion with chickenpox. Acta Trop 1988; 45:297–307.
32. Breman JG. Monkeypox: an emerging infection for humans? In: Scheld
MW, Craig WA, Hughes JM, eds. Emerging infections 4. Washington,
DC: ASM Press, 2000:45–76.
33. United States Department of Agriculture. Agricultural bioterrorism
protection act of 2002: listing of biological agents and toxins and re-
quirements and procedures for notification and possession. Federal
Register 2002; 67:52,383–9.
34. Association for Professionals in Infection Control and Epidemiology
Working Group. April 2002 Interim Bioterrorism Readiness Planning
Sessions. Available at: http://www.apic.org/Content/NavigationMenu/
PracticeGuidance/Topics/Bioterrorism/APIC_BTWG_BTRSugg.pdf.
Accessed 10 November 2005.
35. Seward JF, Galil K, Damon IK, et al. Development and experience with
an algorithm to evaluate suspected smallpox cases in the United States,
2002–2004. Clin Infect Dis 2004; 39:1477–83.
36. Centers for Disease Control and Prevention. Emergency preparedness
and response. 8 October 2005. Available at: http://www.bt.cdc.gov. Ac-
cessed 14 October 2005.
at University of Portland on May 20, 2011cid.oxfordjournals.orgDownloaded from
... Monkeypox data from the DRC accounted for approximately one-third of the eligible articles [5,13,14,[16][17][18][19][20][21][22][23][24][25][26][27][28]. The remaining articles had monkeypox data from the CAR [29][30][31][32][33][34][35], United States (US) [36][37][38][39][40][41], Nigeria [5,[42][43][44], Republic of the Congo [15,[45][46][47], Sierra Leone [42,48,49], Cameroon [5,50], Côte d'Ivoire [51,52], Gabon [53,54], United Kingdom (UK) [55,56], Israel [57], Liberia [42], Singapore [8], and South Sudan [formerly Sudan] [58]. (Note: two articles [5,42] described data for more than one country, therefore the total number of articles per country exceeds 48.) ...
... The three UK cases that originated in Nigeria [7,55] are not among the 183 cases in the Nigeria CDC report.) The third and fourth most affected countries with confirmed, probable, and/or Monkeypox was not reported outside Africa until 2003, when an outbreak of 47 confirmed or probable cases occurred in the US following exposure to infected pet prairie dogs, which had acquired monkeypox virus from infected exotic animals imported from Ghana [6,40]. In recent years, there have been several travel-associated cases of monkeypox, all following exposures in Nigeria. ...
... There are two distinct genetic clades of monkeypox, the Central African (or Congo Basin) clade and the West African clade. Only 10 peer-reviewed articles [8,23,29,35,40,44,48,49,57,58] and one report from the grey literature [63] described specific data on these variants. ...
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Rapid diagnosis and whole genome sequencing confirmed a case of monkeypox in an HIV-positive individual receiving antiretroviral therapy. The patient had a normal CD4+ T-cell count and suppressed HIV viral load and presented with a genital rash in Melbourne, Australia after return from Europe in May 2022. He subsequently developed systemic illness and disseminated rash and 11 days after symptom onset, he was hospitalised to manage painful bacterial cellulitis of the genital area.
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During the course of the recently concluded smallpox eradication program, a new human orthopoxvirus infection was discovered which is caused by monkeypox virus. The disease occurs sporadically in remote villages within tropical rain forests of West and Central Africa. The disease is rare; only 155 cases having been reported from 1970 to 1983. The symptoms and signs of human monkeypox resemble those of smallpox, differing significantly only in the occurrence of lymphadenopathy with human monkeypox disease. Of 155 cases, some 80% are believed to have resulted from infection from an as yet unknown animal reservoir; the rest occurred among unvaccinated close contacts among whom a secondary attack rate of 15% was observed. Although person-to-person spread appears to have occurred in some instances, few cases were observed in the third or fourth generation of transmission and none thereafter. Since 1982, the incidence of human monkeypox infections in Zaire has increased concomitant with an intensified surveillance program. Additional reasons which might explain the increased incidence are discussed. Further surveillance and research of this primarily zoonotic infection are warranted and are in progress.
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▪Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These include tumor necrosis factor α (TNFα), interleukins, platelet activating factor, leukotrienes, thromboxane A2, and activators of the complement cascade. Neutrophil and platelet activation may also play a role. Other agents that may participate in the sepsis cascade include adhesion molecules, kinins, thrombin, myocardial depressant substance, β-endorphin, and heat shock proteins. Endothelium-derived relaxing factor and endothelin-1 are released from the endothelium and seem to exert a regulatory effect, counterbalancing each other. A central mediator of sepsis does not seem to exist, although TNFα has been commonly proposed for this role. Animal studies are difficult to extrapolate to the clinical setting because of cross-species differences and variations in experimental design. Rather than being caused by any single pathogenic mechanism, it is more likely that sepsis is related to the state of activation of the target cell, the nearby presence of other mediators, and the ability of the target cell to release other mediators. Also important is the downregulation or negative feedback of these mediators or the generation of natural inflammation inhibitors, such as interleukin-4 and interleukin-8. Endothelial damage in sepsis probably results from persistent and repetitive inflammatory insults. Eventually, these insults produce sufficient damage that downregulation can no longer occur; this leads to a state of metabolic anarchy in which the body can no longer control its own inflammatory response.
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Preliminary findings from these investigations indicate that the primary route of transmission to humans is from close contact with infected mammalian pets. However, the possibility of human-to-human transmission cannot be excluded. CDC has issued interim guidance for infection control, exposure management, monitoring of exposed persons, and duration of isolation procedures in health-care and community settings for patients with suspected monkeypox (http://www.cdc.gov/ncidod/monkeypox/infectioncontrol.htm). Persons seeking medical care with unexplained fever, rash, or prominent lymphadenopathy should be asked about exposure to unusual or exotic pets, especially small mammals such as prairie dogs or Gambian giant rats. If monkeypox infection is suspected, standard, contact, and airborne precautions should be applied in all health-care settings (http://www. cdc.gov/ncidod/hip/ISOLAT/Isolat.htm). Interim guidance for veterinarians and pet owners also are available at http://www.cdc.gov/ncidod/monkeypox/animalguidance.htm. These recommendations are modeled after human infection-control guidelines, with modifications appropriate for veterinary and home settings where airborne precautions might not be feasible. In addition, these guidelines outline the appropriate management of exposed or ill pets to help prevent further transmission of monkeypox among animals. Introduction of exotic species, such as rodents from Africa, poses a serious public health threat because of the potential of monkeypox virus infection and other nonindigenous pathogens. Serosurveys of various healthy rodents (and nonhuman primates), including Cricetomys emini, captured wild in Africa, have demonstrated orthopoxvirus antibodies.⁷ Monkeypox virus also has been isolated from a rope squirrel (Funisciurus anerythrus) found with skin lesions in the vicinity of monkeypox cases in DRC.⁸ Accordingly, pursuant to 42 CFR 71.32(b), CDC is implementing an immediate embargo on the importation of all rodents from Africa (Order Rodentia). In addition, CDC and the Food and Drug Administration, pursuant to 42 CFR 70.2 and 21 CFR 1240.30, are prohibiting the transportation or offering for transportation in interstate commerce, or the sale, offering for sale, or offering for any other type of commercial or public distribution, including release into the environment of prairie dogs and the following rodents from Africa: tree squirrels (Heliosciurus sp.), rope squirrels (Funisciurus sp.), dormice (Graphiurus sp.), Gambian giant pouched rats (Cricetomys sp.), brush-tailed porcupines (Atherurus sp.), and striped mice (Hybomys sp.). States can elect to enact measures to prohibit the importation, sale, distribution, or display of animals that could result in transmission of infectious agents.⁹,10
Bancroft 1 found twelve instances of the purpuric type in 1,200 cases of smallpox during the Boston epidemic in 1901. The percentage of this type of the disease in any given epidemic has probably never been accurately estimated. Its clinical and laboratory differentiation from the hemorrhagic pustular form has never been stressed by the epidemiologist or the clinician who prefers to include these two forms under one general term of hemorrhagic or malignant smallpox.In the 1924 epidemic in Minnesota, several cases of the undoubted purpuric type of smallpox were reported to the state board of health and recorded as hemorrhagic smallpox. In the fall and winter of the same year, a large number of cases with clinical purpura were recorded in Minneapolis, of which forty-three deaths of purpuric smallpox were reported.At the Minneapolis General Hospital, forty-eight cases were diagnosed as purpuric out of the total admission of 480
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A 5-year-old boy living in a small camp in the rural Ivory Coast had a disease resembling smallpox. This occurred 4 years after smallpox had been eradicated from the Ivory Coast and 1.5 years after the last case of smallpox was detected in West and Central Africa. Clinical, serological, and epidemiological evidence indicated this disease was probably monkeypox, a poxvirus of the variola/vaccina subgroup. A serologic survey of poxvirus antibodies in the wild animal population detected neutralizing antibodies in rodents, larger mammals, primates, and birds. The laboratory and ecological characteristics of poxviruses require further elucidation, especially those which have been found in animals near human monkeypox cases.