Discovery of monkeypox in Sudan.
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Diagnosis, Differential↗
Biomedical subjects
Inger K Damon
Publications and source records attributed to Inger K Damon.
Clinical manifestations of human monkeypox influenced by route of infection.
BACKGROUND: In April 2003, an outbreak of monkeypox occurred in the United States following the importation of monkeypox virus (MPXV)-infected animals in a consignment of exotic pets from West Africa. Transmission of the virus to non-African captive species, including prairie dogs, preceded human disease. METHODS: We evaluated the influence of the route of infection on clinical illness for persons with confirmed and probable cases of human monkeypox. Exposures were categorized as being "noninvasive" (e.g., the person touched an infected animal, cleaned an infected animal's cage, and/or stood within 6 feet of an infected animal) or "complex" (e.g., invasive bite or scratch from an ill prairie dog plus potential noninvasive exposure), and associations between exposure, illness manifestation, and illness progression (i.e., elapsed time from first exposure to an ill prairie dog through various benchmarks of illness) were assessed. RESULTS: Patients with complex exposures were more likely than patients with noninvasive exposures to have experienced pronounced signs of systemic illness (49.1% vs. 16.7%; P=.041) and to have been hospitalized during illness (68.8% vs. 10.3%; P<.001). Complex exposures were also associated with shorter incubation periods (9 days for complex exposures vs. 13 days for noninvasive exposures) and the absence of a distinct febrile prodrome. CONCLUSIONS: The findings of this study indicate that route of infection can influence monkeypox illness manifestations.
Animals↗
Genome sequence diversity and clues to the evolution of variola (smallpox) virus.
Comparative genomics of 45 epidemiologically varied variola virus isolates from the past 30 years of the smallpox era indicate low sequence diversity, suggesting that there is probably little difference in the isolates' functional gene content. Phylogenetic clustering inferred three clades coincident with their geographical origin and case-fatality rate; the latter implicated putative proteins that mediate viral virulence differences. Analysis of the viral linear DNA genome suggests that its evolution involved direct descent and DNA end-region recombination events. Knowing the sequences will help understand the viral proteome and improve diagnostic test precision, therapeutics, and systems for their assessment.
DNA, Viral↗
Detection of monkeypox virus with real-time PCR assays.
BACKGROUND: Human monkeypox, a zoonotic disease, was first reported outside of Africa during the 2003 US outbreak. OBJECTIVES: We present two real-time PCR assays critical for laboratory diagnosis of monkeypox during the 2003 US outbreak. STUDY DESIGN: A TaqMan-based assay (E9L-NVAR) targets the orthopoxvirus DNA polymerase gene and detects Eurasian orthopoxviruses other than Variola. A hybridization assay, utilizing a MGB Eclipsetrade mark (Epoch Biosciences) probe, targets an envelope protein gene (B6R) and specifically detects monkeypox virus (MPXV). Assays were validated using coded orthopoxvirus DNA samples and used to evaluate lesion samples from five confirmed US monkeypox cases. RESULTS: E9L-NVAR did not detect variola (48 strains), North American orthopoxviruses (2), or DNA derived from non-poxviral rash illnesses. The assay reproducibly identified various concentrations of 13 Eurasian orthopoxvirus strains and was sensitive to 12.5 vaccinia genomes. The B6R assay recognized 15 different MPXV strains, while other orthopoxvirus (9) and bacteria (15) strains did not cross-react. Of the 13 human samples tested from confirmed cases, both assays identified 100% as containing MPXV DNA. CONCLUSIONS: E9L-NVAR and B6R assays demonstrate 100% specificity for non-variola Eurasian orthopoxvirus and MPXV, respectively. Using two discrete viral gene targets, these assays together provide a reliable and sensitive method for quickly confirming monkeypox infections.
Adult↗
Monkeypox outbreak diagnostics and implications for vaccine protective effect.
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Animals↗
Ocular vaccinia infection in laboratory worker, Philadelphia, 2004.
We report a case of ocular vaccinia infection in an unvaccinated laboratory worker. The patient was infected by a unique strain used in an experiment performed partly outside a biosafety cabinet. Vaccination should continue to be recommended, but laboratories with unvaccinated workers should also implement more stringent biosafety practices.
Adult↗
Clinical characteristics of human monkeypox, and risk factors for severe disease.
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 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. RESULTS: 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. 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 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.
Adolescent↗
Stability of diluted smallpox vaccine under simulated clinical conditions.
CONTEXT: During a mass smallpox immunization campaign, vaccine may be exposed to ambient temperatures for extended periods of time. OBJECTIVE: To determine the viability of undiluted and 5x diluted DryVax smallpox vaccine after cycling vaccine in and out of refrigeration for 2 weeks, as might occur during an immunization campaign. DESIGN: Two vials of Dryvax vaccine were reconstituted as per manufacturer's instructions (1x) and two vials were reconstituted using 5x the recommended diluent (5x). Every 12h over 2 weeks, vials were cycled between refrigeration and room temperature (1x-RT, 5x-RT) or ice bath (1x-cold, 5x-cold). Each vial was sampled in triplicate at time of reconstitution and thereafter at 24 or 48 h intervals. MAIN OUTCOME MEASURES: Viability measured by viral plaque forming units per ml (pfu/ml). RESULTS: All four vaccine vials showed a decline in virus titer over the 2-week period but remained well above 10(7)pfu/ml. Compared with titers on the day of reconstitution (day 0), titers at the end of the study (day 14) had declined by 0.4--0.6l og in all vials (Table 1). Linear regression analysis suggested that decay in viral titer occurred more rapidly in vials exposed to room temperature compared with vials kept on ice and in vaccine diluted 1x compared with vaccine diluted 5x. CONCLUSIONS: After 2 weeks, viability was greater than 10(7)pfu/ml, the titer suggested by Frey et al. as necessary to ensure successful vaccination in more than 97% of vaccinees. When removed from refrigeration, keeping the vaccine on ice lowers the decline in titer.
Drug Stability↗
Virulence differences between monkeypox virus isolates from West Africa and the Congo basin.
Studies indicate that West African and Congo basin isolates of monkeypox virus (MPXV) are genetically distinct. Here, we show Congo basin MPXV-ZAI-V79 is more virulent for cynomolgus monkeys as compared to presumed West African MPXV-COP-58. This finding may explain the lack of case-fatalities in the U.S. 2003 monkeypox outbreak, which was caused by a West African virus. Virulence differences between West African and Congo basin MPXV are further supported by epidemiological analyses that observed a similar prevalence of antibodies in non-vaccinated humans in both regions, while >90% of reported cases occurred in the Congo basin, and no fatal cases were observed outside of this region. To determine the basis for this difference in virulence, we sequenced the genomes of one human West African isolate, and two presumed West African isolates and compared the sequences to Congo basin MPXV-ZAI-96-I-16. The analysis identified D10L, D14L, B10R, B14R, and B19R as possible virulence genes, with D14L (ortholog of vaccinia complement protein) as a leading candidate.
Africa, Western↗
Safety profile of smallpox vaccine: insights from the laboratory worker smallpox vaccination program.
BACKGROUND: The frequency of mild-to-moderate adverse events following smallpox vaccination was not well documented or reported during the pre-eradication era. This report describes the frequency of such symptoms among 936 adult smallpox vaccinees with and without a history of prior smallpox vaccination. METHODS: Diary cards were distributed to 1006 laboratory workers and members of the Centers for Disease Control and Prevention (CDC) smallpox response team who received smallpox vaccination under an investigational new drug protocol during 2001-2002. Vaccinees were requested to complete the diary card daily and return it to the CDC 28 days after vaccination. The proportion of vaccinees reporting symptoms was determined and compared among subgroups. RESULTS: Ninety-three percent of the diary cards were returned. The most common symptom reported was "itching at vaccination site." Primary vaccines reported statistically higher proportions of the following 11 symptoms: joint pain (25% vs. 11%; P=.0011), muscle pain (46% vs. 19%; P<.0001), fatigue (43% vs. 29%; P=.0161), swelling at vaccination site (58% vs. 33%; P<.0001), itching on the body (31% vs. 17%; P=.0048), abdominal pain (11% vs. 2%; P=.0012), swollen or tender lymph nodes (71% vs. 33%; P<.0001), pain at injection site (48% vs. 30%; P=.0018), headache (40% vs. 25%; P=.0088), backache (17% vs. 7%; P=.0090), and fever (temperature, >or=100 degrees F [37.7 degrees C]; 20% vs. 9%; P=.0047). CONCLUSIONS: This analysis suggests that previously unvaccinated persons aged <30 years experienced more symptoms than did previously vaccinated persons. The findings of increased proportions with joint pain, abdominal pain, backache, and difficulty breathing were unexpected. As with recently described cardiac adverse events, these symptoms are suggestive of systemic involvement and warrant further study.
Adolescent↗
A tale of two clades: monkeypox viruses.
Human monkeypox was first recognized outside Africa in 2003 during an outbreak in the USA that was traced to imported monkeypox virus (MPXV)-infected West African rodents. Unlike the smallpox-like disease described in the Democratic Republic of the Congo (DRC; a Congo Basin country), disease in the USA appeared milder. Here, analyses compared clinical, laboratory and epidemiological features of confirmed human monkeypox case-patients, using data from outbreaks in the USA and the Congo Basin, and the results suggested that human disease pathogenicity was associated with the viral strain. Genomic sequencing of USA, Western and Central African MPXV isolates confirmed the existence of two MPXV clades. A comparison of open reading frames between MPXV clades permitted prediction of viral proteins that could cause the observed differences in human pathogenicity between these two clades. Understanding the molecular pathogenesis and clinical and epidemiological properties of MPXV can improve monkeypox prevention and control.
Animals↗
characterization of acute-phase humoral immunity to monkeypox: use of immunoglobulin M enzyme-linked immunosorbent assay for detection of monkeypox infection during the 2003 North American outbreak.
A monkeypox outbreak occurred in the United States in 2003. Patient's sera were sent to the Centers for Disease Control and Prevention as a part of outbreak response measures. Clinical and epidemiologic information was abstracted from the case investigation forms. Serum samples from patients were tested by using an immunoglobulin M (IgM)-capture and an IgG enzyme-linked immunosorbent assay ELISA against Orthopoxvirus antigen. The detection of antiviral IgG and IgM antibodies and the kinetics of the antiviral IgG and IgM antibody responses were evaluated. Patients were classified as confirmed, probable, or suspect cases or were excluded as cases based on laboratory test results and epidemiologic and clinical criteria. A total of 37 confirmed case patients with monkeypox were identified, and 116 patients were excluded as case patients based on molecular testing or insufficient epidemiology and clinical data to warrant classification as a suspect or probable case. Of 37 confirmed case patients, 36 had a known history (presence or absence) of smallpox vaccination. Of those, 29 of the 36 either had or developed an IgG response, while 34 of the 36 developed an IgM response, regardless of vaccination status. Serum collected > or =5 days for IgM detection or serum collected > or =8 days after rash onset for IgG detection was most efficient for the detection of monkeypox virus infection. IgM ELISA detects recent infection with orthopoxviruses and, in this case, recent infection with monkeypox virus. In addition, analysis of paired sera for IgG and IgM detected seroconversion, another indicator of recent infection. The ELISA results correlated with the virologic PCR and viral culture results, indicating its diagnostic capabilities for monkeypox and potentially other orthopoxvirus infections due to zoonotic transmission or bioterrorism events.
Antibodies, Viral↗
Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction.
The EGF-like domain of smallpox growth factor (SPGF) targets human ErbB-1, inducing tyrosine phosphorylation of certain host cellular substrates via activation of the receptor's kinase domain and thereby facilitating viral replication. Given these findings, low molecular weight organic inhibitors of ErbB-1 kinases might function as antiviral agents against smallpox. Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization. Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading. In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection. Collectively, these findings show that chemical inhibitors of host-signaling pathways exploited by viral pathogens may represent potent antiviral therapies.
Animals↗
Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003.
This report describes the first reported outbreak of human monkeypox in the Republic of Congo. Eleven confirmed and probable monkeypox cases were observed during this outbreak, all were less than 18 years old, and most resided on the grounds of the Government Hospital in Impfondo. Molecular, virologic, and serologic, and diagnostic assays were used to detect evidence of monkeypox (or orthopox) virus infection in individuals with striking dermatologic and other clinical manifestations. The majority of cases in this outbreak experienced significant, symptomatic illnesses; there was one death, possibly involving secondary complications, and one instance of profound sequelae. Up to six sequential transmissions of monkeypox virus from person to person are hypothesized to have occurred, making this the longest uninterrupted chain of human monkeypox fully documented to date. The pattern of sustained human-to-human transmission observed during this outbreak may influence our current perception of the capacity for this zoonotic virus to adapt to humans.
Adolescent↗
Human monkeypox infection: a family cluster in the midwestern United States.
BACKGROUND: The outbreak of monkeypox in the Midwestern United States during June 2003 marks the first documented human infection in the Western Hemisphere. Consistent with those in outbreaks in Africa, most cases in this outbreak were associated with febrile rash illness. We describe a cluster of monkeypox in a family with a spectrum of clinical illness, including encephalitis, and outline the laboratory confirmation of monkeypox. METHODS: Standardized patient information was collected by questionnaire and medical chart review; all cases described were laboratory confirmed. Laboratory methods included nucleic acid detection, viral culture, serologic testing, histopathologic evaluation, and immunohistochemical testing. RESULTS: Of 3 family members with monkeypox, 2 had rash illness only, and 1 required hospitalization for severe encephalitis. The family member with the mildest clinical course had previously received smallpox vaccination. Diagnostic testing by both polymerase chain reaction and culture revealed infectious monkeypox virus in skin lesions of all 3 patients; 2 patients had orthopoxvirus detected by immunohistochemistry in skin lesions. The patient with encephalitis had orthopoxvirus-reactive immunoglobulin M (IgM) in cerebrospinal fluid. All patients had detectable IgM responses to orthopoxvirus antigens. CONCLUSIONS: These 3 patients illustrate a spectrum of clinical illness with monkeypox despite a common source of exposure; manifestation and severity of illness may be affected by age and prior smallpox vaccination. We report that monkeypox, in addition to causing febrile rash illness, causes severe neurologic infection, and we discuss the use of novel laboratory tests for its diagnosis.
Adult↗
Biochemical and functional analysis of smallpox growth factor (SPGF) and anti-SPGF monoclonal antibodies.
Variola, the causative agent of smallpox, is a highly infectious double-stranded DNA virus of the orthopox genus that replicates within the cytoplasm of infected cells. For unknown reasons prominent skin manifestations, including "pox," mark the course of this systemic human disease. Here we characterized smallpox growth factor (SPGF), a protein containing an epidermal growth factor (EGF)-like domain that is conserved among orthopox viral genomes, and investigated its possible mechanistic link. We show that after recombinant expression, refolding, and purification, the EGF domain of SPGF binds exclusively to the broadly expressed cellular receptor, erb-B1 (EGF receptor), with subnanomolar affinity, stimulating the growth of primary human keratinocytes and fibroblasts. High affinity monoclonal antibodies specific for SPGF reveal in vivo immunoprotection in a murine vaccinia pneumonia model by a mechanism distinct from viral neutralization. These findings suggest that blockade of pathogenic factor actions, in general, may be advantageous to the infected host.
Amino Acid Sequence↗
The detection of monkeypox in humans in the Western Hemisphere.
BACKGROUND: During May and June 2003, an outbreak of febrile illness with vesiculopustular eruptions occurred among persons in the midwestern United States who had had contact with ill pet prairie dogs obtained through a common distributor. Zoonotic transmission of a bacterial or viral pathogen was suspected. METHODS: We reviewed medical records, conducted interviews and examinations, and collected blood and tissue samples for analysis from 11 patients and one prairie dog. Histopathological and electron-microscopical examinations, microbiologic cultures, and molecular assays were performed to identify the etiologic agent. RESULTS: The initial Wisconsin cases evaluated in this outbreak occurred in five males and six females ranging in age from 3 to 43 years. All patients reported having direct contact with ill prairie dogs before experiencing a febrile illness with skin eruptions. We found immunohistochemical or ultrastructural evidence of poxvirus infection in skin-lesion tissue from four patients. Monkeypox virus was recovered in cell cultures of seven samples from patients and from the prairie dog. The virus was identified by detection of monkeypox-specific DNA sequences in tissues or isolates from six patients and the prairie dog. Epidemiologic investigation suggested that the prairie dogs had been exposed to at least one species of rodent recently imported into the United States from West Africa. CONCLUSIONS: Our investigation documents the isolation and identification of monkeypox virus from humans in the Western Hemisphere. Infection of humans was associated with direct contact with ill prairie dogs that were being kept or sold as pets.
Adolescent↗
25 years since the eradication of smallpox: why poxvirus research is still relevant.
The World Health Organization (WHO) announced the eradication of smallpox twenty-five years ago this month. This conquest of an infectious disease, which has been the bane of humankind for centuries, still stands as the WHO's greatest achievement. The anniversary of such a scientific and medical landmark provides an appropriate occasion to reflect on this feat and to assess the significance and necessity of the poxvirus research that has followed this.
Animals↗