A Belgian student with black eschars.

BACKGROUND: Human cowpox virus infection is a rare zoonotic disease. Cowpox virus is a member of the Orthopoxvirus genus, like smallpox. Over the last years records of cowpox virus transmission from pet cats and pet rats to humans in Europe have increased. This observation may result from the loss of cross-immunity against orthopoxviruses after discontinuation of routine smallpox vaccination in the 1980s. CASE PRESENTATION: We report the first case of a human cowpox infection in an unvaccinated Belgian citizen. This 19-year-old student presented with multiple necrotic skin lesions on the chin, the scalp and the pubic region, and with cervical lymphadenopathy and flu-like symptoms. The diagnosis of human cowpox was based on electron microscopic findings and PCR examination performed on a skin biopsy of the pubic lesion. Close contact with cats (her domestic cats or cats from a local shelter) was probably the source of transmission. Spreading of the lesions was likely the result of autoinoculation. After six months all lesions spontaneously healed with atrophic scars. DISCUSSION: To enhance awareness of this rare viral zoonosis and to verify the suspected increase in incidence and symptom severity after cessation of smallpox vaccination, one could argue whether human cowpox should become a notifiable disease.

Cowpox: How dangerous could it be for humans? Case report.

Cowpox is a rare zoonosis transmitted to humans mainly from cats. The disease usually causes skin lesions; however, the ocular form may lead to other serious complications. We describe a case of cowpox in a rare location of the upper eyelid of an immunocompetent male, which lead to necrosis of the upper eyelid, keratitis and leucomatous opacity, and the neovascularization of the cornea. The patient underwent several surgeries, including reconstruction surgery of the eyelids, correction of the medial canthus, and corneal neurotization with supraorbicular nerve transplantation. Suspicion of cowpox should be made in patients where there are poorly healing skin lesions accompanied by a painful black eschar with erythema and local lymphadenopathy. Ocular cowpox may lead to serious complications and possibly mimic anthrax. Diagnosis of cowpox can be confirmed by detection of cowpox virus DNA by polymerase chain reaction. Patients should be advised to protect themselves while handling sick animals.

Harm as a Necessary Component of the Concept of Medical Disorder: Reply to Muckler and Taylor.

Wakefield's harmful dysfunction analysis asserts that the concept of medical disorder includes a naturalistic component of dysfunction (failure of biologically designed functioning) and a value (harm) component, both of which are required for disorder attributions. Muckler and Taylor, defending a purely naturalist, value-free understanding of disorder, argue that harm is not necessary for disorder. They provide three examples of dysfunctions that, they claim, are considered disorders but are entirely harmless: mild mononucleosis, cowpox that prevents smallpox, and minor perceptual deficits. They also reject the proposal that dysfunctions need only be typically harmful to qualify as disorders. We argue that the proposed counterexamples are, in fact, considered harmful; thus, they fail to disconfirm the harm requirement: incapacity for exertion is inherently harmful, whether or not exertion occurs, cowpox is directly harmful irrespective of indirect benefits, and colorblindness and anosmia are considered harmful by those who consider them disorders. We also defend the typicality qualifier as viably addressing some apparently harmless disorders and argue that a dysfunction's harmfulness is best understood in dispositional terms.

Atypical Cowpox Virus Infection in Smallpox-Vaccinated Patient, France.

We report a case of atypical cowpox virus infection in France in 2016. The patient sought care for thoracic lesions after injury from the sharp end of a metallic guardrail previously stored in the ground. We isolated a cowpox virus from the lesions and sequenced its whole genome. The patient reported that he had been previously vaccinated against smallpox. We describe an alternative route of cowpox virus infection and raise questions about the immunological status of smallpox-vaccinated patients for circulating orthopoxviruses.

Experimental Cowpox Virus (CPXV) Infections of Bank Voles: Exceptional Clinical Resistance and Variable Reservoir Competence.

Cowpox virus (CPXV) is a zoonotic virus and endemic in wild rodent populations in Eurasia. Serological surveys in Europe have reported high prevalence in different vole and mouse species. Here, we report on experimental CPXV infections of bank voles (Myodes glareolus) from different evolutionary lineages with a spectrum of CPXV strains. All bank voles, independently of lineage, sex and age, were resistant to clinical signs following CPXV inoculation, and no virus shedding was detected in nasal or buccal swabs. In-contact control animals became only rarely infected. However, depending on the CPXV strain used, inoculated animals seroconverted and viral DNA could be detected preferentially in the upper respiratory tract. The highest antibody titers and virus DNA loads in the lungs were detected after inoculation with two strains from Britain and Finland. We conclude from our experiments that the role of bank voles as an efficient and exclusive CPXV reservoir seems questionable, and that CPXV may be maintained in most regions by other hosts, including other vole species. Further investigations are needed to identify factors that allow and modulate CPXV maintenance in bank voles and other potential reservoirs, which may also influence spill-over infections to accidental hosts.

Two Distinct Clinical Courses of Human Cowpox, Germany, 2015.

Here we present two cases of human infection with cowpox virus with distinct clinical courses. A series of clinical photographs documents lesion progression over time. In the first case-an unvaccinated young veterinary assistant-a pustule was treated locally with cortisone. The lesion turned into a large ulcer accompanied by severe lymphadenitis. Based on her close contact to a sick stray cat, infection with cowpox virus was assumed and confirmed by virus isolation, PCR, and serology. The clinical course took up to eleven months until healing of the wound was complete. Transmission of cowpox virus from the cat was likely because a skin swab was PCR-positive and the cat had a high titer of anti-orthopoxvirus antibodies. In contrast, a rather mild clinical course of cowpox was confirmed in a 49-year-old male farmer vaccinated against smallpox. Only a small eschar developed, and wound closure was complete after 6 weeks.

Cowpox virus infection in a child after contact with a domestic cat: a case report.

Human cowpox represents a seldom diagnosed zoonosis but this diagnosis should be considered more frequently as the number of cases has increased in recent years. We describe a case of cowpox in an 11-yearold boy following regular direct daily contact with a domestic cat. The 11-year-old patient, an otherwise healthy boy, demonstrated skin ulceration located at his chin, with enlargement of regional lymph nodes and fever reaching 39°C. The diagnosis of cowpox was made on the basis of PCR involving DNA isolated from a scab covering the skin lesion. Application of PCR involving DNA isolated from the scab covering the lesion with parallel use of OPXV-specific (ORF F4L) and CPXV-specific (ORF B9R) oligonucleotide primer sequences is recommended for rapid laboratory confirmation of the diagnosis.

Fatal disseminated cowpox virus infection in an adolescent renal transplant recipient.

BACKGROUND: A 17-year-old boy on long-term immunosuppression following renal transplantation for chronic kidney disease (CKD), the result of dysplastic kidneys, initially presented with a swelling in his neck while attending hospital for an unrelated problem. A clinical diagnosis of tonsillitis was made, and he was treated with broad-spectrum antibiotics. Over a few days, his condition deteriorated, and he developed multiple vesicopustular skin lesions and required an emergency tonsillectomy due to respiratory distress. CASE DIAGNOSIS/TREATMENT: Histological investigation of the skin and tonsillar tissue suggested a viral aetiology, and subsequent electron microscopy and polymerase chain reaction (PCR) tissue examination proved disseminated cowpox infection. The family cat, which was reported as having self-resolving sores on its skin, was likely the source of the infection. The child failed to respond to antiviral treatment and succumbed to multiorgan failure within a month of admission. CONCLUSIONS: We report this case of fatal disseminated cowpox infection to highlight an increasing risk of this illness in the post-transplant population and to detail some unusual features not previously described, such as tonsillar involvement, disseminated skin lesions and multiorgan failure.

Fatal Cowpox Virus Infection in an Aborted Foal.

The article describes the isolation of a cowpox virus (CPXV) isolate originating from a horse. The skin of a foal, aborted in the third trimester, displayed numerous cutaneous papules. The histological examination showed A-type inclusion bodies within the lesion, typical for CPXV infections. This suspicion was confirmed by real-time PCR where various organs were analyzed. From skin samples, virus isolation was successfully performed. Afterwards, the whole genome of this new isolate "CPXV Amadeus" was sequenced by next-generation technology. Phylogenetic analysis clearly showed that "CPXV Amadeus" belongs to the "CPXV-like 1" clade. To our opinion, the study provides important additional information on rare accidental CPXV infections. From the natural hosts, the voles, species such as rats, cats, or different zoo animals are occasionally infected, but until now only two horse cases are described. In addition, there are new insights toward congenital CPXV infections.

Exposure of rhesus monkeys to cowpox virus Brighton Red by large-particle aerosol droplets results in an upper respiratory tract disease.

We previously demonstrated that small-particle (0.5-3.0 µm) aerosol infection of rhesus monkeys (Macaca mulatta) with cowpox virus (CPXV)-Brighton Red (BR) results in fulminant respiratory tract disease characterized by severe lung parenchymal pathology but only limited systemic virus dissemination and limited classic epidermal pox-like lesion development (Johnson et al., 2015). Based on these results, and to further develop CPXV as an improved model of human smallpox, we evaluated a novel large-particle aerosol (7.0-9.0 µm) exposure of rhesus monkeys to CPXV-BR and monitored for respiratory tract disease by serial computed tomography (CT). As expected, the upper respiratory tract and large airways were the major sites of virus-induced pathology following large-particle aerosol exposure. Large-particle aerosol CPXV exposure of rhesus macaques resulted in severe upper airway and large airway pathology with limited systemic dissemination.

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease.

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log10 PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases.

From lesions to viral clones: biological and molecular diversity amongst autochthonous Brazilian vaccinia virus.

Vaccinia virus (VACV) has had an important role for humanity because of its use during the smallpox eradication campaign. VACV is the etiologic agent of the bovine vaccinia (BV), an emerging zoonosis that has been associated with economic, social, veterinary and public health problems, mainly in Brazil and India. Despite the current and historical VACV importance, there is little information about its circulation, prevalence, origins and maintenance in the environment, natural reservoirs and diversity. Brazilian VACV (VACV-BR) are grouped into at least two groups based on genetic and biological diversity: group 1 (G1) and group 2 (G2). In this study, we went to the field and investigated VACV clonal diversity directly from exanthemous lesions, during BV outbreaks. Our results demonstrate that the G1 VACV-BR were more frequently isolated. Furthermore, we were able to co-detect the two variants (G1 and G2) in the same sample. Molecular and biological analysis corroborated previous reports and confirmed the co-circulation of two VACV-BR lineages. The detected G2 clones presented exclusive genetic and biological markers, distinct to reference isolates, including VACV-Western Reserve. Two clones presented a mosaic profile, with both G1 and G2 features based on the molecular analysis of A56R, A26L and C23L genes. Indeed, some SNPs and INDELs in A56R nucleotide sequences were observed among clones of the same virus population, maybe as a result of an increased mutation rate in a mixed population. These results provide information about the diversity profile in VACV populations, highlighting its importance to VACV evolution and maintenance in the environment.

Emergence of cowpox: study of the virulence of clinical strains and evaluation of antivirals.

The last years, cowpox infections are being increasingly reported through Eurasia. Cowpox viruses (CPXVs) have been reported to have different genotypes and may be subdivided in at least five genetically distinct monophyletic clusters. However, little is known about their in vitro and in vivo features. In this report, five genetically diverse CPXVs, including one reference strain (CPXV strain Brighton) and four clinical isolates from human and animal cases, were compared with regard to growth in cells, pathogenicity in mice and inhibition by antivirals. While all CPXVs replicated similarly in vitro and showed comparable antiviral susceptibility, marked discrepancies were seen in vivo, including differences in virulence with recorded mortality rates of 0%, 20% and 100%. The four CPXV clinical isolates appeared less pathogenic than two reference strains, CPXV Brighton and vaccinia virus Western-Reserve. Disease severity seemed to correlate with high viral DNA loads in several organs, virus titers in lung tissues and levels of IL-6 cytokine in the sera. Our study highlighted that the species CPXV consists of viruses that not only differ considerably in their genotypes but also in their in vivo phenotypes, indicating that CPXVs should not be longer classified as a single species. Lung virus titers and IL-6 cytokine level in mice may be used as biomarkers for predicting disease severity. We further demonstrated the potential benefit of cidofovir, CMX001 and ST-246 use as antiviral therapy.