Confluent gangrene of the face was apparent; The patient developed periorbital oedema concerning for superimposed preseptal cellulitis; The patient subsequently developed pharyngeal oedema; Died due to systemic complications of infections; Possible immune reconstitution inflammatory syndrome; Hospital course was complicated by Sapovirus gastroenteritis, metabolic acidosis, multifactorial renal failure, and severe anaemia; Hospital course was complicated by Sapovirus gastroenteritis, metabolic acidosis, multifactorial renal failure, and severe anaemia; Hospital course was complicated by Sapovirus gastroenteritis, metabolic acidosis, multifactorial renal failure, and severe anaemia; Bacterial superinfection; The patient subsequently developed multifocal pneumonia and became ventilator-dependent; The patient received Jynneos vaccine after the monkeypox developed.; Literature citation:   Case reference number US-BN-2023-000202 is a literature case report, title as stated above, identified on 07-Feb-2023 and concerns a 45-year-old male patient.  The article described first reported example of monkeypox (mpox) progressing to confluent facial gangrene in a 45-year-old male patient who was immunocompromised. It was proposed that like progressive vaccinia, monkeypox virus clinically evolved through contiguous intradermal spread. Expansile cellular necrosis manifested clinically as progressive gangrene rather than a pustular response. Intradermal dissemination of monkeypox virus was proposed which was illustrated by centrifugal progression of necrotic tissue from early lesions. It was hypothesized that gangrenous tissues themselves could have served as viral reservoirs for re-inoculation of the bloodstream or autoinoculation of distant sites, prolonging the disease state.   The patient had a 17-year history of human immunodeficiency virus (HIV) (not on highly active antiretroviral therapy (HAART)), and acquired immune deficiency syndrome (AIDS) for at least one year (CD4+ count 29 cells per µL, viral load 42674 copies per mL), unvaccinated for orthopoxviruses who developed vesiculopapular lesions of the torso, arms, neck, and genitals over one week. On an unspecified date, the patient was vaccinated with a dose of Jynneos vaccine (batch number: unknown), at an unknown dose, route, or site of administration, due to, as reported, suspected mpox and due to being at a high risk for severe disease (explicitly coded as 'off label use in unapproved indication'). The patient was also started on empiric tecovirimat (brand name unknown), at 600 mg, twice daily for two weeks. Swab specimens of the patient's initial lesions were sent for qualitative polymerase chain reaction (PCR), which showed positive result for non-variola Orthopoxvirus DNA, corroborating a clinical diagnosis of mpox. On an unspecified date, reported as one month later, the patient was examined at an emergency department, where it was noted that the patient had ulcerated papules with necrotic centers of the abdomen and face, including the right upper eyelid and the left malar region. On an unspecified date, reported as the following week, the patient was admitted to the hospital after evident progression of the facial lesions, which had become large shallow ulcers with expanded central necrosis. The patient had also developed periorbital oedema concerning for superimposed preseptal cellulitis. By the following week, the patient's right eyelid lesion had expanded further and began to restrict lid function. No ocular surface involvement was noted, and the patient was started on trifluridine (brand name unknown), 1 percent eye drops for prophylaxis and started HAART. During the following two weeks, despite treatment with oral tecovirimat (600 mg twice daily), HAART, and broad-spectrum antibiotics (intravenous daptomycin and levofloxacin), discrete lesions progressed to a necrotic rash of the face, expanding outward from initial foci and becoming confluent. Qualitative PCR analysis of swabs from multiple skin sites consistently returned positive for non-variola Orthopoxvirus DNA, compatible with disseminated mpox. The patient received a dose of intravenous vaccinia immunoglobulin but the skin necrosis continued to progress. On an unspecified date, the patient subsequently developed pharyngeal oedema and was transferred to tertiary-care center for airway monitoring. Confluent gangrene of the face was apparent. A raised skin edge containing vesicles was noted along the borders of necrotic skin. There were similar areas of expansive skin necrosis on the torso and extremities. The patient was administered a single dose of intravenous cidofovir (5 mg/kg) with probenecid (brand name unknown), and tecovirimat was changed to intravenous formulation (200 mg twice daily). Punch biopsy was performed and showed histology consistent with monkeypox virus infection and a striking absence, paucity of T-lymphocytic infiltrate. Skin histology also showed necrosis and viral cytopathic effects. The patient soon developed an unstable airway, and surgical tracheostomy was performed. Two more doses of vaccinia immunoglobulin were administered, again without improvement. Due to worse lesions on HAART, concern was raised for possible immune reconstitution inflammatory syndrome, although CD4+ percentage had only increased by three points. Biopsy was obtained after the skin lesions had progressed substantially despite HAART. The histological findings were inconsistent with known examples of immune reconstitution inflammatory syndrome. The patient received a brief steroid trial, a short course of prednisone (brand name unknown) (100 mg via nasogastric tube for 4 days) that was subsequently discontinued after his condition continued to progress. As reported, it was hypothesized that immune reconstitution inflammatory syndrome was not the central disease process for the patient, in view of the evidence for primary intradermal progression of monkeypox virus. Despite multimodal treatments the patient's symptoms did not remit, as reported, probably due to a combination of overwhelming immunosuppression, bacterial superinfection, and delays in care. Hospital course was complicated by Sapovirus gastroenteritis, metabolic acidosis, multifactorial renal failure, and severe anaemia. On an unspecified day, the patient subsequently developed multifocal pneumonia and became ventilator-dependent.   On an unspecified date, reported as 15 weeks after the onset of mpox symptoms, the patient died due to systemic complications of the patient's infections.  The reporter assessed all reported events as serious due to seriousness criteria of hospitalization and did not provide a causality assessment.  Additional information received from Bavarian Nordic on 08-Feb-2023 included local BN case ID.; Reporter's Comments: A 45-year-old unvaccinated male patient with AIDS had contracted the mpox infection (PCR detected non-variola Orthopoxvirus DNA). Having already developed vesicopapular lesions, the patient was given tecovirimat (600 mg BID for two weeks) and was also vaccinated with the first dose of Jynneos, given via unknown route and at an unknown dose. Since the indication of Jynneos is pre-exposure prophylaxis of mpox, this is considered an off label use for unapproved indication. Initially, the patient declined HAART (highly active antiretroviral therapy). Approximately a month later, the patient was found to have ulcerated papules with necrotic centres of the abdomen and face. The patient was admitted to hospital and the lesions progressed to ulcers with expanded central necrosis, periorbital oedema concerning for superimposed preseptal cellulitis. The patient was started on trifluridine 1% eye drops and HAART, as well as daptomycin and levofloxacin. Despite the treatment, necrotic rash developed. Qualitative PCR of lesion swabs confirmed Orthopoxvirus DNA, compatible with disseminated mpox. The patient also received intravenous vaccinia immunoglobulin, but the skin necrosis progressed. The patient subsequently developed pharyngeal oedema and needed airway monitoring. Confluent facial gangrene was apparent, with vesicles along the borders. The patient received a single shot of cidofovir (5 mg/kg) with probenecid, intravenously, and was switched to IV tecovirimat (200 mg BID). Biopsy confirmed presence of mpox virus infection and an absence of T-lymphocytes. The patient developed an unstable airway and tracheostomy was performed. Two more doses of the vaccinia immunoglobulin were given, with no improvement. Concern was raised for possible immune reconstitution inflammatory syndrome. CD4+ percentage had increased by three points only. The patient received a short cose of prednisone via NG tube. The patient developed a sapovirus gastroenteritis, multifactorial renal failure, severe anemia and multifocal pneumonia. The patient became ventilator-dependent and died from systemic complications of the infections, 15 weeks after the onset of the initial symptoms. Bacterial superinfection and delayed treatment were pointed out as possible contributory factors to the lethal complications. Infection (fatal, with complications), periorbital cellulitis, gangrene, pharyngeal oedema, immune reconstitution inflammatory syndrome, renal failure, gastroenteritis sapovirus, anemia, bacterial superinfection and pneumonia are unexpected and unlisted per the CCDS V4 and USPI for Jynneos. Off label use is considered listed per company conventions. The patient's medical history included HIV (not on HAART) for 17 years and AIDS for at least one year. Concomitant medications were not specified. According to the CCDS v4, vaccination with Jynneos must be postponed in persons with acute infection if used for pre-event prophylaxis. Post-exposure prophylaxis is not indicated in the CCDS and PI for the suspect vaccine, furthermore, the patient had already developed lesions. The concomitant administration of the vaccine with Vaccinia Immune Globulin (VIG) has not been studied. The patient's reported immune naivety (unvaccinated status prior to contracting the infection), as well as the underlying AIDS, and the delayed HAART, provide a plausible explanation as to why the disease progressed with systemic complications despite treatment with tecovirimat, antibiotics, anti-inflammatory course. The suspected immune reconstitution inflammatory syndrome (associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy) is also consistent with the reported data. Anemia has previously been found in patients with mpox. Therefore, the adverse events are assessed as not related to Jynneos. Off label use is considered not related to Jynneos, but to human error. The case is serious due to the hospitalization and fatal outcome.; Sender's Comments: A 45-year-old unvaccinated male patient with AIDS had contracted the mpox infection (PCR detected non-variola Orthopoxvirus DNA). Having already developed vesicopapular lesions, the patient was given tecovirimat (600 mg BID for two weeks) and was also vaccinated with the first dose of Jynneos, given via unknown route and at an unknown dose. Since the indication of Jynneos is pre-exposure prophylaxis of mpox, this is considered an off label use for unapproved indication. Initially, the patient declined HAART (highly active antiretroviral therapy). Approximately a month later, the patient was found to have ulcerated papules with necrotic centres of the abdomen and face. The patient was admitted to hospital and the lesions progressed to ulcers with expanded central necrosis, periorbital oedema concerning for superimposed preseptal cellulitis. The patient was started on trifluridine 1% eye drops and HAART, as well as daptomycin and levofloxacin. Despite the treatment, necrotic rash developed. Qualitative PCR of lesion swabs confirmed Orthopoxvirus DNA, compatible with disseminated mpox. The patient also received intravenous vaccinia immunoglobulin, but the skin necrosis progressed. The patient subsequently developed pharyngeal oedema and needed airway monitoring. Confluent facial gangrene was apparent, with vesicles along the borders. The patient received a single shot of cidofovir (5 mg/kg) with probenecid, intravenously, and was switched to IV tecovirimat (200 mg BID). Biopsy confirmed presence of mpox virus infection and an absence of T-lymphocytes. The patient developed an unstable airway and tracheostomy was performed. Two more doses of the vaccinia immunoglobulin were given, with no improvement. Concern was raised for p ossible immune reconstitution inflammatory syndrome. CD4+ percentage had increased by three points only. The patient received a short dose of prednisone via NG tube. The patient developed a sapovirus gastroenteritis, multifactorial renal failure, severe anemia and multifocal pneumonia. The patient became ventilator-dependent and died from systemic complications of the infections, 15 weeks after the onset of the initial symptoms. Bacterial superinfection and delayed treatment were pointed out as possible contributory factors to the lethal complications. Infection (fatal, with complications), periorbital cellulitis, gangrene, pharyngeal oedema, immune reconstitution inflammatory syndrome, renal failure, gastroenteritis sapovirus, anemia, bacterial superinfection and pneumonia are unexpected and unlisted per the CCDS V4 and PI for Jynneos. Off label use is considered listed per company conventions. The patient's medical history included HIV (not on HAART) for 17 years and AIDS for at least one year. Concomitant medications were not specified. According to the CCDS v4, vaccination with Jynneos must be postponed in persons with acute infection if used for pre-event prophylaxis. Post-exposure prophylaxis is not indicated in the CCDS and PI for the suspect vaccine, furthermore, the patient had already developed lesions. The concomitant administration of the vaccine with Vaccinia Immune Globulin (VIG) has not been studied. The patient's reported immune naivety (unvaccinated status prior to contracting the infection), as well as the underlying AIDS, and the delayed HAART, provide a plausible explanation as to why the disease progressed with systemic complications despite treatment with tecovirimat, antibiotics, anti-inflammatory course. The suspected immune reconstitution inflammatory syndrome (associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy) is also consistent with the reported data. Anemia has previously been found in patients with mpox. Therefore, the adverse events are assessed as not related to Jynneos. Off label use is considered not related to Jynneos, but to human error. The case is serious due to the hospitalization and fatal outcome.; Reported Cause(s) of Death: Died due to systemic complications of infections