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• W4387445571 abstract "Since 2022, monkeypox virus (MPXV) has been causing a multinational epidemic with Brazil as one of the most affected countries.1Mitjà O Alemany A Marks M et al.Mpox in people with advanced HIV infection: a global case series.Lancet. 2023; 401: 939-949Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 2Ministério da SaúdeBoletim epidemiológico de monkeypox n° 17.https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/variola-dos-macacos/boletim-epidemiologico-de-monkeypox-no-17-coe/viewDate: Sept 1, 2023Date accessed: January 30, 2023Google Scholar During the current mpox (formally known as monkeypox) epidemic, men with AIDS are at increased risk of severe illness and death, although it remains unclear whether deaths are directly attributed to MPXV.2Ministério da SaúdeBoletim epidemiológico de monkeypox n° 17.https://www.gov.br/saude/pt-br/centrais-de-conteudo/publicacoes/boletins/epidemiologicos/variola-dos-macacos/boletim-epidemiologico-de-monkeypox-no-17-coe/viewDate: Sept 1, 2023Date accessed: January 30, 2023Google Scholar We report clinical and autopsy findings of two men in their early 20s, who had severe mpox associated with AIDS in São Paulo. Case 1 was a street market worker, declared as bisexual, who presented with fever, myalgia, inguinal lymphadenopathy, and headache in mid-July 2022, then progressing with maculopapular lesions in the perianal region on the 8th day of illness (DOI). He was diagnosed with HIV in 2016, and previously had neurotuberculosis, neurotoxoplasmosis, neurosyphilis, disseminated histoplasmosis, and cytomegalovirus and herpes virus-1 glossitis. He was treated for HIV and tuberculosis irregularly, with right hemiparesis and seizures as sequelae. In early July 2022, his CD4+ T-cell count was 3·0 cells per μl. On the 16th DOI, he sought emergency help for painful perianal vesicles when the mpox diagnosis was made by RT-PCR of vesicular fluid. On the 28th DOI, he was hospitalised at the Instituto de Infectologia Emílio Ribas (IIER) with disseminated mpox lesions and skin and soft tissue sepsis. During hospitalisation, several new lesions appeared, including on the edges of pre-existing lesions in a centrifugal pattern, in places of dressings and venous access, and many with confluence and dermal necrosis that were constantly painful, which required high doses of opioids. Tecovirimat (TPOXX) was started on the 51st DOI; on the following day the patient had two episodes of generalised tonic-clonic seizures that were controlled with benzodiazepines, allowing for TPOXX treatment for 28 days. On the 55th DOI, he had wheezing with focal ground-glass infiltrates on chest tomography, was diagnosed with Influenza A and B infection (RT-PCR of nasal swab), and deep venous thrombosis of the right leg. The HIV viral load became undetectable on the 57th DOI after reintroducing antiretrovirals. On the 68th DOI, he had respiratory worsening, and bronchoscopy showed extensive necrotic ulcers on the tracheobronchial tree, which had obstructed bronchial ostia of the upper segments of both lower lobes. He developed severe hypoxia and cardiopulmonary arrest as an adverse event. In the post-cardiopulmonary arrest period, he had new episodes of nosocomial septic shock (including Acinetobacter baumanii pneumonia) and died on the 91st DOI. During hospitalisation, he was treated for tuberculosis and histoplasmosis with broad-spectrum antibiotics. Case 2 was an assistant cook, declared as homosexual. In mid-September 2022, he presented with high-grade fever and inguinal lymphadenopathy, followed by maculopapular lesions in the genital and perianal area progressing into painful vesicles. He sought medical attention on the 21st DOI and tested positive for MPXV, HIV, and T pallidum infections. The skin lesions spread centrifugally, and he sought medical care thrice for pain management. On the 29th DOI, he was referred to IIER due to sepsis (possible Fournier's gangrene). His first CD4+ T-cell count was 18 cells per μl, and on the 31st DOI he underwent surgical debridement of the perineal lesion. He developed intestinal obstruction with fever and on the 36th DOI, exploratory laparotomy detected diffuse colitis with oedema of the colonic walls, therefore, a transverse loop colostomy was performed. He received linezolid and meropenem and became afebrile. New skin lesions continued to appear on the limbs, trunk, face, scalp, and oral and genital mucosa. The involvement of the oral and labial mucosa intensified and on the 45th DOI, he presented with airway obstruction with cardiac arrest. He died the following day. Both patients had multiple sexual partners without using preventive measures and none of them reported previous close contact with individuals with active mpox. They were treated in intensive care isolation rooms and died of respiratory failure, sepsis, and multiple organ dysfunction. Both patients received treatment for latent syphilis. At the time of their hospitalisations, mpox vaccines were not available and treatment with TPOXX in Brazil was limited. Additional clinical and pathological data are presented in the appendix. The pathology of mpox described here is severe and includes new findings of visceral involvement by MPXV (figure and appendix pp 8–11).3Rodríguez-Cuadrado FJ Nájera L Suárez D et al.Clinical, histopathologic, immunohistochemical, and electron microscopic findings in cutaneous monkeypox: a multicenter retrospective case series in Spain.J Am Acad Dermatol. 2023; 88: 856-863Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 4Mazzotta V Scorzolini L Falasca L et al.Lymphofollicular lesions associated with monkeypox (mpox) virus proctitis.Int J Infect Dis. 2023; 130: 48-51Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Cann JA Jahrling PB Hensley LE Wahl-Jensen V Comparative pathology of smallpox and monkeypox in man and macaques.J Comp Pathol. 2013; 148: 6-21Crossref PubMed Scopus (46) Google Scholar, 6Araujo MF de Brito T Sesso J Osteomyelitis variolosa.Rev Inst Med Trop São Paulo. 1971; 13: 352-355PubMed Google Scholar In both cases, autopsies showed anasarca, cavity effusions, and diffuse MPXV-mediated lesions in various organs confirmed by detectable vaccinia antigens and MPXV-DNA. Besides multiple MPXV-skin lesions with necrotic ulcers and MPXV-dermal vasculitis, the autopsies showed MPXV-induced bilateral necrotising nodular pneumonia, acute pleuritis with pleural effusion, nodular ulcerative gastrointestinal lesions, necrotic glossitis with vasogenic oedema, extensive proctitis, pancreatitis, sialoadenitis, orchitis (including germinative cells within seminiferous tubules), epididymitis, adrenalitis, and haemophagocytosis. Case 1 had mild MPXV-nephritis and case 2 had MPXV myocarditis and hepatitis. The associated tissue inflammatory response was mild, but with extensive MPXV-mediated tissue necrosis. The main inflammatory cells were lymphocytes, macrophages, neutrophils, few eosinophils. Pyknotic nuclei and karyorrhexis were common, indicating inflammatory cell necrosis. Various MPXV–infected tissues had nuclear TdT expression by immunohistochemistry, suggesting cell death by apoptosis. MPXV was associated with epithelial damage, diffuse neural damage with perineural and Schwann cell infections, mesothelium and fibroblast infection, macrophage dysfunction, and systemic vascular involvement (including lymphatic vessels), which resulted in tissue necrosis in several organs. Specifically, we found diffuse endothelial injury by co-infection of MPXV and cytomegalovirus. MPXV–DNA was also detected in various organs by RT–PCR. We looked for fungi and mycobacteria in all tissues for both cases. In case 1, we found peripancreatic lymph nodes with caseous necrosis and acid-fast bacilli by Ziehl–Neelsen stain, indicating active mycobacteriosis. There was no evidence of T. pallidum infection detected after autopsy of either patient. Sequencing of the MPXV genome characterised clade IIb. The genome of MPXV sequenced strains clustered to different geographic areas: strain from case 1 belonged to the B1 lineage that is closely related to Spanish strains, and for case 2, the B1.1 lineage related to German strains. Of note, both cases had co-infections with Herpesviridae virus, mainly cytomegalovirus and herpes simplex. Some limitations of this work are: (1) the lack of cavitary fluids for detecting MPXV–DNA by RT–PCR, and (2) we did not perform ultrastructural analysis for virus characterisation in tissues. However, immunohistochemistry with a pan-orthopoxvirus (anti-vaccinia) antibody correspond to electron microscopy results shown by other authors. Furthermore, we detected MPXV–DNA by RT–PCR in several organs. Our data show that in patients with advanced AIDS, MPXV behaves as an opportunistic agent, with insufficient effect of TPOXX in reducing MPXV-replication. Tecovirimat is recommended for the mpox treatment, however, it is unknown which patients benefit from the antiviral treatment.7Mazzotta V Cozzi-Lepri A Lanini S et al.Effect of tecovirimat on healing time and viral clearance by emulation of a target trial in patients hospitalized for mpox.J Med Virol. 2023; 95e28868Crossref Scopus (2) Google Scholar It is possible that severe immune dysfunction, with low CD4+ T-cell counts, might explain the lack of response of the cases to TPOXX treatment. Several of our findings indicate a weak immunological response to MPXV in both patients, such as widespread, persistent MPXV infection. Reactivation of Herpesviridae virus by direct tissue damage is further evidence of the profound immune dysfunction in these patients. The MPXV-vasculitis is pivotal in the pathogenesis of systemic spread, necrotic skin, and visceral lesions; and neural MPXV-damage might be associated with refractive and painful mpox skin or mucosal lesions. MPXV-mesothelial infection suggests that thoracocentesis or paracentesis could be performed to diagnose MPXV-pneumonia and colitis. MPXV-induces macrophage dysfunction with haemophagocytosis. Co-infection with Herpesviridae virus might be common, with synergic damage in various organs. Finally, in cases of HIV and MPXV coinfection, MPXV appears to be transmitted by a complex mechanism involving contact with infected skin and mucosa, and respiratory and sexual transmission, corroborating previous data on aerosol MPVX animal infection and MPXV–DNA detection in semen.8Zaucha GM Jahrling PB Geisbert TW Swearengen JR Hensley L The pathology of experimental aerosolized monkeypox virus infection in cynomolgus monkeys (Macaca fascicularis).Lab Invest. 2001; 81: 1581-1600Summary Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 9Tesh RB Watts DM Sbrana E Siirin M Popov VL Xiao SY Experimental infection of ground squirrels (Spermophilus tridecemlineatus) with monkeypox virus.Emerg Infect Dis. 2004; 10: 1563-1567Crossref PubMed Scopus (89) Google Scholar, 10Nalca A Livingston VA Garza NL et al.Experimental infection of cynomolgus macaques (Macaca fascicularis) with aerosolized monkeypox virus.PLoS One. 2010; 5e12880Crossref Scopus (52) Google Scholar, 11Liu J Mucker EM Chapman JL et al.Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors.Nat Microbiol. 2022; 7: 1980-1986Crossref PubMed Scopus (6) Google Scholar, 12Lapa D Carletti F Mazzotta V et al.Monkeypox virus isolation from a semen sample collected in the early phase of infection in a patient with prolonged seminal viral shedding.Lancet Infect Dis. 2022; 22: 1267-1269Summary Full Text Full Text PDF PubMed Scopus (115) Google Scholar These autopsies show previously undescribed findings in the pathology of human MPXV infection and are helpful to understand why people living with HIV or AIDS are under high risk for worse mpox-associated outcomes.13Bayer-Garner IB Monkeypox virus: histologic, immunohistochemical and electron-microscopic findings.J Cutan Pathol. 2005; 32: 28-34Crossref PubMed Scopus (86) Google Scholar, 14Alarcón J Kim M Terashita D et al.An mpox-related death in the United States.N Engl J Med. 2023; 388: 1246-1247Crossref PubMed Scopus (6) Google Scholar, 15Fuller R Cederroth T Patel G et al.First case of rapidly fatal mpox from secondary (household) transmission in a kidney transplant recipient.Am J Transplant. 2023; (published online July 28.)https://doi.org/10.1016/j.ajt.2023.07.017Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar We declare no competing interests. We would like to thank all health professionals from IIER who provided medical care to the patients, and all autopsy and pathology laboratory technicians from Departamento de Patologia-FMUSP, who collaborated in the analysis of the cases. We acknowledge support from the Medical Research Council–São Paulo Research Foundation CADDE partnership award (MR/S0195/1; FAPESP18/143890; 2013/17159‐2), Wellcome Trust and Royal Society (Sir Henry Dale Fellowship 204311/Z/16/Z), and the Bill & Melinda Gates Foundation (INV-034540; INV-034652; and INV‐002396), and Bolsa de produtividade em pesquisa: Conselho Nacional de Desenvolvimento Científico e Tecnológico 304987/2017-4 (MD). Download .pdf (6.79 MB) Help with pdf files Supplementary appendix" @default.
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• W4387445571 date "2023-10-01" @default.
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• W4387445571 title "Main autopsy findings of visceral involvement by fatal mpox in patients with AIDS: necrotising nodular pneumonia, nodular ulcerative colitis, and diffuse vasculopathy" @default.
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