Investigation of an mpox outbreak affecting many vaccinated persons in Chicago, IL-March 2023-June 2023.

BACKGROUND: After months of few mpox cases, an increased number of cases were reported in Chicago during May 2023; predominantly among fully vaccinated patients. We investigated the outbreak scope, differences between vaccinated and unvaccinated patients, and hypotheses for monkeypox virus (MPXV) infection after vaccination. METHODS: We interviewed patients and reviewed medical records to assess demographic, behavioral, and clinical characteristics, mpox vaccine status, and vaccine administration routes. We evaluated serum antibody levels after infection and compared patient viral genomes with MPXV sequences in available databases. We discussed potential vaccine compromise with partners who manufactured, handled, and administered vaccine associated with breakthrough infections. RESULTS: During March 18-June 27, 2023, we identified 49 mpox cases; 57% of these mpox patients were fully vaccinated (FV). FV patients received both JYNNEOS doses subcutaneously (57%), intradermally (7%), or via heterologous administration (36%). FV patients had more median sex partners (3, IQR=1-4) versus not fully vaccinated (NFV) patients (1, IQR=1-2). Thirty-six of 37 sequenced specimens belonged to lineage B.1.20 of clade IIb MPXV, which did not demonstrate any amino acid changes relative to B.1, the predominant lineage from May 2022. Vaccinated patients demonstrated expected humoral antibody responses; none were hospitalized. No vaccine storage excursions were identified. Approximately 63% of people at risk for mpox in Chicago were FV during this period. CONCLUSIONS: Our investigation indicated cases were likely due to frequent behaviors associated with mpox transmission, even with relatively high vaccine effectiveness and vaccine coverage. Cases after vaccination might occur in similar populations.

Pathology and Monkeypox virus Localization in Tissues From Immunocompromised Patients With Severe or Fatal Mpox.

BACKGROUND: Pathology and Monkeypox virus (MPXV) tissue tropism in severe and fatal human mpox is not thoroughly described but can help elucidate the disease pathogenesis and the role of coinfections in immunocompromised patients. METHODS: We analyzed biopsy and autopsy tissues from 22 patients with severe or fatal outcomes to characterize pathology and viral antigen and DNA distribution in tissues by immunohistochemistry and in situ hybridization. Tissue-based testing for coinfections was also performed. RESULTS: Mucocutaneous lesions showed necrotizing and proliferative epithelial changes. Deceased patients with autopsy tissues evaluated had digestive tract lesions, and half had systemic tissue necrosis with thrombotic vasculopathy in lymphoid tissues, lung, or other solid organs. Half also had bronchopneumonia, and one-third had acute lung injury. All cases had MPXV antigen and DNA detected in tissues. Coinfections were identified in 5 of 16 (31%) biopsy and 4 of 6 (67%) autopsy cases. CONCLUSIONS: Severe mpox in immunocompromised patients is characterized by extensive viral infection of tissues and viremic dissemination that can progress despite available therapeutics. Digestive tract and lung involvement are common and associated with prominent histopathological and clinical manifestations. Coinfections may complicate mpox diagnosis and treatment. Significant viral DNA (likely correlating to infectious virus) in tissues necessitates enhanced biosafety measures in healthcare and autopsy settings.

How the Orthodox Features of Orthopoxviruses Led to an Unorthodox Mpox Outbreak: What We've Learned, and What We Still Need to Understand.

Orthopoxviruses have repeatedly confounded expectations in terms of the clinical illness they cause and their patterns of spread. Monkeypox virus (MPXV), originally characterized in the late 1950s during outbreaks among captive primates, has been recognized since the 1970s to cause human disease (mpox) in West and Central Africa, where interhuman transmission has largely been associated with nonsexual, close physical contact. In May 2022, a focus of MPXV transmission was detected, spreading among international networks of gay, bisexual, and other men who have sex with men. The outbreak grew in both size and geographic scope, testing the strength of preparedness tools and public health science alike. In this article we consider what was known about mpox before the 2022 outbreak, what we learned about mpox during the outbreak, and what continued research is needed to ensure that the global public health community can detect, and halt further spread of this disease threat.

Prevalence of Undiagnosed Monkeypox Virus Infections during Global Mpox Outbreak, United States, June-September 2022.

Since May 2022, mpox has been identified in 108 countries without endemic disease; most cases have been in gay, bisexual, or other men who have sex with men. To determine number of missed cases, we conducted 2 studies during June-September 2022: a prospective serologic survey detecting orthopoxvirus antibodies among men who have sex with men in San Francisco, California, and a retrospective monkeypox virus PCR testing of swab specimens submitted for other infectious disease testing among all patients across the United States. The serosurvey of 225 participants (median age 34 years) detected 18 (8.0%) who were orthopoxvirus IgG positive and 3 (1.3%) who were also orthopoxvirus IgM positive. The retrospective PCR study of 1,196 patients (median age 30 years; 54.8% male) detected 67 (5.6%) specimens positive for monkeypox virus. There are likely few undiagnosed cases of mpox in regions where sexual healthcare is accessible and patient and clinician awareness about mpox is increased.

The CDC Domestic Mpox Response - United States, 2022-2023.

Monkeypox (mpox) is a serious viral zoonosis endemic in west and central Africa. An unprecedented global outbreak was first detected in May 2022. CDC activated its emergency outbreak response on May 23, 2022, and the outbreak was declared a Public Health Emergency of International Concern on July 23, 2022, by the World Health Organization (WHO),* and a U.S. Public Health Emergency on August 4, 2022, by the U.S. Department of Health and Human Services.† A U.S. government response was initiated, and CDC coordinated activities with the White House, the U.S. Department of Health and Human Services, and many other federal, state, and local partners. CDC quickly adapted surveillance systems, diagnostic tests, vaccines, therapeutics, grants, and communication systems originally developed for U.S. smallpox preparedness and other infectious diseases to fit the unique needs of the outbreak. In 1 year, more than 30,000 U.S. mpox cases were reported, more than 140,000 specimens were tested, >1.2 million doses of vaccine were administered, and more than 6,900 patients were treated with tecovirimat, an antiviral medication with activity against orthopoxviruses such as Variola virus and Monkeypox virus. Non-Hispanic Black (Black) and Hispanic or Latino (Hispanic) persons represented 33% and 31% of mpox cases, respectively; 87% of 42 fatal cases occurred in Black persons. Sexual contact among gay, bisexual, and other men who have sex with men (MSM) was rapidly identified as the primary risk for infection, resulting in profound changes in our scientific understanding of mpox clinical presentation, pathogenesis, and transmission dynamics. This report provides an overview of the first year of the response to the U.S. mpox outbreak by CDC, reviews lessons learned to improve response and future readiness, and previews continued mpox response and prevention activities as local viral transmission continues in multiple U.S. jurisdictions (Figure).

Interim Clinical Treatment Considerations for Severe Manifestations of Mpox - United States, February 2023.

Monkeypox (mpox) is a disease caused by infection with Monkeypox virus (MPXV), an Orthopoxvirus (OPXV) in the same genus as Variola virus, which causes smallpox. During 2022, a global outbreak involving mpox clade IIb was recognized, primarily among gay, bisexual, and other men who have sex with men.* Most affected patients have been immunocompetent and experienced ≤10 rash lesions (1). CDC has recommended supportive care including pain control.† However, some patients have experienced severe mpox manifestations, including ocular lesions, neurologic complications, myopericarditis, complications associated with mucosal (oral, rectal, genital, and urethral) lesions, and uncontrolled viral spread due to moderate or severe immunocompromise, particularly advanced HIV infection (2). Therapeutic medical countermeasures (MCMs) are Food and Drug Administration (FDA)-regulated drugs and biologics that are predominantly stockpiled by the U.S. government; MCMs developed for smallpox preparedness or shown to be effective against other OPXVs (i.e., tecovirimat, brincidofovir, cidofovir, trifluridine ophthalmic solution, and vaccinia immune globulin intravenous [VIGIV]) have been used to treat severe mpox. During May 2022-January 2023, CDC provided more than 250 U.S. mpox consultations. This report synthesizes data from animal models, MCM use for human cases of related OPXV, unpublished data, input from clinician experts, and experience during consultations (including follow-up) to provide interim clinical treatment considerations. Randomized controlled trials and other carefully controlled research studies are needed to evaluate the effectiveness of MCMs for treating human mpox. Until data gaps are filled, the information presented in this report represents the best available information concerning the effective use of MCMs and should be used to guide decisions about MCM use for mpox patients.

Fatal Human Rabies Infection With Suspected Host-Mediated Failure of Post-Exposure Prophylaxis Following a Recognized Zoonotic Exposure-Minnesota, 2021.

BACKGROUND: No human rabies post-exposure prophylaxis (PEP) failure has been documented in the United States using modern cell culture-based vaccines. In January 2021, an 84-year-old male died from rabies 6 months after being bitten by a rabid bat despite receiving timely rabies PEP. We investigated the cause of breakthrough infection. METHODS: We reviewed medical records, laboratory results, and autopsy findings and performed whole-genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close patient contacts. RESULTS: Rabies virus antibodies present in serum and cerebrospinal fluid were nonneutralizing. Antemortem blood testing revealed that the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, 3 (0.9%) warranted PEP. CONCLUSIONS: This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture-based vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Human rabies despite post-exposure prophylaxis: a systematic review of fatal breakthrough infections after zoonotic exposures.

Post-exposure prophylaxis (PEP) for rabies is widely administered and highly effective. Nevertheless, sporadic breakthrough infections (ie, rabies in people who have started PEP) have been reported. We conducted a systematic review of articles published between Jan 1, 1980 and June 1, 2022 to characterise breakthrough infections. After reviewing 3380 articles from across all continents, we identified 52 articles, which included a total of 122 breakthrough infections. We classified breakthrough infections on the basis of adherence to core practices (ie, wound cleaning and vaccine administration). Of 86 breakthrough infections with data, median time from exposure to symptom onset was 20 days (IQR 16-24). Most (89 [77%] of 115) participants received PEP within 2 days of an exposure. Severe wounds (defined as those involving multiple wound sites or bites to the head, face, or neck) were common (80 [69%] of 116 [with data]). Deviations from core practices were reported in 68 (56%) of 122 cases. Other possible causes for breakthrough infections included errors in the administration of rabies immunoglobulin, delays in seeking health care, and comorbidities or immunosuppression. Cold-chain integrity assessments and potency testing of PEP biologics were only rarely assessed (8 [7%] of 122 cases), neither of which were found to be a cause of breakthrough infections. Timely and appropriate administration of PEP is crucial to prevent rabies, and although people with high-risk exposures or immunosuppression can develop rabies despite adherence to core practices, this occurrence remains exceedingly rare.

Rabies experts on demand: A cross-sectional study describing the use of a rabies telehealth service.

Background: Rabies expert on demand (REOD) telehealth service is provided by the U.S. Centers for Disease Control and Prevention (CDC) to assist public health practitioners, health providers, and the public to interpret national and international rabies prevention guidelines. REOD is staffed by subject matter experts of the CDC Poxvirus and Rabies Branch to assess each unique situation and provide evidence-based guidance to stakeholders. This study aims to describe the utilization of a rabies telehealth system and provide insight into common consultations. Methods: A cross-sectional study of the nature of inquiries to REOD was done using the data collected from September 1, 2017 to September 30, 2021. An inquiry tracking form and Microsoft Access database were developed to document all inquiries received. Inquired ones were summarized to determine the frequency of inquiries by month, category, and location. Results: Over a 49-month period, REOD received 5228 inquiries. Peak inquiries (n = 108) occurred during August 2019. The most frequent inquiries received pertained to risk assessment and management of rabies exposures (n = 1109), requests for testing assistance (n = 912), consultation for suspected human rabies (n = 746), rabies exposures and post-bite treatment occurring internationally (n = 310), and consultation for deviations in the recommended pre- and postexposure prophylaxis regimen (n = 300). Conclusion: REOD is a global resource for consultation related to managing rabies exposures, diagnostic issues, and rabies control strategies. REOD is a regularly utilized CDC service, as the demand for up-to-date rabies guidance remains high. REOD fulfills a critical role for the interpretation and consultation on rabies prevention guidelines to stakeholder.

Human Rabies - Texas, 2021.

In late August 2021, a boy aged 7 years was bitten by a bat while he was playing outside his apartment home in Medina County, Texas. He informed his parents; however, no rabies postexposure prophylaxis (PEP) was sought because there were no visible bite marks, and the family was unaware that contact with a bat, including in the absence of visible bite marks, might cause rabies. Approximately 2 months later, the child was hospitalized for altered mental status, seizures, and hypersalivation and ultimately received a diagnosis of rabies. Experimental therapies were attempted; however, the child died 22 days after symptom onset. Fifty-seven persons who met criteria for suspected or known exposure to infectious secretions in this case were advised to consult with a medical provider about the need for rabies PEP in accordance with Advisory Committee on Immunization Practices (ACIP) guidelines (1). Rabies, an acute, progressive neuroencephalitis, is nearly always fatal. Although dogs are the most common source of human rabies deaths worldwide and account for an estimated 59,000 annual cases of human rabies globally (2), bats are the most common source of domestically acquired rabies in the United States and have been implicated in 31 (81.6%) of 38 human infections since 2000 (3). Attempts to prevent death or poor neurologic outcomes once rabies symptoms develop have been largely unsuccessful (4). Administration of rabies PEP, comprising rabies immunoglobulin and a series of doses of rabies vaccine, is critical to preventing rabies after an exposure; enhanced public education about the risk posed by bats, and the availability of PEP to prevent rabies, is needed.

Multiple lineages of monkeypox virus detected in the United States, 2021-2022.

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of monkeypox virus (MPXV) among two 2021 and seven 2022 US monkeypox cases: the major 2022 outbreak variant called B.1 and a minor contemporaneously sampled variant called A.2. Analyses of mutations among these two variants revealed an extreme preference for GA-to-AA mutations indicative of human APOBEC3 cytosine deaminase activity among Clade IIb MPXV (previously West African, Nigeria) sampled since 2017. Such mutations were not enriched within other MPXV clades. These findings suggest that APOBEC3 editing may be a recurrent and a dominant driver of MPXV evolution within the current outbreak.

Ocular Monkeypox - United States, July-September 2022.

As of October 11, 2022, a total of 26,577 monkeypox cases had been reported in the United States.* Although most cases of monkeypox are self-limited, lesions that involve anatomically vulnerable sites can cause complications. Ocular monkeypox can occur when Monkeypox virus (MPXV) is introduced into the eye (e.g., from autoinoculation), potentially causing conjunctivitis, blepharitis, keratitis, and loss of vision (1). This report describes five patients who acquired ocular monkeypox during July-September 2022. All patients received treatment with tecovirimat (Tpoxx)†; four also received topical trifluridine (Viroptic).§ Two patients had HIV-associated immunocompromise and experienced delays between clinical presentation with monkeypox and initiation of monkeypox-directed treatment. Four patients were hospitalized, and one experienced marked vision impairment. To decrease the risk for autoinoculation, persons with monkeypox should be advised to practice hand hygiene and to avoid touching their eyes, which includes refraining from using contact lenses (2). Health care providers and public health practitioners should be aware that ocular monkeypox, although rare, is a sight-threatening condition. Patients with signs and symptoms compatible with ocular monkeypox should be considered for urgent ophthalmologic evaluation and initiation of monkeypox-directed treatment. Public health officials should be promptly notified of cases of ocular monkeypox. Increased clinician awareness of ocular monkeypox and of approaches to prevention, diagnosis, and treatment might reduce associated morbidity.

Monkeypox Virus Infection Resulting from an Occupational Needlestick - Florida, 2022.

In August 2022, the Florida Department of Health notified CDC of a nurse who acquired monkeypox through an occupational exposure while providing care to a patient with monkeypox. To date, occupationally acquired Monkeypox virus (MPXV) infections in health care personnel (HCP) have been rarely reported during the 2022 multinational outbreak (1,2). This report describes the first reported U.S. case and recommends approaches for preventing occupationally acquired MPXV infections in HCP.

Orthopoxvirus Testing Challenges for Persons in Populations at Low Risk or Without Known Epidemiologic Link to Monkeypox - United States, 2022.

Since May 2022, approximately 20,000 cases of monkeypox have been identified in the United States, part of a global outbreak occurring in approximately 90 countries and currently affecting primarily gay, bisexual, and other men who have sex with men (MSM) (1). Monkeypox virus (MPXV) spreads from person to person through close, prolonged contact; a small number of cases have occurred in populations who are not MSM (e.g., women and children), and testing is recommended for persons who meet the suspected case definition* (1). CDC previously developed five real-time polymerase chain reaction (PCR) assays for detection of orthopoxviruses from lesion specimens (2,3). CDC was granted 510(k) clearance for the nonvariola-orthopoxvirus (NVO)-specific PCR assay by the Food and Drug Administration. This assay was implemented within the Laboratory Response Network (LRN) in the early 2000s and became critical for early detection of MPXV and implementation of public health action in previous travel-associated cases as well as during the current outbreak (4-7). PCR assays (NVO and other Orthopoxvirus laboratory developed tests [LDT]) represent the primary tool for monkeypox diagnosis. These tests are highly sensitive, and cross-contamination from other MPXV specimens being processed, tested, or both alongside negative specimens can occasionally lead to false-positive results. This report describes three patients who had atypical rashes and no epidemiologic link to a monkeypox case or known risk factors; these persons received diagnoses of monkeypox based on late cycle threshold (Ct) values ≥34, which were false-positive test results. The initial diagnoses were followed by administration of antiviral treatment (i.e., tecovirimat) and JYNNEOS vaccine postexposure prophylaxis (PEP) to patients' close contacts. After receiving subsequent testing, none of the three patients was confirmed to have monkeypox. Knowledge gained from these and other cases resulted in changes to CDC guidance. When testing for monkeypox in specimens from patients without an epidemiologic link or risk factors or who do not meet clinical criteria (or where these are unknown), laboratory scientists should reextract and retest specimens with late Ct values (based on this report, Ct ≥34 is recommended) (8). CDC can be consulted for complex cases including those that appear atypical or questionable cases and can perform additional viral species- and clade-specific PCR testing and antiorthopoxvirus serologic testing.

Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol - United States, May-August 2022.

Currently, no Food and Drug Administration (FDA)-approved treatments for human monkeypox are available. Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. CDC holds a nonresearch EA-IND protocol that facilitates access to and use of tecovirimat for treatment of monkeypox.§ The protocol includes patient treatment and adverse event reporting forms to monitor safety and ensure intended clinical use in accordance with FDA EA-IND requirements. The current multinational monkeypox outbreak, first detected in a country where Monkeypox virus infection is not endemic in May 2022, has predominantly affected gay, bisexual, and other men who have sex with men (MSM) (1,2). To describe characteristics of persons treated with tecovirimat for Monkeypox virus infection, demographic and clinical data abstracted from available tecovirimat EA-IND treatment forms were analyzed. As of August 20, 2022, intake and outcome forms were available for 549 and 369 patients, respectively; 97.7% of patients were men, with a median age of 36.5 years. Among patients with available data, 38.8% were reported to be non-Hispanic White (White) persons, 99.8% were prescribed oral tecovirimat, and 93.1% were not hospitalized. Approximately one half of patients with Monkeypox virus infection who received tecovirimat were living with HIV infection. The median interval from initiation of tecovirimat to subjective improvement was 3 days and did not differ by HIV infection status. Adverse events were reported in 3.5% of patients; all but one adverse event were nonserious. These data support the continued access to and treatment with tecovirimat for patients with or at risk for severe disease in the ongoing monkeypox outbreak.

Environmental Persistence of Monkeypox Virus on Surfaces in Household of Person with Travel-Associated Infection, Dallas, Texas, USA, 2021.

In July 2021, we conducted environmental sampling at the residence of a person in Dallas, Texas, USA, who had travel-associated human West African monkeypox virus (MPXV-WA). Targeted environmental swab sampling was conducted 15 days after the person who had monkeypox left the household. Results indicate extensive MPXV-WA DNA contamination, and viable virus from 7 samples was successfully isolated in cell culture. There was no statistical difference (p = 0.94) between MPXV-WA PCR positivity of porous (9/10, 90%) vs. nonporous (19/21, 90.5%) surfaces, but there was a significant difference (p<0.01) between viable virus detected in cultures of porous (6/10, 60%) vs. nonporous (1/21, 5%) surfaces. These findings indicate that porous surfaces (e.g., bedding, clothing) may pose more of a MPXV exposure risk than nonporous surfaces (e.g., metal, plastic). Viable MPXV was detected on household surfaces after at least 15 days. However, low titers (<102 PFU) indicate a limited potential for indirect transmission.