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Cutaneous acanthamoebiasis is a rare diagnosis that carries a mortality rate of over 70%. This disease predominantly affects immunocompromised individuals, though infections have been reported in immunocompetent individuals. We report a fatal case of cutaneous Acanthamoeba infection in a patient with granulomatous vasculitis on biopsy, initially thought to be antineutrophil cytoplasmic antibody (ANCA)-negative vasculitis. The patient primarily presented with ulcerating nasal lesions, which subsequently developed into widespread cutaneous lesions. Diagnosis was made months after presentation when amebae were identified during histopathological examination of biopsies obtained repeatedly after the patient failed to improve on standard therapies for ANCA-negative vasculitis. Treatment was unsuccessful, and the patient died due to complications of widespread Acanthamoeba infection. Cutaneous acanthamoebiasis should be considered in the differential diagnosis of granulomatous vasculitis that fails to improve on standard therapies. Early detection and treatment may improve outcomes and reduce mortality in this highly fatal infection.

An important aim of viscoelastic testing (VET) is to implement transfusion algorithms based on coagulation test results to help reduce transfusion rates and improve patient outcomes. Establishing a rapid diagnosis and providing timely treatment of coagulopathy is the cornerstone of management of severely bleeding patients in trauma, postpartum hemorrhage, and major surgery. As the nature of acute bleeding and trauma leads to an unstable and tenuous physiologic state, conventional coagulation tests (CCTs) are too slow to diagnose, manage, and also course correct any hemostatic abnormalities that accompany an acute critical illness. Viscoelastic point-of-care tests strongly correlate with results from standard laboratory tests but are designed to enable clinicians to make timely, informed bleeding management decisions when time to intervene is critical. These assays provide an individualized and goal-oriented approach to patient blood management and are increasingly becoming involved in transfusion algorithms. The scope of this review aims to evaluate the current literature on VETs and their impact on actionable outputs in clinical decision making and their relationship to CCT.

Background Cache Valley virus (CVV) is a mosquito-borne virus that is a rare cause of disease in humans. In the fall of 2020, a patient developed encephalitis 6 weeks following kidney transplantation and receipt of multiple blood transfusions. Methods After ruling out more common etiologies, metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) was performed. We reviewed the medical histories of the index kidney recipient, organ donor, and recipients of other organs from the same donor and conducted a blood traceback investigation to evaluate blood transfusion as a possible source of infection in the kidney recipient. We tested patient specimens using reverse-transcription polymerase chain reaction (RT-PCR), the plaque reduction neutralization test, cell culture, and whole-genome sequencing. Results CVV was detected in CSF from the index patient by mNGS, and this result was confirmed by RT-PCR, viral culture, and additional whole-genome sequencing. The organ donor and other organ recipients had no evidence of infection with CVV by molecular or serologic testing. Neutralizing antibodies against CVV were detected in serum from a donor of red blood cells received by the index patient immediately prior to transplant. CVV neutralizing antibodies were also detected in serum from a patient who received the co-component plasma from the same blood donation. Conclusions Our investigation demonstrates probable CVV transmission through blood transfusion. Clinicians should consider arboviral infections in unexplained meningoencephalitis after blood transfusion or organ transplantation. The use of mNGS might facilitate detection of rare, unexpected infections, particularly in immunocompromised patients.

On April 20, 2018, the Kween District Health Office in Kween District, Uganda reported 7 suspected cases of human anthrax. A team from the Uganda Ministry of Health and partners investigated and identified 49 cases, 3 confirmed and 46 suspected; no deaths were reported. Multiple exposures from handling the carcass of a cow that had died suddenly were significantly associated with cutaneous anthrax, whereas eating meat from that cow was associated with gastrointestinal anthrax. Eating undercooked meat was significantly associated with gastrointestinal anthrax, but boiling the meat for >60 minutes was protective. We recommended providing postexposure antimicrobial prophylaxis for all exposed persons, vaccinating healthy livestock in the area, educating farmers to safely dispose of animal carcasses, and avoiding handling or eating meat from livestock that died of unknown causes.

Summary Background Since August, 2019, US public health officials have been investigating a national outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI). A spectrum of histological patterns consistent with acute to subacute lung injury has been seen in biopsies; however, autopsy findings have not been systematically characterised. We describe the pathological findings in autopsy and biopsy tissues submitted to the US Centers for Disease Control and Prevention (CDC) for the evaluation of suspected EVALI. Methods Between Aug 1, 2019, and Nov 30, 2019, we examined lung biopsy (n=10 individuals) and autopsy (n=13 individuals) tissue samples received by the CDC, submitted by 16 US states, from individuals with: a history of e-cigarette, or vaping, product use; respiratory, gastrointestinal, or constitutional symptoms; and either pulmonary infiltrates or opacities on chest imaging, or sudden death from an undetermined cause. We also reviewed medical records, evaluated histopathology, and performed infectious disease testing when indicated by histopathology and clinical history. Findings 21 cases met surveillance case definitions for EVALI, with a further two cases of clinically suspected EVALI evaluated. All ten lung biopsies showed histological evidence of acute to subacute lung injury, including diffuse alveolar damage or organising pneumonia. These patterns were also seen in nine of 13 (69%) autopsy cases, most frequently diffuse alveolar damage (eight autopsies), but also acute and organising fibrinous pneumonia (one autopsy). Additional pulmonary pathology not necessarily consistent with EVALI was seen in the remaining autopsies, including bronchopneumonia, bronchoaspiration, and chronic interstitial lung disease. Three of the five autopsy cases with no evidence of, or a plausible alternative cause for acute lung injury, had been classified as confirmed or probable EVALI according to surveillance case definitions. Interpretation Acute to subacute lung injury patterns were seen in all ten biopsies and most autopsy lung tissues from individuals with suspected EVALI. Acute to subacute lung injury can have numerous causes; however, if it is identified in an individual with a history of e-cigarette, or vaping, product use, and no alternative cause is apparent, a diagnosis of EVALI should be strongly considered. A review of autopsy tissue pathology in suspected EVALI deaths can also identify alternative diagnoses, which can enhance the specificity of public health surveillance efforts. Funding US Centers for Disease Control and Prevention.

An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Characterization of the histopathology and cellular localization of SARS-CoV-2 in the tissues of patients with fatal COVID-19 is critical to further understand its pathogenesis and transmission and for public health prevention measures. We report clinicopathologic, immunohistochemical, and electron microscopic findings in tissues from 8 fatal laboratory-confirmed cases of SARS-CoV-2 infection in the United States. All cases except 1 were in residents of long-term care facilities. In these patients, SARS-CoV-2 infected epithelium of the upper and lower airways with diffuse alveolar damage as the predominant pulmonary pathology. SARS-CoV-2 was detectable by immunohistochemistry and electron microscopy in conducting airways, pneumocytes, alveolar macrophages, and a hilar lymph node but was not identified in other extrapulmonary tissues. Respiratory viral co-infections were identified in 3 cases; 3 cases had evidence of bacterial co-infection.

INTRODUCTION Blastomycosis is endemic in Wisconsin with Blastomyces dermatitidis and B. gilchristii responsible for infections. Urine antigen testing is a non-invasive diagnostic method for blastomycosis with up to 93% test sensitivity. However, the test's sensitivity has not been evaluated with relationship to B. gilchristii infections. METHODS We aimed to assess physician use of the urine antigen assay and its sensitivity to B. gilchristii and B. dermatitidis infections in a retrospective study. Culture confirmed clinical cases of blastomycosis from 2008-2016 were identified within Marshfield Clinic Health System (MCHS) and UW Hospital and Clinics (UWHC) medical records. Clinical data were abstracted from each medical record and included the following: patient demographics, presence of immune compromising and underlying medical conditions, treatment drugs, presence of isolated pulmonary or disseminated disease, death, urine antigen testing, timeframe of testing, and quantitative test values (EIA units or ng/mL). RESULTS A total of 140 blastomycosis cases were included in this study, with MCHS contributing 114 cases to the study and UWHC contributing 26 cases. The majority of UWHC cases (n=22; 85%) were caused by B. dermatitidis and the majority of MCHS cases (n=73; 64%) were caused by B. gilchristii. UWHC physicians were significantly more likely to treat with multiple drugs during the course of infection and were more likely to prescribe amphotericin B and voriconazole. Urine antigen testing was more frequently used at UWHC (n=24; 92%) than MCHS (n=51; 45%; P < 0.00001). In this study, the urine antigen assay demonstrated 79% sensitivity. Sensitivity was significantly associated with the timeframe of testing (P < 0.05), with most true positive urine antigen tests (83%) being performed ≤ 7 days from diagnosis. In this study, the urine antigen assay was capable of detecting both B. dermatitidis and B. gilchristii at about equal sensitivity. Urine antigen concentration (ng/mL) trended higher in B. dermatitidis infections. CONCLUSION This study found that the urine antigen assay is capable of detecting both species of Blastomyces at about the same sensitivity. We recommend continued use of the urine antigen assay for diagnosis of blastomycosis and recommend that the assay be used early in the diagnostic process to minimize the chance of false negative results.

Jamestown Canyon virus (JCV), a mosquito-borne Orthobunyavirus (within the California serogroup), can cause severe neuroinvasive disease. According to national data during 2000–2013, 42% of the 31 documented JCV disease cases in the United States were detected in residents from Wisconsin. The Wisconsin Division of Public Health enhanced JCV surveillance by implementing routine use of JCV-specific immunoglobulin M (IgM) antibody testing followed by confirmatory JCV-specific plaque reduction neutralization testing on all patients with suspected cases of arboviral infection who had tests positive for arboviral immunoglobin at commercial laboratories. During 2011–2016, of the 287 Wisconsin specimens tested on the Arbovirus IgM Antibody Panel, 30 JCV cases were identified (26 confirmed and four probable). Twenty-seven (90%) JCV cases were detected after 2013. Among all cases, 17 (56%) were male and the median age was 54 years (range: 10–84 years). Fifteen patients had neuroinvasive disease, including meningitis (n = 9) and meningoencephalitis (n = 6). Although historically considered rare, the relatively high rate (0.12 cases/100,000 population) of diagnosis of JCV infections among Wisconsin residents during 2013–2016 compared with that in previous years suggests occurrence is widespread throughout Wisconsin and historically may have been under-recognized. This study aims to raise awareness of JCV infection for differential diagnosis among the arboviral diseases. Improved and timely diagnosis of arboviral disease is important in that it will provide more information regarding emerging infections and promote preventive measures to avoid mosquito-borne exposure and infection among residents of and visitors to affected areas.

Numerous tuberculosis (TB) deaths remain undetected in low-resource endemic settings. With autopsy-confirmed tuberculosis as our standard, we assessed the diagnostic performance of Xpert MTB/RIF Ultra (Ultra; Cepheid) on nasopharyngeal specimens collected postmortem.From October 2016 through May 2019, we enrolled pediatric and adult medical deaths to a prospective autopsy study at two referral hospitals in northern Tanzania with next-of-kin authorization. We swabbed the posterior nasopharynx prior to autopsy and tested the samples later by Ultra. At autopsy we collected lung, liver, and, when possible, cerebrospinal fluid for mycobacterial culture and histopathology. Confirmed tuberculosis was defined as Mycobacterium tuberculosis complex recovery by culture with consistent tissue histopathology findings; decedents with only histopathology findings, including acid-fast staining or immunohistochemistry, were defined as probable tuberculosis.Of 205 decedents, 78 (38.0%) were female and median (range) age was 45 (0,96) years. Twenty-seven (13.2%) were found to have tuberculosis at autopsy, 22 (81.5%) confirmed and 5 (18.5%) probable. Ultra detected M. tuberculosis complex from the nasopharynx in 21 (77.8%) of 27 TB cases (sensitivity 70.4% [95% confidence interval {CI} 49.8-86.2%], specificity 98.9% [95% CI 96.0-99.9%]). Among confirmed TB, the sensitivity increased to 81.8% (95% CI 59.7-94.8%). Tuberculosis was not included as a death certificate diagnosis in 14 (66.7%) of the 21 MTBc detections by Ultra.Nasopharyngeal Ultra was highly specific for identifying in-hospital tuberculosis deaths, including unsuspected tuberculosis deaths. This approach may improve tuberculosis death enumeration in high-burden countries.

We report a case of Rickettsia honei infection in a US tourist returning from India and the Himalayas. This case highlights a need for awareness of various Rickettsia species endemic to India and the importance for physicians to consider rickettsial diseases in returning travelers with eschar or rash-associated febrile illnesses.

Powassan virus (POWV) is a flavivirus of the tick-borne encephalitis serogroup that causes a rare and potentially life-threatening neuroinvasive disease. Viral transmission occurs during zoonotic spillover from mammals by the bite of an infected tick in endemic regions of North America. The number of reported POWV cases has recently increased in the United States. We report a fatal case of POWV meningoencephalomyelitis in Northern Wisconsin following a documented tick bite. Histologic examination of the brain demonstrated widespread intraparenchymal and perivascular lymphohistocytic infiltration, microglial nodule formation, and marked neuronal degeneration, most severely involving the substantia nigra, anterior horn of spinal cord and cerebellum. Although no viral inclusions were seen in routine light microscopy, electron microscopy identified multiple neurons containing cytoplasmic clusters of virus particles ∼50 nm in diameter. POWV infection was confirmed using immunohistochemical analysis and reverse transcription-polymerase chain reaction. This report demonstrates in detail regional central nervous system involvement and ultrastructural characteristics of Powassan viral particles by transmission electron microscopy, while highlighting the utility of evaluating fixed autopsy tissues in cases of unexplained meningoencephalomyelitis.

Background Blastomyces is a dimorphic fungus that infects persons with or without underlying immunocompromise. To date, no study has compared the clinical features and outcomes of blastomycosis between immunocompromised and immunocompetent persons. Methods A retrospective study of adult patients with proven blastomycosis from 2004–2016 was conducted at the University of Wisconsin. Epidemiology, clinical features, and outcomes were analyzed among solid-organ transplantation (SOT) recipients, persons with non-SOT immunocompromise (non-SOT IC), and persons with no immunocompromise (NIC). Results A total of 106 cases met the inclusion criteria including 74 NIC, 19 SOT, and 13 non-SOT IC (malignancy, HIV/AIDS, idiopathic CD4+ lymphopenia). The majority of patients (61.3%) had at least 1 epidemiologic risk factor for acquisition of Blastomyces. Pneumonia was the most common manifestation in all groups; however, immunocompromised patients had higher rates of acute pulmonary disease (P = .03), more severe infection (P = .007), respiratory failure (P = .010), and increased mortality (P = .02). Receipt of SOT primarily accounted for increased severity, respiratory failure, and mortality in immunosuppressed patients. SOT recipients had an 18-fold higher annual incidence of blastomycosis than the general population. The rate of disseminated blastomycosis was similar among NIC, SOT, and non-SOT IC. Relapse rates were low (5.3–7.7%). Conclusions Immunosuppression had implications regarding the acuity, severity, and respiratory failure. The rate of dissemination was similar across the immunologic spectrum, which is in sharp contrast to other endemic fungi. This suggests that pathogen-related factors have a greater influence on dissemination for blastomycosis than immune defense.

Background Invasive mold infections (IMI) such as aspergillosis and mucormycosis are often fatal among immunocompromised patients and cause high-profile outbreaks. Public health surveillance for IMI is challenging; most epidemiologic studies are limited to transplant and cancer patients at greatest risk of IMI. The established Mycoses Study Group (MSG) case definition is useful for clinical trials but lacks sensitivity. To address these challenges, we created IMI surveillance within the Georgia Emerging Infections Program. Here, we describe cases identified through this system, using both the MSG criteria and a novel, more sensitive surveillance case definition. Methods To identify potential IMI cases, we captured 2,363 positive fungal laboratory results, including cultures, histopathology, and galactomannan tests, within a 60-day window at three large Atlanta hospitals during April 2018–March 2019. We excluded yeast and dimorphic fungi, hair and nail specimens, and cystic fibrosis patients. Potential cases underwent chart review and were classified by 2 physicians as proven, probable, or non-case according to MSG criteria. Cases that partially met MSG probable criteria and included antifungal treatment were classified as surveillance cases; definitions were mutually exclusive (Fig 1). Results Of 120 potential IMI cases, 46 (38%) met an IMI case definition: 8 proven, 9 probable, and 29 surveillance cases (Fig 2). Of cases, 14 (30%) involved transplant or cancer in the previous year; 8 of these were proven or probable cases. IMI presented primarily as sinusitis among proven cases (50%), and pulmonary infections among probable (56%) and surveillance (45%) cases. Most surveillance cases were caused by Aspergillus spp. (72%) and accounted for all 5 cutaneous IMI (fig 3). Over 80% of cases vs. 10% of non-cases had antifungal treatment. Conclusion Of IMI cases identified, nearly two thirds had evidence of infection but did not meet an MSG case definition. MSG captured over half of transplant and cancer-associated cases, but these were uncommon overall, revealing most IMI lack classical risk factors. A more sensitive surveillance case definition can capture a broader spectrum of IMI patients receiving antifungal treatment to help guide clinical and public health interventions. Disclosures All Authors: No reported disclosures

INTRODUCTION: Blastomycosis is endemic in Wisconsin with Blastomyces dermatitidis and B. gilchristii responsible for infections. Urine antigen testing is a non-invasive diagnostic method for blastomycosis with up to 93% test sensitivity. However, the test’s sensitivity has not been evaluated with relationship to B. gilchristii infections. METHODS: We aimed to assess physician use of the urine antigen assay and its sensitivity to B. gilchristii and B. dermatitidis infections in a retrospective study. Culture confirmed clinical cases of blastomycosis from 2008-2016 were identified within Marshfield Clinic Health System (MCHS) and UW Hospital and Clinics (UWHC) medical records. Clinical data were abstracted from each medical record and included the following: patient demographics, presence of immune compromising and underlying medical conditions, treatment drugs, presence of isolated pulmonary or disseminated disease, death, urine antigen testing, timeframe of testing, and quantitative test values (EIA units or ng/mL). RESULTS: A total of 140 blastomycosis cases were included in this study, with MCHS contributing 114 cases to the study and UWHC contributing 26 cases. The majority of UWHC cases (n=22; 85%) were caused by B. dermatitidis and the majority of MCHS cases (n=73; 64%) were caused by B. gilchristii. UWHC physicians were significantly more likely to treat with multiple drugs during the course of infection and were more likely to prescribe amphotericin B and voriconazole. Urine antigen testing was more frequently used at UWHC (n=24; 92%) than MCHS (n=51; 45%; P < 0.00001). In this study, the urine antigen assay demonstrated 79% sensitivity. Sensitivity was significantly associated with the timeframe of testing (P < 0.05), with most true positive urine antigen tests (83%) being performed ≤ 7 days from diagnosis. In this study, the urine antigen assay was capable of detecting both B. dermatitidis and B. gilchristii at about equal sensitivity. Urine antigen concentration (ng/mL) trended higher in B. dermatitidis infections. CONCLUSION: This study found that the urine antigen assay is capable of detecting both species of Blastomyces at about the same sensitivity. We recommend continued use of the urine antigen assay for diagnosis of blastomycosis and recommend that the assay be used early in the diagnostic process to minimize the chance of false negative results.

Background Invasive mold infections (IMI) such as aspergillosis and mucormycosis are often fatal among immunosuppressed patients and have caused high-profile outbreaks. Surveillance for IMI is challenging because distinguishing a case from colonization or contamination is complex. The established case definition, Mycoses Study Group (MSG) criteria, lacks sensitivity. Because the need for surveillance remains, we designed a pilot IMI surveillance system within the Georgia Emerging Infections Program. Here, we describe cases identified through this system, using both the MSG criteria and a novel, more sensitive clinical case definition. Methods To identify potential IMI cases, we captured fungal cultures positive for mold, histopathology specimens with evidence of fungal tissue invasion, and positive galactomannan results within a 60-day window at three large hospitals in Atlanta during March 2017–2018. We excluded dimorphic fungi and hair and nail specimens. Of 194 potential cases, we selected 24 for complete medical chart review. Two physicians classified cases as proven, probable, or non-case according to MSG criteria. Cases that partially met MSG probable criteria and included antifungal treatment were classified as clinical cases; definitions were mutually exclusive (Figure 1). Results Of 24 potential IMI cases, 16 (66%) met an IMI case definition, including 5 proven, 2 probable and 9 clinical cases. Inter-rater agreement was 92%., Most (5/7) MSG cases involved Aspergillus and were more likely to have cancer, a transplant, or other immunosuppression compared with clinical cases (Figure 2 and 3). Clinical cases included conditions not specified in MSG criteria, including burns (1), wounds (1) or eye (4) infections. MSG and clinical cases more often had antifungal treatment (16/16 vs. 1/8) or died (4/16 vs. 0/8) compared with non-cases. Conclusion In this preliminary analysis of potential IMI cases, most represented true invasive infections, indicating effective exclusion of most colonization. Most of the 16 cases were classified as clinical, however, and would have been missed in a system relying on the MSG criteria alone. Results suggest that a less-specific clinical case definition incorporating antifungal treatment may improve the sensitivity and utility of IMI surveillance. Disclosures All authors: No reported disclosures.

In addition to tumors arising from the primary mucosal epithelium, the foregut is host to a variety of non-epithelial precursor cells which may give rise to neoplasms of neuroendocrine, mesenchymal, and hematolymphoid lineages. Many of these lesions also occur outside of the gastrointestinal tract, such as the extranodal lymphomas and many of the sarcomas, and in many cases share the features of their non-alimentary counterparts. This heterogeneous collection of malignancies features a wide spectrum of clinical presentations, morphologic and histopathologic features, genetic underpinnings, and treatment considerations. Although encountered less frequently than primary carcinomas, it is important to correctly recognize and classify these lesions to effectively manage and prognosticate the patients in which they occur. In this chapter, we focus on the clinical, morphologic, and genetic features of the primary esophageal and gastric neoplasms of neuroendocrine, mesenchymal, and lymphoid origin.

In addition to tumors arising from the primary mucosal epithelium, the foregut is host to a variety of non-epithelial precursor cells which may give rise to neoplasms of neuroendocrine, mesenchymal, and hematolymphoid lineages. Many of these lesions also occur outside of the gastrointestinal tract, such as the extranodal lymphomas and many of the sarcomas, and in many cases share the features of their non-alimentary counterparts. This heterogeneous collection of malignancies features a wide spectrum of clinical presentations, morphologic and histopathologic features, genetic underpinnings, and treatment considerations. Although encountered less frequently than primary carcinomas, it is important to correctly recognize and classify these lesions to effectively manage and prognosticate the patients in which they occur. In this chapter, we focus on the clinical, morphologic, and genetic features of the primary esophageal and gastric neoplasms of neuroendocrine, mesenchymal, and lymphoid origin.

Esophageal and gastric carcinomas affect millions of individuals worldwide, placing a considerable burden on society. Unfortunately, preventative medicine falls short as screening methods for the upper gastrointestinal tract lack the ability to detect early onset disease. The overwhelming majority of cases present after symptoms appear when individuals have advanced disease with a poor prognosis. Further complicating matters, the anatomic location of these neoplasms engenders rapid tumor progression, which repeatedly thwarts successful surgical treatment. This chapter will focus on the pathological features of malignant neoplasms of the esophagus and stomach.

Esophageal and gastric carcinomas affect millions of individuals worldwide, placing a considerable burden on society. Unfortunately, preventative medicine falls short as screening methods for the upper gastrointestinal tract lack the ability to detect early onset disease. The overwhelming majority of cases present after symptoms appear when individuals have advanced disease with a poor prognosis. Further complicating matters, the anatomic location of these neoplasms engenders rapid tumor progression, which repeatedly thwarts successful surgical treatment. This chapter will focus on the pathological features of malignant neoplasms of the esophagus and stomach.