Last data update: Nov 04, 2024. (Total: 48056 publications since 2009)
Records 1-30 (of 71 Records) |
Query Trace: Shieh WJ[original query] |
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The frequency and function of nucleoprotein-specific CD8(+) T cells are critical for heterosubtypic immunity against influenza virus infection
Amoah S , Cao W , Sayedahmed EE , Wang Y , Kumar A , Mishina M , Eddins DJ , Wang WC , Burroughs M , Sheth M , Lee J , Shieh WJ , Ray SD , Bohannon CD , Ranjan P , Sharma SD , Hoehner J , Arthur RA , Gangappa S , Wakamatsu N , Johnston HR , Pohl J , Mittal SK , Sambhara S . J Virol 2024 e0071124 Cytotoxic T lymphocytes (CTLs) mediate host defense against viral and intracellular bacterial infections and tumors. However, the magnitude of CTL response and their function needed to confer heterosubtypic immunity against influenza virus infection are unknown. We addressed the role of CD8(+) T cells in the absence of any cross-reactive antibody responses to influenza viral proteins using an adenoviral vector expressing a 9mer amino acid sequence recognized by CD8(+) T cells. Our results indicate that both CD8(+) T cell frequency and function are crucial for heterosubtypic immunity. Low morbidity, lower viral lung titers, low to minimal lung pathology, and better survival upon heterosubtypic virus challenge correlated with the increased frequency of NP-specific CTLs. NP-CD8(+) T cells induced by differential infection doses displayed distinct RNA transcriptome profiles and functional properties. CD8(+) T cells induced by a high dose of influenza virus secreted significantly higher levels of IFN-γ and exhibited higher levels of cytotoxic function. The mice that received NP-CD8(+) T cells from the high-dose virus recipients through adoptive transfer had lower viral titers following viral challenge than those induced by the low dose of virus, suggesting differential cellular programming by antigen dose. Enhanced NP-CD8(+) T-cell functions induced by a higher dose of influenza virus strongly correlated with the increased expression of cellular and metabolic genes, indicating a shift to a more glycolytic metabolic phenotype. These findings have implications for developing effective T cell vaccines against infectious diseases and cancer. IMPORTANCE: Cytotoxic T lymphocytes (CTLs) are an important component of the adaptive immune system that clears virus-infected cells or tumor cells. Hence, developing next-generation vaccines that induce or recall CTL responses against cancer and infectious diseases is crucial. However, it is not clear if the frequency, function, or both are essential in conferring protection, as in the case of influenza. In this study, we demonstrate that both CTL frequency and function are crucial for providing heterosubtypic immunity to influenza by utilizing an Ad-viral vector expressing a CD8 epitope only to rule out the role of antibodies, single-cell RNA-seq analysis, as well as adoptive transfer experiments. Our findings have implications for developing T cell vaccines against infectious diseases and cancer. |
Brain tropism acquisition: The spatial dynamics and evolution of a measles virus collective infectious unit that drove lethal subacute sclerosing panencephalitis
Yousaf I , Hannon WW , Donohue RC , Pfaller CK , Yadav K , Dikdan RJ , Tyagi S , Schroeder DC , Shieh WJ , Rota PA , Feder AF , Cattaneo R . PLoS Pathog 2023 19 (12) e1011817 It is increasingly appreciated that pathogens can spread as infectious units constituted by multiple, genetically diverse genomes, also called collective infectious units or genome collectives. However, genetic characterization of the spatial dynamics of collective infectious units in animal hosts is demanding, and it is rarely feasible in humans. Measles virus (MeV), whose spread in lymphatic tissues and airway epithelia relies on collective infectious units, can, in rare cases, cause subacute sclerosing panencephalitis (SSPE), a lethal human brain disease. In different SSPE cases, MeV acquisition of brain tropism has been attributed to mutations affecting either the fusion or the matrix protein, or both, but the overarching mechanism driving brain adaptation is not understood. Here we analyzed MeV RNA from several spatially distinct brain regions of an individual who succumbed to SSPE. Surprisingly, we identified two major MeV genome subpopulations present at variable frequencies in all 15 brain specimens examined. Both genome types accumulated mutations like those shown to favor receptor-independent cell-cell spread in other SSPE cases. Most infected cells carried both genome types, suggesting the possibility of genetic complementation. We cannot definitively chart the history of the spread of this virus in the brain, but several observations suggest that mutant genomes generated in the frontal cortex moved outwards as a collective and diversified. During diversification, mutations affecting the cytoplasmic tails of both viral envelope proteins emerged and fluctuated in frequency across genetic backgrounds, suggesting convergent and potentially frequency-dependent evolution for modulation of fusogenicity. We propose that a collective infectious unit drove MeV pathogenesis in this brain. Re-examination of published data suggests that similar processes may have occurred in other SSPE cases. Our studies provide a primer for analyses of the evolution of collective infectious units of other pathogens that cause lethal disease in humans. |
Updated review on Nocardia species: 2006-2021
Traxler RM , Bell ME , Lasker B , Headd B , Shieh WJ , McQuiston JR . Clin Microbiol Rev 2022 35 (4) e0002721 This review serves as an update to the previous Nocardia review by Brown-Elliott et al. published in 2006 (B. A. Brown-Elliott, J. M. Brown, P. S. Conville, and R. J. Wallace. Jr., Clin Microbiol Rev 19:259-282, 2006, https://doi.org/10.1128/CMR.19.2.259-282.2006). Included is a discussion on the taxonomic expansion of the genus, current identification methods, and the impact of new technology (including matrix-assisted laser desorption ionization-time of flight [MALDI-TOF] and whole genome sequencing) on diagnosis and treatment. Clinical manifestations, the epidemiology, and geographic distribution are briefly discussed. An additional section on actinomycotic mycetoma is added to address this often-neglected disease. |
Pathology and pathogenesis of Lassa fever: Novel immunohistochemical findings in fatal cases and clinico-pathologic correlation
Shieh WJ , Demby A , Jones T , Goldsmith CS , Rollin PE , Ksiazek TG , Peters CJ , Zaki SR . Clin Infect Dis 2021 74 (10) 1821-1830 BACKGROUND: Lassa fever is a zoonotic, acute viral illness first identified in Nigeria in 1969. An estimate shows that the "at risk" seronegative population (in Sierra Leone, Guinea, and Nigeria) may be as high as 59 million, with an annual incidence of all illnesses of three million, and fatalities up to 67,000, demonstrating the serious impact of the disease on the region and global health. METHODS: Histopathologic evaluation, immunohistochemical assay, and electron microscopic examination were performed on postmortem tissue samples from 12 confirmed Lassa fever cases. RESULTS: Lassa fever virus antigens and viral particles were observed in multiple organ systems and cells, including cells in the mononuclear phagocytic system and other specialized cells where it had not been described previously. CONCLUSIONS: The immunolocalization of Lassa fever virus antigens in fatal cases provides novel insightful information with clinical and pathogenetic implications. The extensive involvement of the mononuclear phagocytic system, including tissue macrophages and endothelial cells suggests participation of inflammatory mediators from this lineage with the resulting vascular dilatation and increasing permeability. Other findings indicate the pathogenesis of LF is multifactorial and additional studies are needed. |
Fatal Dengue Acquired in Florida
Sharp TM , Morris S , Morrison A , de Lima Corvino D , Santiago GA , Shieh WJ , Rico E , Kopp E , Muñoz-Jordán JL , Marttos A , Paz-Bailey G , Abbo LM , Stanek D . N Engl J Med 2021 384 (23) 2257-2259 The global burden of dengue, a mosquito-borne viral acute febrile illness common throughout the tropics, is worsening.1,2 Approximately 5% of patients have progression to severe dengue, including plasma leakage, shock, and hemorrhage, but they may also present with acute cholecystitis.1,3 | | In 2019, a total of 413 dengue cases were probably imported to Florida, including 14 cases of severe dengue (3.4%), resulting in 18 locally acquired cases, predominantly in the Miami area (Figs. S1 and S2 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Most persons with travel-associated cases reported recent travel to Cuba and were infected with dengue virus (DENV) serotype 2 (DENV-2). |
Closing the Brief Case: Disseminated Microsporidiosis with Intestinal Cryptosporidium Coinfection in a Patient with Kaposi's Sarcoma and Castleman Disease Presenting with Acute Kidney Injury
Agarwal AN , Shieh WJ , Goldsmith CS , Qvarnstrom Y , Ding Y , Dallas SD , Mais DD . J Clin Microbiol 2021 59 (6) Microsporidia are unicellular obligate parasitic fungi which produce heat-resistant spores. | The spores are infective forms containing a coiled polar tubule, which is extruded in the host cell to inject sporoplasm. | Transmission electron microscopy is the gold standard test for identification of microsporidia. Other tests for identification include Gram stain, Chromotrope 2R, quick-hot Gram chromotrope technique, trichrome blue, acid-fast stain, Warthin-Starry stain, modified trichrome stains, calcofluor white, immunohistochemistry, and PCR. | Encephalitozoon intestinalis commonly infects the gastrointestinal tract. However, it can also infect the kidneys and lungs. Microsporidiosis should be considered as a cause of renal failure in an immunocompromised patient. |
Evidence of SARS-CoV-2 Replication and Tropism in the Lungs, Airways and Vascular Endothelium of Patients with Fatal COVID-19: An Autopsy Case-Series.
Bhatnagar J , Gary J , Reagan-Steiner S , Estetter LB , Tong S , Tao Y , Denison AM , Lee E , DeLeon-Carnes M , Li Y , Uehara A , Paden CR , Leitgeb B , Uyeki TM , Martines RB , Ritter JM , Paddock CD , Shieh WJ , Zaki SR . J Infect Dis 2021 223 (5) 752-764 BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to produce substantial morbidity and mortality. To understand the reasons for the wide-spectrum complications and severe outcomes of COVID-19, we aimed to identify cellular targets of SARS-CoV-2 tropism and replication in various tissues. METHODS: We evaluated RNA extracted from formalin-fixed, paraffin-embedded autopsy tissues from 64 case-patients (age range: 1 month to 84 years; COVID-19 confirmed n=21, suspected n=43) by SARS-CoV-2 RT-PCR. For cellular localization of SARS-CoV-2 RNA and viral characterization, we performed in-situ hybridization (ISH), subgenomic RNA RT-PCR, and whole genome sequencing. RESULTS: SARS-CoV-2 was identified by RT-PCR in 32 case-patients (confirmed n=21 and suspected n=11). ISH was positive in 20 and subgenomic RNA RT-PCR was positive in 17 of 32 RT-PCR-positive case-patients. SARS-CoV-2 RNA was localized by ISH in hyaline membranes, pneumocytes and macrophages of lungs, epithelial cells of airways, and in endothelial cells and vessels wall of brain stem, leptomeninges, lung, heart, liver, kidney, and pancreas. D614G variant was detected in 9 RT-PCR-positive case-patients. CONCLUSIONS: We identified cellular targets of SARS-CoV-2 tropism and replication in the lungs and airways and demonstrated its direct infection in vascular endothelium. This work provides important insights into COVID-19 pathogenesis and mechanisms of severe outcomes. |
Lassa virus antigen distribution and inflammation in the ear of infected strain 13/N guinea pigs
Huynh T , Gary JM , Welch SR , Coleman-McCray J , Harmon JR , Kainulainen MH , Bollweg BC , Ritter JM , Shieh WJ , Nichol ST , Zaki SR , Spiropoulou CF , Spengler JR . Antiviral Res 2020 183 104928 Sudden sensorineuronal hearing loss (SNHL) is reported in approximately one-third of survivors of Lassa fever (LF) and remains the most prominent cause of Lassa virus- (LASV) associated morbidity in convalescence. Using a guinea pig model of LF, and incorporating animals from LASV vaccine trials, we investigated viral antigen distribution and histopathology in the ear of infected animals to elucidate the pathogenesis of hearing loss associated with LASV infection. Antigen was detected only in animals that succumbed to disease and was found within structures of the inner ear that are intimately associated with neural detection and/or translation of auditory stimuli and in adjacent vasculature. No inflammation or viral cytopathic changes were observed in the inner ear or surrounding structures in these animals. In contrast, no viral antigen was detected in the ear of surviving animals. However, all survivors that exhibited clinical signs of disease during the course of infection developed perivascular mononuclear inflammation within and adjacent to the ear, indicating an ongoing inflammatory response in these animals that may contribute to hearing loss. These data contribute to the knowledge of LASV pathogenesis in the auditory system, support an immune-mediated process resulting in LASV-associated hearing loss, and demonstrate that vaccination protecting animals from clinical disease can also prevent infection-associated auditory pathology. |
Transmission of eastern equine encephalitis virus from an organ donor to 3 transplant recipients
Pouch SM , Katugaha SB , Shieh WJ , Annambhotla P , Walker WL , Basavaraju SV , Jones J , Huynh T , Reagan-Steiner S , Bhatnagar J , Grimm K , Stramer SL , Gabel J , Lyon GM , Mehta AK , Kandiah P , Neujahr DC , Javidfar J , Subramanian RM , Parekh SM , Shah P , Cooper L , Psotka MA , Radcliffe R , Williams C , Zaki SR , Staples JE , Fischer M , Panella AJ , Lanciotti RS , Laven JJ , Kosoy O , Rabe IB , Gould CV . Clin Infect Dis 2019 69 (3) 450-458 BACKGROUND: In fall 2017, 3 solid organ transplant (SOT) recipients from a common donor developed encephalitis within 1 week of transplantation, prompting suspicion of transplant-transmitted infection. Eastern equine encephalitis virus (EEEV) infection was identified during testing of endomyocardial tissue from the heart recipient. METHODS: We reviewed medical records of the organ donor and transplant recipients and tested serum, whole blood, cerebrospinal fluid, and tissue from the donor and recipients for evidence of EEEV infection by multiple assays. We investigated blood transfusion as a possible source of organ donor infection by testing remaining components and serum specimens from blood donors. We reviewed data from the pretransplant organ donor evaluation and local EEEV surveillance. RESULTS: We found laboratory evidence of recent EEEV infection in all organ recipients and the common donor. Serum collected from the organ donor upon hospital admission tested negative, but subsequent samples obtained prior to organ recovery were positive for EEEV RNA. There was no evidence of EEEV infection among donors of the 8 blood products transfused into the organ donor or in products derived from these donations. Veterinary and mosquito surveillance showed recent EEEV activity in counties nearby the organ donor's county of residence. Neuroinvasive EEEV infection directly contributed to the death of 1 organ recipient and likely contributed to death in another. CONCLUSIONS: Our investigation demonstrated EEEV transmission through SOT. Mosquito-borne transmission of EEEV to the organ donor was the likely source of infection. Clinicians should be aware of EEEV as a cause of transplant-associated encephalitis. |
Virulent infection of outbred Hartley guinea pigs with recombinant Pichinde virus as a surrogate small animal model for human Lassa fever.
Lan S , Shieh WJ , Huang Q , Zaki SR , Liang Y , Ly H . Virulence 2020 11 (1) 1131-1141 Arenaviruses, such as Lassa virus (LASV), can cause severe and fatal hemorrhagic fevers (e.g., Lassa fever, LF) in humans with no vaccines or therapeutics. Research on arenavirus-induced hemorrhagic fevers (AHFs) has been hampered by the highly virulent nature of these viral pathogens, which require high biocontainment laboratory, and the lack of an immune-competent small animal model that can recapitulate AHF disease and pathological features. Guinea pig infected with Pichinde virus (PICV), an arenavirus that does not cause disease in humans, has been established as a convenient surrogate animal model for AHFs as it can be handled in a conventional laboratory. The PICV strain P18, derived from sequential passaging of the virus 18 times in strain 13 inbred guinea pigs, causes severe febrile illness in guinea pigs that is reminiscent of lethal LF in humans. As inbred guinea pigs are not readily available and are difficult to maintain, outbred Hartley guinea pigs have been used but they show a high degree of disease heterogeneity upon virulent P18 PICV infection. Here, we describe an improved outbred guinea-pig infection model using recombinant rP18 PICV generated by reverse genetics technique followed by plaque purification, which consistently shows >90% mortality and virulent infection. Comprehensive virological, histopathological, and immunohistochemical analyses of the rP18-virus infected animals show similar features of human LASV infection. Our data demonstrate that this improved animal model can serve as a safe, affordable, and convenient surrogate small animal model for studying human LF pathogenesis and for evaluating efficacy of preventative or therapeutic approaches. |
Pathological findings in suspected cases of e-cigarette, or vaping, product use-associated lung injury (EVALI): a case series
Reagan-Steiner S , Gary J , Matkovic E , Ritter JM , Shieh WJ , Martines RB , Werner AK , Lynfield R , Holzbauer S , Bullock H , Denison AM , Bhatnagar J , Bollweg BC , Patel M , Evans ME , King BA , Rose DA , Baldwin GT , Jones CM , Krishnasamy V , Briss PA , Weissman DN , Meaney-Delman D , Zaki SR . Lancet Respir Med 2020 8 (12) 1219-1232 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. |
Pichinde virus infection of outbred Hartley guinea pigs as a surrogate animal model for human Lassa fever: Histopathological and immunohistochemical analyses
Shieh WJ , Lan S , Zaki SR , Ly H , Liang Y . Pathogens 2020 9 (7) Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic fevers (AHFs) requires relevant animal models that can recapitulate clinical and pathological features of AHF diseases in humans. Laboratory mice are generally resistant to LASV infection, and non-human primates, while being a good animal model for LF, are limited by their high cost. Here, we describe a small, affordable, and convenient animal model that is based on outbred Hartley guinea pigs infected with Pichinde virus (PICV), a mammarenavirus that is non-pathogenic in humans, for use as a surrogate model of human LF. We conducted a detailed analysis of tissue histopathology and immunohistochemical analysis of different organs of outbred Hartley guinea pigs infected with different PICV strains that show differential disease phenotypes and pathologies. Comparing to infection with the avirulent PICV strain (P2 or rP2), animals infected with the virulent strain (P18 or rP18) show extensive pathological changes in different organs that sustain high levels of virus replication. The similarity of tissue pathology and viral antigen distribution between the virulent PICV-guinea pig model and lethal human LASV infection supports a role of this small animal model as a surrogate model of studying human LF in order to understand its pathogenesis and for evaluating potential preventative and therapeutic options against AHFs. |
Clinical characteristics, histopathology, and tissue immunolocalization of chikungunya virus antigen in fatal cases
Sharp TM , Keating MK , Shieh WJ , Bhatnagar J , Bollweg BC , Levine R , Blau DM , Torres JV , Rivera A , Perez-Padilla J , Munoz-Jordan J , Sanabria D , Fischer M , Garcia BR , Tomashek KM , Zaki SR . Clin Infect Dis 2020 73 (2) e345-e354 BACKGROUND: Death in patients with chikungunya is rare, and has been associated with encephalitis, hemorrhage, and septic shock. We describe clinical, histologic and immunohistochemical findings in individuals who died following chikungunya virus (CHIKV) infection. METHODS: We identified individuals who died in Puerto Rico during 2014 following an acute illness, and had CHIKV RNA detected by RT-PCR in a pre- or post-mortem blood or tissue specimen. We performed histopathology and immunohistochemistry (IHC) for CHIKV antigen on tissue specimens and collected medical data via record review and family interviews. RESULTS: Thirty CHIKV-infected fatal cases were identified (0.8 per 100,000 population). Median age was 61 years (range: 6 days-86 years), and 19 (63%) were male. Death occurred a median of four days (range: 1-29) after illness onset. Nearly all (93%) had at least one co-morbidity, most frequently hypertension, diabetes, or obesity. Nine had severe co-morbidities (e.g., chronic heart or kidney disease, sickle cell anemia) or co-infection (e.g., leptospirosis). Among 24 fatal cases with tissue specimens, 11 (46%) were positive by IHC. CHIKV antigen was most frequently detected in mesenchymal tissues and mononuclear cells including tissue macrophages, blood mononuclear cells, splenic follicular dendritic cells, and Kupffer cells. Common histopathologic findings were intra-alveolar hemorrhage and edema in the lung, chronic or acute tenosynovitis, and increased immunoblasts in the spleen. CHIKV infection likely caused fatal septic shock in two patients. CONCLUSIONS: Evaluation of tissue specimens provided insights into the pathogenesis of CHIKV, which may rarely result in septic shock and other severe manifestations. |
Pathology and Pathogenesis of SARS-CoV-2 Associated with Fatal Coronavirus Disease, United States.
Martines RB , Ritter JM , Matkovic E , Gary J , Bollweg BC , Bullock H , Goldsmith CS , Silva-Flannery L , Seixas JN , Reagan-Steiner S , Uyeki T , Denison A , Bhatnagar J , Shieh WJ , Zaki SR , Covid-Pathology Working Group . Emerg Infect Dis 2020 26 (9) 2005-2015 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. |
Investigating the histopathological findings and immunolocalization of rickettsialpox infection in skin biopsies: A case series and review of the literature
Vyas NS , Shieh WJ , Phelps RG . J Cutan Pathol 2020 47 (5) 451-458 BACKGROUND: Recognition of rickettsialpox infection on skin biopsy can be challenging. The histopathology is nonspecific and inconsistently described. We assess classic histopathologic features in confirmed cases and review the literature. METHODS: We searched for cases of "rickettsialpox" diagnosed between 2006-2018 with positive immunostaining for Spotted Fever Group Rickettsia species. Original slides were evaluated for vacuolar alterations, granulomatous inflammation, vasculitis, necrosis, fibrin thrombi, microvesiculation, papillary dermal edema and extravasated red blood cells. All biopsies were stained with CD3, CD20, CD68 and myeloperoxidase. RESULTS: Six biopsies were compiled, 3 of which were sampled from vesiculopapules, 1 from a maculopapule, and 2 from eschars. Vacuolar alterations and vasculitis were present in all biopsies (6/6; 100%). Granulomatous inflammation was present in 5 biopsies (5/6; 83.3%). Fibrin thrombi and red blood cells were seen in 3/6 (50%) of biopsies. The eschars showed necrosis of the epidermis and superficial dermis (2/6, 33.3%). Only 1 biopsy showed intraepidermal vesiculation and papillary dermal edema (1/6; 16.7%). All six biopsies showed perivascular infiltration with CD3+ T-cells, and low amounts of CD20+ B-cells and neutrophils. Five of the six biopsies (83.3%) showed significant levels of CD68+ histiocytes. CONCLUSION: The histopathology of rickettsialpox infection is septic lymphocytic and granulomatous vasculitis. This article is protected by copyright. All rights reserved. |
Pathology and telepathology methods in the Child Health and Mortality Prevention Surveillance Network
Martines RB , Ritter JM , Gary J , Shieh WJ , Ordi J , Hale M , Carrilho C , Ismail M , Traore CB , Ndibile BE , Sava S , Arjuman F , Kamal M , Rahman MM , Blau DM , Zaki SR . Clin Infect Dis 2019 69 S322-s332 This manuscript describes the Child Health and Mortality Prevention Surveillance (CHAMPS) network approach to pathologic evaluation of minimally invasive tissue sampling (MITS) specimens, including guidelines for histopathologic examination and further diagnostics with special stains, immunohistochemistry, and molecular testing, as performed at the CHAMPS Central Pathology Laboratory (CPL) at the Centers for Disease Control and Prevention, as well as techniques for virtual discussion of these cases (telepathology) with CHAMPS surveillance locations. Based on review of MITS from the early phase of CHAMPS, the CPL has developed standardized histopathology-based algorithms for achieving diagnoses from MITS and telepathology procedures in conjunction with the CHAMPS sites, with the use of whole slide scanners and digital image archives, for maximizing concurrence and knowledge sharing between site and CPL pathologists. These algorithms and procedures, along with lessons learned from initial implementation of these approaches, guide pathologists at the CPL and CHAMPS sites through standardized diagnostics of MITS cases, and allow for productive, real-time case discussions and consultations. |
Repeated vaccination against matched H3N2 influenza virus gives less protection than single vaccination in ferrets
Music N , Tzeng WP , Liaini Gross F , Levine MZ , Xu X , Shieh WJ , Tumpey TM , Katz JM , York IA . NPJ Vaccines 2019 4 28 Epidemiological studies suggest that humans who receive repeated annual immunization with influenza vaccine are less well protected against influenza than those who receive vaccine in the current season only. To better understand potential mechanisms underlying these observations, we vaccinated influenza-naive ferrets either twice, 10 months apart (repeated vaccination group; RV), or once (current season only group; CS), using a prime-boost regimen, and then challenged the ferrets with A/Hong Kong/4801/2014(H3N2). Ferrets that received either vaccine regimen were protected against influenza disease and infection relative to naive unvaccinated ferrets, but the RV group shed more virus, especially at the peak of virus shedding 2 days post infection (p < 0.001) and regained weight more slowly (p < 0.05) than those in the CS group. Qualitative, rather than quantitative, differences in the antibody response may affect protection after repeated influenza vaccination. |
Risk assessment of fifth-wave H7N9 influenza A viruses in mammalian models
Sun X , Belser JA , Pappas C , Pulit-Penaloza JA , Brock N , Zeng H , Creager HM , Le S , Wilson M , Lewis A , Stark TJ , Shieh WJ , Barnes J , Tumpey TM , Maines TR . J Virol 2018 93 (1) The fifth-wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth-wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and HA cleavability. Here, several low pathogenic avian influenza (LPAI) and HPAI H7N9 human isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that a LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold compared with other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets, but exhibited a limited capacity to transmit by respiratory droplets and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models, and with further adaptation may acquire the ability to cause an H7N9 pandemic.ImportanceThe potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increased number of human infections and the emergence of antigenically distinct LPAI and HPAI H7N9 viruses. In this study, a group of fifth-wave HPAI and LPAI viruses were evaluated for their ability to infect, cause disease, and transmit in small animal models. The ability of HPAI H7N9 viruses to cause more severe disease and to replicate in brain tissues in animal models as well as their ability to fuse at a lower pH threshold compared to LPAI H7N9 viruses suggest that the fifth-wave H7N9 viruses have evolved to acquire novel traits with the potential to pose a higher risk to humans. Although the fifth-wave H7N9 viruses have not yet gained the ability to transmit efficiently by air, continuous surveillance and risk assessment remain essential parts of our pandemic preparedness efforts. |
A call to action for mycetoma
Beer KD , Blaney DD , Kadzik M , Asiedu KB , Shieh WJ , Bower W , Jackson BR , Walke H , Chiller T . Curr Fungal Infect Rep 2018 12 (3) 99-104 Purpose of Review: Here, we discuss the current needs and priorities for mycetoma control and prevention, highlight lessons learned from leprosy and podoconiosis, and motivate an urgent need to accelerate progress toward reducing the burden of mycetoma in endemic areas. Recent Findings: In 2015, the World Health Assembly (WHA) added mycetoma, a progressively debilitating disease caused by fungi and bacteria, to the World Health Organization (WHO) list of priority neglected tropical diseases (NTDs). Designation of other diseases as NTDs has raised awareness, enabled global partnerships, and advanced the capacity to combat disease through integrated programming. Although key mycetoma etiologic agents have been identified, many questions remain and mycetoma may similarly benefit from NTD designation. Summary: In collaboration with experts at WHO and elsewhere, we formed a global mycetoma working group to connect partners from a variety of sectors and specialties. We envision that this group will evolve into a formalized partnership that can prioritize strategic planning, advocacy, and research needs, identify funding sources, and coordinate activities related to mycetoma and other NTDs affecting the skin. The experiences gained from other NTDs can help to guide the global mycetoma working group's activities to better address the goals set forth in the WHA resolution. |
Canine amoebic meningoencephalitis due to Balamuthia mandrillaris
Chien RCC , Telford CR , Roy S , Ali IKM , Shieh WJ , Confer AW . Vet Parasitol Reg Stud Reports 2018 13 156-159 A 1-year-old Siberian Husky dog with acute-onset of seizures, recumbency, paddling, and muscular fasciculations was autopsied. A locally extensive hemorrhagic and malacic focus was noted in the right cerebral frontal cortex, and severe necrotizing and hemorrhagic, neutrophilic meningoencephalitis was diagnosed microscopically. Amoebic trophozoites and cysts were identified within the affected cerebral parenchyma and confirmed by indirect immunofluorescence assay and real-time PCR as Balamuthia mandrillaris. B. mandrillaris is found in soil and water and the infection has been reported in both immunocompromised and immunocompetent humans and rarely in the dog. |
Postmortem findings in patient with Guillain-Barre syndrome and Zika virus infection
Dirlikov E , Torres JV , Martines RB , Reagan-Steiner S , Perez GV , Rivera A , Major C , Matos D , Munoz-Jordan J , Shieh WJ , Zaki SR , Sharp TM . Emerg Infect Dis 2018 24 (1) 114-117 Postmortem examination results of a patient with Guillain-Barre syndrome and confirmed Zika virus infection revealed demyelination of the sciatic and cranial IV nerves, providing evidence of the acute demyelinating inflammatory polyneuropathy Guillain-Barre syndrome variant. Lack of evidence of Zika virus in nervous tissue suggests that pathophysiology was antibody mediated without neurotropism. |
International travelers with infectious diseases determined by pathology results, Centers for Disease Control and Prevention - United States, 1995-2015
Angelo KM , Barbre K , Shieh WJ , Kozarsky PE , Blau DM , Sotir MJ , Zaki SR . Travel Med Infect Dis 2017 19 8-15 BACKGROUND: The failure to consider travel-related diagnoses, the lack of diagnostic capacity for specialized laboratory testing, and the declining number of autopsies may affect the diagnosis and management of travel-related infections. Pre- and post-mortem pathology can help determine causes of illness and death in international travelers. METHODS: We conducted a retrospective review of biopsy and autopsy specimens sent to the Infectious Diseases Pathology Branch laboratory (IDPBL) at the Centers for Disease Control and Prevention (CDC) for diagnostic testing from 1995-2015. Cases were included if the specimen submitted for diagnosis was from a traveler with prior international travel during the disease incubation period and the cause of illness or death was unknown at the time of specimen submission. RESULTS: Twenty-one travelers, six (29%) with biopsy specimens and 15 (71%) with autopsy specimens, met the inclusion criteria. Among the 15 travelers who underwent autopsies, the most common diagnoses were protozoal infections (7 travelers; 47%), including five malaria cases, followed by viral infections (6 travelers; 40%). CONCLUSIONS: Biopsy or autopsy specimens can assist in diagnosing infectious diseases in travelers, especially from pathogens not endemic in the U.S. CDC's IDPBL provides a useful resource for clinicians considering infectious diseases in returned travelers. |
Evaluation of placental and fetal tissue specimens for Zika virus infection - 50 states and District of Columbia, January-December, 2016
Reagan-Steiner S , Simeone R , Simon E , Bhatnagar J , Oduyebo T , Free R , Denison AM , Rabeneck DB , Ellington S , Petersen E , Gary J , Hale G , Keating MK , Martines RB , Muehlenbachs A , Ritter J , Lee E , Davidson A , Conners E , Scotland S , Sandhu K , Bingham A , Kassens E , Smith L , St George K , Ahmad N , Tanner M , Beavers S , Miers B , VanMaldeghem K , Khan S , Rabe I , Gould C , Meaney-Delman D , Honein MA , Shieh WJ , Jamieson DJ , Fischer M , Zaki SR . MMWR Morb Mortal Wkly Rep 2017 66 (24) 636-643 Zika virus infection during pregnancy can cause congenital microcephaly and brain abnormalities (1), and detection of Zika virus RNA in clinical and tissue specimens can provide definitive laboratory evidence of recent Zika virus infection. Whereas duration of viremia is typically short, prolonged detection of Zika virus RNA in placental, fetal, and neonatal brain tissue has been reported and can provide key diagnostic information by confirming recent Zika virus infection (2). In accordance with recent guidance (3,4), CDC provides Zika virus testing of placental and fetal tissues in clinical situations where this information could add diagnostic value. This report describes the evaluation of formalin-fixed paraffin-embedded (FFPE) tissue specimens tested for Zika virus infection in 2016 and the contribution of this testing to the public health response. Among 546 live births with possible maternal Zika virus exposure, for which placental tissues were submitted by the 50 states and District of Columbia (DC), 60 (11%) were positive by Zika virus reverse transcription-polymerase chain reaction (RT-PCR). Among 81 pregnancy losses for which placental and/or fetal tissues were submitted, 18 (22%) were positive by Zika virus RT-PCR. Zika virus RT-PCR was positive on placental tissues from 38/363 (10%) live births with maternal serologic evidence of recent unspecified flavivirus infection and from 9/86 (10%) with negative maternal Zika virus immunoglobulin M (IgM) where possible maternal exposure occurred >12 weeks before serum collection. These results demonstrate that Zika virus RT-PCR testing of tissue specimens can provide a confirmed diagnosis of recent maternal Zika virus infection. |
High clinical suspicion of donor-derived disease leads to timely recognition and early intervention to treat solid organ transplant-transmitted lymphocytic choriomeningitis virus
Mathur G , Yadav K , Ford B , Schafer IJ , Basavaraju SV , Knust B , Shieh WJ , Hill S , Locke GD , Quinlisk P , Brown S , Gibbons A , Cannon D , Kuehnert M , Nichol ST , Rollin PE , Stroher U , Miller R . Transpl Infect Dis 2017 19 (4) Despite careful donor screening, unexpected donor-derived infections continue to occur in organ transplant recipients (OTRs). Lymphocytic choriomeningitis virus (LCMV) is one such transplant-transmitted infection that in previous reports has resulted in a high mortality among the affected OTRs. We report a LCMV case cluster that occurred 3 weeks post-transplant in three OTRs who received allografts from a common organ donor in March 2013. Following confirmation of LCMV infection at Centers for Disease Control and Prevention, immunosuppression was promptly reduced and ribavirin and/or intravenous immunoglobulin therapy were initiated in OTRs. The liver recipient died, but right kidney recipients survived without significant sequelae and left kidney recipient survived acute LCMV infection with residual mental status deficit. Our series highlights how early recognition led to prompt therapeutic intervention, which may have contributed to more favorable outcome in the kidney transplant recipients. This article is protected by copyright. All rights reserved. |
Zika Virus RNA Replication and Persistence in Brain and Placental Tissue.
Bhatnagar J , Rabeneck DB , Martines RB , Reagan-Steiner S , Ermias Y , Estetter LB , Suzuki T , Ritter J , Keating MK , Hale G , Gary J , Muehlenbachs A , Lambert A , Lanciotti R , Oduyebo T , Meaney-Delman D , Bolanos F , Saad EA , Shieh WJ , Zaki SR . Emerg Infect Dis 2017 23 (3) 405-414 Zika virus is causally linked with congenital microcephaly and may be associated with pregnancy loss. However, the mechanisms of Zika virus intrauterine transmission and replication and its tropism and persistence in tissues are poorly understood. We tested tissues from 52 case-patients: 8 infants with microcephaly who died and 44 women suspected of being infected with Zika virus during pregnancy. By reverse transcription PCR, tissues from 32 (62%) case-patients (brains from 8 infants with microcephaly and placental/fetal tissues from 24 women) were positive for Zika virus. In situ hybridization localized replicative Zika virus RNA in brains of 7 infants and in placentas of 9 women who had pregnancy losses during the first or second trimester. These findings demonstrate that Zika virus replicates and persists in fetal brains and placentas, providing direct evidence of its association with microcephaly. Tissue-based reverse transcription PCR extends the time frame of Zika virus detection in congenital and pregnancy-associated infections. |
Surveillance for chikungunya and dengue during the first year of chikungunya virus circulation in Puerto Rico
Sharp TM , Ryff KR , Alvarado L , Shieh WJ , Zaki SR , Margolis HS , Rivera-Garcia B . J Infect Dis 2016 214 S475-s481 After chikungunya virus (CHIKV) transmission was detected in Puerto Rico in May 2014, multiple surveillance systems were used to describe epidemiologic trends and CHIKV-associated disease. Of 28 327 cases reported via passive surveillance, 6472 were tested for evidence of CHIKV infection, and results for 4399 (68%) were positive. Of 250 participants in household cluster investigations, 70 (28%) had evidence of recent CHIKV infection. Enhanced surveillance for chikungunya at 2 hospitals identified 1566 patients who tested positive for CHIKV, of whom 10.9% were hospitalized. Enhanced surveillance for fatal cases enabled identification of 31 cases in which CHIKV was detected in blood or tissue specimens. All surveillance systems detected a peak incidence of chikungunya in September 2014 and continued circulation in 2015. Concomitant surveillance for dengue demonstrated low incidence, which had decreased before CHIKV was introduced. Multifaceted chikungunya surveillance in Puerto Rico resolved gaps in traditional passive surveillance and enabled a holistic description of the spectrum of disease associated with CHIKV infection. |
Novel clinical and pathologic findings in a Heartland Virus-associated death
Fill MA , Compton ML , McDonald EC , Moncayo AC , Dunn JR , Schaffner W , Bhatnagar J , Zaki SR , Jones TF , Shieh WJ . Clin Infect Dis 2016 64 (4) 510-512 We describe an investigation into a Heartland Virus (HRTV)-associated death in Tennessee with novel clinical and pathologic findings. HRTV can cause rapidly fatal, widely disseminated infection with multisystem organ failure in patients without substantial comorbidities. We identified viral antigen in multiple organ tissues where it was not detected previously. |
Pathogenesis and transmission assessments of two H7N8 influenza A viruses recently isolated from turkey farms in Indiana using mouse and ferret models
Sun X , Belser JA , Pulit-Penaloza JA , Zeng H , Lewis A , Shieh WJ , Tumpey TM , Maines TR . J Virol 2016 90 (23) 10936-10944 Avian influenza A H7 viruses have caused multiple outbreaks in domestic poultry throughout North America, resulting in occasional human infections in close contact. In early 2016, the presence of H7N8 highly pathogenic avian influenza (HPAI) viruses and closely related H7N8 low pathogenic avian influenza (LPAI) viruses were confirmed in commercial turkey farms in Indiana. These H7N8 viruses represent the first isolation of this subtype in domestic poultry in North America, with their virulence in mammalian hosts and the potential risk for human infection largely unknown. In this study, we assessed the ability of H7N8 HPAI and LPAI viruses to replicate in vitro in human airway cells and in vivo in mouse and ferret models. Both H7N8 viruses replicated efficiently in vitro and in vivo, but exhibited substantial differences in disease severity in mammals. In mice, while the H7N8 LPAI virus largely remained avirulent, the H7N8 HPAI virus exhibited greater infectivity, virulence, and lethality. Both H7N8 viruses replicated similarly in ferrets, but only the H7N8 HPAI virus caused moderate weight loss, lethargy, and mortality. The H7N8 LPAI virus displayed limited transmissibility in ferrets placed in direct contact, while no transmission of H7N8 HPAI virus was detected. Our results indicate that the H7N8 avian influenza viruses from Indiana are able to replicate in mammals and cause severe disease, but with limited transmission. The recent appearance of H7N8 viruses in domestic poultry highlights the need for continued influenza surveillance in wild birds and close monitoring of the potential risk to human health. IMPORTANCE: H7 influenza viruses circulate in wild birds in the U.S., but when the virus emerges in domestic poultry populations, the frequency of human exposure and the potential for human infections increases. An H7N8 highly pathogenic avian influenza (HPAI) and an H7N8 low pathogenic avian influenza (LPAI) viruses were recently isolated from commercial turkey farms in Indiana. To determine the risk that these influenza viruses pose to humans, we assessed the pathogenesis and transmission in vitro and in mammalian models. We found that the H7N8 HPAI virus exhibited enhanced virulence and, although transmission was only observed with the H7N8 LPAI virus, the ability of this H7 virus to transmit in a mammalian host and quickly evolve to a more virulent strain is cause for concern. Our findings offer important insight into the potential for emerging H7 avian influenza viruses to acquire the ability to cause disease and transmit among mammals. |
Pathology of congenital Zika syndrome in Brazil: a case series
Martines RB , Bhatnagar J , de Oliveira Ramos AM , Davi HP , Iglezias SD , Kanamura CT , Keating MK , Hale G , Silva-Flannery L , Muehlenbachs A , Ritter J , Gary J , Rollin D , Goldsmith CS , Reagan-Steiner S , Ermias Y , Suzuki T , Luz KG , de Oliveira WK , Lanciotti R , Lambert A , Shieh WJ , Zaki SR . Lancet 2016 388 (10047) 898-904 BACKGROUND: Zika virus is an arthropod-borne virus that is a member of the family Flaviviridae transmitted mainly by mosquitoes of the genus Aedes. Although usually asymptomatic, infection can result in a mild and self-limiting illness characterised by fever, rash, arthralgia, and conjunctivitis. An increase in the number of children born with microcephaly was noted in 2015 in regions of Brazil with high transmission of Zika virus. More recently, evidence has been accumulating supporting a link between Zika virus and microcephaly. Here, we describe findings from three fatal cases and two spontaneous abortions associated with Zika virus infection. METHODS: In this case series, formalin-fixed paraffin-embedded tissue samples from five cases, including two newborn babies with microcephaly and severe arthrogryposis who died shortly after birth, one 2-month-old baby, and two placentas from spontaneous abortions, from Brazil were submitted to the Infectious Diseases Pathology Branch at the US Centers for Disease Control and Prevention (Atlanta, GA, USA) between December, 2015, and March, 2016. Specimens were assessed by histopathological examination, immunohistochemical assays using a mouse anti-Zika virus antibody, and RT-PCR assays targeting the NS5 and envelope genes. Amplicons of RT-PCR positive cases were sequenced for characterisation of strains. FINDINGS: Viral antigens were localised to glial cells and neurons and associated with microcalcifications in all three fatal cases with microcephaly. Antigens were also seen in chorionic villi of one of the first trimester placentas. Tissues from all five cases were positive for Zika virus RNA by RT-PCR, and sequence analyses showed highest identities with Zika virus strains isolated from Brazil during 2015. INTERPRETATION: These findings provide strong evidence of a link between Zika virus infection and different congenital central nervous system malformations, including microcephaly as well as arthrogryposis and spontaneous abortions. FUNDING: None. |
Transmission of Balamuthia mandrillaris by organ transplantation
Farnon EC , Kokko K , Budge PJ , Mbaeyi C , Lutterloh E , Qvarnstrom Y , da Silva AJ , Shieh WJ , Roy S , Paddock CD , Sriram R , Zaki SR , Visvesvara G , Kuehnert MJ . Clin Infect Dis 2016 63 (7) 878-888 BACKGROUND: During 2009 and 2010, two clusters of organ transplant-transmitted Balamuthia mandrillaris, a free-living ameba, were detected by recognition of severe unexpected illness in multiple recipients from the same donor. METHODS: We investigated all recipients and the two donors through interview, medical record review, and testing of available specimens retrospectively. Surviving recipients were tested and treated prospectively. RESULTS: In the 2009 cluster of illness, two kidney recipients were infected and one died. The donor had Balamuthia encephalitis confirmed on autopsy. In the 2010 cluster, the liver and kidney-pancreas recipients developed Balamuthia encephalitis and died. The donor had a clinical syndrome consistent with Balamuthia infection and serologic evidence of infection. In both clusters, the two asymptomatic recipients were treated expectantly and survived; one asymptomatic recipient in each cluster had serologic evidence of exposure that decreased over time. Both donors had been presumptively diagnosed with other neurologic diseases prior to organ procurement. CONCLUSIONS: Balamuthia can be transmitted through organ transplantation with an observed incubation time of 17-24 days. Clinicians should be aware of Balamuthia as a cause of encephalitis with high rate of fatality, and should notify public health and evaluate transplant recipients from donors with signs of possible encephalitis to facilitate early diagnosis and targeted treatment. Organ procurement organizations and transplant centers should be aware of the potential for Balamuthia infection in donors with possible encephalitis and also assess donors carefully for signs of neurologic infection that may have been misdiagnosed as stroke or as non-infectious forms of encephalitis. |
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