Search

Fatal complications associated with the Zika virus (ZIKV) have rarely been reported in adults, and detailed postmortem reports are limited (Musso and Gubler, 2016). ZIKV infection is typically a mild uncomplicated febrile illness associated with arthralgia, rash, and conjunctivitis (Duffy et al., 2009). In adults, fatal and non-fatal neurological complications have been reported, including encephalitis and Guillain–Barré syndrome (Soares et al., 2016, Oehler et al., 2014). Non-neurological fatalities have also been reported sporadically in patients from Latin America, who have presented with an acute febrile illness and multi-organ failure (Sarmiento-Ospina et al., 2016, Zonneveld et al., 2016). This report describes the clinical features and postmortem findings of a 61-year-old Malaysian male with co-morbidities, who had a fatal outcome subsequent to an acute febrile and rash illness, with pre- and postmortem evidence of ZIKV infection. Published version

In this review we will discuss the epidemiology, clinical characteristics, diagnostic tests, pathologic features, treatment and disease prevention strategies for four mosquito-borne flaviviruses. West Nile and Zika viruses, once thought to be restricted geographically, emerged on the American continent in the first part of the 21st century. They have been constantly in the lay press and have caused a heightened awareness of emerging infections by the public, particularly given the manifestation of microcephaly in congenital Zika syndrome. Yellow fever and dengue viruses, with mosquito vectors similar to West Nile and Zika viruses, are endemic in many tropical areas of the world and produce frequent outbreaks. The global distribution of yellow fever and dengue viruses could also change and has great potential to do so. Factors that could contribute to reemergence of the diseases in areas of the world where they are currently only seen in travelers, include the presence of yellow fever and dengue virus vectors in temperate climates and growing urbanization. These two factors increase potential contact between vectors and naïve human hosts, thus could result in reemergence of yellow fever or dengue virus infections.

We report a case of spontaneous abortion associated with Zika virus infection in a pregnant woman who traveled from Spain to the Dominican Republic and developed a rash. Maternal Zika viremia persisted at least 31 days after onset of symptoms and 21 days after uterine evacuation.

Zika virus (ZIKV) invades and persists in the central nervous system (CNS), causing severe neurological diseases. However the virus journey, from the bloodstream to tissues through a mature endothelium, remains unclear. Here, we show that ZIKV-infected monocytes represent suitable carriers for viral dissemination to the CNS using human primary monocytes, cerebral organoids derived from embryonic stem cells, organotypic mouse cerebellar slices, a xenotypic human-zebrafish model, and human fetus brain samples. We find that ZIKV-exposed monocytes exhibit higher expression of adhesion molecules, and higher abilities to attach onto the vessel wall and transmigrate across endothelia. This phenotype is associated to enhanced monocyte-mediated ZIKV dissemination to neural cells. Together, our data show that ZIKV manipulates the monocyte adhesive properties and enhances monocyte transmigration and viral dissemination to neural cells. Monocyte transmigration may represent an important mechanism required for viral tissue invasion and persistence that could be specifically targeted for therapeutic intervention., Zika virus (ZIKV) can infect the central nervous system, but it is not clear how it reaches the brain. Here, Ayala-Nunez et al. show in ex vivo and in vivo models that ZIKV can hitch a ride in monocytes in a Trojan Horse manner to cross the endothelium and disseminate the virus.

Background Hand, foot, and mouth disease (HFMD), classically a childhood viral infection, has an atypical and severe clinical presentation in adults. Coxsackievirus A6 is a leading cause of atypical HFMD, but current diagnostic methods utilizing formalin-fixed, paraffin-embedded skin biopsy specimens often lack sensitivity and specificity. Methods Formalin-fixed, paraffin-embedded skin biopsies from seven case patients with clinical and histopathological suspicion of atypical HFMD were evaluated by coxsackievirus A6 (CVA6) immunohistochemistry, enterovirus-specific conventional reverse transcriptase-PCR with subsequent Sanger sequencing targeting the 5’UTR, and CVA6-specific real-time PCR targeting the VP1 gene. Results The CVA6-specific antibody demonstrated appropriate antigen distribution and staining intensity in keratinocytes in all cases. Conventional RT-PCR and sequencing also detected the presence of enterovirus, and CVA6-specific real-time RT-PCR analysis identified CVA6. Conclusion Applying these immunohistochemistry and molecular techniques to formalin-fixed, paraffin-embedded tissues, CVA6 was determined to be the causative infectious agent in seven cases of atypical hand, foot, and mouth disease.

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.

The current clinical practice is based on the assumption of strong correlation between diffuse glutamine synthetase expression and β-catenin activation in hepatocellular adenoma and hepatocellular carcinoma. This high correlation is based on limited data, and may represent an oversimplification as glutamine synthetase staining patterns show wide variability in clinical practice. Standardized criteria for interpreting diverse glutamine synthetase patterns, and the association between each pattern and β-catenin mutations is not clearly established. This study examines the correlation between glutamine synthetase staining patterns and β-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified into one of three patterns: (a) diffuse homogeneous: moderate to strong cytoplasmic staining in more than 90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate to strong staining in 50–90% of lesional cells, without a map-like pattern, and (c) patchy: moderate to strong staining in

Summary 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.

We describe the clinicopathological, immunohistochemical, and molecular features of an unusual case of a hepatocellular adenoma of the placenta presenting as a subchorionic intervillous mass lesion in a diamnionic dichorionic placenta. A well-circumscribed 0.8 cm round nodule was identified in one of the twin placental discs, wherein, on microscopic review, the lesional cells morphologically and immunophenotypically resembled fetal hepatocytes. Given the rarity of this lesion, we performed an updated immunohistochemical and molecular analysis, including makers for β-catenin activation and well-differentiated hepatocellular carcinoma, and the results support the notion that hepatocellular adenoma of the placenta is a benign incidental finding.

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.

Plague is a disease caused by Yersinia pestis. Septicemic and pneumonic plague have a high mortality rate if untreated. Here we describe the challenges of accurately diagnosing a nonfatal pediatric case of septicemic plague with involvement of multiple organs; to our knowledge, the first documented case of multifocal plague osteomyelitis.

Background Prompt and accurate identification and differentiation of Mycobacterium tuberculosis-complex (MTBC) from non-tuberculous mycobacteria (NTM) is crucial for the selection of antimicrobial treatment and appropriate public health response. Diagnosis and characterization of mycobacteria is challenging due to diverse clinical presentations, lack of sensitivity of smear microscopy, and fastidious culture identification. Moreover, because of clinical suspicion of noninfectious conditions, specimens are often not processed for culture and formalin-fixed, paraffin-embedded (FFPE) tissues are the only specimens available. For rapid and accurate identification of Mycobacterium spp. from patient tissues, sensitive and specific molecular assays combined with other tissue-based methods are vital. Methods We extracted DNA from FFPE tissues from 931 patients with clinical and histopathological suspicion of mycobacterial infection (received during 2013–2016) and evaluated by multistage, multigene targeted Mycobacterium-genus, complexes-and species-specific PCR assays (targets including 16S rRNA, rpoB, groEL, IS6110, RLEP) and sequencing. Tissues were also examined by acid-fast bacilli (AFB) stains and mycobacteria immunohistochemistry (IHC). Assays to detect mutations associated with drug resistance were performed on MTBC cases. Results A Mycobacterium species was detected in 465 (50%) cases by PCR and sequencing. Of these, 380 (82%) were positive by Mycobacterium PCR targeting 16S rRNA. 85 cases (18%), including 9 MTBC, 12 M. avium complex and 3 M. leprae, were positive by other PCRs. Co-infection of MTBC and NTM spp. was detected in 5 cases. Of 465 PCR positive cases, 327 (70%) showed immunostaining and 223 (48%) were AFB-positive. Molecular markers for drug resistance were detected in 9 out of 88 (10%) tested MTBC cases. Conclusion FFPE tissue analysis by multigene targeted PCR assays expands the opportunities for rapid identification of Mycobacterium species, allows differentiation of MTBC from NTM, and helps to detect co-infections. Using multigene targeted PCRs in combination with histopathology and IHC improve the accuracy of diagnosis, particularly in the presence of commensal and environmental pathogens. Disclosures All authors: No reported disclosures.

Zika virus is a mosquito-borne flavivirus that is related to dengue virus and transmitted primarily by Aedes aegypti mosquitoes, with humans acting as the principal amplifying host during outbreaks. Zika virus was first reported in Brazil in May 2015 (1). By February 9, 2016, local transmission of infection had been reported in 26 countries or territories in the Americas.* Infection is usually asymptomatic, and, when symptoms are present, typically results in mild and self-limited illness with symptoms including fever, rash, arthralgia, and conjunctivitis. However, a surge in the number of children born with microcephaly was noted in regions of Brazil with a high prevalence of suspected Zika virus disease cases. More than 4,700 suspected cases of microcephaly were reported from mid-2015 through January 2016, although additional investigations might eventually result in a revised lower number (2). In response, the Brazil Ministry of Health established a task force to further investigate possible connections between the virus and brain anomalies in infants (3).