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The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia in the causal pathway to death and the causative pathogens of fatal pneumonia in children aged 1–59 months enrolled in the CHAMPS Network.

Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0–60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0–60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development.

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Stillbirths are a major public health issue and a sensitive marker of the quality of care around pregnancy and birth. The UN Global Strategy for Women's, Children's and Adolescents’ Health (2016–30) and the Every Newborn Action Plan (led by UNICEF and WHO) call for an end to preventable stillbirths. A first step to prevent stillbirths is obtaining standardised measurement of stillbirth rates across countries. We estimated stillbirth rates and their trends for 195 countries from 2000 to 2019 and assessed progress over time.

(Abstracted from Lancet 2021;398:772–785)Stillbirths are a public health issue as well as an example of the inequality of care during pregnancy and birth. Groups such as the UN Global Strategy for Women's, Children's, and Adolescents' Health and the Every Newborn Action Plan aim to prevent stillbirths.

Fatal Lyme carditis caused by the spirochete Borrelia burgdorferirarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues.

Pathological studies on fatal cases caused by 2009 pandemic influenza H1N1 virus (2009 pH1N1) reported extensive diffuse alveolar damage and virus infection predominantly in the lung parenchyma. However, the host immune response after severe 2009 pH1N1 infection is poorly understood. Herein, we investigated viral load, the immune response, and apoptosis in lung tissues from 50 fatal cases with 2009 pH1N1 virus infection. The results suggested that 7 of the 27 cytokines/chemokines showed remarkably high expression, including IL-1 receptor antagonist protein, IL-6, tumor necrosis factor-α, IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-β, and interferon-inducible protein-10 in lung tissues of 2009 pH1N1 fatal cases. Viral load, which showed the highest level on day 7 of illness onset and persisted until day 17 of illness, was positively correlated with mRNA levels of IL-1 receptor antagonist protein, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-β, interferon-inducible protein-10, and regulated on activation normal T-cell expressed and secreted. Apoptosis was evident in lung tissues stained by the TUNEL assay. Decreased Fas and elevated FasL mRNA levels were present in lung tissues, and cleaved caspase-3 was frequently seen in pneumocytes, submucosal glands, and lymphoid tissues. The pathogenesis of the 2009 pH1N1 virus infection is associated with viral replication and production of proinflammatory mediators. FasL and caspase-3 are involved in the pathway of 2009 pH1N1 virus-induced apoptosis in lung tissues, and the disequilibrium between the Fas and FasL level in lung tissues could contribute to delayed clearance of the virus and subsequent pathological damages.

September 2012 marked the beginning of the largest reported outbreak of infections associated with epidural and intra-articular injections. Contamination of methylprednisolone acetate with the black mold, Exserohilum rostratum, was the primary cause of the outbreak, with 13,000 persons exposed to the potentially contaminated drug, 741 confirmed drug-related infections, and 55 deaths. Fatal meningitis and localized epidural, paraspinal, and peripheral joint infections occurred. Tissues from 40 laboratory-confirmed cases representing these various clinical entities were evaluated by histopathological analysis, special stains, and IHC to characterize the pathological features and investigate the pathogenesis of infection, and to evaluate methods for detection of Exserohilumin formalin-fixed, paraffin-embedded (FFPE) tissues. Fatal cases had necrosuppurative to granulomatous meningitis and vasculitis, with thrombi and abundant angioinvasive fungi, with extensive involvement of the basilar arterial circulation of the brain. IHC was a highly sensitive method for detection of fungus in FFPE tissues, demonstrating both hyphal forms and granular fungal antigens, and PCR identified Exserohilumin FFPE and fresh tissues. Our findings suggest a pathogenesis for meningitis involving fungal penetration into the cerebrospinal fluid at the injection site, with transport through cerebrospinal fluid to the basal cisterns and subsequent invasion of the basilar arteries. Further studies are needed to characterize Exserohilumand investigate the potential effects of underlying host factors and steroid administration on the pathogenesis of infection.

The recent influenza pandemic, caused by a novel H1N1 influenza A virus, as well as the seasonal influenza outbreaks caused by varieties of influenza A and B viruses, are responsible for hundreds of thousands of deaths worldwide. Few studies have evaluated the utility of real-time reverse transcription-PCR to detect influenza virus RNA from formalin-fixed, paraffin-embedded tissues obtained at autopsy. In this work, respiratory autopsy tissues from 442 suspect influenza cases were tested by real-time reverse transcription-PCR for seasonal influenza A and B and 2009 pandemic influenza A (H1N1) viruses and the results were compared to those obtained by immunohistochemistry. In total, 222 cases were positive by real-time reverse transcription-PCR, and of 218 real-time, reverse transcription-PCR-positive cases also tested by immunohistochemistry, only 107 were positive. Although formalin-fixed, paraffin-embedded tissues can be used for diagnosis, frozen tissues offer the best chance to make a postmortem diagnosis of influenza because these tissues possess nucleic acids that are less degraded and, as a consequence, provide longer sequence information than that obtained from fixed tissues. We also determined that testing of all available respiratory tissues is critical for optimal detection of influenza virus in postmortem tissues.

In the spring of 2009, a novel influenza A (H1N1) virus emerged in North America and spread worldwide to cause the first influenza pandemic since 1968. During the first 4 months, over 500 deaths in the United States had been associated with confirmed 2009 pandemic influenza A (H1N1) [2009 H1N1] virus infection. Pathological evaluation of respiratory specimens from initial influenza-associated deaths suggested marked differences in viral tropism and tissue damage compared with seasonal influenza and prompted further investigation. Available autopsy tissue samples were obtained from 100 US deaths with laboratory-confirmed 2009 H1N1 virus infection. Demographic and clinical data of these case-patients were collected, and the tissues were evaluated by multiple laboratory methods, including histopathological evaluation, special stains, molecular and immunohistochemical assays, viral culture, and electron microscopy. The most prominent histopathological feature observed was diffuse alveolar damage in the lung in all case-patients examined. Alveolar lining cells, including type I and type II pneumocytes, were the primary infected cells. Bacterial co-infections were identified in 25% of the case-patients. Viral pneumonia and immunolocalization of viral antigen in association with diffuse alveolar damage are prominent features of infection with 2009 pandemic influenza A (H1N1) virus. Underlying medical conditions and bacterial co-infections contributed to the fatal outcome of this infection. More studies are needed to understand the multifactorial pathogenesis of this infection.

ABSTRACTThe CEACAM1 glycoproteins (formerly called biliary glycoproteins; BGP, C-CAM, CD66a, or MHVR) are members of the carcinoembryonic antigen family of cell adhesion molecules. In the mouse, splice variants of CEACAM1 have either two or four immunoglobulin (Ig) domains linked through a transmembrane domain to either a short or a long cytoplasmic tail. CEACAM1 has cell adhesion activity and acts as a signaling molecule, and long-tail isoforms inhibit the growth of colon and prostate tumor cells in rodents. CEACAM1 isoforms serve as receptors for several viral and bacterial pathogens, including the murine coronavirus mouse hepatitis virus (MHV) and Haemophilus influenzae, Neisseria gonorrhoeae,andNeisseria meningitidisin humans. To elucidate the mechanisms responsible for the many biological activities of CEACAM1, we modified the expression of the mouse Ceacam1gene in vivo. Manipulation of the Ceacam1gene in mouse embryonic stem cells that contained the Ceacam1aallele yielded a partial knockout. We obtained one line of mice in which the insert in the Ceacam1agene had sustained a recombination event. This resulted in the markedly reduced expression of the two CEACAM1a isoforms with four Ig domains, whereas the expression of the two isoforms with two Ig domains was doubled relative to that in wild-type BALB/c (+/+) mice. Homozygous (p/p)Ceacam1a-targeted mice (Ceacam1a?4D) had no gross tissue abnormalities and were viable and fertile; however, they were more resistant to MHV A59 infection and death than normal (+/+) mice. Following intranasal inoculation with MHV A59, p/p mice developed markedly fewer and smaller lesions in the liver than +/+ or heterozygous (+/p) mice. The titers of virus produced in the livers were 50- to 100-fold lower in p/p mice than in +/p or +/+ mice. p/p mice survived a dose 100-fold higher than the lethal dose of virus for +/+ mice. +/p mice were intermediate between +/+ and p/p mice in susceptibility to liver damage, virus growth in liver, and susceptibility to killing by MHV. Ceacam1a-targeted mice provide a new model to study the effects of modulation of receptor expression on susceptibility to MHV infection in vivo.

Cells expressing the spike (S) glycoprotein of the neurotropic JHM strain (JHMV) of mouse hepatitis virus (MHV) are susceptible to lysis by B cells derived from naı̈ve mice, including B cells from perforin-deficient mice. Cytolysis requires interaction of the virus receptor and the viral S glycoprotein, is independent of other viral-induced components, and is not a unique property of B cells. Neutralizing anti-S-protein monoclonal antibodies (mAb) and a mAb specific for the viral receptor inhibit lysis. However, cells infected with an MHV strain unable to induce cell–cell fusion are resistant to lysis and lysis of JHMV-infected cells is inhibited by an anti-S-protein nonneutralizing mAb which prevents S-protein-mediated cell fusion. These data suggest that B cells may function as antibody-independent innate immune response during JHMV infection in vivo.

ABSTRACTGene transfer to differentiated airway epithelia with existing viral vectors is very inefficient when they are applied to the apical surface. This largely reflects the polarized distribution of receptors on the basolateral surface. To identify new receptor-ligand interactions that might be used to redirect vectors to the apical surface, we investigated the process of infection of airway epithelial cells by human coronavirus 229E (HCoV-229E), a common cause of respiratory tract infections. Using immunohistochemistry, we found the receptor for HCoV-229E (CD13 or aminopeptidase N) localized mainly to the apical surface of airway epithelia. When HCoV-229E was applied to the apical or basolateral surface of well-differentiated primary cultures of human airway epithelia, infection primarily occurred from the apical side. Similar results were noted when the virus was applied to cultured human tracheal explants. Newly synthesized virions were released mainly to the apical side. Thus, HCoV-229E preferentially infects human airway epithelia from the apical surface. The spike glycoprotein that mediates HCoV-229E binding and fusion to CD13 is a candidate for pseudotyping retroviral envelopes or modifying other viral vectors.

The initial site of virus replication during measles infection is in the epithelial cells of the respiratory tract. We have investigated measles virus infection of two types of polarized epithelial cells to determine if entry and/or release of the virus is confined to either the apical or the basolateral plasma membrane. The Caco-2 line of human intestinal epithelial cells and the polarized Vero C1008 monkey kidney cell line were grown on permeable supports and inoculated either through the apical or basolateral surfaces. Cells exposed to virus in the apical medium showed high levels of synthesis of virus-specific proteins, whereas no synthesis of viral proteins was detected in cells inoculated at the basolateral surface. Virus titers derived from apically infected cells were found to be about 1000-fold greater than titers derived from cells infected at the basolateral surface. Indirect immunofluorescence results also demonstrated that expression of measles viral antigens occurs at high levels only when input virions are inoculated at the apical surface. To investigate the localization of CD46 and moesin, which are receptors for measles virus, Caco-2 cells were incubated with monoclonal antibodies against CD46 or moesin followed by ¹²⁵I-labeled anti-mouse Ig.The results indicate that CD46 is expressed preferentially on the apical membranes while moesin appears to be present at similar levels on both surfaces. Release of the virus was also examined and found to be polarized as well Virus was released into the apical medium at up to 1000-fold higher titers than virus released into the basolateral medium. These results demonstrate that in two epithelial cell types measles virus preferentially enters and is released from epithelial cells in a polarized fashion through the apical plasma membrane. Copyright 1995, 1999 Academic Press

We have previously shown that the Edmonston strain of measles virus enters and is released preferentially at the apical surfaces of polarized epithelial cells. Small amounts of virus were found to be released at the basal surface. In the present study, we passaged the virus in polarized cells and characterized the passaged virus for its pattern of entry and release in epithelial cells as well as the ability to downregulate the receptor CD46. In contrast to the original stock virus, the passaged virus was found to be released at close to the same levels from both the apical and the basal surfaces. Accumulation of viral nucleocapsids and virus budding were observed at both membrane surfaces when cells were infected with the passaged virus. The passaged virus was also found to enter efficiently at the basal surface, unlike the original stock virus. Syncytial formation was observed at earlier times postinfection in cells infected with the passaged virus compared to cells infected with the stock virus. On Caco-2 cells, CD46 is found on both surfaces but is preferentially expressed on the apical membrane. The original Edmonston stock and two other wild-type strains, Chicago and Davis, were found to downregulate CD46 levels on the apical but not on the basolateral membrane of Caco-2 cells, while the passaged Edmonston measles virus did not downregulate CD46 on either surface. These data indicate that passage of measles virus through polarized epithelial cells results in selection of virus which exhibits a bidirectional pattern of entry and release through both the apical and the basolateral surfaces and which no longer downregulates CD46 expression on the cell surface.

Epithelial cells line the body and organ surfaces, and form a barrier to virus entry as well as to dissemination of progeny virus in the infected host. Epithelial cells are typically polarized and exhibit two distinct surface domains. Viruses may enter polarized epithelial cells through only one membrane surface and not the other, thus restricting sites which are susceptible to infection. Furthermore, the release of many viruses from epithelial cells is directional, which may have important implications in pathogenesis. The restricted sites of viral entry and release are also important determinants of the availability of viral components for interaction with the immune system.

ABSTRACTMolecular techniques were used to characterize genetic features of Staphylococcus aureusin 66 fatal cases of pneumonia caused by S. aureusand influenza A or B viruses. Nucleic acids were extracted from formalin-fixed, paraffin-embedded tissues. The majority of cases revealed genetic markers for Panton-Valentine leukocidin, mecA, and spatype t008.

ABSTRACTBackgroundBecause of low acceptance rates and limited capacity, complete diagnostic autopsies (CDAs) are seldom conducted in low- and middle-income countries (LMICs). There have been growing investments in less-invasive postmortem examination methodologies, including needle-based autopsy, known as minimally invasive autopsy or minimally invasive tissue sampling (MITS). MITS has been shown to be a feasible and informative alternative to CDA for cause of death investigation and mortality surveillance purposes.ObjectiveThe aim of this narrative review is to describe historical use and evolution of needle-based postmortem procedures as a tool to ascertain the cause of death, especially in LMICs.MethodsKey word searches were conducted in PubMed and EBSCO in 2018 and 2019. Abstracts were reviewed against inclusion and exclusion criteria. Full publications were reviewed for those abstracts meeting inclusion criteria and a start set was established. A snowball search methodology was used and references for all publications meeting inclusion criteria were manually reviewed until saturation was reached.ResultsA total of 1,177 publications were initially screened. Following an iterative review of references, 79 publications were included in this review. Twenty-nine studies, published between 1955 and 2019, included MITS as part of postmortem examination. Of the publications included, 76% (60/79) have publication dates after 2010. More than 60% of all publications included addressed MITS in LMICs, and a total of nine publications compared MITS with CDA.ConclusionsAlthough there is evidence of less-invasive postmortem sampling starting in the 1800s, more structured needle-based postmortem examination publications started to appear in the mid-twentieth century. Early studies were mostly conducted in high-income countries but starting in 2010 the number of publications began to increase, and a growing number of studies were conducted in LMICs. Initial studies in LMICs were disease-specific but since 2015 have evolved to include more expansive postmortem examination.