Role of respiratory viruses in childhood mortality.

Downham, M. A. P. S.; Gardner, P. S.; McQuillin, Joyce; Ferris, James A.J.

doi:10.1136/bmj.1.5952.235

Cited by 93 publications

(31 citation statements)

References 6 publications

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“…The microscopic anatomy of natural respiratory syncytial virus (RSV) infection is infrequently documented [1][2][3][4][5][6][7] in large part because patients with acute disease are rarely biopsied. Modern day autopsy material typically reflects the features of weeks-old infection, altered by supportive therapies (positive-pressure ventilation, oxygen toxicity) and, often, lung injury from bacterial superinfection, in addition to the late effects of viral infection and host immune response.…”

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confidence: 99%

The histopathology of fatal untreated human respiratory syncytial virus infection

et al. 2007

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The pathology of respiratory syncytial virus (RSV) infection was evaluated 1 day after an outpatient diagnosis of RSV in a child who died in a motor vehicle accident. We then identified 11 children with bronchiolitis from the Vanderbilt University autopsy log between 1925 and 1959 who met criteria for possible RSV infection in the preintensivist era. Their tissue was re-embedded and evaluated by routine hematoxylin and eosin and PAS staining and immunostaining with RSV-specific antibodies. Tissue from three cases was immunostain-positive for RSV antigen and was examined in detail. Small bronchiole epithelium was circumferentially infected, but basal cells were spared. Both type 1 and 2 alveolar pneumocytes were also infected. Although, not possible for archival cases, tissue from the index case was evaluated by immunostaining with antibodies to define the cellular components of the inflammatory response. Inflammatory infiltrates were centered on bronchial and pulmonary arterioles and consisted of primarily CD69 þ monocytes, CD3 þ double-negative T cells, CD8 þ T cells, and neutrophils. The neutrophil distribution was predominantly between arterioles and airways, while the mononuclear cell distribution was in both airways and lung parenchyma. Most inflammatory cells were concentrated submuscular to the airway, but many cells traversed the smooth muscle into the airway epithelium and lumen. Airway obstruction was a prominent feature in all cases attributed to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema, and compounded by compression from hyperplastic lymphoid follicles. These findings inform our understanding of RSV pathogenesis and may facilitate the development of new approaches for prevention and treatment.

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confidence: 99%

The histopathology of fatal untreated human respiratory syncytial virus infection

et al. 2007

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“…Bronchiolitis, the more severe clinical manifestation of RSV infection, is characterized by necrosis and sloughing of the respiratory epithelium and plugging of the small bronchioles with fibrin and mucus. An intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs, with considerable edema (1,8,10). In addition, presence of the granule-associate cytotoxic proteins histamine, eosinophil cationic protein, and major basic protein in nasopharyngeal secretions and tracheobronchial aspirates suggests that RSV infection triggers the migration to the airways and activation of basophils and eosinophils (12,17,37,46).…”

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Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1α in Lung Pathology

Haeberle

Kuziel

Dieterich

et al. 2001

J Virol

170

169

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Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inocuRespiratory syncytial virus (RSV) is the major cause of serious lower respiratory disease in infancy and early childhood (5). Bronchiolitis, the more severe clinical manifestation of RSV infection, is characterized by necrosis and sloughing of the respiratory epithelium and plugging of the small bronchioles with fibrin and mucus. An intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs, with considerable edema (1, 8, 10). In addition, presence of the granule-associate cytotoxic proteins histamine, eosinophil cationic protein, and major basic protein in nasopharyngeal secretions and tracheobronchial aspirates suggests that RSV infection triggers the migration to the airways and activation of basophils and eosinophils (12,17,37,46). The evidence of an inverse correlation between the levels of these cytotoxic mediators and the degree of oxygen saturation in RSV-infected infants further underscores the critical role played by mucosal inflammation in the pathogenesis of RSV airway disease (12,45,46).The mouse model shows close similarity to the pathogenesis of RSV-induced lower airway disease in humans. In BALB/c mice, RSV rapidly replicates in the lungs after intranasal inoculation, and induces mononuclear cell infiltration around peribronchial and perivascular tissues (41) and objective plethysmographic signs of pulmonary dysfunction (i.e., increased respiratory rates and airway hyperresponsiveness) (29, 44).These pathophysiologic changes correlate with the amount of viral inoculum (44), consistent with the observation that more severe disease occurs in infected children who have higher concentrations of RSV in their secretions (4, 16).The mechanisms that regulate selective recruitment of inflammatory cells to the airways and their activation following RSV infection are still largely unknown. Similarly, virus-or host-specific factors that may influence these events have not been yet identified. Much of the cellular response at sites of tissue inflammation is controlled by gradients of chemotactic factors that direct leukocyte transendothelial migration and movement through the extracellular matrix. The composition of this cellular response is dependent upon the discrete target cell selectivity of these chemotactic molecules. Chemokines, a superfamily of small chemotactic cytokines, have emerged as central regulatory molecules in inflammatory, immune, and infectious processes of the lung (28). Chemokines have been primarily divided into two main subfamilies, CXC (␣) and CC (␤), upon their sequence homology and the position of the first two cysteine residues. In general, this subdivision is mirrored by the activity of these two chemokine groups on neutrophils (CXC) or monocytes, eosinophils, and basophils (CC). However, within the CXC subfamily, chemokines such as gamma inte...

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“…A number of proinflammatory cytokines and chemokines, including CXCL8, CXCL10, and CCL5, correlate positively with disease severity (5,6). Gross and microscopic pathology from fatal cases of RSV infection are characterized by edema; small airway necrosis and sloughing; small airway plugs consisting of mucus, neutrophils, and sloughed epithelial cells; peribronchiolar and perivascular cuffing; interstitial infiltration and alveolar filling; and occasional giant cells (7)(8)(9)(10)(11). As a consequence of bronchiolitis, excess mucus production also is characteristic of RSV disease (12,13).…”

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In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

Villenave

Thavagnanam

Sarlang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

170

217

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Respiratory syncytial virus (RSV) is the major viral cause of severe pulmonary disease in young infants worldwide. However, the mechanisms by which RSV causes disease in humans remain poorly understood. To help bridge this gap, we developed an ex vivo/in vitro model of RSV infection based on well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs), the primary targets of RSV infection in vivo. Our RSV/WD-PBEC model demonstrated remarkable similarities to hallmarks of RSV infection in infant lungs. These hallmarks included restriction of infection to noncontiguous or small clumps of apical ciliated and occasional nonciliated epithelial cells, apoptosis and sloughing of apical epithelial cells, occasional syncytium formation, goblet cell hyperplasia/metaplasia, and mucus hypersecretion. RSV was shed exclusively from the apical surface at titers consistent with those in airway aspirates from hospitalized infants. Furthermore, secretion of proinflammatory chemokines such as CXCL10, CCL5, IL-6, and CXCL8 reflected those chemokines present in airway aspirates. Interestingly, a recent RSV clinical isolate induced more cytopathogenesis than the prototypic A2 strain. Our findings indicate that this RSV/WD-PBEC model provides an authentic surrogate for RSV infection of airway epithelium in vivo. As such, this model may provide insights into RSV pathogenesis in humans that ultimately lead to successful RSV vaccines or therapeutics.

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Role of respiratory viruses in childhood mortality.

Cited by 93 publications

References 6 publications

The histopathology of fatal untreated human respiratory syncytial virus infection

The histopathology of fatal untreated human respiratory syncytial virus infection

Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1α in Lung Pathology

In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

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