Chloroquine inhibited virus replication. The inhibition occurred when the drug was added not later than 10 min after inoculation. Chloroquine caused an increase in the lysosomal pH 4.
The drug did not affect virus binding, endocytosis, or envelope fusion at pH 5. More Information about Flu Viruses. Types of Flu Viruses Flu A and B viruses are responsible for seasonal flu epidemics more commonly known as the flu season. How Flu Viruses Can Change Flu viruses can change in two different ways—antigenic drift and antigenic shift. Transmission of Flu Viruses from Animals to People Flu A viruses also are found in many different animals, including ducks, chickens, pigs, horses, whales, and seals.
Learn more, including about past flu pandemics. Images of Flu Viruses Graphics of generic flu viruses Human Serology and Flu CDC conducts human serology work to improve seasonal flu vaccines and prepare against future flu pandemics.
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What CDC Does. The alveolar air spaces contain erythrocytes. The alveolar air spaces contain edema fluid and erythrocytes. Unless successfully prevented by antibiotics, the late stages of influenza virus pneumonia are almost always complicated by secondary bacterial pneumonia, which can also produce hemorrhage. In all of the Camp Devens autopsy cases described by Wolbach 79 , bacteria were either cultured from lung tissue at autopsy or identified on sections.
The earliest death in this series was seven days after on-set. The latest had a clinical course of 32 days. Another histologic feature of the later stages of influenza virus pneumonia is evidence of repair and fibrosis. Regeneration of the epithelial lining of alveoli and bronchial tree with evident mitoses is frequently observed. Squamous metaplasia is common, and regenerating alveolar lining cells frequently show type II pneumocyte hyperplasia.
Interstitial fibrosis of alveolar walls is common as well. Also observed in late stages is erythrocyte phagocytosis by macrophages. In the variable spectrum of influenza virus pneumonia, different areas of the lung frequently demonstrate histologic lesions compatible with different stages of infection.
Later stages may also show typical changes of organization and fibrosis, including interstitial fibrosis, and bronchiolitis obliterans see Figure 9 with or without evidence of organizing pneumonia 19 , 20 , The surrounding alveoli show edema and hemorrhage.
Note that the spectrum of pathologic changes seen in the , , and pandemic cases, including the features of fatal primary influenza virus pneumonia, has also been observed in fatal cases of interpandemic influenza. Noble et al. Five patients recovered two were treated with corticosteroids for bronchiolitis obliterans with organizing pneumonia , and one case was fatal.
A biopsy showed variable features of influenza virus pneumonia that included patchy fibrinous alveolar exudates, alveoli with hyaline membranes, interstitial edema, late-stage severe diffuse alveolar damage, and bronchiolar necrosis. Reparative changes were also seen, defined as the proliferation of type II alveolar pneumocytes and mild interstitial chronic inflammatory infiltrates, as well as organization in air spaces and the interstitium Guarner et al.
Cases were divided into two groups on the basis of predominant histopathology: a tracheobronchitis group and an alveolitis group. The tracheobronchitis group sections showed focal positive immunohistochemical or in situ hybridization staining for influenza virus in intact and necrotic bronchial epithelial cells, as well as varying degrees of epithelial desquamation and necrotic debris in bronchial lumina.
Three of these cases had necrotizing bronchitis. The second group had alveolitis with an abundant mononuclear inflammatory infiltrate. One case showed intraalveolar hemorrhage. In this group, no viral antigens or nucleic acids could be detected. In another study, Guarner et al. Fifty percent of cases had necrosis of bronchial epithelium and submucosal hemorrhage.
Positive staining was observed in bronchial epithelial cells; submucosal mucus glands of the trachea, bronchi, bronchioli; and in single cells in alveolar lumina thought to represent sloughed bronchial epithelial cells, not alveolar lining cells.
The best immunohistochemical staining was seen in those patients dying in less than three days. Hemophagocytosis was also reported in both the and pandemics 1 , The lack of detection of influenza virus antigens or nucleic acids in alveolar epithelial cells is interesting, especially in cases showing alveolar epithelial cell desquamation and diffuse alveolar damage, but this may be related to the time course of these cases.
Since , documented cases of human H5N1 influenza viral infection have been reported 64 , with fatalities. To et al. Both had clinical courses of greater than one month, with deaths attributed to multi-organ failure. The findings in the respiratory tree consisted of extensive hemorrhage, organizing diffuse alveolar damage with interstitial fibrosis, and cystically dilated air spaces.
One case showed an interstitial lymphoplasmacytic infiltrate and scattered histiocytes with reactive hemophagocytic activity. All these features are compatible with late-stage cases described by Winternitz et al. Neither case showed evidence of a secondary bacterial pneumonia. Both, however, showed a reactive hemophagocytic syndrome in hematopoietic organs, which the authors postulated may have been triggered by reactive hypercytokinemia.
Uiprasertkul et al. In this case, the respiratory tree showed a proliferative phase of diffuse alveolar damage, interstitial pneumonia, focal hemorrhage, and bronchiolitis. Alveolar pneumocytes with reactive hyperplasia were seen without evident cytopathic changes.
A secondary infection with a fungus, morphologically resembling an aspergillus species, was noted. No hemophagocytosis was observed. Immunohistochemical analysis for H5N1 detected positive staining in alveolar epithelial cells. Double staining with antibodies against surfactant demonstrated that these were type II pneumocytes. Interestingly, immunohistochemistry stains were negative in the tracheal epithelium. RTP-CR was negative in plasma and other organs.
A recent clinical study of human H5N1 infections demonstrated higher cytokine and chemokine levels in peripheral blood than in control patients with seasonal, endemic human influenza infection 29 , and was highest in fatal H5N1 infections.
The H5N1 cases were also characterized by high pharyngeal virus titers, and H5N1 virus was detected in one case in the rectum, suggesting the possibility of limited replication outside the respiratory respiratory tract. Respiratory tract cytokine and chemokine levels were not measured in this study, and no comparison is possible between these blood cytokine results and what would have been observed in past pandemic virus infections such as those of and Shope isolated the first influenza A virus from pigs in 86 , 87 , and after the subsequent isolation of human influenza A viruses in 80 , ferrets were identified as an excellent laboratory model for human influenza.
In a series of landmark papers, Shope reported on the histopathologic changes in the respiratory tract of pigs, ferrets, and mice, describing changes compatible with those in human influenza virus infection, namely, desquamation of the ciliated epithelium of the tracheobronchial airways and peribronchial mononuclear cell inflammatory infiltrates 86 , 88 , The lungs of infected pigs and ferrets showed hyperemia and capillary congestion and mononuclear and neutrophilic inflammatory cell infiltrates in alveolar septa often marked , necrosis and desquamation of alveolar epithelial cells, and interstitial and intraalveolar edema.
Mice were susceptible to infection with human and swine influenza viruses 90 , but could not transmit the infection to other mice In contrast, Shope showed that both ferrets and swine were able to transmit the virus to contact animals 86 , In , Hers et al. Although these experimental animal models and humans infected with influenza A viruses share many histologic features—including evidence of viral degeneration of alveolar lining, hyperemia and congestion, septal inflammatory infiltrates, the appearance of macrophages with necrotic cellular debris in air spaces, and intraalveolar edema and hemorrhage—human cases additionally demonstrate the formation of hyaline membranes and capillary thrombosis.
The use of nonhuman primates for human influenza virus infection has also been recently reevaluated. He reported histopathologic findings of bronchopneumonia, with necrotizing bronchiolitis, intraalveolar edema and fibrin, and a mixed inflammatory infiltrate. Murphy and colleagues published a series of studies on experimental influenza virus infection in various nonhuman primates in the s 93 — Recently, Baskin et al. They found histopathologic findings comparable to human influenza virus pneumonia with intraalveolar edema and interstitial inflammatory cell infiltrates, and changes including alveolar epithelial hyperplasia at day seven.
Studies in both animals show a similar pathologic spectrum with bronchopneumonia, desquamation of bronchial and bronchiolar epithelial cells, diffuse alveolar interstitial inflammation, intraalveolar edema, and alveolar pneumocyte hyperplasia. Immunohistochemical analysis for the distribution of viral antigens shows positive staining in bronchial epithelial cells, alveolar pneumocytes, and alveolar macrophages. In both systems, viral encephalitis was also observed. Kuiken et al.
The histopathologic changes in the monkeys included extensive desquamation of bronchiolar and alveolar epithelium, interstitial inflammation and edema, intraalveolar edema, and hemorrhage admixed with numerous neutrophils and macrophages. One animal showed diffuse alveolar hyaline membrane formation. Upper airway changes were of a mild nature, but showed focal epithelial desquamation, ulceration, and inflammation.
With the completion of the project to sequence the influenza virus genome from autopsy tissues of influenza victims 57 , it has become possible using reverse genetic techniques to produce infectious viruses containing the influenza virus open reading frames — and to study experimental animal infections using mouse and cynomolgus monkey models.
In both animals, the influenza virus replicated to high titers. In mice, infection with the virus produced a necrotizing bronchitis and bronchiolitis with a marked alveolitis, with infiltrates of neutrophils and macrophages.
Alveolar edema was also observed. No evidence of systemic nonrespiratory system infection was noted. Gene expression array analysis demonstrated a marked activation of pre-inflammatory and cell death pathways one day after infection In the monkeys, infection with the reconstructed influenza virus produced a fatal acute respiratory distress syndrome Gene expression array analysis in this case demonstrated a dysregulation of the innate immune response and that the response was insufficient for protection.
Influenza viruses continue to be a major health threat in both endemic and pandemic forms. The rapid, continuous, and unpredictable nature of influenza viral evolution makes vaccine strategies and pandemic planning difficult.
It is crucial that future pathology studies be performed on autopsies of victims with fatal influenza infections, whether caused by endemic strains, seasonal strains, or zoonotic strains such as the recent H5N1 viruses.
Careful analysis of the histopathological changes of infection coupled with molecular genetic, virologic, and immunologic analyses will contribute to our understanding of the variable pathogenesis of influenza viruses. Influenza viruses can cause serious infections, leading to the development of pneumonia. Influenza A viruses, because of their host-range diversity, their genetic and antigenic diversity, and their ability to reassort genetically, are continual sources of novel influenza viruses that lead to the emergence of periodic pandemics.
Pandemic influenza viruses cause much higher morbidity and mortality than annual, epidemic influenza virus outbreaks. Influenza virus infection includes both upper and lower respiratory tract involvement. Influenza virus pneumonia, either alone or with secondary bacterial pneumonias, can often be fatal. The worst influenza pandemic on record, the influenza, killed up to 50 million people globally.
The pathologic spectrum of fatal influenza virus infections during the pandemic was not significantly different from that observed in other pandemics or even from fatal cases in seasonal influenza outbreaks. The authors are not aware of any biases that might be perceived as affecting the objectivity of this review. National Center for Biotechnology Information , U. Annu Rev Pathol. Author manuscript; available in PMC Aug Jeffery K. Taubenberger and David M.
Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Annu Rev Pathol. See other articles in PMC that cite the published article. Abstract Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics.
Keywords: pandemic, pneumonia, bronchitis, alveolitis, influenza, H5N1. Hers: Influenza 1 Influenza virus an antigenically and genetically diverse group of viruses of the family Orthomyxoviridae that contains a negative-sense, single-stranded, segmented RNA genome. Pandemic a global outbreak caused by a new strain of influenza A virus that contains an antigenically novel hemagglutinin protein; efficiently transmitted from person to person. Pneumonia an inflammation of the lungs the lower respiratory tree caused by a wide variety of microorganisms, including bacteria and viruses.
Seasonal interpandemic or epidemic influenza an outbreak of influenza A or influenza B virus occurring in annual cycles, usually in the winter months in temperate climates.
Highly pathogenic avian influenza HPAI a variant of avian influenza virus in which mutations in the cleavage site of hemagglutinin produce a virus that causes lethal infections in poultry. Clinical Course of Disease Influenza is an acute respiratory disease characterized in its full form by the sudden onset of high fever, coryza, cough, headache, prostration, malaise, and inflammation of the upper respiratory tree and trachea.
ILI influenza-like illness. NA neuraminidase. Biology of Influenza Viruses Influenza viruses of the family Orthomyx-oviridae are enveloped negative-strand RNA viruses with segmented genomes containing seven to eight gene segments Avian influenza a genetically and antigenically diverse group of influenza A viruses replicating in the gastrointestinal or respiratory tracts of wild birds and domestic poultry, usually causing no or only mild symptoms.
HA hemagglutinin. RT-PCR reverse-transcriptase polymerase chain reaction. Tracheobronchial Changes in Influenza Starting with the first pathological studies of influenza associated with the pandemic 15 , 68 , 69 , involvement of epithelial cells lining the upper respiratory tract has been universally recognized and corresponds to the clinical signs and symptoms of pharyngitis and tracheobronchitis.
Ciliated pseudostratified epitheepithelium of trachea and bronchi Early structural changes caused by influenza virus in the epithelium of the upper airway are variable, including cytonecrosis initially involving shrinkage and vacuolization, followed by desquamation of these cells into the luminal space.
Ducts of the mucus glands Opie 20 and Winternitz et al. Epithelium of the bronchioli Changes in the smaller airways are similar to those described above for larger airways. Open in a separate window. Figure 1. Figure 2. Other histologic changes Influenza infection of the epithelium of the upper airway passages is also associated with vascular congestion and hyperemia, edema, and an inflammatory cell infiltration of the tunica propria and submucosa.
In situ hybridization or immunohisto-chemical analysis for influenza virus in sections of the upper airway Studies performed in the s and s 1 , and more recent studies 12 , 13 , have consistently demonstrated the presence of influenza virus in tracheobronchial epithelial cells. Evidence of epithelial repair and regeneration Mitotic activity in regenerating respiratory epithelium can be seen focally.
Figure 3. Alveolitis an inflammation of the alveoli, the air sacs of the lungs. Histopathology of Primary Influenza Virus Pneumonia The alveolar epithelial cell lining is as much a target of influenza infection as the epithelial covering of the bronchi and bronchioles.
Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Figure 9. Influenza Virus Pneumonia in Interpandemic, Seasonal Influenza Cases Note that the spectrum of pathologic changes seen in the , , and pandemic cases, including the features of fatal primary influenza virus pneumonia, has also been observed in fatal cases of interpandemic influenza.
Experimental Animal Models of Influenza Virus Infection Shope isolated the first influenza A virus from pigs in 86 , 87 , and after the subsequent isolation of human influenza A viruses in 80 , ferrets were identified as an excellent laboratory model for human influenza. Groningen: Wolters-Noordhoff; Fields Virology.
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Regist Pathol. Armed Forces Inst. The Pathology of Influenza. New Haven: Yale Univ. Press; Wolbach SB. Comments on the pathology and bacteriology of fatal influenza cases, as observed at Camp Devens, Mass. Johns Hopkins Hosp. Pathologic features of lung biopsy specimens from influenza pneumonia cases.
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