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Annu Rev Pathol. Author manuscript; available in PMC 2008 August 11.
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Annu Rev Pathol. 2008 ; 3: 499–522.

The Pathology of Influenza Virus Infections

Jeffery K. Taubenberger and David M. Morens
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland 20892

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic
infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed
approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic
avian influenza viruses have raised concern about the emergence of another pandemic. The
histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed
here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not
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significantly different from the histopathology observed in other less lethal pandemics or even in
deaths occurring during seasonal influenza outbreaks.

pandemic; pneumonia; bronchitis; alveolitis; 1918 influenza; H5N1

“We regret very much the fact that an influenza virologist is unable to live say 200
years, so that he himself would be able to see what has developed from his earlier
J. Mulder and J.F.P. 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
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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
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)

The authors are not aware of any biases that might be perceived as affecting the objectivity of this review.

Taubenberger and Morens Page 2

a variant of avian influenza virus in which mutations in the cleavage site of hemagglutinin
produce a virus that causes lethal infections in poultry
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Influenza viruses are among the most common causes of human respiratory infections (2), and
among the most significant because they cause high morbidity and mortality. Influenza
outbreaks have apparently occurred since at least the Middle Ages, if not since ancient times
(3). In the elderly, in infants, and in people with chronic diseases, influenza is associated with
especially high mortality. In the United States, influenza results in approximately 200,000
hospitalizations and 36,000 deaths in a typical endemic season (4).

In addition to annual winter outbreaks, pandemic influenza viruses occasionally emerge (5,
6), as they have every 8 to 41 years for at least several centuries. Up to 50% of the population
can be infected in a single pandemic year, and the number of deaths caused by influenza can
dramatically exceed what is normally expected (7,8).

Since 1700, there have been approximately a dozen influenza A virus pandemics; in the past
120 years there were pandemics in 1889, 1918, 1957, and 1968 (9). The 1957 pandemic caused
66,000 excess deaths in the United States (8). In 1918, the worst pandemic in recorded history
caused approximately 546,000 excess deaths (675,000 total deaths) in the United States (6)
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and killed up to 50 million people worldwide (10). It is very likely that influenza will return
in pandemic form (5,6,9). Influenza B viruses can periodically cause large epidemics but do
not cause pandemics. Influenza C viruses are endemic and sporadically cause mild respiratory
disease. This review concentrates primarily on the pathology of influenza A viruses, by far the
most important human influenza pathogens.

The spectrum of influenza A histopathology is variable. Because pathology studies have
emphasized autopsy material, only changes associated with lethal outcomes and predominantly
late-stage disease have been well characterized. There is a broad spectrum of changes
associated with influenza infection, varying with both clinical picture and length of the disease
course before death. Coincident or secondary bacterial pneumonias are not only extremely
common in severe influenza but also complicate the histopathologic appearance. Nevertheless,
the spectrum of observed pathologic changes appears to vary little from pandemic to pandemic
or in interpandemic years (1,11–22). What separates the 1918 influenza cases from cases seen
in less severe pandemics and in seasonal influenza infections is not the spectrum of observed
pathology in severe and fatal cases but the significantly higher case fatality rate and—in the
1918 pandemic only—an unusual age distribution of deaths. In 1918, many previously healthy
young adults succumbed to fatal influenza infection, whereas the elderly had lower than
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expected fatality rates. In the past two pandemics and especially in interpandemic seasonal
influenza cases, fatal cases tended to occur in people with underlying chronic illnesses or at
the extremes of age (4,8).

Concern about the emergence of an influenza pandemic caused by a highly pathogenic avian
influenza (HPAI) virus of H5N1 subtype (23–26) makes reviewing the pathology of previous
pandemics relevant. Unfortunately, only three autopsy examinations have been reported for
individuals dying after H5N1 infection (27,28). Whether the typical spectrum of influenza
pathology would be observed if additional pathology studies were performed remains unclear.
It has been proposed that the pathogenesis of H5N1 influenza virus infection may feature a
unique hypercytokinemia (29,30). Data also suggest that the H5N1 virus may replicate outside
the respiratory tree (28). It is crucial for pandemic preparedness planning that additional careful
and complete autopsy studies of H5N1 influenza viral infection be performed and reported to
answer important questions about natural history, pathology, and pathogenesis.

Annu Rev Pathol. Author manuscript; available in PMC 2008 August 11.

approximately one-third of isolates from patients with ILI will be positive for influenza A (31). but the prevalence is greatest in school-age children. are at high risk of developing severe complications from influenza A viruses. or demonstration of viral genetic material (in clinical specimens). People of all ages are afflicted. . cough. Acute symptoms and fever often persist for 7 to 10 days. prostration. At the peak of an influenza epidemic. People with chronic pulmonary or cardiac disease. disease severity is greatest in infants. Studies of healthy young adults have shown influenza vaccine to be 70% to 90% effective in preventing influenza A illness. coryza. in any case. Antiviral drugs can have both therapeutic and prophylactic effects. respiratory syncytial viruses. or diabetes mellitus. Weakness and fatigue may linger for weeks. parainfluenza viruses. Author manuscript. malaise. headache. ILI influenza-like illness Bronchitis/bronchiolitis an inflammation of the bronchi and bronchioli of the respiratory tree NA neuraminidase NIH-PA Author Manuscript Effective measures against influenza A and B diseases include prevention of infection by either vaccination with inactivated or live attenuated vaccines. or administration of antiviral drugs prophylactically or therapeutically (33). and those with underlying illnesses. The importance of predicting the emergence of new circulating influenza strains for subsequent annual vaccine development cannot be underestimated (35). which may include hemorrhagic bronchitis. including influenza C viruses. but other pathogens also cause ILI. Fulminant fatal influenza viral pneumonia occasionally occurs. In most cases. with little virus shed after about six days. with moderately lower efficacy rates in the elderly. vaccines normally protect only for a matter of months. However. demonstration of viral antigens. or rises/ falls in specific antibody titers in serum or respiratory secretions (32). The diagnosis of influenza can be established by viral culture. dyspnea. hemoptysis. viral antigen can be detected in cells and secretions of infected individuals for several days (2). and death. Matrix 2 ion channel Annu Rev Pathol. Such surveillance is the cornerstone of the World Health Organization influenza surveillance network (36). available in PMC 2008 August 11. pneumonic involvement is not clinically prominent. Hemorrhagic bronchitis and pneumonia can develop within hours. Even after the infectious virus can no longer be recovered. cyanosis. and death may proceed in as little as 48 hours after the onset of symptoms. NIH-PA Author Manuscript Influenza A viral replication peaks approximately 48 hours after inoculation into the nasopharynx and declines slowly. pulmonary edema. Influenza A and B viruses are the most common causes of influenza-like illness (ILI). Influenza usually occurs in winter outbreaks or epidemics (in temperate climates). The virus replicates in both the upper and lower respiratory tract. and inflammation of the upper NIH-PA Author Manuscript respiratory tree and trachea. Croup (laryngotracheitis) can be a serious complication in small children. the aged. Taubenberger and Morens Page 3 Clinical Course of Disease Influenza is an acute respiratory disease characterized in its full form by the sudden onset of high fever. but to prevent disease they must be administered continuously at times of high influenza activity. and Mycoplasma pneumoniae. pneumonia (primary viral or secondary bacterial). Annual revaccination is thus recommended for those at high risk. continuous viral antigenic drift (gradually accumulating mutations that allow escape from population immunity) of influenza A viruses makes once effective vaccines ineffective after a few years' time (34).

Influenza A viruses are subdivided by antigenic characterization of the hemagglutinin (HA) and NA surface glycoproteins that project from the virion. zanamivir and NIH-PA Author Manuscript oseltamivir. Avian influenza viruses in aquatic birds serve as the natural reservoir for all known subtypes of influenza A virus and probably are the ultimate source of human pandemic influenza strains (46). but resistant viral strains develop rapidly and have been recognized in approximately one-third of treated patients. Sixteen HA and 9 NA subtypes are known (47). A/Wisconsin/67/2005 (H3N2)-like. NIH-PA Author Manuscript 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. and other mammals. or C). humans. The three virus types differ in host range and pathogenicity. Each influenza RNA segment is encapsidated by nucleoproteins to form ribonucleotide- nucleoprotein complexes (43). The 1918 pandemic virus was an H1N1 strain. H1N1 strains from NIH-PA Author Manuscript the pre-1957 period reappeared. The more recently developed neuraminidase (NA) inhibitors. Influenza A and B viruses have a similar structure.45). 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 (43). Author manuscript. however. Influenza A viruses. and since then both influenza A subtypes H3N2 and H1N1 have co-circulated in humans (46). First. One genus includes influenza A and B viruses. strains included in the most recent trivalent vaccine for the 2006–2007 season in the United States were: A/New Caledonia/ 20/1999 (H1N1). each of them coding for at least one protein. and the other comprises influenza C viruses. Influenza viruses accumulate point mutations during replication because their RNA polymerase complex has no proofreading activity (43). B. Type B and C influenza viruses are isolated almost exclusively from humans. NA. although influenza B viruses have been isolated from seals and influenza C viruses have been isolated from pigs and dogs (44. whereas influenza C is more divergent. H2N2 viruses circulated until 1968 when replaced by H3N2viruses of the 1968 pandemic. For example. In 1977. Its descendants circulated in humans until 1957 when they were replaced by an H2N2 subtype pandemic strain. including birds. isolation number. place of isolation. HA (H1–H16) and NA (N1–9) subtypes are noted in horses. They are covered with projections of three proteins: HA. A and B type viruses contain eight discrete gene segments. Both classes of drugs are effective in preventing influenza when administered prophylactically (37–42). and matrix 2 (M2). Their genes have high mutation rates (ranging from approximately 1 × 10−3 to 8 × 10−3 substitutions per site per year) (49). available in PMC 2008 August 11. swine. and year of isolation (separated by slashes). Mutations that change amino acids in the antigenic portions of surface glycoproteins may produce Annu Rev Pathol. Taubenberger and Morens Page 4 blockers (amantadine and rimantadine) are effective against influenza A viruses. and B/Malaysia/2506/2004-like (48). infect a wide variety of warm-blooded animals. Influenza C viruses have seven segments and only one surface glycoprotein (43). then the host (if non-human). usually causing no or only mild symptoms HA hemagglutinin World Health Organization guidelines for the nomenclature of influenza viruses are as follows. are effective against both influenza A and B viruses. For influenza A. . the type of virus is designated (A.

Author manuscript. Antibodies against the HA protein prevent receptor binding and are effective at preventing re-infection with the NIH-PA Author Manuscript same strain. the previously circulating postpandemic human virus imported an HA from an unidentified avian or avian-like virus (50). yielding a case fatality rate of 59%. with children under 15 years of age Annu Rev Pathol. As of April 2007. human infections with animal-adapted influenza virus of novel HA subtype have been observed in which the virus is not transmitted efficiently from person to person. The HA and NA can evade previously acquired immunity by either (a) antigenic drift. two people developed influenza conjunctivitis during a 2004 H7N3 HPAI outbreak in Canada (63). Sixteen HA subtypes are known to exist in wild birds and provide a source of HAs novel to humans (46. . NA. the ongoing H5N1 HPAI epizootic continued to produce spillover infections in humans. In 1968. causing concern that adaptation of this virus to humans could cause a pandemic (26). Concerns about the emergence of an H5N1 pandemic virus hinges not only upon transmission events between NIH-PA Author Manuscript infected poultry and individual humans. There was one fatality among those with direct contact to poultry (62). an HPAI H7N7 virus caused a poultry epizootic in the Netherlands and spread regionally. After reemergence in 2003. It is unknown whether this represents infection associated with particularly intimate or prolonged contact. Similarly. three genes from the circulating H1N1 human influenza virus were replaced by avian-like genes: HA. New Jersey. and the vast majority of cases were self-limited. In 2003. at least 86 poultry workers and three contacts had been infected and developed conjunctivitis with or without an ILI. in which mutations limit or prevent antibody binding. the HA and PB1 genes were similarly replaced (50. suggesting that stable adaptation to humans by reassortment or whole genome adaptation is required for the emergence of a pandemic strain (26). Several case clusters of H5N1 infections have been reported (65). the extent to which the rest of the virus can or must change is not known.51). and a subunit of the polymerase complex (PB1). there was one death (60. In 1957. Most communities experienced morbidity of 25%–40%. Although one of the absolute requirements for a pandemic is that HA must change. For example. is hypothesized to have arisen instead by whole genome adaptation (6. in both cases. NIH-PA Author Manuscript Although an antigenically novel HA subtype is a likely requirement for the emergence of an influenza pandemic. Age- specific morbidity was similar to other pandemics. Before the epizootic was contained. in the 1976 exposure of a limited number of soldiers to a swine-adapted H1N1 influenza virus in Fort Dix. unlike the 1957 and 1968 viruses. in which the virus acquires HA of a new subtype by reassortment between two influenza A viruses (2).61). The emergence in human circulation of an influenza strain with a novel subtype by antigenic shift has been the cause of the past two influenza pandemics (in 1957 and 1968). of which 172 were fatal (64).47). or (b) antigenic shift. Taubenberger and Morens Page 5 selective advantages for viral strains by allowing them to evade preexisting immunity. The HA molecule initiates infection by binding to receptors on specific host cells. or shared but unidentified host factors affecting either infection risk or virus transmissibility. 291 confirmed cases of human H5N1 infection had been documented. available in PMC 2008 August 11. The 1918 influenza pandemic virus has an avian-like genome and. but also upon the development of sustained human- to-human transmission. Although epidemiologic information has been limited.57–59). usually involving family members. The 1918 virus was recently completely sequenced using archevirologic techniques in which reverse-transcriptase polymerase chain reaction (RT-PCR) for small fragments of viral RNA were analyzed from lung tissues of 1918 influenza victims (52–57). RT-PCR reverse-transcriptase polymerase chain reaction The 1918 pandemic was the most lethal influenza pandemic on record. person-to-person transmission of H5N1 has been suggested in a few instances.

In later stages. respectively (67). As histologic changes are nonspecific. Tracheobronchial Changes in Influenza Starting with the first pathological studies of influenza associated with the 1889 pandemic (15. (73) reported a series of 126 autopsies performed in 1918. and the pulmonary alveoli were primary sites of influenza viral replication.5%. however. . In contrast. a substantially higher percentage of cases developed severe pneumonic complications. and. clearly recognized that the epithelium of the trachea. diagnosis typically requires supporting diagnostic tests such as viral isolation. Clinically. sometimes overlaid with mucopurulent Annu Rev Pathol. the disease was similar to other pandemics in that severe complications were confined largely to NIH-PA Author Manuscript the respiratory tract (20. bronchi. The large number of autopsy studies reported during and after the 1918 influenza pandemic all report such changes. Edema and congestion of the submucosa are often marked (20). Often only a basal layer of the epithelium remains.21). They were among the only observers of the 1918 pandemic to reach such a conclusion (20). People under the age of 65 accounted for more than 99% of excess influenza-related deaths in 1918.69). Askanazy observed evidence of epithelial regeneration with the formation of a nonkeratinizing stratified squamous metaplasia in 38 of 90 cases (70). the almost constant NIH-PA Author Manuscript coexistence of secondary bacterial infections of the air passages in fatal interpandemic and pandemic influenza complicates the picture.70–72). several times higher than the current rate. the 1918 pandemic presented generally the same symptoms and course as influenza of other years. Although the clinical course was usually self-limiting. rapid diagnostic tests (including RT-PCR). mortality during the 1918 pandemic was concentrated in an unusually young age group (6). and this group accounted for almost half of influenza deaths during the pandemic. Taubenberger and Morens Page 6 experiencing the highest rates of infection (66). in the 1957 and 1968 pandemics. (20) reported similar findings. the 1918 pandemic differed from other pandemics in several important clinical and epidemiologic aspects. Lucke et al.68. The trachea and bronchi had markedly reddened and swollen mucosal surfaces. Moreover. However. In the acute stage. available in PMC 2008 August 11. pathologically. multifocal destruction and desquamation of the pseudostratified pseudostratified columnar epithelium of the trachea and bronchi are characteristic. Author manuscript. At autopsy. Non-fatal influenza viral infections predominantly involve the upper respiratory tract and trachea. or a biopsy or autopsy tissue section confirmed by in situ hybridization or immunohistochemical techniques (32). INFLUENZA PATHOLOGY Influenza virus replicates in the epithelial cells throughout the respiratory tree. people less than 65 years old accounted for only 36% and 48% of excess deaths due to influenza. As a result. making it difficult to ascribe observed changes solely to influenza virus infection. These changes were carefully described by several distinguished pathologists in the aftermath of the 1918 influenza (20. The reasons for these unexpected patterns remain obscure. 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. but fatal cases of influenza usually show evidence of pneumonia. serologic studies. The age group affected most severely by the 1918 pandemic was that between 20 and 40 years. particularly severe tracheitis. the case mortality rate in the United States averaged 2. This review concentrates on the pathology of the lower respiratory tract. histologic analysis alone NIH-PA Author Manuscript is insufficient to make a specific diagnosis (19). Winternitz and his coworkers. with virus being recoverable from both the upper and lower respiratory tract of people naturally or experimentally infected (2).Winternitz et al.

As in the overlying epithelium. in early cases. often accompanied by ulceration. Complete separation of the remaining epithelium may be a histologic artifact. edema. Goodpasture (75) described the pathology of small. They noted submucosal capillary congestion and thrombi and NIH-PA Author Manuscript found that the bronchiolar wall was sometimes entirely necrotic and associated with a polymorphonuclear cell infiltrate. peribronchial hemorrhage. based predominantly on NIH-PA Author Manuscript 1957 pandemic autopsy cases. Photomicrographs of necrotizing bronchiolitis from two 1918 pandemic autopsy cases are shown in Figures 1 and 2. These structural changes to the epithelium are often irregularly distributed. Ducts of the mucus glands NIH-PA Author Manuscript Opie (20) and Winternitz et al. Other histologic changes Influenza infection of the epithelium of the upper airway passages is also associated with vascular congestion and hyperemia. edema. Common changes include focal epithelial necrosis to necrosis of the entire wall. Mulder & Hers (1) made similar observations about the 1957 pandemic. (74) both initially described the degeneration of epithelial cells in the tracheal and bronchial mucus glands in influenza infection. In later cases. however. In Mulder & Hers' (1) meticulous cytopathologic and histopathologic examinations of influenza cases. and peribronchial pneumonia. Author manuscript. . Epithelium of the bronchioli Changes in the smaller airways are similar to those described above for larger airways. The final stage of desquamation of the affected epithelium frequently shows only a single layer of flattened basalar epithelial cells covering the basement membrane. the epithelia are necrotic. Taubenberger and Morens Page 7 material. Later stages show mononuclear inflammatory cell infiltrates in the walls of bronchi (20). these cells migrate in. Because of the simpler structure of the bronchiolar epithelium. available in PMC 2008 August 11. and an inflammatory infiltrate. thinning and flattening of these cells can be more pronounced than in the larger airways. Their findings reiterate pathologic changes observed in 1918 and are concordant with the smaller number of influenza pathology studies published in recent decades.and medium-sized bronchioles in 1919. The lumina contained large amounts of frothy blood-stained material. A neutrophilic exudate may be present in the bronchiolar lumen. The interstitium may show congestion. Infiltration of neutrophils penetrating from capillaries into virus- infected areas in the absence of any evidence of secondary bacterial infection may be observed. but as epithelial cell necrosis occurs. changes consist of cytonecrosis and desquamation. Lucke et al. and an inflammatory cell infiltration of the tunica propria and submucosa. fibrin. Air spaces may be filled with edema. Necrotic cells may also undergo phagocytosis by macrophages. the epithelial linings are erythematous and filled with thin blood-stained froth or fluid. Hemorrhagic tracheitis and bronchitis were observed in 50% of cases. (73) reported desquamative bronchiolitis. An outstanding feature in early stages of infection is the absence of neutrophils in the infiltrate. these pathologic changes are described in great detail. often associated with the formation of hyaline membranes at these sites. Complete loss of the epithelial layer can be seen (both ciliated and goblet cells). Opie et al. followed by desquamation of these cells into the luminal space. Ciliated pseudostratified epitheepithelium of trachea and bronchi Early structural changes caused by influenza virus in the epithelium of the upper airway are variable. The presence of many neutrophils within Annu Rev Pathol. Grossly. (71) described the profound changes in smaller bronchi and felt that they were a characteristic feature of influenza virus infection. and varying numbers of neutrophils (19). including cytonecrosis initially involving shrinkage and vacuolization. neutrophilic infiltration is never massive. and regions of pathology can abut areas appearing histologically normal.

In 11 cases in which death occurred in less than 5 days. and plasma cells is frequently found in the tunica propria and submucosa of influenza-infected airways. In such cases. This fits the clinical picture of influenza viral pneumonia. A mononuclear-cell-inflammatory infiltrate of lymphocytes. and alveolar hemorrhage and edema are less pronounced than in primary influenza virus pneumonia (73). and those of the 1918 pandemic (20). An example of the massive neutrophil infiltration in acute bacterial bronchopneumonia is shown in Figure 3. compatible with findings reported in the aftermath of the 1889 pandemic. Chronic effects include NIH-PA Author Manuscript squamous metaplasia and interstitial fibrosis (19). In 14 cases of interpandemic influenza (1947–1954) Mulder & Hers found regeneration in 3 cases. MacCallum (72). with patients showing marked dyspnea and developing cyanosis. Taubenberger and Morens Page 8 the epithelial layer strongly suggests a coincident or secondary bacterial infection. available in PMC 2008 August 11. Influenza Virus Pneumonia Classic histopathologic studies of influenza autopsies have clarified the changes characteristic of severe influenza viral pneumonia. varying degrees of acute intraalveolar edema and/or hemorrhage. Early pathologic descriptions of influenza pneumonia were made in the 1889 pandemic. Author manuscript. and diffuse alveolar damage in addition to necrotizing bronchitis and bronchiolitis. blood-tinged. Wolbach (21).69). Later stages show organizing diffuse alveolar damage. Secondary or coincident bacterial pneumonias frequently occur and complicate the pathologic picture. epithelial regeneration.13). hemorrhagic bronchopneumonia (15. (20). namely. NIH-PA Author Manuscript In situ hybridization or immunohisto-chemical analysis for influenza virus in sections of the upper airway Studies performed in the 1950s and 1960s (1). and squamous metaplasia. Mononuclear inflammatory cells may also stain positively.77).74). capillary and small vessel thromboses. interstitial edema and inflammatory infiltrates. fibrosis. histiocytes. Large-scale autopsy studies by prominent pathologists during the 1918 influenza pandemic first described the spectrum of changes associated with influenza virus pneumonia. hemorrhagic bronchopneumonia often occurring concurrently with focal bacterial pneumonia was reported by many physicians and pathologists. and Wolbach & Frothingham (79). have consistently demonstrated the presence of influenza virus in tracheobronchial epithelial cells. depicting a gross pathologic picture of an edematous. and more recent studies (12. Both necrotic and histologically-normal-appearing cells can be positively stained. a massive infiltration of neutrophils into alveolar air spaces is observed. they found 13 cases out of 241 with regenerating epithelium (1). Walker (78). an edematous. LeCount (14. Additional changes associated with secondary bacterial pneumonias vary by causative agent and time course to death and are not further described in this review. Never before or since have so many pathological studies of influenza pneumonia been described. Evidence of epithelial repair and regeneration Mitotic activity in regenerating respiratory epithelium can be seen focally. (71. all with courses of 5–14 days after onset of illness. as described by Leichtenstern in 1896 (15). From these studies. Influenza viral pneumonia patients often produce massive amounts of foamy. Winternitz et al. During the 1918 pandemic. staining is usually focal. Most notable among them are the classic 1918 pandemic studies by Goodpasture (75). the formation of hyaline membranes in alveoli and alveolar ducts. . it appears likely that in influenza infection epithelial regeneration starts after approximately 5 days. In pandemic material. Annu Rev Pathol. Opie et al. NIH-PA Author Manuscript 68. or frankly hemorrhagic sputum (15). they found variable mitotic activity but no evidence of true regeneration of the epithelial layer. Klotz (76). Like the variable and multifocal histopathology.

Wolbach performed large autopsy studies in Boston and at nearby Camp Devens during the pandemic (21) and in 1923 wrote. and a sharp separation between lesions produced by the virus of the epidemic disease and the complicating organisms has not been made (79). a number of excellent autopsy studies of influenza viral infection were reported (17. In the 1968 pandemic. Mulder & Hers published a comprehensive study of changes observed in these more recent fatal influenza pneumonias (1). NIH-PA Author Manuscript recognizable clinically only by its epidemiologic proportions and extreme infectiousness. However. previously healthy individuals with no underlying chronic illnesses succumbed to fatal influenza viral pneumonias. One difference they noted was that acute alveolar edema was not as prominent a feature of influenza pneumonia as in 1918. other groups also reported on the pathologic changes observed in fatal influenza pneumonia cases (11. MacCallum (72) and Winternitz et al. most interpandemic influenza cases had longer courses and secondary bacterial pneumonias. capillary thrombosis with necrosis of the alveolar septa (necrotizing alveolitis). characterized pathologically by peculiar lesions in the lungs. with changes of diffuse alveolar damage. In 1972. (20) confirmed the above observations and described the underlying primary pulmonary lesion as most probably caused by an unknown nonbacterial (viral) agent. as compared with the 1957 pandemic. and caused by an unknown virus which gains entrance through the respiratory tract (75). During and after the 1957 pandemic. In both the 1957 and 1968 pandemics. Pathologists who have reported on the pulmonary lesions have not always endeavored to separate the lesions due to the virus of the epidemic and those dependent on the complicating organisms.82. The histopathologic pattern that emerged from these studies matches the modern view of viral pneumonia. the air sacs of the lungs NIH-PA Author Manuscript Even though the first isolation of human influenza virus did not occur until 1933 (80). In a reexamination of autopsy material of fatal interpandemic seasonal influenza cases from 1922–1947. which remains NIH-PA Author Manuscript the definitive source on influenza pathology.83). the same spectrum of pathology was observed. Author manuscript. and cells with pyknotic nuclei in the alveolar air spaces (desquamated alveolar epithelial cells). Annu Rev Pathol. Even though overall case mortality was low in the 1968 pandemic. manifold gross pathologic appearances have been described.16. Many pathologists in 1918 rejected the hypothesis that Bacillus (now Haemophilus) influenzae (Pfeiffer's bacillus) was the causative agent of influenza because in a number of series it was recovered in only a minority of cases at autopsy (81). On account of the variety of complicating organisms. available in PMC 2008 August 11. Goodpasture similarly wrote of his autopsy experiences in 1918: One feels justified in formulating the opinion that influenza is a distinct disease. although it was still observed. LeCount described the focal capillary and small vessel thromboses typical of influenza viral pneumonia (77). the formation of hyaline membranes in dilated alveolar ducts and alveoli. although changes typical of influenza were seen in the air passages. intraalveolar hemorrhage and edema.84). Wolbach described the hyaline membranes and the diffuse alveolar damage (21). . they reported that changes of primary influenza virus pneumonia were not frequently observed. many pathologists had long suspected an underlying primary influenza viral pneumonia could be described separately from secondary bacterial pneumonias. Taubenberger and Morens Page 9 Alveolitis an inflammation of the alveoli. prominent necrosis of the alveolar epithelium.18.

Megakaryocytes lying within the capillary bed are also commonly observed (1). NIH-PA Author Manuscript Necrosis of the alveolar wall may be a result of capillary thrombosis (77). Hemorrhage into the alveolar air spaces is often observed near necrotic areas. Infiltration is never dense except in areas showing septal necrosis. Alveolar lining cells also undergo necrotic changes and desquamation. leukocytes. Immunofluorescence studies documented influenza virus replication in alveolar epithelial cells in 1957 pandemic cases (1). partly hemorrhagic edematous pneumonia that develops with infection (1). and development of hyaline membranes. whereas 4 of 11 cases showed thromboses in the capillaries of the alveolar septa. fibrin. Necrotic areas are associated with leukocytic infiltrates. Early lesions of the alveolar epithelium are often difficult to detect because of the hyperemic. first described by LeCount in 1919. . Vast numbers of desquamated cells may be observed in the luminal spaces of alveoli. This dilatation is responsible for the diffuse red color of the affected areas (20). desquamated alveolar lining cells. At a certain stage in influenza virus pneumonia. Author manuscript. In 8 of these 11 cases.76). The cytologic changes are similar to those seen in ciliated cells of the upper air passages NIH-PA Author Manuscript (72). Later stages of influenza virus pneumonia also show interstitial infiltrates of mononuclear leukocytes. and bronchioli together with macrophages showing phagocytosed cellular debris. Degenerative changes include cytoplasmic vacuolization and nuclear pyknosis. focal necrosis of the alveolar wall. then develop on the alveolar walls (21). This 1918 autopsy lung tissue sample was positive by RT-PCR for influenza A virus A/New York/1/1918 (53). inflammatory cells. and disappearance of alveolar lining cells. The leukocytes are predominantly neutrophils and occasionally eosinophils. Hyaline membranes first appear in respiratory bronchioles and alveolar ducts. When hyperemic alveolar septa show no leukocytic infiltration. The alveolar septa are considerably thickened by dilatation of the alveolar capillary bed. exudation of fibrin. A photomicrograph of necrotizing alveolitis with intraalveolar edema. Leukocyte infiltration of the hyperemic alveolar septa is always present in the early stages of influenza virus pneumonia. and desquamated alveolar epithelial cells is shown in Figure 4. in 11 of 44 cases. alveolar ducts.19). Mulder & Hers (1) found these changes in 52 of 79 cases from the 1957 pandemic. They can demonstrate phagocytosis of degenerate. and sometimes erythrocytes. Hyperemia of the alveolar wall caused by marked capillary congestion is invariably present in influenza virus pneumonia. the diagnosis of influenza pneumonia should be doubted.75). alveolar cells partially or completely disappear (20. Fibrinous capillary thrombi. alveolar macrophages are sometimes present in large numbers and may show mitotic activity.72. Endothelial cell necrosis with pyknotic nuclei may be observed. Late stages show the presence of regenerating alveolar epithelium (type II alveolar hyperplasia) (1. Taubenberger and Morens Page 10 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. The extent and number of necrotic sites vary. associated with the exudation of plasma and strands of fibrin. are found in both the walls of alveolar ducts and in the alveolar septa (77). available in PMC 2008 August 11. Alveolar air spaces adjacent to areas of necrosis of the alveolar walls usually contain an accumulation of desquamated alveolar cells (1. Three characteristic alveolar changes are seen in early NIH-PA Author Manuscript influenza virus pneumonia: capillary thrombosis. he also observed hyaline membranes. In affected areas. These cytologic changes were observed in alveolar lining cells in influenza virus pneumonia. as seen in a photomicrograph from another 1918 autopsy case (Figure Annu Rev Pathol. Some show degenerate changes and may also be infected primarily with influenza virus (supported by in situ hybridization studies). predominantly lymphocytes and plasma cells. as described by MacCallum.

In the variable spectrum of influenza virus pneumonia. In general their presence is associated with necrosis of the alveolar wall. A biopsy showed variable features of influenza virus pneumonia that included patchy fibrinous alveolar exudates. bacteria were either cultured from lung tissue at autopsy or identified on sections. Good-pasture (75) found these features in all cases dying within a few days. described a massive edematous exudate in lung tissue and bronchioles on cut section. Seasonal Influenza Cases Note that the spectrum of pathologic changes seen in the 1918. different areas of the lung frequently demonstrate histologic lesions compatible NIH-PA Author Manuscript with different stages of infection. This picture of a meshwork of hyaline membranes within alveoli is a NIH-PA Author Manuscript characteristic finding in fully developed influenza virus pneumonia. All these cases occurred in healthy young soldiers or civilians. and one case was fatal. which can also produce hemorrhage. and bronchiolar necrosis.74). the late stages of influenza virus pneumonia are almost always complicated by secondary bacterial pneumonia. late-stage severe diffuse alveolar damage. . Taubenberger and Morens Page 11 5). Regeneration of the epithelial lining of alveoli and bronchial tree with evident mitoses is frequently observed. a finding less prominent in the 1957 pandemic material (see Figure 8) (1). Intraalveolar hemorrhage is often. and bronchiolitis obliterans (see Figure 9) with or without evidence of organizing pneumonia (19. hyaline membranes may occur as coarse strands or fine strands merging into a network of fibrin in the alveolar air spaces. Later stages may also show typical changes of organization and fibrosis. available in PMC 2008 August 11. Also observed in late stages is erythrocyte phagocytosis by macrophages. Large hemorrhagic areas can sometimes be the result of secondary bacterial pneumonias. Intraalveolar edema and hemorrhage are outstanding features of influenza virus pneumonia. Wolbach & Frothingham (79) observed evidence of intraalveolar hemorrhage and edema and the formation of hyaline membranes in all of his cases. but not always. Influenza Virus Pneumonia in Interpandemic. Mulder & Hers (73) described 11 cases with a clinical course ranging from 8 to 21 days. in 4. and in 70% of cases with pneumonias accompanying influenza.20. and regenerating alveolar lining cells frequently show type II pneumocyte hyperplasia.21). Five patients recovered (two were treated with corticosteroids for bronchiolitis obliterans with organizing pneumonia). 1957. including interstitial fibrosis. Hyaline membranes may also be observed covering small epithelial defects in bronchioli and small bronchi. this bloody edema fluid “pours out of the nostrils so as to stain a large part of the white sheets in which bodies are wrapped” (14). Unless successfully prevented by antibiotics. Reparative Annu Rev Pathol. Dilatation of the alveolar ducts is also a common feature in the acute stage of fatal influenza virus pneumonia described by many authors in 1918. associated with areas of necrosis of the alveolar wall. Squamous metaplasia is common. epithelial regeneration was found in respiratory bronchioles and adjacent alveoli. and 1968 pandemic cases. The earliest death in this series was seven days after on-set. LeCount. alveoli with hyaline membranes. In later stages (usually after a clinical course of approximately one week). Noble et al. In all of the Camp Devens autopsy cases described by Wolbach (79). including examples of mitotic figures. summarizingfindings from 200 influenza autopsies in 1918. including the features of fatal primary influenza virus pneumonia. He wrote that after the development of NIH-PA Author Manuscript rigor mortis. Hemorrhage can sometimes be extensive and may be grossly visible on a cut section as tiny or large hemorrhagic areas. Yeldandi & Colby (22) reported a histopathologic analysis of six cases with lung biopsies. Another histologic feature of the later stages of influenza virus pneumonia is evidence of repair and fibrosis. Author manuscript. has also been observed in fatal cases of interpandemic influenza. The latest had a clinical course of 32 days. Interstitial fibrosis of alveolar walls is common as well. A number of cases in 1918 demonstrated massive amounts of edema (see Figures 6 and 7) (20. and also beneath the pleura (74). interstitial edema. (85) reported such a case in 1973 in which an open lung biopsy revealed necrotizing bronchitis and bronchiolitis.

90% of cases having submucosal congestion and 73% a mononuclear submucosal inflammatory infiltrate. available in PMC 2008 August 11. 50% showed evidence of intraalveolar hemorrhage. with 200 fatalities. which the authors postulated may have been triggered by reactive hypercytokinemia. Hemophagocytosis was also reported in both the 1918 and 1957 pandemics (1. . with deaths attributed to multi-organ failure. but reported that primary influenza virus pneumonia was not a commonly observed feature of interpandemic influenza autopsy cases from 1942–1947. Histopathologic Changes in H5N1 Highly Pathogenic Avian Influenza Infections Since 2003. One case showed an interstitial lymphoplasmacytic infiltrate and scattered histiocytes with reactive hemophagocytic activity. The second group had alveolitis with an abundant mononuclear inflammatory infiltrate. All these features are compatible with late-stage cases described by Winternitz et al. defined as the proliferation of type II alveolar pneumocytes and mild interstitial chronic inflammatory infiltrates. The lack of detection of influenza virus antigens or nucleic acids in alveolar epithelial cells is interesting. as well as varying degrees of epithelial desquamation and necrotic debris in bronchial lumina. Uiprasertkul et al. Both had clinical courses of greater than one month. no viral antigens or nucleic acids could be detected.20). In this case. 66% had a mononuclear interstitial inflammation and formation of hyaline membranes. not alveolar lining cells). however. In this group. bronchioli. bronchi. showed a reactive hemophagocytic syndrome in hematopoietic organs. Taubenberger and Morens Page 12 changes were also seen. and cystically dilated air spaces. The best immunohistochemical staining was seen in those patients dying in less than three days. The findings in the respiratory tree consisted of extensive hemorrhage. especially in cases showing alveolar epithelial cell desquamation and diffuse alveolar damage. Author manuscript. the respiratory tree showed a proliferative phase of diffuse alveolar damage. (27) described the autopsy findings of two of the six NIH-PA Author Manuscript individuals who died in the initial H5N1 human outbreak in Hong Kong in 1997. Guarner et al. Three of these cases had necrotizing bronchitis. 328 documented cases of human H5N1 influenza viral infection have been reported (64). (28) reported a single autopsy study from a fatal case in a six-year-old boy who developed acute respiratory distress and died after 17 days. changes were seen in the trachea and bronchi. (12) reviewed autopsy material on 47 pediatric deaths occurring during the 2003–2004 influenza season. Positive staining was observed in bronchial epithelial cells. focal Annu Rev Pathol. (13) reported eight fatal cases of influenza infection with both histopathology and antiviral detection by immunohistochemistry and in situ hybridization. Both. NIH-PA Author Manuscript Guarner et al. Fifty percent of cases had necrosis of bronchial epithelium and submucosal hemorrhage. Mulder & Hers (1) reported positive in situ hybridization results for influenza RNA in the 1957 pandemic cases. In another study. as well as organization in air spaces and the interstitium (22). and in single cells in alveolar lumina (thought to represent sloughed bronchial epithelial cells. One case showed intraalveolar hemorrhage. NIH-PA Author Manuscript Immunohistochemistry for influenza viral antigens was positive in 57% of cases. but this may be related to the time course of these cases. As in the other studies. Neither case showed evidence of a secondary bacterial pneumonia. The tracheobronchitis group sections showed focal positive immunohistochemical or in situ hybridization staining for influenza virus in intact and necrotic bronchial epithelial cells. Cases were divided into two groups on the basis of predominant histopathology: a tracheobronchitis group and an alveolitis group. Hemophagocytosis was observed in 50% of cases. interstitial pneumonia. in their review of 1918 pandemic autopsies (20). bacterial bronchopneumonia was also observed in 50% of cases. the authors speculated that it might have been associated with hypercytokinemia. In the lower respiratory tree. To et al. submucosal mucus glands of the trachea. organizing diffuse alveolar damage with interstitial fibrosis. Neutrophilic.

ferrets were identified as an excellent NIH-PA Author Manuscript laboratory model for human influenza. (91) demonstrated. intraalveolar edema and fibrin. endemic human influenza infection (29). the appearance of macrophages with necrotic cellular debris in air spaces. and H5N1 virus was detected in one case in the rectum. Murphy and colleagues published a series of studies on experimental influenza virus infection in various nonhuman primates in the 1980s (93–97). Double staining with antibodies against surfactant demonstrated that these were type II pneumocytes. Respiratory tract cytokine and chemokine levels were not measured in this study. Author manuscript. Shope reported on the histopathologic changes in the respiratory tract of pigs. but also in the large intestines. In contrast. septal inflammatory infiltrates. Baskin et al. They found histopathologic findings comparable to human influenza virus pneumonia with intraalveolar edema and interstitial inflammatory cell infiltrates.RTP-CR was negative in plasma and other organs. and interstitial and intraalveolar edema. and was highest in fatal H5N1 infections. desquamation of the ciliated epithelium of the tracheobronchial airways and peribronchial mononuclear cell inflammatory infiltrates (86. describing changes compatible with those in human influenza virus infection. A recent clinical study of human H5N1 infections demonstrated higher cytokine and chemokine levels in peripheral blood than in control patients with seasonal. Shope showed that both ferrets and swine were able to transmit the virus to contact animals (86. In 1962. suggesting the possibility of limited replication outside the respiratory respiratory tract. (98) reported the pathology of a pigtail macaque (M. nemestrina) infected with a contemporary human H1N1 influenza virus. namely. A secondary infection with a fungus. with necrotizing bronchiolitis. Mice were susceptible to infection with human and swine influenza viruses (90). Annu Rev Pathol. was noted. Recently. (99) analyzed host gene expression profiles in these animals. 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. and Baas et al. viral replication in alveolar cells in experimental influenza infection in ferrets and mice. No hemophagocytosis was observed.89). Alveolar pneumocytes with reactive hyperplasia were seen without evident cytopathic changes.88). NIH-PA Author Manuscript Immunohistochemical analysis for H5N1 detected positive staining in alveolar epithelial cells. ferrets. RT-PCR for replicative H5N1 RNA was positive not only in the lung tissue. but could not transmit the infection to other mice (89). . and changes including alveolar epithelial hyperplasia at day seven. In a series of landmark papers. and after the subsequent isolation of human influenza A viruses in 1933 (80). 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 1918 and 1957. and a mixed inflammatory infiltrate. and mice. He reported histopathologic findings of bronchopneumonia. available in PMC 2008 August 11. and intraalveolar edema and hemorrhage—human cases additionally demonstrate the formation of hyaline membranes and capillary thrombosis. Taubenberger and Morens Page 13 hemorrhage. necrosis and desquamation of alveolar epithelial cells. by in situ hybridization.88.87). NIH-PA Author Manuscript The use of nonhuman primates for human influenza virus infection has also been recently reevaluated. and bronchiolitis. Interestingly. The lungs of infected pigs and ferrets showed hyperemia and capillary congestion and mononuclear and neutrophilic inflammatory cell infiltrates in alveolar septa (often marked). Burnet (92) reported experimental influenza virus infection of cynomolgus monkeys (Macaca fascicularis) in 1941 with a variant of A/WS/33 (H1N1). Experimental Animal Models of Influenza Virus Infection Shope isolated the first influenza A virus from pigs in 1930 (86. The H5N1 cases were also characterized by high pharyngeal virus titers. morphologically resembling an aspergillus species. immunohistochemistry stains were negative in the tracheal epithelium. hyperemia and congestion.

In mice. In the monkeys. Gene expression array analysis in this case demonstrated a dysregulation of the innate immune response and that the response was insufficient for protection. and inflammation. seasonal strains. infection with the 1918 virus produced a necrotizing bronchitis and bronchiolitis with a marked alveolitis. continuous. available in PMC 2008 August 11. Upper airway changes were of a mild nature. are continual sources of novel influenza viruses that lead to the emergence of periodic pandemics. the 1918 influenza virus replicated to high titers. and alveolar pneumocyte hyperplasia. (105) reported on the pathology of cynomolgus monkeys with a 1997 H5N1 virus. because of their host-range diversity. alveolar pneumocytes. or zoonotic strains such as the recent H5N1 viruses. and immunologic analyses will contribute to our understanding of the variable pathogenesis of influenza viruses. Author manuscript. intraalveolar edema. Annu Rev Pathol. 2. whether caused by endemic strains. including mice and ferrets (100–104). viral encephalitis was also observed. NIH-PA Author Manuscript No evidence of systemic (nonrespiratory system) infection was noted. Studies in both animals show a similar pathologic spectrum with bronchopneumonia. Alveolar edema was also observed. and hemorrhage admixed with numerous neutrophils and macrophages. CONCLUSION Influenza viruses continue to be a major health threat in both endemic and pandemic forms. it has become possible using reverse genetic techniques (106) to produce infectious viruses containing the 1918 influenza virus open reading frames (107–109) and to study experimental animal infections using mouse and cynomolgus monkey models. It is crucial that future pathology studies be performed on autopsies of victims with fatal influenza infections. One animal showed diffuse alveolar hyaline membrane formation. their genetic and antigenic diversity. infection with the reconstructed 1918 influenza virus produced a fatal acute respiratory distress syndrome (109). and alveolar macrophages. Kuiken et al. NIH-PA Author Manuscript diffuse alveolar interstitial inflammation. but showed focal epithelial desquamation. Taubenberger and Morens Page 14 Numerous studies have examined HPAI H5N1 viruses in experimental animal models. . ulceration. intraalveolar edema. In both systems. and unpredictable nature of influenza viral evolution makes vaccine strategies and pandemic planning difficult. Careful analysis of the histopathological changes of infection coupled with molecular genetic. 4. The rapid. and their ability to reassort genetically. Influenza viruses are common respiratory pathogens in humans. leading to the development of pneumonia. with infiltrates of neutrophils and macrophages. With the completion of the project to sequence the 1918 influenza virus genome from autopsy tissues of 1918 influenza victims (57). epidemic influenza virus outbreaks. In both animals. NIH-PA Author Manuscript SUMMARY POINTS 1. interstitial inflammation and edema. Immunohistochemical analysis for the distribution of viral antigens shows positive staining in bronchial epithelial cells. Influenza A viruses. Pandemic influenza viruses cause much higher morbidity and mortality than annual. virologic. The histopathologic changes in the monkeys included extensive desquamation of bronchiolar and alveolar epithelium. Influenza viruses can cause serious infections. desquamation of bronchial and bronchiolar epithelial cells. 3. Gene expression array analysis demonstrated a marked activation of pre-inflammatory and cell death pathways one day after infection (108).

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available in PMC 2008 August 11. A mixed inflammatory cell infiltrate is present throughout (original magnification 40×). and necrotic epithelial cells are present in the lumen. with submucosal edema and vascular congestion. H&E-stained section of the lung from a 1918 influenza victim showing necrotizing bronchiolitis. Author manuscript. There is necrosis of the bronchiolar wall. Taubenberger and Morens Page 20 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 1. NIH-PA Author Manuscript Annu Rev Pathol. The epithelial layer is desquamating. .

Taubenberger and Morens Page 21 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2. and necrotic epithelial cells are present in the lumen. available in PMC 2008 August 11. Author manuscript. H&E-stained section of the lung from a 1918 influenza victim showing necrotizing bronchiolitis. NIH-PA Author Manuscript Annu Rev Pathol. There is necrosis of the bronchiolar wall. The epithelial layer is desquamating. A mixed inflammatory cell infiltrate is present throughout (original magnification 200×). .

available in PMC 2008 August 11. Taubenberger and Morens Page 22 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 3. H&E-stained section of the lung from a 1918 influenza victim showing a massive infiltrate of neutrophils that fills the alveolar air spaces in early bacterial bronchopneumonia. Alveolar capillary congestion is prominent (original magnification 200×). NIH-PA Author Manuscript Annu Rev Pathol. Author manuscript. .

desquamated epithelial cells. and alveolar air spaces contain edema fluid. NIH-PA Author Manuscript Annu Rev Pathol. . Taubenberger and Morens Page 23 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 4. Author manuscript. H&E-stained section of the lung from a 1918 influenza victim showing a pattern of necrotizing alveolitis. available in PMC 2008 August 11. The alveolar walls are necrotic. and inflammatory cells (original magnification 200×).

desquamated epithelial cells. NIH-PA Author Manuscript Annu Rev Pathol. and inflammatory cells (original magnification 200×). Taubenberger and Morens Page 24 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 5. available in PMC 2008 August 11. . The alveolar air spaces contain edema fluid. strands of fibrin. H&E-stained section of the lung from a 1918 influenza victim showing hyaline membranes lining an alveolar duct and adjacent alveoli. Author manuscript.

The alveolar air spaces contain edema fluid. Author manuscript. H&E-stained section of the lung from a 1918 influenza victim showing massive pulmonary edema. Taubenberger and Morens Page 25 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 6. . A mild interstitial inflammatory cell infiltrate is also present (original magnification 40×). NIH-PA Author Manuscript Annu Rev Pathol. available in PMC 2008 August 11.

Interstitial edema and a mild interstitial inflammatory cell infiltrate are also present (original magnification 40×). available in PMC 2008 August 11. NIH-PA Author Manuscript Annu Rev Pathol. Author manuscript. H&E-stained section of the lung from a 1918 influenza victim showing massive pulmonary hemorrhage. Taubenberger and Morens Page 26 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 7. The alveolar air spaces contain erythrocytes. .

. NIH-PA Author Manuscript Annu Rev Pathol. available in PMC 2008 August 11. H&E-stained section of the lung from a 1957 influenza victim showing massive pulmonary edema and hemorrhage in early bronchopneumonia. Author manuscript. The alveolar air spaces contain edema fluid and erythrocytes. Taubenberger and Morens Page 27 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 8. A bronchiole shows necrotizing bronchiolitis with epithelial desquamation and necrotic epithelial cells in the bronchiolar lumen (original magnification 20×).

H&E-stained section of the lung from a 1918 influenza victim showing bronchiolitis obliterans. and a peribronchiolar vessel shows a thrombus (original magnification 40×). Taubenberger and Morens Page 28 NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 9. Author manuscript. There is interstitial capillary congestion. . NIH-PA Author Manuscript Annu Rev Pathol. available in PMC 2008 August 11. The surrounding alveoli show edema and hemorrhage.