J Inf Dis: Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

[Giuseppe]

The Journal of Infectious Diseases 2008;198:000–000 - This article is in the public domain, and no copyright is claimed. - 0022-1899/2008/19807-00XX - DOI: 10.1086/591708 - MAJOR ARTICLE

Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

David M. Morens, Jeffery K. Taubenberger, and Anthony S. Fauci - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Background.

Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics.

Methods.

We examined relevant information from the most recent influenza pandemic that occurred during the era prior to the use of antibiotics, the 1918–1919 “Spanish flu” pandemic.

We examined lung tissue sections obtained during 58 autopsies and reviewed pathologic and bacteriologic data from 109 published autopsy series that described 8398 individual autopsy investigations.

Results.

The postmortem samples we examined from people who died of influenza during 1918–1919 uniformly exhibited severe changes indicative of bacterial pneumonia.

Bacteriologic and histopathologic results from published autopsy series clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory–tract bacteria in most influenza fatalities.

Conclusions.

The majority of deaths in the 1918–1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory–tract bacteria.

Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings.

If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs).

Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.

Received 13 June 2008; accepted 8 July 2008; electronically published 18 August 2008. - (See the editorial commentary by McCullers, on pages XXX–XXX.) [See below for the first paragraph and for the link to the free full text of the editorial. ioh]

Reprints or correspondence: David M. Morens, MD, Bldg. 31, Room 7A-10, 31 Center Dr., MSC 2520, National Institute of Allergy and Inectious Diseases, National Institutes of Health, Bethesda, MD 20892–2520 (dmorens@niaid.nih.gov).

Free full texts at: http://www.journals.uchicago.edu/doi...10.1086/591708
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The Journal of Infectious Diseases 2008;198:000–000 - © 2008 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2008/19807-00XX$15.00 - DOI: 10.1086/592165 - EDITORIAL COMMENTARY

Planning for an Influenza Pandemic: Thinking beyond the Virus

Jonathan A. McCullers - Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee
Received 23 July 2008; accepted 29 July 2008; electronically published 18 August 2008. - Potential conflicts of interest: none reported. - Financial support: US Public Health Service (grant AI-66349); American Lebanese Syrian Associated Charities. (See the article by Morens et al., on pages XXX–XX.)
Reprints or correspondence: Jonathan A. McCullers, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 (jon.mccullers@stjude.org).

R. Théophile H. Laennec was the first to describe the pathology of pandemic influenza.

The inventor of the stethoscope and of the technique of auscultation, Laennec published in the early 19th century a series of observations on diseases of the chest which remain relevant reading today.

Among his many contributions to science was his recognition while practicing in Paris during the 1803 pandemic that pneumonia was a frequent, fatal complication of influenza [1].

He described an increase in expectoration of yellow to greenish-tinged sputum, an increased frequency of “double” pneumonia, and noted that in most fatal cases, the lungs were at the early pneumonic stage of “engorgement” when examined by autopsy. (...)
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Free full text at: http://www.journals.uchicago.edu/doi...10.1086/592165
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[JJackson]

Re: J Inf Dis: Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

Ironorehopper: Thanks for posting this.

Everyone please read the commentary that accompanies this. I have written many post trying to argue for certain things over the last couple of years and this commentary makes the same argument for many of them but Jonathan McCullers manages to do it coherently, eloquently and with references.

JJ

EDITORIAL COMMENTARY Planning for an Influenza Pandemic: Thinking beyond the Virus Jonathan A. McCullers
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee
Received 23 July 2008; accepted 29 July 2008; electronically published 18 August 2008.

• <LI id=fn1>Potential conflicts of interest: none reported.
  Financial support: US Public Health Service (grant AI-66349); American Lebanese Syrian Associated Charities.
• (See the article by Morens et al., on pages XXX?XX.)

Reprints or correspondence: Jonathan A. McCullers, Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 (jon.mccullers@stjude.org). R. Th?ophile H. Laennec was the first to describe the pathology of pandemic influenza. The inventor of the stethoscope and of the technique of auscultation, Laennec published in the early 19th century a series of observations on diseases of the chest which remain relevant reading today. Among his many contributions to science was his recognition while practicing in Paris during the 1803 pandemic that pneumonia was a frequent, fatal complication of influenza [1]. He described an increase in expectoration of yellow to greenish-tinged sputum, an increased frequency of ?double? pneumonia, and noted that in most fatal cases, the lungs were at the early pneumonic stage of ?engorgement? when examined by autopsy.
This general pattern of increased incidence, increased mortality, and typical pathologic findings of bacterial pneumonia was repeated in virtually all of the generally recognized epidemics and pandemics through the modern era, when rigorous pathologic examination of fatal pneumonia cases fell out of use as a diagnostic modality. Indeed, Edwin O. Jordan, in his comprehensive survey of all literature relevant to the 1918 pandemic, argued that the general clinical and epidemiologic character of the pandemics of 1889?1890 and 1918?1919 were indistinguishable, including the disproportionately high attack rate in young adults which has been regarded to be pathognomonic of the 1918 pandemic [2]. This contention runs counter to the prevailing view espoused in both the scientific and lay media that the 1918 pandemic strain was uniquely virulent, and that factors intrinsic to the behavior of the virus and the pathogenesis of the viral infection must account for the strikingly high worldwide mortality associated with this pandemic.
In this issue of the Journal, Morens et al. review 109 published autopsy series from the 1918 pandemic and add new data for an additional 58 autopsies from which lung sections had been preserved [3]. Their findings are striking in the context of modern conceptions of the 1918 pandemic; the great majority of deaths could be attributed to secondary bacterial pneumonia caused by common respiratory pathogens, particularly pneumococci, group A streptococci, and staphylococci, and not to the virus itself. In fact, although evidence of severe viral bronchiolitis was found, often the primary viral insult appeared to be resolving at the time of the secondary infection responsible for the fatality. Their conclusions are strengthened by the remarkable consistency in theme, if not details, displayed across the many studies reviewed and the inclusion in their review of not only gross pathologic findings but blood and lung tissue culture data. In only 4% of the more than 8000 cases reviewed was no bacterial superinfection documented.
One insight offered by the authors is that this information is not new?we have simply lost this perspective over the last 50?60 years during the shift in modern medicine towards sophisticated imaging studies and molecular diagnostics and away from gross pathology. In similar fashion, the design of the current study is itself not new; a reexamination of pathology from a past pandemic was undertaken by a German scientist during the 1918 pandemic [4], much as has been done by Morens et al. [3]. Otto Lubarsch compared preserved autopsy specimens from the 1889?1890 pandemic to fresh autopsy samples from 1918?1919 and concluded the pathologic processes were nearly identical. This homogeneity in findings reinforces the idea that the end result, death from bacterial pneumonia, is a common feature of all pandemics in the preantibiotic era. If this supposition is correct, the virulence of the virus itself may not be the key predictor of mortality; the ability to interact with bacteria may be the more important factor [5]. In this light, the study of virulence factors that increase the incidence or enhance the case fatality rate of secondary bacterial infections is as important as understanding the basic biology of influenza viruses with pandemic potential.
Current interest in the pathogenesis of deaths during the 1918 pandemic must be put into the context of concern over, and preparation for, the next pandemic?an occurrence that history tells us is inevitable, although unpredictable. An intense global effort to prepare for this potentiality has been ongoing for approximately 5 years, following the reemergence in 2003 of highly pathogenic avian influenza viruses of the H5N1 subtype [6]. The majority of pandemic preparation has centered around prevention or treatment of the virus itself by developing vaccines against pandemic candidates and stockpiling antiviral drugs [7]. Little to no attention has been paid to prevention and treatment of potential bacterial superinfections, which, as Morens et al. remind us [3], have historically caused the great majority of deaths during pandemics. Part of this failure can be traced to our collective amnesia regarding the 1918 pandemic, as discussed above, and part can be attributed to assumptions about the clinical features of a theoretical H5N1 pandemic.
The clinicopathologic syndrome suffered by persons infected with avian influenza viruses of the H5N1 subtype over the last 10 years does not closely resemble that reported during previous pandemics in the preantibiotic era. Instead, illness manifests as severe, progressive pneumonia that rapidly acquires characteristics of acute respiratory distress syndrome, leading in most cases to death [8]. Rather than wound healing and regeneration, proceeding to resolution of viral disease with superimposed bacterial infection [3], the few pathologic examinations done after H5N1 infection show diffuse alveolar damage, necrosis, squamous metaplasia, and hemorrhage [8, 9]. Bacterial infections have been shown to complicate H5N1 infections in a minority of cases, but they have not been a prominent cause of death, likely due to modern intensive care and provision of broad-spectrum antimicrobial agents.
More important in the context of pandemic planning, however, is the difficulty inherent in extrapolating data from a limited series of zoonotic infections to the broader range of possibilities inherent in a full pandemic. Currently circulating influenza viruses of the H5N1 subtype are not fully adapted to humans; they lack the capacity to easily be transmitted from person to person. Because acquisition of this trait will require adaptation or reassortment with human influenza viruses, the pathogenesis of these theoretical pandemic strains cannot be predicted with any assurance. In addition, there is no guarantee that the next pandemic will be caused by viruses of the H5N1 subtype, and there is an equally compelling argument to be made for several other candidates [8]. The assumption implicit in some pandemic plans, that the disease course during the next pandemic will be similar to that seen in the limited clinical experience with H5N1 viruses in Eurasia, may be entirely wrong. Deaths due to the next pandemic strain, even if it is an adapted H5N1, may follow precisely the pattern evident from history, and bacterial superinfections may be the predominant fatal events. Even if a clinical course similar to our recent H5N1 experience occurs in the next pandemic, our ability to provide modern intensive care and administer broad-spectrum antibiotics will certainly be compromised if clinical attack rates approach the 25%?30% range seen in previous pandemics. In this scenario, bacterial infections are likely to emerge as a major complication in survivors of the primary influenzal disease.
What is to be done? At this point pandemic planners have started to recognize the issue but have not yet begun to deal with it. A shift in focus is required. Pandemic planning must take into account the possibility that secondary bacterial pneumonia will be a frequent complication of pandemic influenza. Basic research into the interactions between influenza viruses and bacteria is needed. Modeling studies extrapolating the breadth of potential risk should be undertaken. Planning for prevention of disease must include pneumococcal vaccines as well as influenza vaccines [10]. A comprehensive survey of the sources, supply, and surge capacity of important antibiotics should be undertaken. This should include analysis of distribution patterns, as has been done for influenza vaccines [11]; it is likely that many of the countries in the developing world, where complications of pandemic influenza are likely to be worst, will have little to no access to appropriate antimicrobials in this scenario. Planners should consider strengthening and diversifying these pipelines?in the United States alone in the last 3 years, there have been shortages of more than a dozen antibiotics [12]. Included among these is vancomycin, an important drug used in the treatment of antibiotic-resistant infections due to Streptococcus pneumoniae and Staphylococcus aureus, the 2 most common secondary pathogens in the infections that follow influenza. If these shortages are occurring in times of constant demand, it seems likely that worse will occur when there is a surge in demand.
Since the 1997 H5N1 outbreak in Hong Kong, a tremendous amount of work has been done to understand influenza viruses and prepare for the next pandemic. As Morens et al. have reminded us, however, the virus is only half of the story, and the bacterial superinfections may be the more deadly half [3]. Harry S. Truman may have summed it up best, ?The only thing new in the world is the history you don't know? [13]. This timely reminder of our past should act as an impetus to help prevent the history of the 1918 pandemic from repeating itself.
References

• <LI id=rf1>1. Laennec RTH. Signs of peripneumonia. In: Hale-White W, trans. and ed. Translation of selected passages from De l'Auscultation Mediate. 1st ed. New York: Williams Wood & Co., 1923; 82?95. First citation in article <LI id=rf2>2. Jordan EO. Epidemic influenza. 1st ed. Chicago, IL: American Medical Association, 1927: 9?19. First citation in article <LI id=rf3>3. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008; 198: XXX?XX (in this issue). First citation in article <LI id=rf4>4. Lubarsch O. Die anatomischen Befunde von 14 t?dlich verlaufenen F?llen von Grippe. Berl Klin Wchnschr 1918; 55:768?9. First citation in article <LI id=rf5>5. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 2006; 19:571?82. First citation in article, CrossRef, PubMed <LI id=rf6>6. Webby RJ, Webster RG. Are we ready for pandemic influenza? Science 2003; 302:1519?22. First citation in article, CrossRef, PubMed <LI id=rf7>7. Monto AS, Whitley RJ. Seasonal and pandemic influenza: a 2007 update on challenges and solutions. Clin Infect Dis 2008; 46:1024?31. First citation in article, Abstract, PubMed <LI id=rf8>8. Peiris JS, de Jong M, Guan Y. Avian influenza virus (H5N1): a threat to human health. Clin Microbiol Rev 2007; 20:243?67. First citation in article, CrossRef, PubMed <LI id=rf9>9. bdel-Ghafar AN, Chotpitayasunondh T, Gao Z, et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358:261?73. First citation in article, CrossRef, PubMed <LI id=rf10>10. Klugman KP, Madhi SA. Pneumococcal vaccines and flu preparedness. Science 2007; 316:49?50. First citation in article, CrossRef, PubMed <LI id=rf11>11. Stohr K, Esveld M. Public health. Will vaccines be available for the next influenza pandemic? Science 2004; 306:2195?6. First citation in article, CrossRef, PubMed <LI id=rf12>12. American Society of Health System Pharmacists. Drug Shortages. Available at: http://www.ashp.org/s_ashp/cat2cn.asp?CID=480&DID=522. Accessed 22 July 2008. First citation in article
• 13. Miller M. Plain speaking: an oral biography of Harry S. Truman. New York: Berkeley Publishing Corporation, 1974:26. Cited at: http://en.wikiquote.org/wiki/Harry_S._Truman. Accessed 11 August 2008. First citation in article

[gsgs]

Re: J Inf Dis: Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

my summary:

5% of deaths are due to cytokene storm,
95% are due to bacterial pneumonia
however, apparantly more young people died from bacterial
pneumonia than in other pandemics.

[Sally Furniss]

Re: J Inf Dis: Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

The Role of Bacterial Pneumonia in Pandemic Influenza

By Eric Toner, M.D., September 12, 2008

A paper¹ in the October issue of the Journal of Infectious Diseases by Morens, Taubenberger, and Fauci from the National Institute of Allergy and Infectious Diseases concludes that, contrary to what some scholars of the 1918 pandemic had believed, most deaths during the 1918 flu pandemic appear to have involved bacterial pneumonia rather than purely viral pneumonia. This finding contrasts with data from current human cases of H5N1 that manifest as purely viral pneumonia, for reasons that are not clear. This new study by Morens and colleagues is important because the role that bacterial suprainfections may play in causing illness and death from pneumonia during an influenza pandemic has been under appreciated in most pandemic planning, and it has important implications for flu planners as they project likely health consequences, identify medical surge capacity needs, and stockpile antimicrobials.
With seasonal influenza, pneumonia is the usual reason for both hospitalization and death. A minority of cases are caused by purely viral infections, but most are due to combined viral and bacterial infections or are the result of secondary bacterial infection due to impaired host defenses. Historical accounts of the 1918 pandemic include many cases of fulminant pneumonia, with clinical descriptions suggesting viral pneumonia. However, this study by Morens and colleagues is the first to report large numbers of contemporaneous culture results and to examine tissue specimens from victims.
The researchers reviewed the pathologic and bacteriologic results of 109 autopsy series representing 8398 cases from the 1918 pandemic. They also examined actual lung tissue specimens from 58 autopsies of American soldiers who died of the flu in 1918-1919. The specimens had been saved in the National Tissue Repository of the Armed Forces Institute of Pathology. The researchers found that nearly all the tissue specimens had pathological features consistent with acute bacterial pneumonia, either alone or in conjunction with evidence of viral pneumonia.
Of 68 high-quality autopsy series in which post mortem bacteriologic cultures of the lung were performed, bacterial growth was observed in 93% of the cases. The most common isolates were Streptococcus pneumoniae and Streptococcus pyogenes or mixed cultures of pneumopathogens. Staphylococcus aureus and Haemophilus influenzae were found less commonly. Cultures of blood and pleural fluid provided similar results (see table below).
Post mortem bacterial culture results
<table style="border: 1px solid rgb(169, 169, 169);" border="1" cellpadding="3" cellspacing="0"><tbody><tr><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">Specimen</td><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">No. of series (cases)</td><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">S. pneumoniae</td><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">S. pyogenes</td><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">Mixed or other</td><td class="bodyCell" colspan="1" rowspan="1" style="white-space: normal;" align="center" bgcolor="#d8ddc8" valign="bottom">No growth</td></tr><tr><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">Lung</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">68 (3074)
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">23%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">18%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">52%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">7%
</td></tr><tr><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">Blood</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">42 (1887)
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">27%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">20%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">23%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">30%
</td></tr><tr><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">Pleural</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">35 (1245)
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">21%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">43%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">16%
</td><td colspan="1" rowspan="1" style="white-space: normal;" align="center" valign="bottom">20%
</td></tr></tbody></table>These results provide strong evidence that many, if not most, of the pneumonia deaths during the 1918 pandemic involved bacterial infections. This suggests that many patients might have survived the 1918 pandemic had antibiotics been available, and suggests as well that if a future flu pandemic is similar to that of 1918, most patients with pneumonia will require antibiotics in addition to antivirals. Pandemic planners should therefore be assuring an adequate supply of antibiotics as well as antivirals.
References

1. Morens DM, Taubenberger JK, and Fauci AS. Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness. J Inf Dis 2008;198:962?970
2. Korteweg C and Gu J. Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans. Am J Pathol 2008 172: 1155-1170.

http://www.upmc-cbn.org/

[mixin]

Re: J Inf Dis: Predominant Role of Bacterial Pneumonia as a Cause of Death in Pandemic Influenza: Implications for Pandemic Influenza Preparedness

It seems like this should be a really important issue.

If this supposition is correct, the virulence of the virus itself may not be the key predictor of mortality; the ability to interact with bacteria may be the more important factor [5]. In this light, the study of virulence factors that increase the incidence or enhance the case fatality rate of secondary bacterial infections is as important as understanding the basic biology of influenza viruses with pandemic potential.

When I summarized the bacterial complications of the 1918 pandemic here
http://www.flutrackers.com/forum/showthread.php?t=77325, the Dr. said this:

That is to say, the secondary invasion may be a different one in two separate cases of the same disease, different in two different localities during the same epidemic, different, on the whole, in different epidemics. Once such a secondary invader has achieved success, it tends to become exalted in virulence by the ordinary mechanism of animal passage and, by repetition of the process, still further exaltation of virulence may be brought about till it can attack healthy persons.

And then, here's a comment I didn't quote in my summary:

it may- be said that during the earlier outbreak of the disease in the summer of 1918 Pfeiffer's bacillus was found in some countries in a large proportion of the cases, sometimes in nearly all. In other countries it was sometimes found and sometimes not; in one country?Germany?it was found only exceptionally during the summer. Our troops in Mesopotamia experienced both the summer and autumn epidemics in 1918, yet Dr. Ledingham, who was then acting as pathological consultant, informs us that Pfeiffer's bacillus was not found during the epidemic in that country. In the autumn epidemic it was found more regularly everywhere, even in Germany.

Those comments lead me to wonder if there was something unique about the 1918 virus that enabled infection by whatever bacteria was prevalent in the population, or even in each person, as the virus spread from place to place.