New Insights from 1918 Flu Pandemic:

Recently, Drs. David Morens, Jeff Taubenberger, and Anthony Fauci of the US National Institute for Allergy and Infectious Diseases concluded that much of the mortality in the 1918-1919 “Spanish flu” pandemic was likely due to secondary bacterial pneumonia. The authors conclusions were based on pathologic review of autopsy specimens from 58 influenza victims in 1918-1919, and epidemiologic, pathologic, and microbiologic data from published reports for 8398 postmortem examinations. Similar findings were reported from 1957 and 1968 pandemics, although the data were less substantial. 

Moreover, Brundage, and Shanks set forth a sequential-infection hypothesis for the 1918 flu pandemic in a recent issue of Emerging Infectious Diseases in which the atypical flu strain weakened its hosts and allowed a secondary bacterial respiratory infection to take hold. Further to the work of Fauci, et al, samples taken during that year’s epidemic have shown that the most commonly isolated secondary organisms were S. pneumoniae, H. influenzae and S. aureus. The authors hypothesize that these secondary infections actually caused the majority of deaths associated with the epidemic and examined historical data and first-hand accounts. Evidence such as the patterns of disease progression and severity, high case fatality in unlikely risk groups, common isolation of respiratory bacteria and a close association with mortality rates and pneumonia rates all support this hypothesis.

Pandemic Flu Preparedness:

Given their analysis of data from the 1918 flu pandemic implicating an important role for bacterial respiratory agents, Brundage and Shanks suggest that preparations for a future pandemic flu outbreak should include: 1) removing barriers to pneumococcal vaccination before a pandemic 2) during a pandemic, universal flu vaccination with a strain-specific vaccine in as-yet unaffected communities and 3) during a local epidemic, treatment of all serious cases with antibacterials effective against pneumococcus, Hib and S. aureus, isolating affected patients and conducting thorough surveillance and research into influenza epidemiology, outcomes and determinants and effects of secondary infections.

A recent article by Gupta et al also discusses the role of bacterial co-infection context of current preparedness activities, and looks specifically at guidelines regarding antimicrobial drug stockpiling and deployment. The authors support the inclusion of a vaccination strategy using both polysaccharide and conjugate vaccines in pandemic planning, stating that the measure has the potential to reduce the amount of disease caused by secondary pneumococcal pneumonia, given the pathogen’s role in community-acquired-pneumonia and influenza complications. Pneumococcal vaccination in HIV-infected persons, the authors state, is particularly important and vaccination strategies are likely to save lives in the short term as well as provide protection in the event of a pandemic. 

Although pandemic preparedness efforts continue in many countries, The World Health Organization (WHO) is concerned that donor governments' and organizations' apathy towards avian influenza may undermine disease detection and control systems. During the past decade health authorities have monitored the H5N1 strain of avian influenza in the developing world finding fewer than 400 people infected with the illness. As a result, WHO officials are concerned that the low incidence may engender misconceptions about the pandemic threat and “sap investment in surveillance for bird flu as well as other infectious diseases.” Avian influenza has been discovered in more than 60 countries infecting over 6,500 poultry. WHO officials argue that as a result of population density, global warming, and increasing poultry production, the world is the closest it has been to another influenza pandemic since the last pandemic in 1968. As a result, WHO officials are encouraging donor governments and organizations to pledge their support for the long-term investment required to prevent future epidemics.

For further discussion of pandemic preparedness and insights into the mechanisms and interactions between flu and pneumonia, please see the following interview with Prof. Keith Klugman. In addition, several websites provide information and updates related to pandemic flu preparedness, including:
-The US Government – www.pandemicflu.gov
-The Centers for Disease Control – www.cdc.gov/flu/pandemic
-The World Health Organization – www.who.int/csr/disease/influenza/pandemic/en/

In-Depth Interview on Interactions between Flu and Pneumonia with Prof. Keith Klugman, Professor, Emory University 

Recently a number of publications have pointed out that influenza is often followed by bacterial pneumonia.  Could you briefly outline for us what is the biologic relationship between flu and bacterial pneumonia? How would a flu infection lead to bacterial pneumonia?

"Our understanding of the role of bacteria in the etiology of the pneumonia has been frustrated by our lack of sensitive diagnostic tools to identify the major bacterial causes of pneumonia. Nonetheless, a series of recent papers and reviews have defined our knowledge of the specific biologic processes that lead viral infections to increase susceptibility to pneumococcal pneumonia, otitis and invasive disease (1).

While influenza has specific virulence factors such as neuraminidase which facilitate pneumococcal infection, there are numerous biological responses to viral infections such as reduced ciliary clearance, increased bacterial adhesion to respiratory epithelium, apoptosis and decreased function of macrophages, that can all facilitate bacterial disease (1). Perhaps the most persuasive new biological data come from Sun and Metzger (2) who have recently shown that interferon gamma, which is an essential part of the adaptive response to influenza (and all respiratory viruses), leads to a temporary malfunction of the innate response to the pneumococcus."

Among the bacterial causes of pneumonia following influenza, how important is pneumococcal pneumonia likely to be?

"Among the causes of pneumonia the role of pneumococcus has always been assumed to be primary, and all rational empiric antibiotic regimens for pneumonia cover pneumococcal infections. The exact percentage of pneumonias caused by the pneumococcus will depend on age, geography and many host factors, but recent probe studies using conjugate vaccines suggest that 25% – 37% of childhood severe X – ray confirmed pneumonias are prevented by 7 – 9 valent vaccines (3-5). Given the likelihood that these vaccines prevent less than 100% of pneumonia due to vaccine types, and that 30% – 60% of pneumococcal pneumonia is caused by types not in the vaccine, the published data support a role for the pneumococcus in at least 50% of severe pneumonias. The 16% reduction in all cause mortality observed in recipients of 9 valent conjugate vaccine in the Gambia (4) is consistent with a primary role for the pneumococcus in severe and potentially life – threatening pneumonias in young children. Although there are limited data suggesting an increased role for Staphylococci following influenza, it is likely that the great majority of bacterial pneumonias follow acute respiratory infections and that the pneumococcus is the dominant pathogen. Direct evidence in support of this is the 45% reduction in influenza related hospitalization for severe pneumonia in recipients of 9 valent conjugate vaccine in South Africa (6). Studies on patients with pneumonia following the 1918 influenza support the idea that the pneumococcus was the predominant pathogen (7,8)."

Is there any reason to believe that the serotypes that cause bacterial pneumonia following flu would be different from the ones in the available vaccines?

"The pneumococcal serotype distribution following influenza likely depends on the prevailing circulation of pneumococci as the risk for disease may be greatest if there is new colonization with the pneumococcal serotype during the acute and early recovery phase of influenza. The magnitude of the reduction in influenza related severe hospitalization following the 9 valent vaccine in South Africa (6), as well as the limited serotype specific data from 1918 all suggest that the frequently colonizing pneumococci are the most likely to be implicated, rather than epidemic serotypes. Should a pneumococcal epidemic however coincide with a pandemic of influenza in a particular region such as the meningitis belt, then the epidemic type would be expected to predominate."

In your opinion should pneumococcal vaccination be considered a priority for pandemic influenza preparedness?

"I believe and have published the message that the major cause of death (much more than 50% of deaths) in pandemic influenza are bacterial infections and that as pneumococcal vaccine is the only bacterial vaccine available to prevent these infections, it should be an essential part of pandemic planning (9). There are at least two potential strategies. For countries that do not have pneumococcal conjugate vaccine in their pediatric routine vaccination schedule, this is an important reason to consider its speedy implementation, not only to protect infants, but also to protect adults from the vaccine serotypes through herd immunity. In those countries such as the US, where the conjugate vaccine has been introduced, there are strategies available to increase coverage with the booster dose in children less than 5 years of age to maximize herd immunity, as well as to consider 23 valent vaccine to prevent bacteremic pneumonia in at risk adults as well as first line responders to the epidemic, as the burden of pneumococcal bacteremia in 1918 was greatest in young people. These latter strategies could be implemented should an influenza epidemic appear imminent (WHO pandemic phase V)."

Do you think the impact of pneumococcal vaccination on flu mortality should be included in cost effective analysis regarding the value of vaccination?

"I am currently engaged in a cost effectiveness analysis of conjugate vaccination as part of pandemic planning that I will present orally at the upcoming ICAAC meeting in Washington, DC, in October. That analysis has been conducted in association with colleagues at Harvard University and was sponsored by Wyeth vaccines. Impact on mortality prevention is the major focus of that analysis. Similar studies are needed for the 23-valent vaccine."

Could you briefly tell us about any ongoing or future studies in South Africa that have examined the interactions between pneumococcal disease/vaccine and influenza, and studies in HIV-infected individuals?

"The initial study on influenza, RSV and para-influenza virus hospitalizations prevention by conjugate pneumococcal vaccine was published in Nature Medicine in 2004 (6). A follow-up paper addressing the interaction of human  metapneumovirus was published in 2006 (10). In collaboration with Professor Madhi we are currently looking at the role of other respiratory pathogens and with the imminent introduction of conjugate vaccine into that country will be able to set up surveillance to measure the impact on viral associated pneumonias in both HIV infected and HIV uninfected children. Such surveillance will need support for viral studies which are urgently needed in most developing countries. I am engaged in ongoing analyses in the US to measure the impact of conjugate vaccination on influenza and other respiratory virus associated morbidity in this country."

What areas should be priorities for further research in bacterial pneumonia and influenza interactions?

"Further research should use the mouse model to explore the biological basis of interactions between respiratory viruses other than influenza and the pneumococcus, as well as interactions between influenza and other respiratory bacterial pathogens. Epidemiologic studies on the role of respiratory viruses in bacterial transmission are needed as well as additional studies on the impact of conjugate vaccine introduction on influenza related morbidity in developed as well as developing countries."

Key References:

(1) McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 2006;19: 571-82.
(2) Sun K, Metzger DW. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 2008;14: 558-64.
(3) Hansen J, Black S, Shinefield H, Cherian T, Benson J, Fireman B, Lewis E, Ray P, Lee J. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs. Pediatr Infect Dis J 2006; 25: 779-81.
(4) Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, Oluwalana C, Vaughan A, Obaro SK, Leach A, McAdam KP, Biney E, Saaka M, Onwuchekwa U, Yallop F, Pierce NF, Greenwood BM, Adegbola RA; Gambian Pneumococcal Vaccine Trial Group. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365: 1139-46.
(5) Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N; Vaccine Trialists Group. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349: 1341-8.
(6) Madhi SA, Klugman KP; Vaccine Trialist Group. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004; 10: 811-3.
(7) Brundage JF. Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. Lancet Infect Dis. 2006; 6: 303-12.
(8) Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis. 2008; 14: 1193-9.
(9) Klugman KP, Madhi SA. Pneumococcal vaccines and flu preparedness.
Science 2007; 316: 49-50.
(10) Madhi SA, Ludewick H, Kuwanda L, Niekerk N, Cutland C, Little T, Klugman KP. Pneumococcal coinfection with human metapneumovirus. J Infect Dis 2006; 193: 1236-43.