Connect
MJA
MJA

Pandemic influenza: clinical issues

Mark Boyd, Kate Clezy, Richard Lindley and Rod Pearce
Med J Aust 2006; 185 (10): S44. || doi: 10.5694/j.1326-5377.2006.tb00706.x
Published online: 20 November 2006
Uncomplicated influenza

Uncomplicated influenza is typically characterised by acute onset of symptoms of an upper respiratory tract infection (eg, dry cough, sore throat) accompanied by a constitutional illness (eg, various combinations of fever, headache, chills, myalgias, anorexia and malaise). The typical incubation period for influenza is 1–4 days, with an average of 2 days.1 In the context of a declared influenza pandemic, the presence of cough and fever may be diagnosed as influenza infection with a reasonable degree of certainty.2

History
Examination and investigation

Abnormal physical findings are sparse in patients with uncomplicated influenza. One hospital series found that only half the patients with proven influenza satisfied the criteria for influenza-like illness (temperature > 37.8°C, cough or sore throat), so a high index of suspicion is required to recognise influenza.11 Examination of the chest is usually unremarkable. The respiratory rate, estimated haemoglobin oxygen saturation (assessed by pulse oximetry) and chest x-ray are usually normal.

The full blood examination in uncomplicated influenza may be normal or consistent with the presence of a viral infection — that is, the blood haemoglobin concentration will likely be normal; the platelet count and total white cell count may be normal, decreased, or raised; and a blood film will probably suggest infection, with a neutrophil “left shift”, “band forms”, and “toxic” changes. In general, the serum urea, creatinine and electrolytes will be normal, or exhibit mild, clinically insignificant abnormalities. Liver function tests may demonstrate a mild hepatitis (raised serum alanine aminotransferase or asparagine aminotransferase concentrations) or non-specific cholestatic changes (eg, raised serum gamma glutamyl transferase and alkaline phosphatase concentrations). Study of C-reactive protein (CRP) in assessment of respiratory viral infections suggests that uncomplicated infection with influenza A or B viruses tends to produce higher CRP levels when compared with other upper respiratory viruses.12,13 However, it is neither sufficiently sensitive nor specific to support its use as a marker of influenza infection.

Immunopathogenesis

The major target of influenza infection is the ciliated epithelial cells in the mucous layer of the respiratory tract, leading to their necrosis, with oedema and infiltration by lymphocytes, plasma cells, histiocytes and neutrophils. In uncomplicated infection, repair starts about 3–5 days after illness, corresponding with the time of defervescence. However, restoration of ciliated cell function and normal mucous production may be delayed for 2 or more weeks after the onset of the illness. In fatal cases of influenza pneumonia, there have been varying degrees of interstitial cellular infiltrate, alveolar oedema and hyalin membrane deposition described. The virus may also infect neutrophils and lymphocytes, resulting in a reduced response to chemotactic stimuli and cellular function in general. This, together with necrosis and desquamation of the ciliated epithelial cells and abnormal mucus secretion, favours the development of secondary bacterial infection, including bronchitis and pneumonia, as well as other complications such as middle ear infections and sinusitis.14,15

The severity of clinical disease during an influenza pandemic is determined by intrinsic properties of the virus and the immunological status of the affected individual. For instance, the “cleavability” of the haemagglutinin (HA) glycoprotein has an association with viral pathogenicity. Anti-HA antibodies are the primary neutralising antibodies, and participate in complement-mediated lysis of infected cells, aggregation of virions, and cell cytotoxicity. Anti-neuraminidase reduces the number of infectious particles released from infected cells, and may reduce disease severity. The replication of influenza in a new host activates an inflammatory cytokine cascade, which leads to the febrile response and symptoms. Lavage specimens of nasal secretions typically contain interleukin 6 (IL-6), tumour necrosis factor (TNF), interferon γ, interleukin 10, monocyte chemotactic protein 1, and macrophage inflammatory proteins. While these cytokines may be associated with decreases in viral titre, very high levels of cytokines (eg, IL-6 and TNF) have been found in patients who manifest complicated disease.14,16,17

Complicated influenza

There are a number of individuals who are at increased risk for complicated influenza infection. They are:

Avian influenza A/H5N1 in birds and humans

In 1997, an epizootic avian influenza A/H5N1 virus of high pathogenicity began to cross the species barrier from birds to humans. This first epidemic occurred in China and Hong Kong, and 18 human infections were described (six deaths), which ceased after a mass cull of the entire Hong Kong chicken population. In mid 2003, the H5N1 virus began to circulate widely in poultry in the South-East Asian region as a result of the commercial flow of poultry stocks between neighbouring countries. Its adaptation to migratory birds in 2005 has allowed widespread dissemination of the virus, which is now present in at least 50 countries in Asia, the Indian subcontinent, Africa and Europe.

Since December 2003, 10 of those 50 countries have reported a total of 256 laboratory-confirmed human cases of H5N1 influenza, of which two were asymptomatic cases detected on contact screening.26 The case fatality rate (of symptomatic cases) was 59%. Although this mortality rate is high, it must be recognised that the extent of subclinical infection or mild illness is not certain — it cannot be assumed that these confirmed cases are representative of all human H5N1 infections. However, recent epidemiological surveys have detected only very low rates of asymptomatic seropositive cases of H5N1 virus among health care contacts of patients with documented H5N1 infection, suggesting a substantial symptomatic infection rate.27

Most cases of confirmed human H5N1 influenza to date have been in previously healthy young children or adults, probably reflecting the age-related behaviours that increase risk of exposure to infected birds (ie, poultry workers in the affected countries often tend to be young women). Median duration from symptom onset to hospitalisation was 4–5 days. The median time from symptom onset to death was 9 days. Case fatalities have been highest in those aged 10–39 years, lowest among those older than 50 years, and intermediate among children younger than 10 years. This age profile differs from the typical age-related case fatality for seasonal influenza, in which the highest mortality is seen among people at the extremes of age. The age distribution is similar to that described for the 1918 “Spanish flu” epidemic, in which fatality rates were higher among young adults.28

The clinical presentation of H5N1 infection has been with fever (typically > 38°C) and an influenza-like illness, with lower respiratory tract symptoms more frequent than upper respiratory tract symptoms. Most patients (> 88%) have had pulmonary infiltrates at time of diagnosis.29 Limited microbiological data gathered to date suggest that this pneumonic process is a primary viral pneumonia. Gastrointestinal manifestations have been a relatively prominent aspect of the presentation; watery diarrhoea has preceded respiratory manifestations by up to 1 week.29 The fatality rate of hospitalised patients since 2003 is 78%.26

Common laboratory findings have included leukopenia (particularly lymphopenia), mild to moderate thrombocytopenia, and mild to moderately elevated serum aminotransferase levels. In Thailand, an increased risk of death was associated with decreased leukocyte, platelet, and, particularly, lymphocyte counts at admission.30

H5N1 infection may be associated with a higher frequency of viral detection and higher viral DNA levels in pharyngeal than in nasal samples.17 Commercial rapid antigen tests have been less sensitive than reverse transcription polymerase chain reaction assays in detecting H5N1 influenza.30

Most hospitalised patients with H5N1 influenza have required ventilatory support within 48 hours of admission, and intensive management for multiorgan failure.30,31 Empirical therapy has generally consisted of broad-spectrum antibiotics and antiviral agents, alone or with corticosteroids; the emergency situation has not allowed a rigorous assessment of their effectiveness. Initiation of antibiotics and antivirals relatively late in the disease course has not resulted in any apparent reduction in mortality, although early initiation of antivirals does appear to be of some benefit.27,30,31 After treatment with oseltamivir, it has not been possible to culture the virus from patients who survived, and reductions in pharyngeal viral load have been described within 72 hours of oseltamivir initiation. However, clinical deterioration and eventual death have occurred despite these observations. Observations like this, as well as the apparent risk of serious disease in the otherwise healthy, have suggested a possible role of the innate immune response in the pathogenesis of H5N1 influenza. Elevations of various cytokines, including IL-6, TNF-α, interferon γ, soluble interleukin 2 receptor, interferon-inducible protein 10, monocyte chemoattractant protein 1, and monokine induced by interferon γ, have been described. In one study, the average levels of plasma interferon α in people who died of H5N1 influenza were about three times that found in healthy controls. Such responses may account, at least in part, for the sepsis syndrome, acute lung injury and multiorgan failure seen in many patients who died.17,27

  • Mark Boyd1
  • Kate Clezy2
  • Richard Lindley3
  • Rod Pearce4

  • 1 Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Adelaide, SA.
  • 2 Department of Infectious Diseases, Prince of Wales Hospital, Sydney, NSW.
  • 3 Department of Geriatric Medicine, Discipline of Medicine, Westmead Hospital, University of Sydney, Sydney, NSW.
  • 4 Athelstone and Beulah Park Medical Clinic, Adelaide, SA.


Correspondence: mark.boyd@fmc.sa.gov.au

Acknowledgements: 

Professor Lindley is supported by an infrastructure grant from NSW Health.

Competing interests:

Mark Boyd has received grants to attend conferences from Merck, Sharpe and Dohme, Roche, and Gilead Sciences, and is an advisor to Roche. Rodney Pearce is an Executive Member of the Influenza Specialist Group, which receives funding from various companies, including CSL, GlaxoSmithKline, Merck, Sharpe and Dohme, and Aventis, but operates as an incorporated independent body. He has received travel expenses from the Influenza Specialist Group, and Roche paid travel expenses for him to attend the Lancet pandemic influenza meeting in Singapore, April 2006. Richard Lindley has received a donation of oseltamivir (Tamiflu) from Roche for a research project.

  • 1. Cox NJ, Subbarao K. Influenza. Lancet 1999; 354: 1277-1282.
  • 2. Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2000; 160: 3243-3247.
  • 3. Klimov AI, Rocha E, Hayden FG, et al. Prolonged shedding of amantadine-resistant influenzae A viruses by immunodeficient patients: detection by polymerase chain reaction-restriction analysis. J Infect Dis 1995; 172: 1352-1355.
  • 4. Englund JA, Champlin RE, Wyde PR, et al. Common emergence of amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults. Clin Infect Dis 1998; 26: 1418-1424.
  • 5. Boivin G, Goyette N, Bernatchez H. Prolonged excretion of amantadine-resistant influenza a virus quasi species after cessation of antiviral therapy in an immunocompromised patient. Clin Infect Dis 2002; 34: E23-E25.
  • 6. Long CE, Hall CB, Cunningham CK, et al. Influenza surveillance in community-dwelling elderly compared with children. Arch Fam Med 1997; 6: 459-465.
  • 7. Frank AL, Taber LH, Wells CR, et al. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis 1981; 144: 433-441.
  • 8. Munoz FM. The impact of influenza in children. Semin Pediatr Infect Dis 2002; 13: 72-78.
  • 9. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B virus infections in children. Clin Infect Dis 2003; 36: 299-305.
  • 10. Goodman RA, Orenstein WA, Munro TF, et al. Impact of influenza A in a nursing home. JAMA 1982; 247: 1451-1453.
  • 11. Babcock HM, Merz LR, Fraser VJ. Is influenza an influenza-like illness? Clinical presentation of influenza in hospitalized patients. Infect Control Hosp Epidemiol 2006; 27: 266-270.
  • 12. Melbye H, Hvidsten D, Holm A, et al. The course of C-reactive protein response in untreated upper respiratory tract infection. Br J Gen Pract 2004; 54: 653-658.
  • 13. Rabagliati BR, Serri VM, Perret PC, et al. Clinical and epidemiological characteristics of respiratory virus infections among adults hospitalized during 2004 influenza season. Rev Chilena Infectol 2006; 23: 111-117.
  • 14. Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 6th ed. Philadelphia: Elsevier, 2005.
  • 15. Beadling C, Slifka MK. How do viral infections predispose patients to bacterial infections? Curr Opin Infect Dis 2004; 17: 185-191.
  • 16. Togashi T, Matsuzono Y, Narita M, Morishima T. Influenza-associated acute encephalopathy in Japanese children in 1994–2002. Virus Res 2004; 103: 75-78.
  • 17. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006; 12: 1203-1207.
  • 18. Sintchenko V, Gilbert GL, Coiera E, Dwyer D. Treat or test first? Decision analysis of empirical antiviral treatment of influenza virus infection versus treatment based on rapid test results. J Clin Virol 2002; 25: 15-21.
  • 19. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003; 326: 1235.
  • 20. Dell KM, Schulman SL. Rhabdomyolysis and acute renal failure in a child with influenza A infection. Pediatr Nephrol 1997; 11: 363-365.
  • 21. Fujimoto S, Kobayashi M, Uemura O, et al. PCR on cerebrospinal fluid to show influenza-associated acute encephalopathy or encephalitis. Lancet 1998; 352: 873-875.
  • 22. Salonen O, Koshkiniemi M, Saari A, et al. Myelitis associated with influenza A virus infection. J Neurovirol 1997; 3: 83-85.
  • 23. Wells CE, James WR, Evans AD. Guillain-Barre syndrome and virus of influenza A (Asian strain); report of two fatal cases during the 1957 epidemic in Wales. AMA Arch Neurol Psychiatry 1959; 81: 699-705.
  • 24. Varma RR, Riedel DR, Komorowski RA, et al. Reye’s syndrome in nonpediatric age groups. JAMA 1979; 242: 1373-1375.
  • 25. Waldman RJ, Hall WN, McGee H, Van Amburg G. Aspirin as a risk factor in Reye’s syndrome. JAMA 1982; 247: 3089-3094.
  • 26. World Health Organization. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. 16 October 2006. http://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_10_16/en/index.html (accessed Oct 2006).
  • 27. Beigel JH, Farrar J, Han AM, et al; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 353: 1374-1385. Erratum in N Engl J Med 2006; 354: 884.
  • 28. Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998; 178: 53-60.
  • 29. Apisarnthanarak A, Kitphati R, Thongphubeth K, et al. Atypical avian influenza (H5N1). Emerg Infect Dis 2004; 10: 1321-1324.
  • 30. Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis 2005; 11: 201-209.
  • 31. Tran TH, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004; 350: 1179-1188.

Author

remove_circle_outline Delete Author
add_circle_outline Add Author

Comment
Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.