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Features & treatment

Up Features & treatment Intensive Care implications References

Pascale Gruber, Charles Gomersall, Gavin Joynt

First posted 224th April 2006

This page is based on: Gruber PC, Gomersall CD, Joynt GM. Avian influenza (H5N1): implications for intensive care, published in Intensive Care Medicine. Reproduced here, in part, with the permission of Springer Verlag. Click here to download the published version (requires subscription).

As influenza A/H5N1 spreads around the globe the risk of an epidemic increases. Review of the cases of influenza A/H5N1 reported to date suggests that it causes a severe illness with a high proportion of patients (63%) requiring advanced organ support. Of these approximately 68% develop multiorgan failure, at least 52% develop acute respiratory distress syndrome and 90% die. Disease progression is rapid with a median time from presentation to hospital to requirement for advanced organ support of only 2 days. The infectious nature, severity and clinical manifestations of the disease and its potential for pandemic spread have considerable implications for Intensive Care.

Data sources

  • literature search using the terms {avian influenza} and {H5N1} limiting the search to:

    • human studies

    • published after 1996

    • in English

  • search supplemented by inspection of the reference lists of all relevant articles identified by the search.

  • data from case reports and case series that gave individual patient data pooled to determine the characteristics and proportion of patients requiring advanced organ support (defined as invasive mechanical ventilation or administration of inotropes or vasopressors).


  • close contact with dead or sick birds is the principle source of infection for H5N1 virus

  • some evidence of human to human transmission [3,4], however, at present it remains inefficient and transmission from patients to healthcare workers is rare [5,6]

  • most likely mode of transmission is via respiratory droplets, although droplet nuclei have also been implicated in the transmission of influenza virus [7]

  • presence of H5N1 ribonucleic acid (RNA) in human faeces raises the possibility of faecal spread

  • although controversial, humans infected with human influenza virus may be infectious for a short time when still asymptomatic [8,9] If this is also true of avian influenza viruses it would have significant implications for quarantine in the event of a pandemic.


  • likely to be caused by both direct viral infection of tissues and immunological responses

    • detection of H5N1 RNA has been reported in lung, cerebrospinal fluid, blood, intestine, spleen and faeces [10,11].

    • plasma concentrations of inflammatory mediators are elevated [12,13]  and the marked lymphopenia together with the post-mortem observation of a reactive haemophagocytic syndrome in bone marrow, lymph nodes, spleen, lung and liver suggests the multiorgan failure may be mediated by cytokines

The clinical features of fever, lower respiratory tract symptoms, headache, myalgia, diarrhea, vomiting, abdominal and chest pain, coma and bleeding from mucosal membranes are too non-specific for a clinical diagnosis to be made. History of exposure to birds should be sought. Interestingly, secondary bacterial infection appears uncommon [15]. Manifestations of H5N1 are often severe with 41 of the 65 reported cases (63%, 95% CI: 51-75%) requiring advanced organ support [3,11,12,14,16-24]. However, reported cases may represent only the severe end of the spectrum as there is evidence of asymptomatic and mild infection [4,25]. Details of patients requiring advanced organ support are given in table 1. Important points to note are:

  • the number of children affected

  • short duration of hospital stay prior to requirement for advanced organ support

  • high mortality and high incidence of multiorgan failure, especially cardiovascular failure. NB These figures only provide a rough estimate as in many cases definitions of organ failures or ARDS were not documented and patients were reported as having multiorgan failure without specific organ failures being given.

Table 1.


Summary data

Age (median (interquartile range)) (n=41)

13 (6-24) years

Sex (M:F) (n=41)


Hospital mortality (95% confidence intervals) (n=41)

90% (81-99%)

Duration of symptoms prior to hospital admission (median (interquartile range) (n=30)

5 (4-6) days

Duration of hospital stay prior to requirement for advanced organ support (median (interquartile range) (n=16)

2 (0.75-3.25) days

Time from hospital admission to death (median (interquartile range) (n=21)

6 (5-13) days

Percentage of patients with organ failures (n=41)

Multiorgan failure
Respiratory failure
Cardiovascular failure
Central nervous system



Percentage of patients with ARDS (n=41)


Percentage of patients with pneumothorax (n=41)


Twenty two of the 41 cases who required advanced organ support (54%) developed ARDS but this is likely to be an underestimate. Many patients with severe respiratory failure were reported with insufficient detail to establish whether they had ARDS. Pneumothorax was common (17%). All pneumothoraces occurred during mechanical ventilation.


Typical laboratory findings [15]:

  • leukopenia

  • lymphopenia

  • impaired liver function

  • abnormal clotting

  • renal impairment

Detection of viral RNA in respiratory samples appears to offer the greatest sensitivity for early identification of avian (H5N1) flu. Unlike human influenza virus, H5N1 is associated with a higher frequency of virus detection in pharyngeal than in nasal samples [15].

Diagnosis can be confirmed by one or more of the following:

  • positive viral culture

  • positive PCR assay for influenza A (H5N1) RNA,

  • positive immunofluorescence test for antigen with the use of monoclonal antibody against H5

  • fourfold rise in H5 specific antibody titre in paired serum samples

Commercial rapid antigen tests may help provide support for a diagnosis of influenza A infection but have a poor negative predictive value and lack specificity for H5N1

Definitive treatment

Neuraminidase inhibitors (oseltamivir and zanamivir) specifically target one of two surface structures of influenza virus, the neuraminidase protein. The presently circulating genotype Z of the avian influenza H5N1 virus carries mutations in the M2 gene and is therefore resistant to adamantanes (amantadine and rimanadine).

Current guidelines recommend that oseltamivir should be administered within 48 hours at a dose of 75mg twice daily for five days in adults, with weight adjusted doses for children. In more severe cases higher doses and a longer course of therapy has been recommended [15]. The efficacy of neuramidase inhibitors diminishes substantially if administered after 60 hours of infection and efficacy suboptimal when instituted later in the course of illness. However antiviral treatment could still be of benefit if there is ongoing viral replication [26].

At present there are no data to support the use of steroids or other immunomodulatory agents in H5N1 infections [26].

Prevention & prophylaxis

No influenza (H5) vaccines are currently commercially available for human use. Although vaccination against human influenza A is unlikely to protect against avian influenza it does reduce the risk of concurrent infection with both viruses, which may lead to an exchange in genetic material between human and avian viruses, resulting in a reassorted transmissible pandemic virus [30]. Chemoprophylaxis with oseltamivir 75 mg daily for 7-10 days is warranted for persons who have had a possible unprotected exposure [15].


  • Hospital mortality 90% (95% CI: 81-99%) amongst those reported to require advanced organ support

  • In the 1997 epidemic, risk factors for poor outcome [14]:

    • older age

    • being symptomatic for longer before admission

    • pneumonia

    • leukopenia

    • lymphopenia

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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