164 Clinical Presentation

veloping, severe and sometimes refractory hypotension (Chesney 1981). The TSS diagnosis is based on a clinical case definition (Reingold 1981), and toxinproducing Staphylococcus aureus can usually be demonstrated in sputum specimens.

The differential diagnosis of sudden shock in this clinical setting includes myocarditis and septic shock. The differentiation of these illnesses can be difficult, often requiring haemodynamic monitoring, serologic testing, and cultures from appropriate clinical specimens (CDC 1986).

Reye’s Syndrome

Reye’s syndrome is characterised by the combination of liver disease and noninflammatory encephalopathy. It is a non-specific clinicopathological entity and a descriptive term which covers a group of heterogeneous disorders. It is almost always associated with previous viral infections, such as influenza, cold, or chickenpox. Differential diagnoses include encephalitis, meningitis, diabetes, drug overdose, poisoning, or psychiatric illness.

In influenza, Reye’s syndrome is a serious complication that may occur in children, in particular with influenza B virus. There is a strong link between the administration of aspirin and Reye’s syndrome (Starko 1980, Waldman 1982, Halpin 1983). When this association was recognised, the use of salicylates among children and teenagers with acute viral respiratory infections was discouraged. As a result, the incidence of Reye’s syndrome markedly decreased (Barrett 1986).

In the first outbreak of avian influenza among humans in Hong Kong in 1997, one child died from influenza pneumonia, acute respiratory distress syndrome, Reye’s syndrome, multiorgan failure, and disseminated intravascular coagulation (Claas 1998).

Complications in HIV-infected patients

The clinical presentation of influenza in patients infected with HIV is no different from other patient groups (Skiest 2001). Unusual clinical manifestations are rare and the rate of pulmonary complications is similar to that of HIV-negative patients. However, in small series, the hospitalisation rate has been reported to be higher than that commonly seen in HIV-negative individuals (Skiest 2001, Fine 2001). Only HAART seems to be able to reduce the number of influenza-associated hospitalisations (Neuzil 2003).

Influenza may be less benign in patients with AIDS, i.e., in more advanced stages of immunosuppression. In these patients, influenza has been associated in the US with excess death rates substantially higher than that of the general population and comparable to the general population aged 65 years and older (Lin 2001).

Avian Influenza Virus Infections in Humans

Avian influenza virus strains have only recently been identified as the cause of human disease. For most of these, the clinical manifestations in humans are mild. In 1996, an avian H7 virus was isolated from a woman with conjunctivitis (Kurtz

Avian Influenza Virus Infections in Humans 165

1996). In 1999, a H9N2 strain was isolated in Hong Kong from two children with mild influenza symptoms (Peiris 1999, Horimoto 2001). 4 years later, in an outbreak of a highly pathogenic subtype H7N7 strain in the Netherlands, conjunctivitis was the prominent feature among 89 persons infected; only 7 individuals had an influenza-like illness that was generally mild. However, one fatal case of pneumonia occurred in a man (Fouchier 2004): two days after visiting a poultry farm affected by avian influenza, the 57-year-old veterinarian developed malaise, headache and fever. Eight days later he developed pneumonia, and his condition then deteriorated. He died four days later of acute pneumonia.

The only avian influenza strain to cause repeatedly severe disease in humans is the H5N1 serotype, first diagnosed in humans in Hong Kong in 1997 (CDC 1997, Yuen 1998). So far, the number of human cases has fortunately been relatively low (152 as of 23 January 2006), but the case-fatality rate is high (83/152) (WHO 20051223). The clinical manifestations of influenza H5N1 infection in humans is not well-defined as current knowledge is based on the description of a few hospitalised patients. The spectrum ranges from asymptomatic infection (Katz 1999, Buxton Bridges 2000, Thorson 2006) to fatal pneumonitis and multiple organ failure.

Presentation

Initial symptoms of H5N1 influenza may include fever (typically > 38°C), headache, malaise, myalgia, sore throat, cough, and rhinitis (although upper respiratory symptoms may be absent), gastrointestinal manifestations and conjunctivitis (Yuen 1998, Chan 2002). All these symptoms are non-specific and may also be associated with the currently circulating human influenza virus subtypes, H1N1 and H3N2. In two reports, diarrhoea (Hien 2004) was a prominent feature along with shortness of breath (Hien 2004, Chotpitayasunondh 2005). Watery diarrhoea may be present well before pulmonary symptoms develop (Apisarnthanarak 2004). Another report describes a four-year-old boy with severe diarrhoea, followed by seizures, coma, and death, suggesting the clinical diagnosis of encephalitis – avian influenza H5N1 was later detected in cerebrospinal fluid, faecal, throat, and serum specimens (de Jong 2005).

Laboratory findings of patients with severe avian influenza H5N1 include leucopenia, lymphopenia, impaired liver function with elevated liver enzymes, prolonged clotting times, and renal impairment. The lymphocyte count appears to be the most valuable parameter for identification of patients who are at risk of progression to severe illness (Chan 2002).

Clinical Course

As of December 2005, about half of the patients diagnosed with clinical avian H5N1 influenza infection have died. Most of these patients had severe disease on admission to hospital. In patients with respiratory failure and fatal outcome, dyspnoea developed after a median of 5 days (range 1–16) in one series (Chotpitayasunondh 2005). Abnormal chest radiographs include interstitial infiltration, patchy lobar infiltrates in a variety of patterns (single lobe, multiple lobes, unilateral or bilateral distributions). Finally, the radiographic pattern progresses to a diffuse bilateral ground-glass appearance, with clinical features compatible with ARDS (Chotpitayasunondh 2005). In the report from Vietnam, major x-ray abnor-