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1. Influenza

2. Avian Influenza

3. Virology

4. Pathogenesis and Immunology

5. Pandemic Preparedness

6. Vaccines

7. Laboratory Findings

8. Clinical Presentation

9. Treatment and Prophylaxis

10. Drugs

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Amedeo Influenza





Clinical Presentation

Christian Hoffmann and Bernd Sebastian Kamps


Uncomplicated Human Influenza

(Green links: Free full-text articles)

After a short incubation period of 1-2(-4) days, onset of the disease is usually abrupt with typical systemic symptoms: high fever and chills, severe malaise, extreme fatigue and weakness, headache or myalgia, as well as respiratory tract signs such as non-productive cough, sore throat, and rhinitis (CDC 2005) (Tables 1 and 2). Among children, otitis media, nausea, and vomiting are also common (Peltola 2003). In rare cases, the initial presentation may be atypical (febrile seizures, Ryan-Poirier 1995; bacterial sepsis, Dagan 1984).


Table 1. Typical symptoms of uncomplicated influenza

Abrupt onset

Systemic: feverishness, headaches, myalgias (extremities, long muscles of the back; eye muscles; in children: calf muscles), malaise, prostration

Respiratory: dry cough, nasal discharge - may be absent in elderly people who may present with lassitude and confusion instead

Hoarseness, dry or sore throat often appear as systemic symptoms diminish

Croup (only in children)


Table 2: Frequency of baseline symptoms*

Symptom

(%)

Fever ≥ 37.8C

68

Feverishness**

90

Cough

93

Nasal congestion

91

Weakness

94

Loss of appetite

92

Sore throat

84

Headache

91

Myalgia

94

*In 2,470 patients with laboratory-confirmed influenza (adapted from Monto 2000)
**Defined as the patient's subjective feeling that they had a fever or chill

The severity of clinical presentation varies from afebrile respiratory symptoms mimicking the common cold to severe prostration without major respiratory signs and symptoms, especially in the elderly. The severity of symptoms is related to the severity of the fever.

Fever and systemic symptoms typically last 3 days, occasionally up to 4-8 days, and gradually diminish; however, cough and malaise may persist for more than 2 weeks. Second fever spikes are rare. The physical findings are summarised in table 3. Full recovery may take 1-2 weeks, or longer, especially in the elderly.


Table 3. Physical findings of uncomplicated influenza

Fever: rapidly peaking at 38-40C (up to 41C, especially in children), typically lasting 3 days (up to 4-8 days), gradually diminishing; second fever spikes are rare.

Face: flushed

Skin: hot and moist

Eyes: watery, reddened

Nose: nasal discharge

Ear: otitis

Mucous membranes: hyperaemic

Cervical lymph nodes: present (especially in children)



Adults are infectious from as early as 24 hours before the onset of symptoms until about seven days thereafter. Children are even more contagious: young children can shed virus for several days before the onset of their illness (Frank 1981) and can be infectious for > 10 days (Frank 1981). Severely immunocompromised persons can shed influenza virus for weeks or months (Klimov 1995, Boivin 2002).

During non-epidemic periods, respiratory symptoms caused by influenza may be difficult to distinguish from symptoms caused by other respiratory pathogens (see Laboratory Findings). However, the sudden onset of the disease, fever, malaise, and fatigue are characteristically different from the common cold (Table 4).


Table 4. Influenza or common cold ?

Symptoms

Influenza

Cold

Fever

Usually high, lasts 3-4 days

Unusual

Headache

Yes

Unusual

Fatigue and/or weakness

Can last up to 2-3 weeks

Mild

Pains, aches

Usual and often severe

Slight

Exhaustion

Early and sometimes severe

Never

Stuffy nose

Sometimes

Common

Sore throat

Sometimes

Common

Cough

Yes

Unusual

Chest discomfort

Common and sometimes severe

Mild to moderate

Complications

Bronchitis, pneumonia; in severe cases life-threatening

Sinus congestion

 

Complications of Human Influenza

The most frequent complication of influenza is pneumonia, with secondary bacterial pneumonia being the most common form, and primary influenza pneumonia the most severe. In addition, mixed viral and bacterial pneumonia frequently occurs during outbreaks.

Influenza may exacerbate heart or lung diseases or other chronic conditions. Influenza infection has also been associated with encephalopathy (McCullers 1999, Morishima 2002), transverse myelitis, myositis, myocarditis, pericarditis, and Reye's syndrome.

Secondary Bacterial Pneumonia

Secondary bacterial pneumonia is most commonly caused by Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Typically, patients may initially recover from the acute influenza illness over 2 to 3 days before having rising temperatures again. Clinical signs and symptoms are consistent with classical bacterial pneumonia: cough, purulent sputum, and physical and x-ray signs of consolidation. Gram staining and culture of sputum specimens may determine the aetiology. Chronic cardiac and pulmonary disease predispose to secondary bacterial pneumonia, as does older age. Institution of an appropriate antibiotic regimen is usually sufficient for a prompt treatment response.

Primary Viral Pneumonia

Clinically, primary viral pneumonia presents as an acute influenza episode that does not resolve spontaneously. The clinical situation worsens with persistent fever, dyspnoea, and cyanosis. Initially, physical findings may be unimpressive. In more severe cases, diffuse rales may sometimes be present. At this stage, x-ray findings show diffuse interstitial infiltrates and acute respiratory distress syndrome (ARDS) with marked hypoxia. Viral titres are high in specimen cultures of respiratory secretions or lung tissue.

Primary influenza pneumonia with pulmonary haemorrhages was a prominent feature of the 1918 pandemic. In addition, pregnant women and individuals with cardiac disease (mitral stenosis) and chronic pulmonary disorders were found to be at increased risk during the 1957 pandemic.

Mixed Viral and Bacterial Pneumonia

Mixed influenza pneumonia has clinical features of both primary and secondary pneumonia. It most often occurs in patients with underlying chronic pulmonary or cardiovascular diseases. Some patients have a slowly progressive course, others may show a transient improvement in their condition, followed by clinical exacerbation. Treatment aims at eradicating the bacterial pathogens involved.

Exacerbation of Chronic Pulmonary Disease

Infectious pathogens have long been recognised as playing an important role in the pathogenesis of chronic respiratory disease (Monto 1978). In patients with chronic bronchitis, clinical influenza infection may lead to a permanent loss of pulmonary function. In children, influenza-induced asthma may continuously deteriorate during the first two days of illness and reconvalescence is typically longer (at least seven days) (Kondo 1991). Influenza virus is also implicated in the pathogenesis of asthma attacks in adults (Techtahl 1997).

Croup

Croup is a typical complication of influenza infection in children. The clinical picture of croup caused by influenza viruses may be more severe than that caused by parainfluenza viruses (Peltola 2002).

Failure of Recovery

In epidemic influenza outbreaks, severely compromised elderly people are at particular risk. Pneumonia and influenza death rates have ranged from fewer than ten to more than 600 per 100,000 among healthy versus chronically ill adults. In one study, the highest death rates (870 per 100,000) occurred in individuals with both cardiovascular and pulmonary disease (Barker 1982). More importantly, the risk of death may extend well beyond the first weeks after influenza complications. Some people may simply never recover from influenza complications - and eventually die from deterioration of underlying pulmonary, cardiovascular, or renal function (Saah 1986).

Myositis

Myositis is a rare complication of influenza B virus infection, and to a lesser extent influenza A. It has mainly been reported in children, with boys being more commonly affected than girls. The median interval between the onset of influenza and the onset of benign acute childhood myositis is 3 days (Agyeman 2004). The calf muscles are involved alone or together with other muscle groups in 69 % and 31 % of cases, respectively. Blood creatine phosphokinase concentration is generally elevated (Hu 2004). Symptoms usually resolve within 3 days and may rarely persist for a couple of weeks. When myositis occurs in elderly patients, it is important to distinguish influenzal myositis from other forms of myopathy (Oba 2000).

Cardiac Complications

Myocarditis is a rare event during influenza infection. In an unselected cohort of patients with serologically confirmed acute influenza infection (n=152), the prevalence of elevated creatine kinase levels was 12 %. Of note, cardiac troponin I and T levels were not raised in any of the patients. The authors concluded that the prevalence of myocarditis during acute influenza infection is substantially lower than previously thought, whereas skeletal muscle injury is relatively common (Greaves 2003).

In a study determining the frequency, magnitude, and duration of myocardial dysfunction in previously healthy young adult patients, abnormal electrocardiogram findings have been noted in 53 %, 33 %, 27 %, and 23 % of patients on days 1, 4, 11, and 28, respectively, but none of the findings were considered to be clinically significant. No patients had significant changes in the ejection fraction or abnormal wall motions. None of the patients had an elevated CK-MB index or troponin I level (Ison 2005).

Toxic Shock Syndrome

Toxic shock syndrome (TSS) can occur as a complication of influenza (CDC 1986, MacDonald 1987, Tolan 1993). One of the hallmarks of the disease is rapidly developing, severe and sometimes refractory hypotension (Chesney 1981). The TSS diagnosis is based on a clinical case definition (Reingold 1981), and toxin-producing 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 non-inflammatory 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 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) (< FONT COLOR="#008000">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 > 38C), 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 abnormalities include extensive bilateral infiltration, lobar collapse, focal consolidation, and air bronchograms. All patients had dramatic worsening of findings on chest radiography during hospitalisation. The median time from onset of fever to ARDS was 6 days (range 4-13) in one series (Chotpitayasunondh 2005). Pneumothorax may develop in patients during mechanical ventilation (Hien 2004). Pleural effusions are uncommon.

There is conflicting information as to the risk factors associated with severe disease and fatal outcome. In the 1997 outbreak in Hong Kong, the factors associated with severe disease included older age, delay in hospitalisation, lower respiratory tract involvement, and a low total peripheral white blood cell count or lymphopenia on admission (Yuen 1998). In this report, patients aged below 6 years usually had a self-limiting acute respiratory disease with fever, rhinorrhoea, and sore throat. In contrast, recent avian H5N1 infections have caused high rates of death among infants and young children (Chotpitayasunondh 2005). The numbers reported are too small to understand whether local factors - i.e., time between onset of symptoms and admission to hospital - or viral virulence factors are responsible for these differences. As H5N1 strains have evolved over the past 10 years (Webster 2006), clinical features of avian influenza infection in humans may well have different characteristics over time.

The progression of severe H5N1 infection seems to be different from that of severe diseases observed during earlier influenza pandemics. None of the patients with severe disease reported from Hong Kong (Yuen 1998) and Vietnam (Hien 2004) had evidence of secondary bacterial pneumonia, suggesting that the fatal outcome was due to an overwhelming primary viral pneumonia. This feature is reminiscent of the 1918 pandemic and may pathogenetically be due to a "cytokine storm" (Barry 2004).






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