Authors :
Dr Nima Afshar Assistant Clinical Professor of Medicine University of California San Francisco
Dr Nima Afshar Assistant Clinical Professor of Medicine University of California San Francisco
2008-10-08
Influenza (Flu)
Introduction
Influenza, also known as the flu, is a severe respiratory illness caused by an influenza virus. In temperate climates it is a disease of the winter. When the highly contagious virus is inhaled it attacks the respiratory tract, causing sudden fever, a general feeling of illness, cough, and other debilitating symptoms. Often people are unable to work during the height of the illness. Vulnerable people, especially the elderly with chronic lung or heart disease, can become extremely sick and may die. Two medications, oseltamivir (Tamiflu) and zanamivir (Relenza), target the virus, shortening the illness and preventing complications in the vulnerable. Vaccines are produced annually and are usually effective in preventing the flu; high-risk people and those who have close contact with them should be vaccinated every year.
Influenza pandemics occur a few times per century when a new influenza strain evolves that is unrecognized by our immune system. Millions worldwide may die. The most infamous pandemic was the Spanish flu of 1918-1919, which killed 25-100 million people. Today avian influenza, popularly known as bird flu, poses the threat of another pandemic. The birds are poultry in Asia, Europe, and parts of Africa, which are circulating an influenza virus called H5N1 that is highly lethal. In the rare cases in which humans have been infected, most of the victims have died. If the virus acquires an affinity for humans, the consequences could be devastating. Governments around the world are stockpiling anti-influenza medication and upgrading vaccine production capacity to prepare for this threat.
Of note, the term “flu” is sometimes used to refer to an intestinal infection with symptoms of diarrhea and/or vomiting, but this is a misnomer and should be avoided. “Stomach flu” or the medical term “gastroenteritis” are better names for this unrelated illness.
Influenza, also known as the flu, is a severe respiratory illness caused by an influenza virus. In temperate climates it is a disease of the winter. When the highly contagious virus is inhaled it attacks the respiratory tract, causing sudden fever, a general feeling of illness, cough, and other debilitating symptoms. Often people are unable to work during the height of the illness. Vulnerable people, especially the elderly with chronic lung or heart disease, can become extremely sick and may die. Two medications, oseltamivir (Tamiflu) and zanamivir (Relenza), target the virus, shortening the illness and preventing complications in the vulnerable. Vaccines are produced annually and are usually effective in preventing the flu; high-risk people and those who have close contact with them should be vaccinated every year.
Influenza pandemics occur a few times per century when a new influenza strain evolves that is unrecognized by our immune system. Millions worldwide may die. The most infamous pandemic was the Spanish flu of 1918-1919, which killed 25-100 million people. Today avian influenza, popularly known as bird flu, poses the threat of another pandemic. The birds are poultry in Asia, Europe, and parts of Africa, which are circulating an influenza virus called H5N1 that is highly lethal. In the rare cases in which humans have been infected, most of the victims have died. If the virus acquires an affinity for humans, the consequences could be devastating. Governments around the world are stockpiling anti-influenza medication and upgrading vaccine production capacity to prepare for this threat.
Of note, the term “flu” is sometimes used to refer to an intestinal infection with symptoms of diarrhea and/or vomiting, but this is a misnomer and should be avoided. “Stomach flu” or the medical term “gastroenteritis” are better names for this unrelated illness.
In
the U.S. 5-15% of people catch the flu every year. On average almost
two days of work are missed per case.[1] Considering direct medical
costs and the indirect costs of loss of productivity, the economic
burden of influenza in the U.S. is $27 billion.1 This makes it one of
the ten costliest diseases in the nation.
The flu leads to 30 million physician visits, 300,000 hospitalizations, and 3 million hospital days in the U.S. annually.[1] It takes about 36,000 lives as well, mostly in the elderly, placing it in the top ten causes of death.[2]
The Elderly
Perhaps more than any other infectious disease, seasonal influenza disproportionately victimizes the elderly, especially the very old. While they are not infected by the flu virus at a higher rate than are other age groups, seniors suffer more severe disease. Influenza often leads to secondary bacterial pneumonia or worsening of underlying health problems.[2] About 90% of seasonal influenza-related deaths occur among persons aged 65 years and older.[3] This special vulnerability to severe infection is probably due to an age-related decline in specific immune functions that limit influenza's attack on the body.Young Children
Recently there has been an increasing appreciation of the burden of influenza on young children (<5 years old), particularly infants. Young children acquire influenza infection at a higher rate than any age group, with up to 50% of day-care children being infected annually4. The rate of hospitalization of children <5 years old is about the same as that of the elderly, although per episode of influenza illness the risk of hospitalization and death is lower.[4] Importantly, children, including those of school-age, are major culprits in spreading the virus to the community during epidemics.Seasonal Epidemics
In temperate climates influenza infection is highly seasonal, causing epidemics in the winter months. These annual winter outbreaks typically last 5-10 weeks. The reasons underlying this clockwork seasonality are not well understood, but may involve multiple factors such as prolonged virus survival in cold weather, weakened immune system function in winter, crowding and use of indoor heat (which recirculates and dries the air, promoting virus survival).[5] Confirming the importance of the cold weather season, in the temperate regions of the Southern Hemisphere (e.g. Australia) flu season occurs from ~April to September.In the Northern Hemisphere the annual epidemic begins in East Asia where viral strains develop minor changes over months, a process called antigenic drift, that enable the virus to evade the human immune system adequately to initiate infection. Southern China is probably the major breeding ground. There influenza circulates year-round and the population density is high, promoting antigenic drift.[6] Influenza variants can be detected in this region up to 2 years before they spread to temperate regions of the North America, Europe, and elsewhere in the global North. In the tropics infections occur more evenly throughout the year, though spikes seem to arise during rainy months.[7]
Pandemic Influenza
About three times each century a novel influenza virus emerges, spreads globally within months and causes tremendous illness and death. Such pandemics usually arise when human and avian influenza viruses exchange genetic material, producing a new influenza strain that is unrecognized by the human immune system, making humans vulnerable. This exchange of genes may occur in pigs, as they can be infected simultaneously by human and avian influenza viruses.[6] Southern China is again the likely origin of many of these pandemics. The proximity of dense populations of humans, birds, and pigs is a perfect environmental set-up for the emergence of a new and dangerous strain.The Virus and How it Attacks
The Virus
There are three influenza viruses, types A, B, and C. Influenza A is generally the most virulent (aggressive) of the three types and is responsible for most human infections and epidemics. Though it primarily infects aquatic birds it often jumps to other species, including poultry, dogs, cats, and of course humans. Type B causes a substantial minority of infections and epidemics, and though it is usually considered less virulent than type A, it can be as severe as some type A strains. Type C causes only mild colds and is the least important.[8-10]
Figure: Influenza virus particle in a negative-stained transmission electron micrograph,
from CDC Public Health Image Library
[Here we will place a small box link here updating the strains of the 2007-2008 season: currently 46% H3N2, 38% H1N1, 16% type B – from MMWR]
The Attack
Influenza uses hemagglutinin to bind to and enter cells lining the respiratory tract, initiating infection. Once in the cell, it uses a protein called M2 to help it “uncoat” and begin its hijacking of the cell. The virus shuts down the cell’s normal functions and hijacks the cell’s machinery to reproduce itself. The resulting fresh copies of viral RNA and viral proteins combine to form complete virus particles, often over 100 of them in a single infected cell. Neuraminidase allows the new influenza particles to escape the cell and to squirm through mucous to reach another cell. Meanwhile the invaded cell is dying either because its normal functions have been paralyzed or because the virus has activated the cell’s self-destruction mechanism (called apoptosis).[8, 10]In a typical case of the flu, the virus attacks the upper respiratory tract (nose, throat, larynx) and the upper section of the lower respiratory tract (trachea and bronchi). In children extension into the middle ear, which is contiguous with the upper respiratory tract, is common. In very severe cases, particularly in pandemics, influenza invades the lungs, causing a viral pneumonia. When influenza infects any part of the lower respiratory tract it impairs the structural defense provided by the airway lining, leaving the host vulnerable to bacterial pneumonia. Rarely the virus may penetrate beyond the lungs into the bloodstream, brain, and elsewhere.
Our Defense
The immune system employs its complex web of coordinated weapons to combat influenza. Cells that have been infected by a virus release signaling proteins called interferons (so-named because they “interfere” with viral replication in test tubes), which instruct infected cells to degrade viral RNA and uninfected cells to sabotage their own protein-making machinery to prevent invading viruses from using it. They also help the immune system’s “natural killer” cells to recognize infected cells and destroy them with the virus still inside. This front-line “innate” branch of our immune system does not need to recognize the type of virus that is attacking; its disadvantage is that it is inefficient.
The
efficient “adaptive” branch is crucial for ultimately halting viral
spread and destroying remaining virus. The B-cells of this branch are
capable of producing an infinite variety of antibodies, with each
variety having a unique shape that perfectly complements a key
structural element, or antigen, of an invading organism. By binding to
an antigen on a free floating influenza virus, the antibody tags the
virus for easy recognition and destruction by various immune cells.
T-cells have antibody equivalents on their surface, allowing them to
target infected cells (which have “presented” viral antigens on their
own surfaces), instructing them to self-destruct before the virus inside
can reproduce and escape. Antibodies linger for many years, helping to
prevent future infections by the same strain of virus. In the case of
influenza, antibodies against hemagglutinin and neuraminidase are most
important in combating active flu, while only those against
hemagglutinin prevent the flu.
Catching the Flu
When is it contagious?
In adults, influenza virus is detectable at low levels in respiratory mucous about 1 day before the onset of symptoms. Virus levels abruptly peak on day 1 of illness, decrease slowly through day 4, then drop off more quickly.[12] Adults are contagious primarily from up to one day before the onset of illness through the fifth day.
Young
children, because their immune systems are more naïve to influenza,
continue to shed the virus for over a week. This combined with their
innocent disregard for hygiene make them important propagators of flu
epidemics.
Transmission
Influenza virus is spread primarily by air.[13] Coughing, sneezing, and even talking releases virus particles in the air in the form of invisible droplet nuclei, which are a mixture of virus and respiratory mucus. These droplet nuclei linger in the air for hours and may be able to travel long distances if picked up by air currents. Influenza is highly infectious - very few particles are required to initiate an infection.[5] Acquisition by direct contact, such as the touching of a contaminated hand, probably occurs but plays a minor role.Symptoms
Adults and Older Children
The classic flu starts abruptly and fiercely, often rising to a crescendo within a matter of hours. High fever with chills, diffuse muscle aches, and a generalized ill feeling are cardinal features early on. The following are common symptoms of the flu, though most people will not have all of them during a single episode:[10]
- Systemic:
Fever/chills*
Myalgia (muscle aches)
Malaise (general feeling of illness)
Anorexia (loss of appetite)
- Local:
Cough*
Headache
Sore throat
Nasal congestion
Runny nose
Other (uncommon)
Conjunctivitis (eye pain, redness, and tearing)
Gastrointestinal complaints (nausea, diarrhea, abdominal pain)
Symptoms begin on average two days after exposure to the virus, an interval known as the “incubation period.” Day 1 is often the worst, with intense systemic symptoms. The fever is typically high, often above 102°F and sometimes above 104°F. The systemic symptoms usually improve slowly over three to four days.[9, 10] Local symptoms, especially cough, may linger for over two weeks.[9, 10]
Not all flu-like illnesses are caused by influenza – at least 1/3 of patients who present with a flu-like illness during the winter epidemic are infected by a non-influenza virus, such as respiratory syncytial virus (RSV) or adenovirus.[14] The symptoms most predictive of a true influenza infection are fever (>100°F as measured by a thermometer) and cough.[14, 15]
Fever/chills*
Myalgia (muscle aches)
Malaise (general feeling of illness)
Anorexia (loss of appetite)
- Local:
Cough*
Headache
Sore throat
Nasal congestion
Runny nose
Other (uncommon)
Conjunctivitis (eye pain, redness, and tearing)
Gastrointestinal complaints (nausea, diarrhea, abdominal pain)
Symptoms begin on average two days after exposure to the virus, an interval known as the “incubation period.” Day 1 is often the worst, with intense systemic symptoms. The fever is typically high, often above 102°F and sometimes above 104°F. The systemic symptoms usually improve slowly over three to four days.[9, 10] Local symptoms, especially cough, may linger for over two weeks.[9, 10]
Not all flu-like illnesses are caused by influenza – at least 1/3 of patients who present with a flu-like illness during the winter epidemic are infected by a non-influenza virus, such as respiratory syncytial virus (RSV) or adenovirus.[14] The symptoms most predictive of a true influenza infection are fever (>100°F as measured by a thermometer) and cough.[14, 15]
The Elderly
As is the case in many diseases, symptoms of the flu in older adults are often more subtle. The most common symptom is cough, present in two-thirds, followed by malaise. Fever, which is the norm in non-elderly adults and children, only occurs in 1/3 of cases.[16] For debilitated older patients, confusion and global weakness may predominate. Shortness of breath or labored breathing is concerning, as they indicate that influenza may have led to pneumonia, the major cause of hospitalization and death in this disease.Young Children
Young children (<5 years old) with influenza are very difficult to distinguish from those with other viral infections. They vast majority have the typical pediatric upper respiratory symptoms of fever, runny nose, and cough.[17] Children may have symptoms of an ear infection and are more likely than adults to have gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain.[18]Why do I feel so sick?
The classic flu is not just a version of the common cold. It is distinctly more severe, with fever, malaise, myalgia, and low energy debilitating the sufferer. Such systemic symptoms (as well as the local symptoms) are caused by our own immune system’s counterattack against the virus. Interferon is a signaling molecule, or cytokine, that figures prominently in the early immune defense, helping to limit influenza’s spread. It is made by immune cells close to the site of infection but circulates throughout the body. Interferon “interferes” not only with virus function but also with that of our own cells, making us feel miserable. Some people with chronic viral infections such as hepatitis B or C require treatment with interferon, and they often suffer flu-like symptoms as a side effect. Other immune system cytokines - such as interleukin 1 and interleukin 6, which cause fever and malaise – act similarly.[19] Influenza, more than other respiratory viruses, seems to induce this cytokine burst. Fortunately the consequent systemic symptoms are not necessary to fight off the virus, and there are effective treatments for them.Complications
Pneumonia in the Elderly
The most important complication of influenza infection is pneumonia. Typically one is recovering from the flu and then develops recurrence of fever, cough with phlegm, and shortness of breath. Chest pain associated with the cough may occur. The pneumonia is usually caused by bacteria that take advantage of a respiratory tract weakened by influenza. Though this can occur in persons of any age, it is by far most common and most deadly in the elderly, in whom bacterial pneumonia is the major cause of death during the winter influenza epidemics. The most common culprit bacteria is pneumococcus (Streptococcus pneumoniae) though a disproportionate number of post-influenza pneumonia cases are due to Staphylococcus aureus, which causes severe lung destruction and often death despite appropriate antibiotic treatment. Influenza may itself cause pneumonia, but this is uncommon unless the host has a very compromised immune system or the virus is novel and aggressive, as seen in pandemics.[10]Exacerbation of Chronic Lung Disease
Persons with asthma or chronic obstructive pulmonary disease (COPD), which is nearly always caused by smoking and includes emphysema and chronic bronchitis, often experience exacerbations of their underlying lung disease when infected with respiratory viruses. Exacerbations are episodes of worsened lung function associated with symptoms such as shortness of breath and wheezing that require medical attention. The bulk of costs, morbidity, and mortality from these chronic lung diseases are attributable to these flares, and about half of flares and most consequent hospitalizations are due to viral respiratory infections.[20] Usually the culprit is a common cold virus, but influenza accounts for a significant minority of flares during flu season.Ear Infections in Young Children
Similar to other respiratory viruses, influenza leads to ear infections
more than any other complication. Ear infections occur in 25-30% of
influenza infections in children under 5 years of age. The infection
may be due to influenza itself, a superimposing bacteria, or both.
Other complications such as pneumonia, asthma, croup, and febrile
seizures occur much less often.[4, 17]
Laboratory testing can be valuable in the elderly, persons with underlying medical conditions, and those with non-classic symptoms. Typically a sample of nasal secretions is obtained by squirting water into the nose and drawing it back into a tube. In the lab antibodies against influenza are added to the sample – if binding to influenza antigens occurs, then a color change indicates a positive test. Variations on this method exist.10 Such testing is rapid, yielding results in less than one hour. Accuracy is not perfect, however. When influenza is present, these rapid tests detect it 70-75% of the time.[21]
Diagnosis
Many cases of influenza are diagnosed based on the presence of typical flu symptoms alone. This applies especially to otherwise healthy persons during a community outbreak of flu – in this setting a doctor’s diagnosis without tests is 80-90% accurate.[10]Laboratory testing can be valuable in the elderly, persons with underlying medical conditions, and those with non-classic symptoms. Typically a sample of nasal secretions is obtained by squirting water into the nose and drawing it back into a tube. In the lab antibodies against influenza are added to the sample – if binding to influenza antigens occurs, then a color change indicates a positive test. Variations on this method exist.10 Such testing is rapid, yielding results in less than one hour. Accuracy is not perfect, however. When influenza is present, these rapid tests detect it 70-75% of the time.[21]
Treatment – Stopping the Virus
The Neuraminidase Inhibitors
Currently, oseltamivir (Tamiflu) and zanamivir (Relenza) are the only effective anti-influenza medications recommended for treatment of the flu. They both work by blocking the action of influenza’s neuraminidase enzyme, which is required for new copies of the virus to escape from infected cells and reach new host cells. They were approved by the U.S. Food and Drug Administration in 1999. The table below shows basic information about these drugs in the treatment of the flu.[22]
Table 1: The Neuraminidase Inhibitors
Drug Route Age
group Dose
Major side effects
| Oseltamivir (Tamiflu) | Oral (pill or liquid) | Adults and children ≥1 year old | 75mg (1 pill) 2x/day x 5 days | - Nausea, vomiting, and/or abdominal pain in 5-10% of patients - Possible psychiatric effects |
| Zanamivir (Relenza) | Inhaled (dry powder in a disc) | Adults and children ≥7 years old | 10mg (2 inhalations) 2x/day x 5 days | - Rare shortness of breath and wheezing in persons with chronic lung disease - Possible psychiatric effects |
The Benefit
In general, both medications reduce the duration of the flu by 1-2 days
if started within 48 hours of the onset of illness.[22] The earlier
treatment is initiated, the greater the benefit.[23] The details of the
medical evidence for these two medications are as follows:
· Oseltamivir (Tamiflu)
o Healthy adults:
Several studies with a total of 2700 patients showed that oseltamivir,
when started within 24-48 hours in patients with laboratory-confirmed
influenza, shortened the duration of illness by 1-2 days.[22, 24] In
one study with a total of 1426 patients, initiation of treatment within 6
hours shortened illness by 4 days and within 6-24 hours shortened
illness by 3 days.[23]
o Elderly and high-risk patients:
Surprisingly, there are few studies in this population. Manufacturer
supplied-data showed a marginal half-day reduction of duration of
illness when oseltamivir was started within 48 hours.[24] One study
found that for every 15 elderly or high-risk patients with
laboratory-confirmed influenza treated with oseltamivir, one lower
respiratory tract infection requiring antibiotics was prevented.[25]
o Children: One
study of 695 children 1-12 years old found that oseltamivir, when
started within 48 hours of illness (2/3 had laboratory-confirmed
influenza), reduced the duration of illness by 1.5 days.[22, 26]
· Zanamivir (Relenza)
o Healthy adults: Several
studies with a total of 2600 patients showed that zanamivir, when
started within 36-48 hours for influenza or influenza-like illness,
shortened the duration of illness by 1-2 days.[22]
o Elderly and high-risk patients:
One study, which pooled results from over 400 influenza-confirmed
cases, found that zanamivir shortened the duration of illness by 2
days.[24]
o Children:
One study of 346 children 5-12 years old with laboratory-confirmed
influenza found that zanamivir, when initiated within 36 hours of
illness, reduced the duration of symptoms by 1.25 days.[26, 27]
Zanamivir may be superior to oseltamivir for influenza B.[28]
Side effects
· Oseltamivir (Tamiflu)
o Nausea,
vomiting, and/or abdominal pain - reported in 5-10% of patients. This
occurs mostly after the first dose, is rarely severe, and usually
resolves in 1-2 days.[11, 22]
o Psychiatric
side effects, mostly in children in Japan, have been reported. These
include delirium, hallucinations, and injurious behavior, with the
latter leading to death in several cases.[29] It is unclear whether
these effects are due to the drug or to the illness itself. Most cases
have occurred after the first one or two doses, suggesting an effect of
the drug. However, early flu often causes high fever, which can cause
psychiatric side effects, especially in children. In many cases,
though, there was no fever at the time of the adverse event. Adding to
the confusion, in about 90 cases the drug was continued despite the side
effects: in half the cases the psychiatric effects persisted and in
half they resolved.[29] There have been no definite reports of these
effects when the drug has been used to prevent influenza. In November
of 2007 the FDA recommended updating the warning label for oseltamivir,
with special attention to close monitoring of children for behavioral
changes during the first few doses.
· Zanamivir (Relenza)
o Bronchospasm
(narrowing of the airway causing shortness of breath and wheezing) has
been reported in patients with chronic lung diseases such as asthma or
COPD.[11] However, these events have been rare, and a study of
zanamivir in patients with chronic lung disease showed no adverse effect
on lung function.[22]
o Psychiatric
side effects, again mostly in children in Japan, have been reported.
The reports are similar in character to those for oseltamivir, though
without any deaths.[29] Zanamivir in inhaled and thus acts almost
exclusively in the airways and lungs; very little enters the circulation
with potential to cross into and act upon the brain. Thus, although it
is possible that the drug is causing these effects, it is more likely
that flu itself is the major contributor. The FDA did also recommend
the addition of a warning about abnormal behavior to the label for
zanamivir.
The Adamantanes
Amantadine and rimantidine block influenza A’s M2 protein, preventing
viral “uncoating” and subsequent attack of the host cell. Ten years ago
they were the only effective drugs against influenza. Over the last
few years influenza has become very resistant to these medications,
rendering them nearly useless in much of the world.[11] Thus far in the
2007-2008 flu season, 99% of H3N2 and 5% of H1N1 strains have been
resistant to this class of medications.[30] They have no activity
against influenza B. At this time, the adamantanes should not be used
to prevent or treat influenza.
Treatment - Relieving the Symptoms
There are several classes of medications that are commonly used to treat different symptoms of the flu. Below we list these medications, make conclusions about their effectiveness, and in smaller print provide details about how they work as well as a summary of the medical evidence for or against each treatment. The studies referenced here mostly enrolled patients with the common cold. However, the results probably apply to any illness with similar symptoms, which are caused largely by our immune response rather than the virus itself. In this section, we frequently refer to “randomized controlled trials.” These are studies in which patients are randomly assigned to receive either the treatment or a placebo (and are unaware of which they are taking). The effectiveness of the treatment is determined by comparing its impact on symptoms or other parameters to that of the placebo. This study design was also used to prove the effectiveness of the neuraminidase inhibitors described above.Pain and Fever Medications
· Acetaminophen/Paracetamol (Tylenol): Effective. Should be the first-line pain reliever and fever reducer for most people.
o How
acetaminophen, better known internationally as paracetamol, relieves
pain is still being studied. It may work in part by blocking an enzyme
called COX that mediates inflammation (though somehow this does not lead
to a significant anti-inflammatory effect), but new evidence shows that
perhaps it mostly works by indirectly stimulating cannabanoid
receptors, the same ones that are stimulated by THC, the active
ingredient in marijuana.
o Few
randomized controlled trials have tested acetaminophen in patients with
colds or flu, but all of them have shown a substantial benefit over
placebo for reduction of pain – sore throat, muscle aches, headache – as
well as reduction of fever, in both adults and children.[31] Besides
these small studies, this medication has a long track record of efficacy
in the experience of physicians and the public. Acetaminophen is very
safe when taken at recommended doses. The total dose of acetaminophen
should never exceed 4 grams per 24 hours – note that acetaminophen is a
part of many combination prescription narcotic medications such as
Vicodin and Percocet, so its dose in these preparations must be added to
the dose from any other form (i.e. Tylenol) to come up with the total
dose taken. Exceeding the recommended dose can lead to life-threatening
liver damage.
· NSAIDs – Ibuprofen (Motrin, Advil), Naproxen (Alleve): Effective.
o NSAID
stands for “non-steroidal anti-inflammatory drug.” These drugs work by
blocking COX, an enzyme that promotes inflammation.
o Like
acetaminophen, NSAIDs have been sparsely tested in patients with colds
or flu. The studies that do exist, mostly using ibuprofen, have shown a
similar benefit for pain and fever compared with acetaminophen, in both
adults and children. NSAIDs are generally safe, though there are a few
potential serious side effects: gastrointestinal bleeding, kidney
dysfunction, and allergic reactions. The first two problems are rarely
seen with short-term use, unless one is susceptible (e.g., a history of
stomach bleeding or pre-existing kidney disease). Allergic reactions
can occur with any medication, but are more common with NSAIDs than
acetaminophen. Of note, aspirin is another NSAID, but it is not
recommended for pain or fever as it has more frequent and dangerous side
effects compared with other NSAIDs without any additional benefit.[31]
Cough medications
· Guiafenisin: Possibly effective.
o This
drug is an expectorant – it works by loosening secretions so that they
are better expectorated (coughed out), leaving fewer secretions behind,
thus reducing an airway irritant that causes cough.
o Two
randomized controlled trials have been done. The larger one, with 239
patients, found a 75% reduction of cough in the treatment group vs. 31%
reduction in the placebo group. The smaller one, with 65 patients,
found no reduction in cough but a 40% reduction in phlegm thickness.[32]
· Dextromethorphan: Questionably effective.
o Dextromethorphan
is thought to suppress cough by multiple mechanisms of action,
including activation of opioid receptors in the brain.
o One
meta-analysis of 6 pharmaceutical company-sponsored randomized
controlled trials totaling 710 patients showed an average of a 15%
reduction in various cough parameters with dextromethorphan (an earlier
meta-analysis in the literature likely included the same original
studies). Two smaller trials (48 and 108 patients) showed no reduction
in cough in patients with colds.[33]
· Codeine: Probably not effective.
o Codeine is thought to suppress cough by activating opioid receptors in the brain.
o Two
randomized controlled trials with 80 patients each failed to show any
reduction of coughing with codeine in patients with colds.[32]
Decongestants
· Topical – Oxymetazoline (Afrin) and others: Effective for nasal congestion.
o Topical
decongestants usually are in the form of sprays that deliver
vasoconstrictors to the nasal lining; these shrink the enlarged blood
vessels that cause congestion.
o Two
randomized controlled trials with a total of ~900 patients showed that
these medications provide substantial relief of nasal congestion.[34,
35] They should not be used for more than 3 days, as doing so may cause a
rebound effect leading to recurrent congestion.
· Oral – Phenylephrine (Sudafed PE), Pseudoephedrine (Sudafed), and others: Minimally effective for nasal congestion.
o These
medications are also vasoconstrictors that get to the nasal lining via
the bloodstream (after being absorbed across the intestines).
o A
review of 6 randomized controlled trials with a total of ~650 patients
concluded that oral decongestants (pseudoephedrine mainly studied)
provide minimal benefit – only about a 5% reduction in congestion.[36]
Because they get absorbed into the bloodstream and they act by
constricting blood vessels, they can sometimes cause a modest elevation
of high blood pressure. This is not a problem in people whose blood
pressure is well-controlled, but it can be dangerous for those with
uncontrolled hypertension or certain medical conditions. Because
pseudoephedrine can be used to synthesize methamphetamine, an
increasingly common drug of abuse, sales of this drug in the U.S. are
now limited and regulated. Thus, phenylephrine is becoming a more
common ingredient in over-the-counter preparations, though it has not
been tested adequately and may not be effective.
Antihistamines
· First-generation – Diphenhydramine (Benadryl) and others: Modestly effective for runny nose.
o These
drugs block histamine, a compound in the body that causes allergies.
They also block acetylcholine, a neurotransmitter that leads to
secretions in the nose and airway.
o A
review of 27 randomized controlled trials including thousands of
patients found that this class of medication has minimal benefit for
runny nose - certainly <15% improvement. The side effect of sedation
limits use for some during the day, though in the above trials this
effect was surprisingly small (only 3% more than placebo).[37] The
elderly and those with even mild dementia should avoid these
medications, as they can cause severe sleepiness and/or confusion in
such persons.
· Non-sedating – Loratidine (Claritin), Fexofenadine (Allegra): Ineffective in colds and flu.
o These
second-generation antihistamines do not get into the brain, so they
spare most of the side effects of the first-generation class.
o
They were developed for allergies (and are effective in this setting),
though they are sometimes used for colds or flu as well. A review of 8
randomized controlled trials showed no benefit for these medications in
patients with colds.[37]
Prevention – The Vaccine and Beyond
Influenza Vaccination
Annual
influenza vaccination is effective in reducing the occurrence and
severity of influenza infections. There are two types of influenza
vaccine, and both are effective. The more common one is the trivalent
inactivated vaccine (TIV), which contains killed viruses and thus cannot
cause the flu. The newer one is the live attenuated influenza vaccine
(LAIV), which as the name suggests contains living influenza virus
strains that have been weakened. It may cause mild and brief flu-like
symptoms and is only approved for healthy people aged 5-49. Its
advantage is that it is a nasal spray that can be self-administered
painlessly. It takes two weeks to develop protective antibodies after
vaccination. These antibodies block influenza’s hemagglutinin surface
protein, preventing the virus from entering host cells.
The
vaccines are made from three strains of influenza – H3N2, H1N1, and a
strain of influenza B. Experts survey regions such as southern China to
determine which variants of these strains should be used to produce the
vaccine.
Table 2: Influenza Vaccines
Inactivated vaccine (TIV) Live vaccine (LAIV)
|
Vaccine type
|
Killed
|
Live
|
|
Route of administration
|
Intramuscular injection
|
Intranasal spray
|
|
Virus strains included
| - 2 influenza A (H3N2 & H1N1) - 1 influenza B | - 2 influenza A (H3N2 & H1N1) - 1 influenza B |
|
Approved persons
|
Ages 6 months and older
|
Ages 5-49 and healthy
|
|
Frequency of administration
|
Annually
|
Annually
|
Data
adapted from CDC 2007-08 INFLUENZA PREVENTION & CONTROL
RECOMMENDATIONS Influenza Vaccine Composition & Major Differences.
Vaccinating
vulnerable people to prevent influenza and its complications is a major
public health goal. The Centers for Disease Control and Prevention
(CDC) recommends annual influenza vaccination for the following groups
of people:[38]
- Anyone who wants to reduce the risk of acquiring influenza or transmitting it to others
- All persons aged 50 years and older
- All children aged 6 months to 5 years (until their 5th birthday)
- Any child aged 6 months to 18 years who is required to take long-term aspirin (these children have are at risk for a deadly disease called Reye syndrome if they acquire influenza)
- Women who will be pregnant during flu season
- Adults and children with chronic lung (including asthma), heart, kidney, liver, blood, or metabolic (including diabetes) disorders
- Adults and children whose immune systems are suppressed or abnormal (including HIV and medications that suppress the immune system)
- Adults or children who have any condition (e.g. uncontrolled seizure disorder, spinal cord injury) that can compromise respiratory function or the handling of respiratory secretions
- Residents of nursing homes and long-term care facilities
- Healthy household contacts (including children) of all of the above groups, as well as contacts of infants <6 months old
- Health care workers
Antiviral medications
Neuraminidase
inhibitors, either oseltamivir (Tamiflu) or zanamivir (Relenza), may be
used to prevent the flu during a community outbreak. Tamiflu is 60-90%
effective in preventing influenza11 and is FDA approved for prevention
for adults and children >1 year old at a dose of 75mg (1 tablet)
daily for adults. Relenza is 55-85% effective in preventing
influenza11, [39] and is FDA approved for prevention for adults and
children >5 years old at a dose of 10mg inhaled (2 inhalations) daily
for adults. The decision to use these medications for such
“prophylaxis” is based largely upon an individual’s risk of
complications of influenza. Though broad consensus is lacking on this
issue, there are roughly two risk categories that can guide the use of
these medications for prophylaxis:
Low to medium risk
Most adults and children fall into this category. They should consider preventive treatment only if they are in close contact with a person with known influenza infection and are inadequately immunized against influenza – which means either they have not been vaccinated, they have been vaccinated less than two weeks prior, or the influenza strain in their community is not covered by the vaccine. This most often applies to household members or caretakers of those with influenza. Either Tamiflu or Relenza should be taken during the entire period of close contact with person(s) who have influenza and should not be stopped until one week after the onset of the last case of influenza in a close contact.
Most adults and children fall into this category. They should consider preventive treatment only if they are in close contact with a person with known influenza infection and are inadequately immunized against influenza – which means either they have not been vaccinated, they have been vaccinated less than two weeks prior, or the influenza strain in their community is not covered by the vaccine. This most often applies to household members or caretakers of those with influenza. Either Tamiflu or Relenza should be taken during the entire period of close contact with person(s) who have influenza and should not be stopped until one week after the onset of the last case of influenza in a close contact.
High-risk
The elderly (the older the person
the higher the risk), those with serious chronic diseases (especially
of the lungs or heart), and those with compromised immune systems (e.g.
HIV) are included in this category. These groups should consider
prophylaxis (as above) if they are in close contact with a person with
known influenza regardless of whether or not they are adequately
immunized. In addition, they should consider continuous prophylaxis for
the several peak weeks of the local flu season if they are inadequately
immunized.
Elderly nursing home residents are especially high-risk, as they have high exposure to influenza (due to the institutional setting) and are often frail and debilitated with chronic disease. One study showed that even when such people are adequately immunized, prophylactic Tamiflu given for six weeks during the peak of flu season prevented influenza infection and complications: treating 25 people prevented one case of influenza, with no significant side effects.[40] Such aggressive prophylaxis is not widely instituted and it is not clear that it would be cost-effective, but this data at least underscores the importance of vigilant surveillance for influenza outbreaks within nursing homes.
Elderly nursing home residents are especially high-risk, as they have high exposure to influenza (due to the institutional setting) and are often frail and debilitated with chronic disease. One study showed that even when such people are adequately immunized, prophylactic Tamiflu given for six weeks during the peak of flu season prevented influenza infection and complications: treating 25 people prevented one case of influenza, with no significant side effects.[40] Such aggressive prophylaxis is not widely instituted and it is not clear that it would be cost-effective, but this data at least underscores the importance of vigilant surveillance for influenza outbreaks within nursing homes.
Hygiene
Limiting
exposure to airborne virus is a key to preventing the flu. The
duration of close proximity between those with and those without
influenza, even in the absence of physical contact, increases the risk
of transmitting the virus. So limiting the amount of time spent in
small rooms with an infected person may reduce this risk. Also, those
with the flu can practice simple hygiene measures such as sneezing into
disposable tissues or coughing/sneezing onto a sleeve rather than into
the hands.
Limiting direct contact (hand to hand, etc.) may be helpful as well, though it is not clear that influenza is transmitted in this way. Hand cleaning with alcohol gels is probably more effective than hand washing with soap and water.[41]
Limiting direct contact (hand to hand, etc.) may be helpful as well, though it is not clear that influenza is transmitted in this way. Hand cleaning with alcohol gels is probably more effective than hand washing with soap and water.[41]
Avian Influenza H5N1 – The Bird Flu Virus
The Disease
The
medical world is very concerned about a new strain of influenza virus
found in birds – mainly poultry – across Asia, Africa, and Europe.
Called avian influenza H5N1, it is a highly pathogenic (disease-causing)
virus that is uniformly lethal in birds. When it infects humans it is
also deadly, with a mortality rate above 60%. It was first reported in
2003 in east and southeast Asia. Since then it has spread to poultry
populations throughout Eurasia as well as a few countries in north and
west Africa. Human infections have been reported in countries as
widespread as Thailand, Egypt, and Nigeria. H5N1 has spread to birds
and poultry throughout most of Europe, although the only European
country with reported human cases has been Turkey. The virus has not
been detected in North America or South America.[42]
Avian
influenza viruses are common, usually causing only mild disease in birds
and virtually no disease in humans. Once in a while, though, a highly
pathogenic variety appears that is dangerous. Several such varieties
have appeared since the late 19th century, when a bird flu epidemic was
first described in Italy. It was long thought that even during such
outbreaks these viruses rarely infect humans and cause mild symptoms in
such cases. But in 2005, at the same time that H5N1 was spreading
across much of the world, U.S. researchers using molecular genetic
techniques painstakingly reassembled the infamous 1918 Spanish flu
virus. They found that this virus, which caused perhaps the worst
pandemic in human history with a death toll of 25-100 million worldwide,
had originated in birds.[43] They also found that its genetic make-up
was similar to H5N1. Recently it has been shown that perhaps only two
genes from the Spanish virus are needed to make H5N1 highly
transmissible between humans.[44]
At this point H5N1 is largely confined to poultry. Human infection is rare, with less than 400 cases reported worldwide since its discovery, with Indonesia and Vietnam alone accounting for about 2/3 of all human cases and deaths. In these cases, the virus is transmitted directly from poultry to humans, though rare instances of non-sustained human-human transmission have occurred. Handling sick or dead poultry, consuming undercooked poultry, or even just visiting a live poultry market can lead to infection. Symptoms begin within one week of exposure, and initially they may be similar to a bad case of regular flu. But H5N1 quickly spreads to the lungs, causing an overwhelming pneumonia – symptoms include high fever, severe cough, and progressive shortness of breath. The lungs become so damaged that a life-support ventilator is usually required. The virus may then invade the bloodstream, causing blood cell and blood clotting abnormalities, and in some cases it attacks multiple organs, including the brain. In fatal cases death typically occurs about 10 days after the onset of symptoms. This appears to be a disease of the young, as 90% of cases occur in persons under 40 years of age, most of whom were previously healthy. Teenagers have the highest mortality rate of any age group, while those over 50 years old do best, quite the opposite of the effect of human influenza virus.[45]
At this point H5N1 is largely confined to poultry. Human infection is rare, with less than 400 cases reported worldwide since its discovery, with Indonesia and Vietnam alone accounting for about 2/3 of all human cases and deaths. In these cases, the virus is transmitted directly from poultry to humans, though rare instances of non-sustained human-human transmission have occurred. Handling sick or dead poultry, consuming undercooked poultry, or even just visiting a live poultry market can lead to infection. Symptoms begin within one week of exposure, and initially they may be similar to a bad case of regular flu. But H5N1 quickly spreads to the lungs, causing an overwhelming pneumonia – symptoms include high fever, severe cough, and progressive shortness of breath. The lungs become so damaged that a life-support ventilator is usually required. The virus may then invade the bloodstream, causing blood cell and blood clotting abnormalities, and in some cases it attacks multiple organs, including the brain. In fatal cases death typically occurs about 10 days after the onset of symptoms. This appears to be a disease of the young, as 90% of cases occur in persons under 40 years of age, most of whom were previously healthy. Teenagers have the highest mortality rate of any age group, while those over 50 years old do best, quite the opposite of the effect of human influenza virus.[45]
Patients who seek
medical care earlier have a better prognosis, as treatment can be
initiated when the illness is milder. The usual rapid tests for
influenza (based on sampling of nasal secretions) perform poorly in
detecting H5N1, so physicians must maintain a high index of suspicion
for the diagnosis in the right setting. The treatment of choice is
oseltamivir (Tamiflu), the same medication used against human influenza
virus. The usual dose should be doubled (150mg, rather than 75mg, twice
daily), as should the duration of therapy (10 days rather than 5).
Amantidine provided additional benefit in mouse studies. Zanamavir
(Relenza), a neuraminidase inhibitor like oseltamivir but delivered via
inhalation, is an alternative that has yet to be studied in H5N1
disease. Drug-resistant H5N1 strains, though uncommon, do exist.[45]
Are We Ready?
It
appears that at least two and perhaps more genetic mutations would be
required for avian influenza H5N1 to develop the affinity for humans
required for a pandemic flu outbreak. If a human form of H5N1 ever does
evolve, early recognition will be a key to preventing a devastating
pandemic. Infected persons would need to be isolated and treated with
oseltamivir immediately. Vulnerable people in affected communities
ideally would be able to take oseltamivir and/or receive a vaccine to
prevent infection. Vaccines for H5N1 have been developed, and one has
been approved by the U.S. Food and Drug Administration. Produced by
sanofi pasteur Inc., it was about 50% effective in inducing high
antibody levels in a small study of 103 volunteers, though even lower
antibody levels may confer some protection.[46] Like any influenza
virus, H5N1 changes from year to year, so current vaccines will be only
partially protective against a pandemic strain. This partial
protection, however, might be enough to avert severe infection until a
more tailored vaccine is produced.
Many nations and the
World Health Organization (WHO) are in the process of stockpiling
oseltamivir and H5N1 vaccines. The U.S. federal government, in
collaboration with state governments, is aiming to have enough
oseltamivir stored by the end of 2008 to cover over ¼ of the nation’s
population. Other developed countries have reached similar coverage
levels. Vaccine stockpiling has not reached such levels – 6 million
two-dose courses in the U.S. as of July 2007.[47] WHO stockpiles are
currently the major potential source of drug and vaccine for the world’s
developing countries, which are most likely to be affected first by a
pandemic, and the stockpiles are currently inadequate. The U.S. and
Japan are funding the development of vaccine manufacturing capacity in
six developing countries, while recent technological breakthroughs have
increased projected worldwide vaccine production capacity (for tailored
vaccines) in the event of a pandemic to over 4 billion two-dose courses
by 2010.[48] A nasal powder vaccine has been developed by DelSite
Biotechnologies Inc. and is undergoing early clinical testing; if it is
successful, it will be self-administered and will not require
refrigeration for storage or distribution, qualities valuable in a
pandemic.
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