Acute Upper and Lower Respiratory Tract Diseases: diagnosis and protocols of treatment in the Outpatient Department of Family Doctor. Principles of patients’ management in Influenza (Flu) and other respiratory infections, quarantine measures and prophylactic vaccination. Pre-conditions of hospitalization. Inpatient home treatment. Medical and Labour Expert Examination. Rehabilitation

UPPER RESPIRATORY TRACT INFECTION

The VIDARIS trial, a randomized, placebo-controlled study from New Zealand that enrolled 322 adults older than age 18 years who were in good health, found that adding vitamin D supplements to the diet neither prevented upper respiratory tract infections (URIs) nor hastened recovery from them.

Before this study, it had been unclear whether vitamin D supplementation played a role in preventing or mitigating URIs. Several previous observational studies showed an inverse association between 25-hydroxyvitamin D levels and the presence of URIs, and basic research suggested that vitamin D could help clear bacteria, build up epithelial barriers to infection, and enhance antigen-presenting cells. However, there had been no definitive trial to determine whether vitamin D therapy actually reduces URI rates in adults.

Participants in the trial were randomly assigned to 1 of the following 2 groups:

· Active intervention group – An initial oral vitamin D3 dose of 200,000 IU, followed by a second dose of 200,000 IU the following month and then by monthly doses of 100,000 IU for 16 months

· Placebo group – Matched placebo on the same dosing schedule

Researchers determined the number, duration, and severity of URI episodes, as well as their effect on the patient’s productivity at work (quantified in terms of days missed because of URIs). Results were as follows:

· No significant difference between treatment and placebo groups in total number of URIs (593 events in the intervention group and 611 in the placebo group)

· No significant difference in number of URIs per person (mean, 3.7 per person in the intervention group and 3.8 per person in the placebo group)

· No significant difference in symptom duration per URI episode (mean, 12 days in each group)

· No significant difference in severity of URIs

· No significant difference in number of days missed from work because of URIs (mean, 0.76 days in each group)

The findings did not change significantly when the analysis was repeated by season and by baseline 25-OHD (25-hydroxyvitamin D) levels.

Although the authors did not find a benefit of vitamin D supplementation in their study, they note that other populations (eg, a population with a higher prevalence of vitamin D deficiency) might benefit from vitamin D supplementation. Although at present, clear evidence of the benefit of vitamin D exists only for bone health, investigation into ways in which vitamin D intake might be related to improving immune function and preventing infection remains an important area for future research.

Seasonal variation of selected upper respiratory tract infection pathogens. PIV is parainfluenza virus, RSV is respiratory syncytial virus, MPV is metapneumovirus, and Group A Strept is group A streptococcal disease.

Background

URI represents the most common acute illness evaluated in the outpatient setting. URIs range from the common cold--typically a mild, self-limited, catarrhal syndrome of the nasopharynx--to life-threatening illnesses such as epiglottitis. Viruses account for most URIs. Bacterial primary infection or superinfection may require targeted therapy.

The upper respiratory tract includes the sinuses, nasal passages, pharynx, and larynx, which serve as gateways to the trachea, bronchi, and pulmonary alveolar spaces. Rhinitis, pharyngitis, sinusitis, epiglottitis, laryngitis, and tracheitis are specific manifestations of URIs. Further information can be found in the Medscape Reference articles Emergent Management of Acute Otitis Media, Bronchiolitis, andBronchitis, and in articles about specific infectious agents.

Common URI terms are defined as follows:

· Rhinitis - Inflammation of the nasal mucosa

· Rhinosinusitis or sinusitis - Inflammation of the nares and paranasal sinuses, including frontal, ethmoid, maxillary, and sphenoid

· Nasopharyngitis (rhinopharyngitis or the common cold) - Inflammation of the nares, pharynx, hypopharynx, uvula, and tonsils

· Pharyngitis - Inflammation of the pharynx, hypopharynx, uvula, and tonsils

· Epiglottitis (supraglottitis) - Inflammation of the superior portion of the larynx and supraglottic area

· Laryngitis - Inflammation of the larynx

· Laryngotracheitis - Inflammation of the larynx, trachea, and subglottic area

· Tracheitis - Inflammation of the trachea and subglottic area

Pathophysiology

URIs involve direct invasion of the mucosa lining the upper airway. Person-to-person spread of viruses accounts for most URIs. Patients with bacterial infections may present in similar fashion, or they may present with a superinfection of a viral URI. Inoculation by bacteria or viruses begins when secretions are transferred by touching a hand exposed to pathogens to the nose or mouth or by directly inhaling respiratory droplets from an infected person who is coughing or sneezing.

After inoculation, viruses and bacteria encounter several barriers, including physical, mechanical, humoral, and cellular immune defenses. Hair lining the nose filters and traps some pathogens. Mucus coats much of the upper respiratory tract, trapping potential invaders. The angle resulting from the junction of the posterior nose to the pharynx causes large particles to impinge on the back of the throat. Ciliated cells lower in the respiratory tract trap and transport pathogens up to the pharynx; from there they are swallowed into the stomach.

Adenoids and tonsils contain immune cells that respond to pathogens. Humoral immunity (immunoglobulin A) and cellular immunity act to reduce infections throughout the entire respiratory tract. Resident and recruited macrophages, monocytes, neutrophils, and eosinophils coordinate to engulf and destroy invaders. A host of inflammatory cytokines mediates the immune response to invading pathogens. Normal nasopharyngeal flora, including various staphylococcal and streptococcal species, help defend against potential pathogens. Patients with suboptimal humoral and phagocytic immune function are at increased risk for contracting a URI, and they are at increased risk for a severe or prolonged course of disease.

Viral agents include a vast number of serotypes, which undergo frequent changes in antigenicity, posing challenges to immune defense. Pathogens resist destruction by a variety of mechanisms, including the production of toxins, proteases, and bacterial adherence factors, as well as the formation of capsules that resist phagocytosis.

Incubation times before the appearance of symptoms vary among pathogens. Rhinoviruses and group A streptococci may incubate for 1-5 days, influenza and parainfluenza may incubate for 1-4 days, and respiratory syncytial virus (RSV) may incubate for a week. Pertussis typically incubates for 7-10 days or even as long as 21 days before causing symptoms. Diphtheria incubates for 1-10 days. The incubation period of Epstein-Barr virus (EBV) is 4-6 weeks.

Most symptoms of URIs, including local swelling, erythema, edema, secretions, and fever, result from the inflammatory response of the immune system to invading pathogens and from toxins produced by pathogens. An initial nasopharyngeal infection may spread to adjacent structures, resulting in sinusitis, otitis media, epiglottitis, laryngitis, tracheobronchitis, and pneumonia. Inflammatory narrowing at the level of the epiglottis and larynx may result in a dangerous compromise of airflow, especially in children, in whom a small reduction in the luminal diameter of the subglottic larynx and trachea may be critical. Beyond childhood, laryngotracheal inflammation may also pose serious threats to individuals with congenital or acquired subglottic stenosis.

Epidemiology

United States

URIs are the most common infectious illness in the general population. URIs are the leading reasons for people missing work or school, and they represent the leading acute diagnosis in the office setting.

Nasopharyngitis

The incidence of the common cold varies by age. Rates are highest in children younger than 5 years. Children who attend school or daycare are a large reservoir for URIs, and they transfer infection to those who care for them. Children have about 3-8 viral respiratory illnesses per year. Adolescents and adults have approximately 2-4 colds a year, and people older than 60 years have fewer than 1 cold per year.

Pharyngitis

Acute pharyngitis accounts for 1% of all ambulatory office visits.^[3] The incidence of viral and bacterial pharyngitis peaks in children aged 4-7 years.

Rhinosinusitis

Sinusitis is common in persons with viral URIs. Transient changes in the paranasal sinuses are noted on CT scans in more than 80% of patients with uncomplicated viral URIs. However, bacterial rhinosinusitis occurs as a complication in only about 2% of persons with viral URIs.

Epiglottitis

Epiglottitis occurs at a rate of 6-14 cases per 100,000 children, based on estimates from other countries. This condition typically occurs in children aged 2-7 years and has a peak incidence in those aged 3 years. Epiglottitis is estimated to occur at annual incidence of 9.7 cases per million adults. The occurrence of epiglottitis has decreased dramatically in the United States since the introduction of the Haemophilus influenzae type B (Hib) vaccine.

Laryngitis and laryngotracheitis

Croup, or laryngotracheobronchitis, may affect people of any age, but usually occurs in children aged 6 months to 6 years. The peak incidence is in the second year of life. Thereafter, the enlarging caliber of the airway reduces the severity of the manifestations of subglottic inflammation. Vaccination has dramatically reduced rates of pertussis, including whooping cough. However, the incidence of whooping cough cases in the United States has increased in recent years, reaching 5.3 cases per 100,000 population in 2006. Adolescents and infants younger than 5 months account for many of these cases. In 2004, adults aged 19-64 years accounted for 7,008 (27%) of 25,827 reported cases of pertussis in the United States. Challenges in laboratory diagnosis and overreliance on polymerase chain reaction (PCR) tests have resulted in reports of respiratory illness outbreaks mistakenly attributed to pertussis.

Frequency of selected pathogens

Group A streptococcal bacteria cause approximately 5-15% of all pharyngitis infections, accounting for several million cases of streptococcal pharyngitis each year. This infection is rarely diagnosed in children younger than 2 years.

Approximately 5-20% of Americans have the flu during each flu season. Early presentations include symptoms of URI.

EBV infection affects as many as 95% of American adults by age 35-40 years. Childhood EBV infection is indistinguishable from other transient childhood infections. Approximately 35-50% of adolescents and young adults who contract EBV infection have mononucleosis.

After the advent of the diphtheria vaccine, case rates dramatically decreased in the United States. Since 1980, the prevalence has been approximately 0.001 case per 100,000 population. Diphtheria remains endemic in developing countries. Sporadic cases have recently affected adults.

Seasonality

Although URIs may occur year round, in the United States, most colds occur during fall and winter. Beginning in late August or early September, rates of colds increase over several weeks and remain elevated until March or April.^[14]Epidemics and miniepidemics are most common during cold months, with a peak incidence in late winter to early spring. Cold weather means more time spent indoors (eg, at work, home, school) and close exposure to others who may be infected. Humidity may also affect the prevalence of colds, because most viral URI agents thrive in the low humidity characteristic of winter months. Low indoor air moisture may increase friability of the nasal mucosa, increasing a person's susceptibility to infection. Laryngotracheobronchitis, or croup, occurs in fall and winter. Seasonality does not affect rates of epiglottitis.

The figure below illustrates the peak incidences of various agents by season. Rhinoviruses, which account for a substantial percentage of URIs, are most active in spring, summer, and early autumn. Coronaviral URIs manifest primarily in the winter and early spring. Enteroviral URIs are most noticeable in summer and early fall, when other URI pathogens are at a nadir. Adenoviral respiratory infections are most common in the late winter, spring, and early summer, yet they can occur throughout the year.

Seasonal variation of selected upper respiratory tract infection pathogens. PIV is parainfluenza virus, RSV is respiratory syncytial virus, MPV is metapneumovirus, and Group A Strept is group A streptococcal disease.

Seasonal influenza typically lasts from November until March. In 2009, H1N1 influenza activity was present throughout summer and autumn, overlapping with seasonal influenza. Some parainfluenza viruses (PIVs) have a biennial pattern. Human PIV type 1, the leading cause of croup in children, currently causes autumnal outbreaks in the United States during odd-numbered years. Human PIV type 2 may cause annual or biennial fall outbreaks. Peak activity for human PIV type 3 is during the spring and early summer months; however, the virus may be isolated throughout the year. Human metapneumovirus (hMPV) infection may also occur year round, peaking between December and February.

Mortality/Morbidity

URIs cause people to spend time away from their usual daily activities. Alone, URIs rarely cause permanent sequelae or death, although URIs may serve as a gateway to infection of adjacent structures, resulting in otitis media, bronchitis, bronchiolitis, pneumonia, sepsis, meningitis, intracranial abscess, and other infections. Serious complications may result in clinically significant morbidity and rare deaths.

Common cold

This is the leading cause of acute morbidity and missed days from school or work. The common cold is also the leading acute cause of office visits to a physician in the United States.

Untreated group A streptococcal pharyngitis

This infection can result in acute rheumatic fever (ARF), acute glomerulonephritis, peritonsillar abscess, and toxic shock syndrome. Mortality from group A streptococcal pharyngitis is rare, but serious morbidity or death may result from one of its complications. Pharyngitis without complications rarely poses significant risk for morbidity. However, retropharyngeal, intraorbital, or intracranial abscesses may cause serious sequelae.

Sinusitis

The condition itself is rarely life threatening, but sinusitis can lead to serious complications if the infection extends into surrounding deep tissue. Examples include orbital cellulitis, subperiosteal abscess, orbital abscess, frontal and maxillary osteomyelitis, subdural abscess, meningitis, and brain abscess.

Epiglottitis

This infection poses a risk of death due to sudden airway obstruction and other complications, including septic arthritis, meningitis, empyema, and mediastinitis. In adults, epiglottitis has a fatality rate of approximately 1%.

Selected pathogens

Approximately 3-6% of cases of Hib disease are fatal.

Each year, more than 200,000 people are hospitalized for influenza and approximately 36,000 people die from seasonal influenza and its complications. CDC estimates the overall death rate associated with 2009 H1N1 influenza was 0.97 per 100,000 persons across all age groups.

Complications from whooping cough, or pertussis, reported from 2001-2003 included 56 pertussis-related deaths. Fifty-one (91%) of these deaths were among infants younger than 6 months, and 42 (75%) were among infants younger than 2 months.

Approximately 5-10% of patients with diphtheria die. Fatality rates up to 20% are reported in patients younger than 5 years or older than 40 years.

Race

No notable racial difference is observed with URIs. However, Alaskan Natives have rates of Hib disease higher than those of other groups.^[17]

Sex

Rhinitis: Hormonal changes during the middle of the menstrual cycle and during pregnancy may produce hyperemia of the nasal and sinus mucosa and increase nasal secretions. URI may be superimposed over these baseline changes and may increase the intensity of symptoms in some women.

Nasopharyngitis: The common cold occurs frequently in women, especially those aged 20-30 years. This frequency may represent increased exposure to small children, who represent a large reservoir for URIs. However, hormonal effects on the nasal mucosa may also play a role.

Epiglottitis: A male predominance is reported, with a male-to-female ratio of approximately 3:2.

Laryngotracheobronchitis, or croup, is more common in boys than in girls, with male-to-female ratio of approximately 3:2.

Age

Nasopharyngitis: The incidence of the common cold varies by age. Rates are highest in children younger than 5 years. Children have approximately 3-8 viral respiratory illnesses per year. Adolescents and adults have approximately 2-4 colds a year, and people older than 60 years have fewer than 1 cold per year.

Pharyngitis: The incidence of viral and bacterial pharyngitis peaks in children aged 4-7 years.

Epiglottitis: This typically occurs in children aged 2-7 years and has a peak incidence in those aged 3 years.

Laryngitis and laryngotracheitis: Croup, or laryngotracheobronchitis, may affect people of any age, but it usually occurs in children aged 6 months to 6 years. The peak incidence is in the second year of life.

History

Details of the patient's history aid in differentiating a common cold from conditions that require targeted therapy, such as group A streptococcal pharyngitis, bacterialsinusitis, and lower respiratory tract infections. The table below contrasts symptoms of URI with symptoms of allergy and seasonal influenza (adapted from the National Institute of Allergy and Infectious Diseases).

Table. Symptoms of Allergies, URIs, and Influenza

Symptom	Allergy	URI	Influenza
Itchy, watery eyes	common	rare; conjunctivitis may occur with adenovirus	soreness behind eyes, sometimes conjunctivitis
Nasal discharge	common	common	common
Nasal congestion	common	common	sometimes
Sneezing	very common	very common	sometimes
Sore throat	sometimes (postnasal drip)	very common	sometimes
Cough	sometimes	common, mild to moderate, hacking cough	common, dry cough, can be severe
Headache	uncommon	rare	common
Fever	never	rare in adults, possible in children	very common, 100-102°F or higher (in young children), lasting 3-4 days; may have chills
Malaise	sometimes	sometimes	very common
Fatigue, weakness	sometimes	sometimes	very common, can last for weeks, extreme exhaustion early in course
Myalgias	never	slight	very common, often severe
Duration	weeks	3-14 days	7 days, followed by additional days of cough and fatigue

Viral nasopharyngitis

Symptoms of the common cold usually begin 2-3 days after inoculation. Viral URIs typically last 6.6 days in children aged 1-2 years in home care and 8.9 days for children older than 1 year in daycare. Cold symptoms in adults can last from 3-14 days, yet most people recover or have symptomatic improvement within a week. If symptoms last longer than 2 weeks, consider alternative diagnoses, such as allergy, sinusitis, or pneumonia.

· Nasal symptoms: Rhinorrhea, congestion or obstruction of nasal breathing, and sneezing are common early in the course. Clinically significant rhinorrhea is more characteristic of a viral infection rather than a bacterial infection. In viral URI, secretions often evolve from clear to opaque white to green to yellow within 2-3 days of symptom onset. Thus, color and opacity do not reliably distinguish viral from bacterial illness.

· Pharyngeal symptoms: These include sore or scratchy throat, odynophagia, or dysphagia. Sore throat is typically present in the first days of illness, although it lasts only a few days. If the uvula or posterior pharynx is inflamed, the patient may have an uncomfortable sensation of a lump when swallowing. Nasal obstruction may cause mouth breathing, which may result in a dry mouth, especially after sleep.

· Cough: This may represent laryngeal involvement, or it may result from upper airway cough syndrome related to nasal secretions (postnasal drip). Cough typically develops on the fourth or fifth day, subsequent to nasal and pharyngeal symptoms.

· Foul breath: This occurs as resident flora process the products of the inflammatory process. Foul breath may also occurs with allergic rhinitis.

· Hyposmia: Also termed anosmia, it is secondary to nasal inflammation.

· Headache: This symptom is common with many types of URI.

· Sinus symptoms: These may include congestion or pressure and are common with viral URIs.

· Photophobia or conjunctivitis: These may be seen with adenoviral and other viral infections. Influenza may evoke pain behind the eyes, pain with eye movement, or conjunctivitis. Itchy, watery eyes are common in patients with allergic conditions.

· Fever: This is usually slight or absent, but temperatures can reach 39.4°C (103°F) in infants and young children. If present, fever typically lasts for only a few days. In influenza infection, fevers may result in temperatures as high as 40°C (104°F).

· Gastrointestinal symptoms: Symptoms such as nausea, vomiting, and diarrhea may occur in persons with seasonal or H1N1 influenza, especially in children. Nausea and abdominal pain may be present in individuals with strep throat and viral syndromes.

· Severe myalgia: This is typical of influenza infection, especially in the setting of sudden-onset sore throat, fever, chills, nonproductive cough, and headache.

· Fatigue or malaise: Any type of URI can produce these symptoms. Extreme exhaustion is typical of influenza infection.

Bacterial pharyngitis

History alone is rarely a reliable differentiator between viral and bacterial pharyngitis. If symptoms persist beyond 10 days or progressively worsen after the first 5-7 days, a bacterial illness is suggested. Assessment for group A streptococci warrants special attention. A personal history of rheumatic fever (especially carditis or valvular disease) or a household contact with a history of rheumatic fever increases a person's risk. Fever increases the suspicion for infection with group A streptococci, as does the absence of cough, rhinorrhea, and conjunctivitis, because these are common in viral syndromes. Other factors include occurrence from November through May and a patient age of 5-15 years.

· Pharyngeal symptoms: Sore or scratchy throat, odynophagia, or dysphagia are common. If the uvula or posterior pharynx is inflamed, the patient may have an uncomfortable feeling of a lump when swallowing. Nasal obstruction may cause mouth breathing, which may result in dry mouth, especially in the morning. Group A streptococcal infections often produce a sudden sore throat.

· Secretions: These may be thick or yellow; however, these features do not differentiate a bacterial infection from a viral one.

· Cough: It may be due to laryngeal involvement or upper airway cough syndrome related to nasal secretions (postnasal drip).

· Foul breath: This symptom may occur because resident flora process the products of the inflammatory process. Foul breath may also occur with allergic rhinitis.

· Headache: While common with group A streptococci and mycoplasma infections, it also may reflect URI from other causes.

· Fatigue or malaise: These may occur with any URI. Extreme exhaustion is typical of influenza infection.

· Fever: While usually slight or absent, temperatures may reach 38.9°C (102°F) in infants and young children.

· Rash: A rash may be seen with group A streptococcal infections, particularly in children or adolescents younger than 18 years.

· Abdominal pain: This symptom may occur in streptococcal disease or with influenza and other viral conditions.

· History of recent orogenital contact: This is relevant in cases of gonococcal pharyngitis. However, most gonococcal infections of the pharynx are asymptomatic.

Acute viral or bacterial rhinosinusitis

The presentation of rhinosinusitis is often similar to that of nasopharyngitis because many viral URIs directly involve the paranasal sinuses. Symptoms may have a biphasic pattern, wherein coldlike symptoms initially improve but then worsen. Acute bacterial rhinosinusitis is not common in patients whose symptoms have lasted fewer than 7 days. Unilateral and localizing symptoms raise the suspicion for sinus involvement.

· Nasal discharge: This may be persistent and purulent, and sneezing may occur. Mucopurulent secretions are seen with both viral and bacteria infections. Secretions may be yellow or green; however, the color does not differentiate a bacterial sinus infection from a viral one, because thick, opaque, yellow secretions may be seen with uncomplicated viral nasopharyngitis. Rhinorrhea is typically minimal or does not respond to decongestants or antihistamines. Congestion and nasal stuffiness predominate in some individuals.

· Hyposmia or anosmia: This may occur secondary to nasal inflammation.

· Facial or dental pressure or pain: In older children and adults, symptoms tend to localize to the affected sinus. Frontal, facial, or retroorbital pain or pressure is common. Maxillary sinus inflammation may manifest as pain in the upper teeth on the affected side. Pain radiating to the ear may represent otitis media or a peritonsillar abscess.

· Oropharyngeal symptoms: Sore throat may result from irritation from nasal secretions dripping on the posterior pharynx. Nasal obstruction may cause mouth breathing, which may result in dry mouth, especially in the morning. Mouth breathing may especially be noted in children. Dry mouth may be prominent, especially after sleep.

· Halitosis: Foul breath may be noted because resident florae process the products of the inflammatory process. This symptom may also occur with allergic rhinitis.

· Cough: Upper airway cough syndrome related to nasal secretions (postnasal drip) may result in frequent throat clearing or cough. Rhinosinusitis-related cough is usually present throughout the day. The cough may also be most prominent on awakening, occurring in response to the presence of secretions that have gathered in the posterior pharynx overnight. Daytime cough that lasts more than 10-14 days suggests sinus disease, asthma, or other conditions. Nighttime-only cough is common in numerous disorders, and many forms of cough are most noticeable at night. Upper airway cough syndrome related to nasal secretions occasionally precipitates posttussive emesis. Clinically significant amounts of purulent sputum may suggest bronchitis or pneumonia.

· Fever: This is more likely to occur in children than adults with rhinosinusitis. Fever may occur concomitantly with purulent nasal secretions in persons with sinus disease. In those with viral URI, fever, if present, typically precedes the development of purulent nasal secretions.

· Fatigue or malaise: These may be seen with any URI.

Epiglottitis

This condition is more often found in children aged 1-5 years who present with a sudden onset of symptoms:

· Sore throat

· Drooling, odynophagia or dysphagia, difficulty or pain during swallowing, globus sensation of a lump in the throat

· Muffled dysphonia or loss of voice

· Dry cough or no cough, dyspnea

· Fever, fatigue or malaise (may be seen with any URI)

Laryngotracheitis

· Nasopharyngeal symptoms: Nasopharyngitis often precedes laryngitis and tracheitis by several days. Odynophagia or dysphagia may be reported. Swallowing may be difficult or painful. Patients may experience a globus sensation of a lump in the throat.

· Hoarseness or loss of voice: This is a key manifestation of laryngeal involvement.

· Dry cough: In adolescents and adults, laryngotracheal infection may manifest as severe dry cough following a typical URI prodrome. Mild hemoptysis may be present.

· Barking cough: Children with laryngotracheitis or croup may have the characteristic brassy, seal-like barking cough. Symptoms may be worse at night. Diphtheria also produces a barking cough.

· Whooping cough: The classic whoop sound is an inspiratory gasping squeak that rises in pitch, typically interspersed between hacking coughs. The whoop is more common in children. Coughing often comes in paroxysms of a dozen coughs or more at a time and is often worst at night. The cough may persist for several weeks.

· Posttussive symptoms: Posttussive gagging or emesis may be present after paroxysms of whooping cough. Subconjunctival hemorrhage may result from severe cough. Rib pain, with pinpoint tenderness worsening with respiration, may result from rib fracture associated with severe cough.

· Dyspnea and increased work of breathing: Symptoms may be worse at night because of changes in airway mechanics while the patient is recumbent. Apnea may be a chief feature in infants with pertussis, or whooping cough. Apnea may also result from upper airway obstruction due to other causes.

· Other symptoms: Myalgias are characteristic in influenza infection, especially in the setting of hoarseness with sudden sore throat, fever, chills, nonproductive cough, and headache. Fever may be present, but it is not typical in persons with croup. Fatigue or malaise may occur with any URI.

Laboratory Studies

Diagnostic tests for specific agents are helpful when targeted URI therapy depends on the results. Specific bacterial or viral testing is warranted only in select other situations, such as in immunocompromised patients or during epidemics. Targeted therapy is not available for most viruses that cause URI. Therefore, viral testing is rarely indicated for uncomplicated viral URIs in the outpatient setting. However, confirmation of a viral condition such as influenza may reduce inappropriate use of antibiotics.

Suspected group A streptococcal infection

The diagnosis should be pursued on the basis of clinical findings supported by results of rapid-detection assays and cultures.

Patients with a personal history of rheumatic fever or a household contact with a history of rheumatic fever are at high risk for group A streptococcal infection. In addition, the following features may raise suspicion for group A streptococcal disease:

· Erythema, swelling, or exudates of tonsils or pharynx

· Fever with a temperature of at least 38.3°C (100.9°F) in the preceding 24 hours

· Tender anterior cervical lymph nodes (1 cm or larger)

· Absence of cough, rhinorrhea, and conjunctivitis (common in viral illness)

· Patient age 5-15 years

· Occurrence in the season with highest prevalence (ie, November to May)

A 5-point decision rule for streptococcal pharyngitis likelihood incorporates the following features: absence of cough, swollen tender anterior cervical nodes, temperature over 100.4 º F (38 º C), tonsillar exudates or swelling, and age younger 14 years. Those with high scores may warrant empiric antibiotics; further testing or antibiotics are not indicated for those with low scores. Testing with rapid test and/or culture may be used to guide decision-making in those with intermediate scores.

Rapid antigen tests for group A streptococci have excellent specificity, and yield results in 10-20 minutes. Culture specimens may be obtained at the time of presentation. Negative results on rapid antigen testing have traditionally been followed up with culturing because the rapid antigen test is imperfectly sensitive. In one study of children aged 3-18 years, a culture obtained in the office had greater sensitivity (81%) than that of a rapid antigen-detection test (70%). Rapid test plus culture combined had even greater sensitivity (85%); sensitivity was higher in patients who had a higher pretest likelihood of group A streptococcus pharyngitis. As individual practice sites gain experience with newer rapid detection tests, combination rapid test plus culture is encouraged to verify level of concordance before deciding to forego confirmatory cultures for an individual practice.

Streptococcal antibodies (antistreptolysin O) levels do not peak until 4-5 weeks after the onset of pharyngitis. Therefore, testing for these antibodies has no role in the diagnosis of acute pharyngitis.

Suspected acute bacterial rhinosinusitis

Laboratory studies are generally not indicated in cases of suspected acute bacterial rhinosinusitis because the causative agents in immunocompetent individuals are well characterized. Sinus puncture is also rarely indicated in acute disease. However, maxillary sinus puncture aspirate performed by an otolaryngologist may be indicated in patients with complex and persistent disease, in those with suppurative extensions of disease, in seriously immunocompromised patients, and in those with nosocomial sinus infection. Sinus puncture is a standard diagnostic procedure; rigid nasal endoscopy is a less robust option because of specimen contamination by nasal flora. Respiratory flora also commonly contaminate nasal swabs and washes (see Procedures).

Suspected influenza

For testing and case management of suspected H1N1 or seasonal influenza, see the Medscape Reference article on Influenza.

Immunocompromised individuals

Specific information about infection may help tailor antimicrobial choices, herald potential complications, and aid in determining the appropriateness of hospitalization. Viral testing may be used for making the diagnosis, monitoring the patient, or predicting the prognosis in immunocompromised individuals (eg, transplant recipients).

Other situations in which testing may be considered

· Extended duration: Testing may be required if progressive symptoms last longer than 14 days and have no other identifiable cause, such as asthma or allergic rhinitis.

· Seasonal influenza: In cases of suspected influenza, confirmation of a serotype-specific diagnosis may direct options for antiviral therapy. Testing may also assist the clinician in avoiding unnecessary prescriptions for antibacterials.

· Mononucleosis: In a young person with sore throat, lymphadenopathy, hepatosplenomegaly, testing may be required to confirm infectious mononucleosis. Confirmation may be helpful in guiding outpatient care and expectations.

· HSV infection: Suspected URI due to HSV warrants diagnosis because specific therapy is available for this infection.

· Sexually transmitted disease–related oropharyngeal disease: Specific therapy exists for pathogens such as N gonorrhoeae.

· Epiglottitis: If endoscopy is performed during an evaluation for epiglottitis, a swab sample may be taken for culturing. However, because of contamination with upper airway flora, such cultures are not ideal unless an aspirate is taken from an epiglottic abscess. Therefore, blood cultures should also be ordered. Blood cultures for H influenzae are positive in more than 80% of children and in approximately 25% of adults

Laboratory techniques

· Nasopharyngeal samples for bacteria: Culturing of throat swabs, nasal swabs or washes, or nasal aspirates remains the standard for confirming bacterial URI pathogens (see Procedures). Samples should be taken from the posterior pharynx or tonsils, not the oral cavity. Nasopharyngeal aspirates are recommended for pertussis.^[25] Cultures may be falsely negative for group A streptococci because of inadequate specimen collection, covert use of antibiotics, or suboptimal laboratory practices. Prolonged illness may reduce the sensitivity of culture. Specimens are optimally obtained in the first 4 days of illness. Some patients may be chronically colonized with group A streptococcus.

· Nasopharyngeal samples for viruses: Viral cultures remain the standard for confirming infection. Throat swabs, nasal swabs or washes, or sputum may be cultured on special viral media to detect influenza virus, PIV, adenovirus, RSV, and other viruses. Culturing may require days to weeks.

· Rapid tests for bacteria: Rapid antigen tests for group A streptococci have excellent specificity and yield results in 10-20 minutes; individual practices wherein excellent correlation has been verified between rapid tests and culture results may choose not to routinely culture in every instance. Rapid direct fluorescent antibody testing is available to test for pertussis. PCR testing for pertussis is emerging as a sensitive detection tool. However, recent respiratory illness outbreaks mistakenly attributed to pertussis highlight the limitations of relying solely on PCR tests to confirm pertussis. The positive predictive value is lower when PCR testing is used as a screening tool without culture confirmation during a suspected pertussis outbreak.

· Rapid tests for viruses: Various antigen, immunofluorescence, and PCR assays are available to detect viruses in secretions. Rapid tests for influenza can be conducted on specimens from nasopharyngeal swabs, washes, or aspirates, yielding results within 30 minutes. Most rapid tests to detect influenza that are performed in a physician's office are approximately greater than 70% sensitive and approximately greater than 90% specific. Therefore, viral culture may yield a positive result in up to 30% of the cases with negative rapid influenza test results. Enzyme immunoassays are available to detect PIV. Reverse transcriptase PCR may detect various viruses in nasopharyngeal samples. PCR detection of various viruses from blood samples is emerging as a way to track certain viral infections.

· Titer comparison: Antibody titers compared between paired specimens obtained weeks apart may help in retrospectively identifying a particular pathogen in immunocompetent patients. The first sample should be obtained during the first week of illness, and the second should be obtained 2-4 weeks later.

· Monospot: In a patient with symptoms of infectious mononucleosis due to EBV, a positive result on a monospot heterophile antibody test is diagnostic. levels are moderate to high in the first month of illness and decrease rapidly thereafter. Monospot results are positive in more than 85% of cases. False-positive results are seen in a few patients; false-negative results are seen in 10-15% of patients, primarily in children younger than 10 years.

Special laboratory considerations for specific pathogens

· Pertussis: This infection is clinically diagnosed on the basis of symptoms of whooping cough. When bacteriologic confirmation is sought, the receiving laboratory should be contacted for special instructions on specimen collection. Culture of a nasopharyngeal aspirate is the criterion standard, although PCR and serology are available. Nasopharyngeal aspirates are ideally collected 0-2 weeks after symptom onset, but may provide accurate results for as long as 4 weeks in infants or unvaccinated patients. Serology is optimally timed 2-8 weeks post symptom onset, when antibody titers are highest, yet testing may be performed on specimens as long as 12 weeks after symptom onset.

· Diphtheria: Special selective growth media are required for C diphtheriae. This organism must be distinguished from the diphtheroids that commonly inhabit the nasopharynx.

· HSV: In patients with mucocutaneous lesions suggestive of HSV infection, isolation of the virus in cell culture is the preferred virologic testing strategy. As lesions begin to heal, the sensitivity of culturing rapidly declines. Cytologic detection of cellular changes of HSV infection is insensitive and nonspecific and should not be relied on for diagnosis of HSV infection.PCR is available in some laboratories.

· Gonorrhea: N gonorrhoeae requires special culture media.

· Atypical bacteria: Insufficient evidence suggests that testing for atypical bacteria, such as C pneumoniae or M pneumoniae, would improve clinical outcomes in persons with pharyngitis.

Other laboratory tests

· CBC count with differential: Patients with URIs may have an increased WBC count with a left shift. Atypical lymphocytes, lymphocytosis, or lymphopenia may be seen in some viral infections. However, a CBC count is not likely to be helpful in differentiating the infectious agent or in directing therapy in uncomplicated URIs in the outpatient setting.

· Blood cultures: These are appropriate in hospitalized patients.

Imaging Studies

Nasopharyngitis and pharyngitis

Imaging studies are not indicated for the common cold. Suspected mass lesions, such as a peritonsillar abscess or intracranial suppurative lesions, warrant imaging. If the patient's history and physical findings suggest lower respiratory tract disease, chest imaging may be useful.

Rhinosinusitis

· Routine acute rhinosinusitis: Defined as the first 4 weeks of symptoms, it does not require imaging. Greater than 80% of patients with the common cold have transient abnormalities of the paranasal sinuses on CT scans. Imaging studies do not help in distinguishing bacterial from viral disease because no diagnostic signs are unique to bacterial sinus infection. Therefore, images must always be interpreted in the context of the clinical picture. A negative study may be helpful in ruling out rhinosinusitis.

· Complicated or persistent disease: If rhinosinusitis symptoms persist despite therapy or if complications (eg, extension of disease into surrounding tissue) are suspected, sinus imaging may be appropriate to evaluate the anatomy. Signs or symptoms consistent with intracranial extension of infection warrant CT scanning to evaluate the possibility of an intracranial abscess or other suppurative complication. Such symptoms may include proptosis, impaired intraocular movements, decreased vision, papilledema, changes in mental status, or other neurologic findings.

· Choice of sinus imaging: The lack of fully developed sinuses in children poses challenges in image interpretation. The frontal sinuses do not typically appear until age 5-8 years, and they may not develop fully in all individuals.

· CT scanning: This study yields more detailed information than plain radiography, especially regarding the ostiomeatal complex. Such information may be relevant to surgical planning. Although sinus CT scanning is highly sensitive, its specificity for demonstrating acute sinusitis is low because 40% of asymptomatic patients and 87% of those with common colds have sinus abnormalities. Common CT findings include mucosal thickening, air-fluid levels, and obstruction of the ostiomeatal complex. Not all patients with acute rhinosinusitis have air-fluid levels. The image below reveals sinusitis on a CT scan. See the image below

.

CT scan of the sinuses demonstrates maxillary sinusitis. The left maxillary sinus is completely opacified (asterisk), and the right has mucosal thickening (arrow). Courtesy of Omar Lababede, MD, Cleveland Clinic Foundation.

· Plain radiography: If a patient cannot tolerate CT scanning, a plain radiographic Waters view of the frontal and maxillary sinuses may be considered. Most cases of rhinosinusitis involve the maxillary and frontal sinuses, so views that include these sinuses are important. Common radiographic findings include air-fluid levels and mucosal thickening, although not all sinusitis patients have air-fluid levels.

· Ultrasonography: Sinus ultrasonography may be considered when pregnancy or radiation exposure is a concern. Ultrasonography may also be useful in the intensive care unit to evaluate nosocomial sinusitis.

· MRI: This may be optimal for evaluation of suspected fungal sinusitis or suspected tumor.

Epiglottitis

· Direct visualization by laryngoscope: This is the standard for confirming epiglottitis. Before ordering radiography, consider whether imaging may unnecessarily delay patient care. Note that patients with epiglottitis breathe most comfortably when they are upright; the supine position may precipitate respiratory compromise. For patients in whom the diagnosis of epiglottitis is uncertain, a lateral neck image obtained in the erect position with soft tissue technique may be indicated.

· Lateral neck radiographs: In one small retrospective study, neck films were 33% specific for epiglottitis, with a positive predictive value of only 50%; the negative predictive value was 100%.Given the high false-positive rate, the authors concluded that the role of radiography was limited. However, neck imaging may help rule out epiglottitis. Radiographic findings include a swollen epiglottis with a shape similar to the human thumb. The image below illustrates epiglottitis on a neck radiograph.

· CT scanning: This study may be superior in delineating the soft tissue structures in the upper airway. However, CT scanning may unnecessarily delay therapeutic management, and recumbent positioning may precipitate respiratory compromise. See the image below

.

Lateral neck radiograph demonstrates epiglottitis. Courtesy of Marilyn Goske, MD, Cleveland Clinic Foundation.

Laryngitis

Radiographs are of little use except to exclude foreign-body aspiration.

Laryngotracheitis and laryngotracheitis

Laryngotracheitis in a patient with typical symptoms that respond appropriately to treatment does not require imaging. In croup, soft tissue neck images may reveal the classic steeple sign that represents subglottic narrowing. However, this sign is not always present and is not specific for croup.

Procedures

Diagnostic procedures include throat swabs, nasal washes, sinus puncture and aspiration, and laryngoscopy.

Throat swab

For pharyngitis, a throat swab may be performed by vigorously rubbing a dry swab over the posterior pharynx and both tonsils to obtain a sample of exudates, if any. Avoid touching other surfaces of the oropharynx. Samples should be transported dry.

Nasal wash

To perform a nasal wash, a small syringe (3-5 mL) is filled with sodium chloride solution and attached to a short length of flexible tubing. The solution is rapidly instilled into the nostril, with the patient's head tilted back. Secretions are immediately aspirated back into the syringe and transferred to laboratory specimen containers.

Sinus puncture and aspiration

An otorhinolaryngologist may perform this procedure in complex, persistent cases of rhinosinusitis. However, sinus puncture and aspiration has no role in the routine assessment of acute rhinosinusitis.

Laryngoscopy

In cases of suspected epiglottitis, aggressive instrumentation may precipitate spasm and airway compromise. If the diagnosis is suspected in patients not in extremis, an otorhinolaryngologist may perform direct visualization to confirm the disease. Immediate access to intubation and cricothyroidotomy equipment is required. This diagnostic procedure is often performed in the operating room. In cases of laryngotracheitis, laryngoscopy may be considered if the patient is not in extremis. Laryngoscopy provides an opportunity for obtaining culture samples; however, contamination of the samples by upper airway flora is common.

Differential Diagnoses

· Acute Laryngitis

· Allergic and Environmental Asthma

· Allergic Fungal Sinusitis

· Apnea, Sleep

· Asthma

· Bronchiectasis

· Bronchiolitis

· Bronchitis

· Bronchitis, Acute and Chronic

· Chlamydial Pneumonias

· Chronic Bronchitis

· Disorders of Taste and Smell

· Drooling

· Farmer's Lung

· Gastroesophageal Reflux Disease

· Goiter

· Gonococcal Infections

· H1N1 Influenza (Swine Flu)

· Halitosis

· Herpes Simplex

· Histoplasmosis

· HIV Disease

· Hypersensitivity Pneumonitis

· Immunoglobulin A Deficiency

· Infectious Mononucleosis

· Influenza

· Kawasaki Disease

· Legionnaires Disease

· Mumps

· Otitis Media

· Pneumococcal Infections

· Pneumonia

· Pneumonia, Bacterial

· Pneumonia, Community-Acquired

· Pneumonia, Viral

· Psittacosis

· Reflux Laryngitis

· Retropharyngeal Abscess

· Rhinitis Medicamentosa

· Rhinitis, Allergic

· Rhinitis, Nonallergic

· Sinusitis, Chronic

· Sinusitis, Fungal

· Toxoplasmosis

· Tracheal Tumors

· Vocal Cord Dysfunction

MEDICAL CARE

Most URIs are self-diagnosed and self-treated at home. Patients who present with infections often benefit from reassurance, education, and instructions for symptomatic home treatment. Antimicrobial therapy is appropriate in selected patients (see Medication). Several URIs warrant special attention. These are described below.

Epiglottitis

The risk for airway compromise is notable, especially in children. Immediately transfer the patient to the nearest hospital. Adults with epiglottitis typically have a relatively gradual course. However, some older children and adults may have respiratory compromise, especially those with congenital or acquired subglottic stenosis. The treatment of epiglottitis in adults requires individual tailoring of therapy on the basis of the severity of disease at presentation and the course of the disease as it unfolds under observation.

· Instrumentation: Avoid instrumentation. In suspected epiglottitis, limit the examination to observation and an assessment of the vital signs. Tongue depressors or other instruments may provoke airway spasm and precipitate respiratory compromise. Keep the patient comfortable, and avoid unnecessary examinations.

· Specialist consult: An anesthesiologist or otorhinolaryngologist should be involved early in the management of epiglottitis.

· Monitoring: Patients must be monitored for respiratory fatigue visually and with continuous pulse oximetry. Accessibility to equipment and expertise for immediate intubation is required in the event of respiratory failure. If endotracheal intubation is not possible, cricothyroidotomy may be required.

· Oxygen: Oxygen is administered according to pulse oximetry results. Dry air may worsen inflammation. Use of humidified oxygen or a room humidifier is recommended.

· Antibiotics: Presumptive intravenous antibiotics are indicated, tailored to results from blood cultures.

· Glucocorticoids: Either intravenous or inhaled glucocorticoids are sometimes given to reduce inflammation. However, controlled trials of the effectiveness of this approach in epiglottitis are limited.

· Volume deficits: Correct volume deficits with intravenous fluids.

· Sedatives: Avoid sedatives that may suppress the respiratory drive.

· Other medications: In patients with croup, aerosolized racemic epinephrine is sometimes used to reduce mucosal edema; however, the role of this drug in persons with epiglottitis is not defined. Adverse events have been reported in patients with epiglottitis.^[32] Beta-2 agonists are not typically used in patients who do not have asthma.

Laryngotracheitis

Patients may require hospitalization, especially infants and young children who have hypoxemia, volume depletion, a risk for airway compromise, or respiratory fatigue. Mild cases of croup (ie, laryngotracheobronchitis) may be managed at home with moist air inhalation. Patients with diphtheria may require isolation and hospitalization for airway management. The following measures apply to hospitalized patients:

· Monitoring: Patients are monitored for respiratory fatigue visually and with continuous pulse oximetry. Expertise for immediate intubation and access to the necessary equipment are required if respiratory failure is a possibility. If endotracheal intubation is not possible, cricothyroidotomy is indicated for respiratory failure. Keep the patient comfortable, and avoid unnecessary procedures and examinations.

· Oxygen therapy: Administer humidified oxygen to all hypoxemic patients. In patients who do not require oxygen therapy, a cool-mist humidifier may be used. Dry air may worsen inflammation. Heliox, a mixture of helium and oxygen, compared favorably with inhaled racemic epinephrine in a small study of pediatric patients with moderate-to-severe croup.^[33]

· Glucocorticoids: Intravenous or oral glucocorticoids are commonly used to reduce symptoms and shorten hospitalization in patients with moderate-to-severe croup. Inhaled steroids may be considered in cases that are not severe; however, evidence from large controlled trials regarding the use of inhaled steroids in croup is lacking.

· Antibiotic therapy: Antibiotics are appropriate for whooping cough (pertussis); however, croup is typically a viral condition. Blood cultures are ordered.

· Volume deficit: Correct volume deficits with intravenous fluids.

· Sedatives: Avoid sedatives that may suppress the patient's respiratory drive.

· Other medications: Inhaled racemic epinephrine may temporarily dilate the airways by relaxing bronchial smooth muscle and causing vasoconstriction that may reduce mucosal inflammation. Epinephrine may be considered in patients with persistent stridor. Because rebound edema may occur when inhaled epinephrine is stopped, monitoring and observation is required for several hours afterward. The use of steroids may reduce the need for epinephrine to manage croup. In persons with whooping cough, evidence is insufficient to justify the use of long-acting beta-agonists, antihistamines, or pertussis immunoglobulin.^[34]

Deep tissue infections

Retropharyngeal abscess, intracranial abscess, or other deep tissue infection may compromise the airway, vision, or neurologic function. Patients with evidence of intraorbital or intracranial extension of suppurative infection warrant hospitalization, imaging, and surgical consultation. Antibacterial therapy is often warranted.

Patients with immunocompromise

Special attention is warranted in patients with suboptimal immune defenses. This includes patients without a spleen, those with HIV infection, patients with cancer or those undergoing cancer therapy, patients receiving dialysis, those undergoing stem cell or organ transplantation, or those with congenital immunodeficiency. Splenectomy lowers a patient's ability to fight infections with encapsulated organisms. Appropriate antimicrobial therapy and close follow-up may be appropriate because a simple URI may quickly progress to a systemic illness in immunocompromised patients. Although the threshold for hospitalization is lowered for these patients, their risks of nosocomial infections must be weighed against the benefits of close monitoring in the inpatient setting.

Surgical Care

Deep tissue infections of adjacent structures, such as a peritonsillar, oropharyngeal, or intracranial abscess, warrant immediate consultation with a surgeon.

Repeated streptococcal infection may be an indication for surgical intervention. In patients with 4-5 confirmed group A streptococcal infections in a single year or in those with chronic sore throat with adenopathy that is not responsive to treatment over 6 months, tonsillectomy may be considered.

In a study of children aged 1-6 years with recurrent URI in the Netherlands, where adenoidectomy rates are several times that of the United States, adenoidectomy did not reduce URI episodes compared with initial watchful waiting.

Complicated sinus disease may warrant surgical intervention, but surgery is rarely warranted in acute rhinosinusitis. Surgery may be considered when the condition has not responded to months of medical therapy, when a mucopyocele is present, when a fungal sinus infection occurs, or when infection extends to the bone. If possible, the sinus mucosa should be left intact. Functional endoscopic sinus surgery is designed to promote drainage of the sinuses by altering the ostiomeatal complex. For surgical management of chronic sinusitis, see the Medscape Reference article Chronic Sinusitis.

Consultations

· Surgeon: Airway obstruction from epiglottitis, tonsillar hypertrophy, peritonsillar abscess, retropharyngeal abscess, or other mass requires emergency consultation by a surgeon. Sleep apnea associated with tonsillar hypertrophy may also prompt surgical consultation.

· Neurosurgeon: Neurologic findings or mental status changes in the setting of suspected intracranial suppurative complications warrant emergency consultation with a neurosurgeon.

· Infectious disease specialist: Consider consulting an infectious disease specialist when patients have HIV infection, cancer-related or congenital immunodeficiency, or other immunocompromise.

· Pulmonologist or otorhinolaryngologist: Patients with a chronic cough after a URI may benefit from a consultation with a pulmonologist or otorhinolaryngologist to evaluate persistent infection, asthma, gastroesophageal reflux disease, or other causes of chronic cough. Patients with 4-5 confirmed group A streptococcal infections in a single year or those with a chronic sore throat and adenopathy unresponsive to treatment over 6 months should be examined by an infectious disease specialist and/or surgeon. Persistent hoarseness after 2 weeks warrants consultation with an otorhinolaryngologist.

Diet

· Fluid intake: Increased fluids are warranted to replace insensible losses and reduced oral intake.

· Probiotics: Antibiotics alter the gastrointestinal flora, and some foods may not be as digestible for days or weeks after antibiotics are used. Consumption of yogurt containing active cultures has been advocated as an aid to restoring normal flora after antibiotic therapy. A meta-analysis suggests that probiotics may prevent antibiotic-associated diarrhea; Saccharomyces boulardii and lactobacilli may be particularly useful in this situation.

· Alcohol intake: Alcohol may cause swelling of the nasal and paranasal sinus mucosae.

Activity

· Rest: Patients with the common cold may consider returning to their usual physical activity, including aerobic activity, if their symptoms are limited to the nose and throat. However, if cough, fever, or other systemic symptoms are present, rest is indicated. Rest is helpful for recovery from an URI.

· Contact sports: Patients with infectious mononucleosis should be instructed to avoid contact sports for 6 weeks because of the possibility of splenic rupture.

· Voice rest: This is indicated for patients with laryngitis or laryngotracheitis.

· Air travel: Patients may experience increased discomfort from upper airway infection during air travel. As atmospheric pressure drops during takeoff, expansion of soft tissues may block the eustachian tubes and increase pressure sensations in the sinuses.

· Swimming: Chlorine from pools may be irritating to inflamed nasal membranes. Diving, especially at depth, may cause uncomfortable pressure and impair drainage of the paranasal sinuses.

Medication Summary

Therapy addressing specific symptoms is the mainstay for most URIs. Most URIs are self-limited viral infections that resolve without prescription drugs.

In terms of symptomatic treatment, combination analgesic-antihistamine-decongestants have shown mixed results in studies. A Cochrane review suggested some benefit in terms of recovery and symptoms with combination antihistamine-decongestants in adults and older children. However, any benefits need to be weighed against the risk of adverse effects such as drowsiness, dizziness, dry mouth and insomnia.

Recognizing viral and bacterial diseases for which specific therapy is available is important. Antibacterial therapy is appropriate for patients with group A streptococcal pharyngitis, bacterial sinusitis, epiglottitis, pertussis, or diphtheria. Patients with HSV infection or gonococcal upper airway disease also benefit from specific treatment. In immunocompromised patients, treatment of RSV and cytomegalovirus infections may be appropriate, especially if lower airway disease is suspected.

In general, antivirals do not provide clinical benefits in persons with viral pharyngitis. However, in patients who are immunocompromised, antivirals have a role in treating illness that might progress. Acyclovir, famciclovir, and valacyclovir are recommended for patients with severe HSV pharyngitis and for immunocompromised patients. Foscarnet or ganciclovir are recommended for the treatment of cytomegalovirus infections in immunocompromised patients. For management of patients with suspected or confirmed seasonal or H1N1 influenza, see the Medscape Reference articles Influenza and H1N1 Influenza (Swine Flu).

Antibiotics used in specific conditions are as follows:

Group A streptococcal infection

· Penicillin V (Beepen-VK, Betapen-VK, Veetids, V-Cillin K)

· Amoxicillin (Trimox, Wymox)

· Penicillin G benzathine (Bicillin L-A, Permapen)

· Cefadroxil (Duricef)

· Erythromycin (E.E.S., Erythrocin, E-Mycin, Eryc)

· Amoxicillin and clavulanate (Augmentin)

· Cefaclor (Ceclor)

· Cefuroxime (Ceftin)

· Ceftriaxone (Rocephin)

· Azithromycin (Zithromax)

Epiglottitis

· Cefuroxime (Ceftin)

· Ceftriaxone (Rocephin)

· Cefotaxime (Claforan)

Pertussis

· Clarithromycin (Biaxin)

· Erythromycin (E-Mycin, Erythrocin, Eryc, Ery-Tab, E.E.S.)

· Azithromycin (Zithromax)

Antibiotics

Class Summary

· Group A streptococcal infections: Antibiotics are appropriate for patients with group A streptococcal pharyngitis.

· Epiglottitis: For epiglottitis, cephalosporins such as cefuroxime, ceftriaxone, or cefotaxime are commonly used empirically. Oxacillin, nafcillin, and clindamycin are also options.

· Pertussis: Pertussis is treated with macrolides.

Penicillin V (Beepen-VK, Betapen-VK, Veetids, V-Cillin K)

Considered antimicrobial agent of choice for treatment of group A streptococcal pharyngitis.

Amoxicillin (Trimox, Wymox)

Equivalent for bacteriologic eradication of group A streptococcal infection from tonsillopharynx. Appropriate for uncomplicated bacterial rhinosinusitis.

Penicillin G benzathine (Bicillin L-A, Permapen)

Antimicrobial agent of choice for treatment of group A streptococcal pharyngitis.

Cefadroxil (Duricef)

Used for epiglottitis and for resistant rhinosinusitis.

Erythromycin (E.E.S., Erythrocin, E-Mycin, Eryc)

Group A streptococcal infection

Macrolides are appropriate for patients with penicillin sensitivity, for some with rhinosinusitis, and for those with pertussis and diphtheria.

Pertussis

Recommended dosing schedule of erythromycin may result in GI upset, causing prescription of alternative macrolide or change to tid dosing. Covers most potential etiologic agents, including Mycoplasma species.

Erythromycin is less active against H influenzae.

Although 10 d seems to be standard course of treatment, treating until patient has been afebrile for 3-5 d seems more rational. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Indicated for staphylococcal and streptococcal infections.

In children, age, weight, and severity of infection determine proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.

Has the added advantage of being a good anti-inflammatory agent by inhibiting migration of polymorphonuclear leukocytes.

Amoxicillin and clavulanate (Augmentin)

Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. Addition of clavulanate inhibits beta-lactamase producing bacteria.

Good alternative antibiotic for patients allergic to or intolerant of macrolide class. Usually well tolerated and provides good coverage of most infectious agents. Not effective against Mycoplasma and Legionella species. Half-life of oral form is 1-1.3 h. Has good tissue penetration but does not enter cerebrospinal fluid.

For children >3 mo, base dosing on amoxicillin content. Due to different amoxicillin/clavulanic acid ratios in 250-mg tab (250/125) vs 250 mg chewable-tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Cefaclor (Ceclor)

Second-generation cephalosporin that binds to one or more of the penicillin-binding proteins, which, in turn, inhibits cell wall synthesis and results in bactericidal activity. Has gram-positive activity that first-generation cephalosporins have and adds activity against Proteus mirabilis, H influenzae, E coli, Klebsiella pneumoniae, and M catarrhalis. Indicated for management of infections caused by susceptible mixed aerobic-anaerobic microorganisms. Determine proper dosage and route based on condition of patient, severity of infection, and susceptibility of causative organism.

Cefuroxime (Ceftin)

Second-generation cephalosporin maintains gram-positive activity of first-generation cephalosporins; adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis.

Binds to penicillin-binding proteins and inhibits final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. Condition of patient, severity of infection, and susceptibility of microorganism determine proper dose and route of administration. Resists degradation by beta-lactamase.

Azithromycin (Zithromax)

Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Treats mild-to-moderate microbial infections.

Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life. Shown to be effective for pertussis in several small studies.

Clarithromycin (Biaxin)

Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

Cefotaxime (Claforan)

Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more penicillin-binding proteins, which, in turn, inhibits bacterial growth. Safety profile more favorable than aminoglycosides.

Analgesic antipyretics

Class Summary

These agents reduce pain and fever.

Acetaminophen (Tylenol, Feverall, Tempra)

DOC for pain in patients with documented hypersensitivity to aspirin, NSAIDs, upper GI disease, or those taking oral anticoagulants. Reduces fever by directly acting on hypothalamic heat-regulating centers, increasing dissipation of body heat by means of vasodilation and sweating.

Anticholinergic agents

Class Summary

Parasympatholytic inhalers inhibit vagally mediated reflexes by antagonizing the action of acetylcholine released by the vagus nerve. This action prevents the increase in intracellular concentration of cGMP caused by interaction of acetylcholine and muscarinic receptors on bronchial smooth muscle. Help reduce mucus in lungs and relax smooth muscles of large and medium bronchi. May be used with short-acting beta2-adrenergic bronchodilators.

Ipratropium (Atrovent)

Chemically related to atropine. Has antisecretory properties. When applied locally, inhibits secretions from serous and seromucous glands lining nasal mucosa.

Antihistamines

Class Summary

These agents act by competitively inhibiting histamine at the H1 receptor. This effect mediates bronchial constriction, mucous secretion, smooth muscle contraction, and edema.

Diphenhydramine (Benadryl, Benylin)

First-generation antihistamine with anticholinergic effects.

Chlorpheniramine (Aller-Chlor, Chlo-Amine, Chlor-Trimeton, Telachlor)

First-generation agent that competes with histamine or H1-receptor sites on effector cells in blood vessels and respiratory tract. One of the safest antihistamines to use during pregnancy.

Brompheniramine (Bromphen, Dimetane Extentabs, Nasahist B)

Does not tend to cause drowsiness and is suitable to use on a day-to-day basis. Oral H1 blocker used for allergic conjunctivitis and rhinitis, angioedema, pruritus, and urticaria.

Antitussives

Class Summary

Several agents are intended for the symptomatic relief of cough. However, evidence is mixed regarding effectiveness of these agents. While codeine may inhibit cough under various circumstances, data are limited regarding its effectiveness in reducing acute cough due to URI. Dextromethorphan has resulted in cough reduction compared with placebo in some studies. However, one study showed that honey was superior to dextromethorphan in reducing cough symptoms and improving sleep in children with URI. Guaifenesin studies have shown mixed results. Cough and cold medicines should be used with caution in children younger than 2 years because serious adverse reactions and fatalities have occurred with OTC preparations. Many OTC cough and cold preparation labels state that the product should not be used in children younger than 4 years.

Guaifenesin and dextromethorphan (Benylin, Humibid, DM, Mytussin, Robitussin DM, Tuss DM)

Treats minor cough resulting from bronchial and throat irritation.

Codeine

Centrally acting antitussive. Helps manage pain of intercostal muscle strain associated with cough.

Adrenergic agonists

Class Summary

Alpha stimulation causes mucosal vasoconstriction, decreasing edema of the subglottic region of the larynx. Although inhaled epinephrine is sometimes given in epiglottitis, its benefit is unproven.

Epinephrine (Adrenalin)

For severe bronchoconstriction, especially with underlying reactive airway disease. Alpha-agonist effects include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta2-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropy.

Corticosteroids

Class Summary

Steroids are used to decrease edema by suppressing local inflammation. They are frequently used to manage croup, and they may reduce the need for racemic epinephrine inhalation.

Dexamethasone (Decadron, AK-Dex, Alba-Dex, Baldex)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Prednisone in equivalent doses may be substituted if administered over 5 d.

Decongestants

Class Summary

These drugs are typically used to relieve nasal symptoms in a variety of URIs. Decongestants and antihistamines should be used with caution in children younger than 2 years because serious adverse reactions and fatalities have occurred with OTC cough and cold preparations. In 2008, the Consumer Healthcare Products Association modified many OTC cough and cold product labels to state "do not use" in children younger than 4 years.

Pseudoephedrine (Actifed, Afrin, Sudafed)

Stimulates vasoconstriction by directly stimulating alpha-adrenergic receptors in respiratory mucosa. Used for symptomatic relief of nasal congestion due to common cold, upper respiratory tract allergies, and sinusitis. Promotes nasal or sinus drainage.

Phenylephrine nasal (Neo-Synephrine)

Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body.

Oxymetazoline (Allerest, Afrin, Dristan, Chlorphed)

Stimulates alpha-adrenergic receptors and causes vasoconstriction when applied directly to mucous membranes. Decongestion occurs without drastic changes in blood pressure, vascular redistribution, or cardiac stimulation.

Further Inpatient Care

In most immunocompetent patients with URIs who require hospitalization, the infection resolves within several days. Reduction in the following parameters signals resolution:

· Tachypnea

· Tachycardia

· Use of accessory muscles of respiration

· WBC abnormalities

· Hypoxemia

· Fever

Acute viral nasopharyngitis, or acute coryza, usually known as the common cold, is a highly contagious, viral infectious disease of the upper respiratory system, primarily caused by picornaviruses (including rhinoviruses) or coronaviruses.

Common symptoms are sore throat, runny nose, nasal congestion, sneezing and cough; sometimes accompanied by 'pink eye', muscle aches, fatigue, malaise, headaches, muscle weakness, and/or loss of appetite. Fever and extreme exhaustion are more usual in influenza. The symptoms of a cold usually resolve after about one week, but can last up to two. Symptoms may be more severe in infants and young children. Although the disease is generally mild and self-limiting, patients with common colds often seek professional medical help, use over-the-counter drugs, and may miss school or work days. The annual cumulative societal cost of the common cold in developed countries is considerable in terms of money spent on remedies, and hours of work lost.

The primary method to prevent infection is hand-washing to minimize person-to-person transmission of the virus. There are no antiviral drugs approved to treat or cure the infection. Most available medications are palliative and treat symptoms only. Megadoses of vitamin C, preparations from echinacea, and zinc gluconate have been studied as treatments for the common cold although none has been approved by the Food and Drug Administration or European Medicines Agency.

Epidemiology

Upper respiratory tract infections are the most common infectious diseases among adults and teens, who have two to four respiratory infections annually. Children may have six to ten colds a year (and up to 12 colds a year for school children). In the United States, the incidence of colds is higher in the fall and winter, with most infections occurring between September and April. The seasonality may be due to the start of the school year, or due to people spending more time indoors (thus in closer proximity with each other) increasing the chance of transmission of the virus.

Virus

Common colds are most often caused by infection by one of the more than 100 serotypes of rhinovirus, a type of picornavirus. Other viruses causing colds are coronavirus, human parainfluenza viruses, human respiratory syncytial virus, adenoviruses, enteroviruses, or metapneumovirus. Due to the many different types of viruses, it is not possible to gain complete immunity to the common cold.

Transmission

The common cold is a disease of the upper respiratory tract

The common cold virus is transmitted between people by one of two mechanisms:

· in aerosol form generated by coughing, sneezing.

· from contact with the saliva or nasal secretions of an infected person, either directly or from contaminated surfaces.

Symptoms are not necessary for viral shedding or transmission, as a percentage of asymptomatic subjects exhibit viruses in nasal swabs.

The virus enters the cells of the lining of the nasopharynx (the area between the nose and throat), and rapidly multiplies. The major entry point is normally the nose, but can also be the eyes (in this case drainage into the nasopharynx would occur through the nasolacrimal duct).

Symptoms

After initial infection, the viral replication cycle begins within 8 to 12 hours. Symptoms can occur shortly thereafter, and usually begin within 2 to 5 days after infection, although occasionally in as little as 10 hours after infection. The first indication of a cold is often a sore or scratchy throat. Other common symptoms are runny nose, congestion, sneezing and cough. These are sometimes accompanied by muscle aches, fatigue, malaise, headache, weakness, or loss of appetite. Colds occasionally cause fever and can sometimes lead to extreme exhaustion. (However, these symptoms are more usual in influenza, and can differentiate the two infections.) The symptoms of a cold usually resolve after about one week, but can last up to 14 days, with a cough lasting longer than other symptoms. Symptoms may be more severe in infants and young children, and may include fever and hives.

Complications

The common cold can lead to opportunistic coinfections or superinfections such as acute bronchitis, bronchiolitis, croup, pneumonia, sinusitis, otitis media, or strep throat. People with chronic lung diseases such as asthma and COPD are especially vulnerable. Colds may cause acute exacerbations of asthma, emphysema or chronic bronchitis.

Economic cost

USA

An American poster from World War II describing the cost of the common cold

In the USA, the common cold leads to 75 to 100 million physician visits annually at a conservative cost estimate of $7.7 billion per year. Americans spend $2.9 billion on over-the-counter drugs and another $400 million on prescription medicines for symptomatic relief.

More than one-third of patients who saw a doctor received an antibiotic prescription, which not only contributes to unnecessary costs ($1.1 billion annually on an estimated 41 million antibiotic prescriptions in the United States), but also has implications for antibiotic resistance from overuse of such drugs.

An estimated 22 to 189 million school days are missed annually due to a cold. As a result, parents missed 126 million workdays to stay home to care for their children. When added to the 150 million workdays missed by employees suffering from a cold, the total economic impact of cold-related work loss exceeds $20 billion.

Prevention

Poster encouraging citizens to "Consult your Physician" for treatment of the common cold

The best way to avoid a cold is to avoid close contact with existing sufferers; to wash hands thoroughly and regularly; and to avoid touching the mouth and face. Anti-bacterial soaps have no effect on the cold virus; it is the mechanical action of hand washing with the soap that removes the virus particles.

In 2002, the Centers for Disease Control and Prevention recommended alcohol-based hand gels as an effective method for reducing infectious viruses on the hands of health care workers. As with hand washing with soap and water, alcohol gels provide no residual protection from re-infection.

The common cold is caused by a large variety of viruses, which mutate quite frequently during reproduction, resulting in constantly changing virus strains. Thus, successful immunization is highly improbable.

Exposure to cold weather

Exposure to cold weather has not been proven to increase the likelihood of "catching" a cold

Although common colds are seasonal, with more occurring during winter, experiments so far have failed to produce evidence that short-term exposure to cold weather or direct chilling increases susceptibility to infection, implying that the seasonal variation is instead due to a change in behaviors such as increased time spent indoors at close proximity to others.

With respect to the causation of cold-like symptoms, researchers at the Common Cold Centre at the Cardiff University conducted a study to "test the hypothesis that acute cooling of the feet causes the onset of common cold symptoms." The study measured the subjects' self-reported cold symptoms, and belief they had a cold, but not whether an actual respiratory infection developed. It found that a significantly greater number of those subjects chilled developed cold symptoms 4 or 5 days after the chilling. It concludes that the onset of common cold symptoms can be caused by acute chilling of the feet. Some possible explanations were suggested for the symptoms, such as placebo, or constriction of blood vessels, however "further studies are needed to determine the relationship of symptom generation to any respiratory infection."

Treatment

As there is no medically proven and accepted medication directly targeting the causative agent, there is no cure for the common cold. Treatment is limited to symptomatic supportive options, maximizing the comfort of the patient, and limiting complications and harmful sequelae.

The common cold is self-limiting, and the host's immune system effectively deals with the infection. Within a few days, the body's humoral immune response begins producing specific antibodies that can prevent the virus from infecting cells. Additionally, as part of the cell-mediated immune response, leukocytes destroy the virus through phagocytosis and destroy infected cells to prevent further viral replication. In healthy, immunocompetent individuals, the common cold resolves in seven days on average.

Palliative care

The National Institute of Allergy and Infectious Diseases suggests getting plenty of rest, drinking fluids to maintain hydration, gargling with warm salt water, using cough drops, throat sprays, or over-the-counter pain or cold medicines. Saline nasal drops may help alleviate congestion.

The American Lung Association recommends avoiding coffee, tea or cola drinks that contain caffeine and avoiding alcoholic beverages, saying that both caffeine and alcohol cause dehydration. However, a study reported in 2000, as well as the U.S. Institute of Medicine in 2004, say that caffeinated beverages and non-caffeinated beverages equally meet the need for fluids.

Antibiotics

Antibiotics, targeted primarily to microorganisms like bacteria and fungus, do not have any beneficial effect against the common cold. Their use in cases of common cold infection is ineffective as they have no effect on viruses.

Antivirals

There are no approved antiviral drugs for the common cold.

ViroPharma and Schering-Plough are developing an antiviral drug, pleconaril, that targets picornaviruses, the viruses that cause the majority of common colds. Pleconaril has been shown to be effective in an oral form. Schering-Plough is developing an intra-nasal formulation that may have fewer adverse effects.

Over-the-counter symptom medicines

There are a number of effective treatments which, rather than treat the viral infection, focus on relieving the symptoms. For some people, colds are relatively minor inconveniences and they can go on with their daily activities with tolerable discomfort. This discomfort has to be weighed against the price and possible side effects of the remedies.

· analgesics such as aspirin or paracetamol (acetaminophen), as well as localised versions targeting the throat (often delivered in lozenge form)

· nasal decongestants such as pseudoephedrine or oxymetazoline which reduce the inflammation in the nasal passages by constricting dilated local blood vessels

· cough suppressants such as dextromethorphan which suppress the cough reflex.

· first-generation anti-histamines such as brompheniramine, chlorpheniramine, diphenhydramine and clemastine (which reduce mucus gland secretion and thus combat blocked/runny noses but also may make the user drowsy). Second-generation anti-histamines do not have a useful effect on colds.

Herbal remedies

Herbs often used in naturopathic cold remedies
Chamomile	Liquorice	Garlic	Ginger

Herbal teas, such as chamomile tea, or lemon or ginger root tisanes may soothe some symptoms and comfort the patient. Liquorice and garlic preparations have been suggested as treatments for the common cold, although their effectiveness is unproven.

Echinacea

Echinacea flower

Echinacea, commonly called coneflowers, is a plant commonly used in herbal preparations for the treatment of the common cold.

Although there have been scientific studies evaluating echinacea, its effectiveness has not been convincingly demonstrated. For example, a peer-reviewed clinical study published in the New England Journal of Medicine concluded that "…extracts of E. angustifolia root, either alone or in combination, do not have clinically significant effects on rhinovirus infection or on the clinical illness that results from it." Recent randomized, double-blind, placebo-controlled studies in adults have not shown a beneficial effect of echinacea on symptom severity or duration of the cold. A structured review of 9 placebo controlled studies suggested that the effectiveness of echinacea in the treatment of colds has not been established. Conversely, two recent meta-analyses of published medical articles concluded that there is some evidence that echinacea may reduce either the duration or severity of the common cold, but results are not fully consistent. However, there have been no large, randomized placebo-controlled clinical studies that definitively demonstrate either prophylaxis or therapeutic effects in adults. A randomized, double-blind, placebo-controlled study in 407 children of ages ranging from 2 to 11 years showed that echinacea did not reduce the duration of the cold, nor reduce the severity of the symptoms. Most authoritative sources consider the effect of echinacea on the cold unproven.

Other

Vitamin C

Blackcurrants are a good source of vitamin C

A well-known supporter of the theory that Vitamin C megadosage prevented infection was Nobel Prize winner Linus Pauling, who wrote the bestseller Vitamin C and the Common Cold. A meta-analysis published in 2005 found that "the lack of effect of prophylactic vitamin C supplementation on the incidence of common cold in normal populations throws doubt on the utility of this wide practice".

A follow-up meta-analysis supported these conclusions:

Prophylactic use "...of vitamin C has no effect on common cold incidence ... [but] reduces the duration and severity of common cold symptoms slightly, although the magnitude of the effect was so small its clinical usefulness is doubtful. Therapeutic trials of high doses of vitamin C ... starting after the onset of symptoms, showed no consistent effect on either duration or severity of symptoms. ... More therapeutic trials are necessary to settle the question, especially in children who have not entered these trials."

Most of the studies showing little or no effect employ doses of ascorbate such as 100 mg to 500 mg per day, considered "small" by vitamin C advocates. Equally important, the plasma half life of high dose ascorbate above the baseline, controlled by renal resorption, is approximately 30 minutes, which implies that most high dose studies have been methodologically defective and would be expected to show a minimum benefit. Clinical studies of divided dose supplementation, predicted on pharmacological grounds to be effective, have only rarely been reported in the literature.

Zinc preparations

Zinc acetate and zinc gluconate have been tested as potential treatments for the common cold, in various dosage form including nasal sprays, nasal gels, and lozenges. Some studies have shown some effect of zinc preparations on the duration of the common cold, but conclusions are diverse. About half of studies demonstrate efficacy. Even studies that show clinical effect have not demonstrated the mechanism of action. The studies differ in the salt used, concentration of the salt, dosage form, and formulation, and some suffer from defects in design or methods. For example, there is evidence that the potential efficacy of zinc gluconate lozenges may be affected by other food acids (citric acid, ascorbic acid and glycine) present in the lozenge. Furthermore, interpretation of the results depends on whether concentration of total zinc or ionic zinc is considered.

There are concerns regarding the safety of long-term use of cold preparations in an estimated 25 million persons who are haemochromatosis heterozygotes. Use of high doses of zinc for more than two weeks may cause copper depletion, which leads to anemia. Other adverse events of high doses of zinc include nausea, vomiting gastrointestinal discomfort, headache, drowsiness, unpleasant taste, taste distortion, abdominal cramping, and diarrhea. Some users of nasal spray applicators containing zinc have reported temporary or permanent loss of sense of smell.

Although widely available and advertised in the United States as dietary supplements or homeopathic treatments, the safety and efficacy of zinc preparations have not been evaluated or approved by the Food and Drug Administration. Authoritative sources consider the effect of zinc preparations on the cold unproven.

A recent study showed that zinc acetate lozenges (13.3 mg zinc) shortened the duration and reduced the severity of common colds compared to placebo in a placebo-controlled, double blind clinical trial. Intracellular Adhesion Molecule-1 (ICAM-1) was inhibited by the ionic zinc present in the active lozenges, and the difference was statistically significant between the groups.

Steam inhalation

Many people believe that steam inhalation reduces symptoms of the cold. However, a double-blind, placebo-controlled, randomized study found no effect of steam inhalation on cold symptoms. A scientific review of medical literature concluded that "there is insufficient evidence to support the use of steam inhalation as a treatment." There have been reports of children being badly burned when using steam inhalation to alleviate cold symptoms leading to the recommendation to "...start discouraging patients from using this form of home remedy, as there appears to be no significant benefit from steam inhalation."

Chicken soup

In the twelfth century, Moses Maimonides wrote, "Chicken soup...is recommended as an excellent food as well as medication." Since then, there have been numerous reports in the United States that chicken soup alleviates the symptoms of the common cold. Even usually staid medical journals have published tongue-in-cheek humorous articles on the alleged medicinal properties of chicken soup.

Historical research

"Definition of a Cold." Benjamin Franklin's notes for a paper he intended to write on the common cold.

The name "common cold" came into use in the 16th century, due to the similarity between its symptoms and those of exposure to cold weather. Norman Moore relates in his history of the Study of Medicine that James I continually suffered from nasal colds, which were then thought to be caused by polypi, sinus trouble, or autotoxaemia.

In the 18th century, Benjamin Franklin considered the causes and prevention of the common cold. After several years of research he concluded: "People often catch cold from one another when shut up together in small close rooms, coaches, etc. and when sitting near and conversing so as to breathe in each other's transpiration." Although viruses had not yet been discovered, Franklin hypothesized that the common cold was passed between people through the air. He recommended exercise, bathing, and moderation in food and drink consumption to avoid the common cold. Franklin's theory on the transmission of the cold was confirmed some 150 years later.

Bronchitis is an inflammation of the large bronchi (medium-size airways) in the lungs. It can progress to pneumonia. Acute bronchitis is usually caused by viruses or bacteria and may last several days or weeks. Acute bronchitis is characterized by cough and sputum (phlegm) production and symptoms related to the obstruction of the airways by the inflamed airways and the phlegm, such as shortness of breath and wheezing. Diagnosis is by clinical examination and sometimes microbiological examination of the phlegm. Treatment may be with antibiotics (if a bacterial infection is suspected), bronchodilators (to relieve breathlessness) and other treatments.

Cause/Etiology

Acute bronchitis can be caused by contagious pathogens. In about half of instances of acute bronchitis a bacterial or viral pathogen is identified. Typical viruses include respiratory syncytial virus, rhinovirus, influenza, and others.

Acute bronchitis can also result from breathing irritating fumes, such as those of tobacco/marijuana smoke, or breathing polluted air (from unwashed bed linens for example).

Signs and symptoms

Bronchitis may be indicated by an expectorating cough, shortness of breath (dyspnea) and wheezing. Occasionally chest pains, fever, and fatigue or malaise may also occur. Additionally, Bronchitis caused by Adenoviridae may cause systemic and gastrointestinal symptoms as well. However the coughs due to bronchitis can continue for up to three weeks or more even after all other symptoms have subsided.

Diagnosis

A physical examination will often reveal decreased intensity of breath sounds, wheezing, rhonchi and prolonged expiration. Most doctors rely on the presence of a persistent dry or wet cough as evidence of bronchitis.

A variety of tests may be performed in patients presenting with cough and shortness of breath:

· A chest X-ray that reveals hyperinflation; collapse and consolidation of lung areas would support a diagnosis of pneumonia. Some conditions that predispose to bronchitis may be indicated by chest radiography.

· A sputum sample showing neutrophil granulocytes (inflammatory white blood cells) and culture showing that has pathogenic microorganisms such as Streptococcus spp.

· A blood test would indicate inflammation (as indicated by a raised white blood cell count and elevated C-reactive protein).

· Neutrophils infiltrate the lung tissue, aided by damage to the airways caused by irritation.

· Damage caused by irritation of the airways leads to inflammation and leads to neutrophils being present.

· Mucosal hypersecretion is promoted by a substance released by neutrophils.

· Further obstruction to the airways is caused by more goblet cells in the small airways. This is typical of chronic bronchitis.

· Although infection is not the reason or cause of chronic bronchitis it is seen to aid in sustaining the bronchitis.

Treatment

Antibiotics

In most cases, acute bronchitis is caused by viruses, not bacteria, and will go away on its own without antibiotics. To treat acute bronchitis that appears to be caused by a bacterial infection, or as a precaution, antibiotics may be given. Also, a meta-analysis found that antibiotics may reduce symptoms by one-half day.

Smoking cessation

To help the bronchial tree heal faster and not make bronchitis worse, smokers should quit smoking completely to allow their lungs to recover from the layer of tar that builds up over time.

Antihistamines

Using over-the-counter antihistamines may be harmful in the self-treatment of bronchitis.

An effect of antihistamines is to thicken mucus secretions. Expelling infected mucus via coughing can be beneficial in recovering from bronchitis. Expulsion of the mucus may be hindered if it is thickened. Antihistamines can help bacteria to persist and multiply in the lungs by increasing its residence time in a warm, moist environment of thickened mucus.

Using antihistamines along with an expectorant cough syrup may be doubly harmful encouraging the production of mucus and then thickening that which is produced. Using an expectorant cough syrup alone might be useful in flushing bacteria from the lungs. Using an antihistamine along with it works against the intention of using the expectorant.

Prognosis

Acute bronchitis usually lasts a few days. It may accompany or closely follow a cold or the flu, or may occur on its own. Bronchitis usually begins with a dry cough, including waking the sufferer at night. After a few days it progresses to a wetter or productive cough, which may be accompanied by fever, fatigue, and headache. The fever, fatigue, and malaise may last only a few days; but the wet cough may last up to several weeks.

Should the cough last longer than a month, some doctors may issue a referral to an otorhinolaryngologist (ear, nose and throat doctor) to see if a condition other than bronchitis is causing the irritation. It is possible that having irritated bronchial tubes for as long as a few months may inspire asthmatic conditions in some patients.

In addition, if one starts coughing mucus tinged with blood, one should see a doctor. In rare cases, doctors may conduct tests to see if the cause is a serious condition such as tuberculosis or lung cancer.

Acute bronchitis may lead to asthma or pneumonia.

Prevention

In 1985, University of Newcastle, Australia Professor Robert Clancy developed an oral vaccine for acute bronchitis. This vaccine was commercialised four years later.

Influenza

Influenza

Classification and external resources

TEM of negatively stained influenza virons, magnified approximately 100,000 times

Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae (the influenza viruses). The name influenza comes from the Italian: influenza, meaning "influence", (Latin: influentia). In humans, common symptoms of the disease are chills and fever, sore throat, muscle pains, severe headache, coughing, weakness and general discomfort. In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Although it is sometimes confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus. Influenza can produce nausea and vomiting, especially in children, but these symptoms are more characteristic of the unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu".

Typically influenza is transmitted from infected mammals through the air by coughs or sneezes, creating aerosols containing the virus, and from infected birds through their droppings. Influenza can also be transmitted by saliva, nasal secretions, faeces and blood. Infections also occur through contact with these body fluids or with contaminated surfaces. Flu viruses can remain infectious for about one week at human body temperature, over 30 days at 0 °C (32 °F), and for much longer periods at very low temperatures. Most influenza strains can be inactivated easily by disinfectants and detergents.

Flu spreads around the world in seasonal epidemics, killing millions of people in pandemic years and hundreds of thousands in non-pandemic years. Three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing flu virus to humans from other animal species. A deadly avian strain named H5N1 has posed the greatest risk for a new influenza pandemic since it first killed humans in Asia in the 1990s. Fortunately, this virus has not mutated to a form that spreads easily between people.

Vaccinations against influenza are usually given to people in developed countries with a high risk of contracting the disease and to farmed poultry. The most common human vaccine is the trivalent influenza vaccine that contains purified and inactivated material from three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant. Antiviral drugs can be used to treat influenza, with neuraminidase inhibitors being particularly effective.

Etymology

The word influenza comes from the Italian language and refers to the cause of a disease; initially, this ascribed illness to unfavorable astrological influences. Changes in medical thought led to its modification to influenza del freddo, meaning "influence of the cold". The word influenza was first used in English in 1743 when it was adopted, with an anglicized pronunciation, during an outbreak of the disease in Europe. Archaic terms for influenza include epidemic catarrh, grippe (from the French), sweating sickness, and Spanish fever (particularly for the 1918 pandemic strain).

History

The influenza viruses that caused Hong Kong Flu. (magnified approximately 100,000 times)

The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago. Since then, the virus has caused numerous pandemics. Historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other diseases, such as diphtheria, pneumonic plague, typhoid fever, dengue, or typhus. The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Asia and spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.

The most famous and lethal outbreak was the so-called Spanish flu pandemic (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. Older estimates say it killed 40–50 million people, while current estimates say 50 million to 100 million people worldwide were killed. This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death. This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms. Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred." The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.

The Spanish flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%. Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old. This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.

Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.

Known flu pandemics
Name of pandemic	Date	Deaths	Subtype involved	Pandemic Severity Index
Asiatic (Russian) Flu	1889–1890	1 million	possibly H2N2	?
Spanish Flu	1918–1920	40 to 100 million	H1N1	5
Asian Flu	1957–1958	1 to 1.5 million	H2N2	2
Hong Kong Flu	1968–1969	0.75 to 1 million	H3N2	2

The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Schope in 1931. This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933. However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.

The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr.. This built on work by Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen's eggs. Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first influenza vaccine, with support from the U.S. Army. The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.

Although there were scares in New Jersey in 1976 (with the Swine Flu), worldwide in 1977 (with the Russian Flu), and in Hong Kong and other Asian countries in 1997 (with H5N1 avian influenza), there have been no major pandemics since the 1968 Hong Kong Flu. Immunity to previous pandemic influenza strains and vaccination may have limited the spread of the virus and may have helped prevent further pandemics.

Microbiology

Types of influenza virus

Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase (NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).

Diagram of influenza virus nomenclature (for a Fujian flu virus)

The influenza virus is an RNA virus of the family Orthomyxoviridae, which comprises five genera:

· Influenza virus A

· Influenza virus B

· Influenza virus C

· Isavirus

· Thogotovirus

Influenza virus A

· This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses.

Influenza virus B

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2–3 times lower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

Influenza virus C

This genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children.

Influenza A and B viruses usually alternate in causing epidemics but may circulate concurrently in a given year or appear as consecutive outbreaks in the same influenza season. The influenza viruses cause acute respiratory illness, although less severe clinical presentations may not be distinguishable from other respiratory viruses that may be circulating in a population at the same time. Respiratory syncytial virus (RSV) causes significant morbidity and occasional mortality in infants and young children and may appear clinically similar to influenza A virus in the elderly. Additionally, influenza A virus and RSV were the most common dual respiratory virus infections identified in a retrospective review. A clinical diagnosis, therefore, may not be reliable. The availability of amantadine and rimantadine for prophylactic and therapeutic use against influenza A virus but not against influenza B virus and the use of ribavirin for RSV emphasize the need for a rapid and definitive diagnosis.

Isolation in cell culture and the definitive identification of influenza virus and RSV isolates require several days, thereby compromising the efficacy of the focused use of antiviral agents; application of the shell vial technique can reduce the time required to 24 h (6, 9). Direct immunofluorescence (DIF) and enzyme immunosorbent assay have commonly been applied for rapid detection of influenza viruses and RSV.

Enzyme immunomembrane filter assays are available commercially and require less than 15 min to complete. DIF offers the advantages of being able to assess specimen quality and to test for multiple viruses in the same specimen. Nevertheless, nasopharyngeal washes and throat or nasopharyngeal swabs often yield insufficient numbers of cells to evaluate for multiple viruses by DIF. It would be desirable to evaluate the same cells for different viral antigens. This problem has been addressed for other viruses by using a combination of direct and indirect fluorescent-antibody procedures and by using different fluorescent probes. Our approach was to exploit the differences in isotypes between monoclonal antibodies (MAbs) that are used for the diagnosis of influenza A and B viruses and RSV in a rapid DIF method

Murine MAbs that were prepared and are used in this laboratory for the diagnosis of influenza A and B viruses and of RSV were typed by the Isotype Ab-STAT-I test (Sang-Stat Medical Corporation, Menlo Park, Calif.). The MAbs used for influenza A and B viruses were found to be murine immunoglobulin G1 (IgG1) and IgG2b, respectively; two MAbs were pooled for detection of RSV and were typed as IgG2a and IgG3. Goat anti-IgG1 labeled with fluorescein isothiocyanate (emission at 528 nm) and goat anti-IgG2a, anti IgG2b, and anti-IgG3 labeled with Texas Red (TXRD) (emission at 615 nm) were obtained from Southern Biotechnology Associates, Inc., Birmingham, Ala. Each antibody-conjugate combination was block titered in a conventional indirect immunofluorescent-antibody test and adapted to the rapid procedure as previously described (11); primary rhesus monkey kidney (PRMK) cell cultures infected with influenza A/Shanghai (H3N2) or influenza B/Yamagata virus and HEp-2 cells infected with the Long strain of RSV served as the source of antigen. The rapid immunofluorescence procedure, which required 20 min to perform, was employed throughout the study; reagents were diluted in phosphate-buffered saline (0.01 M, pH 7.0). To avoid nonspecific background emission in preparations stained with TXRD conjugate, an Evans blue counterstain was not used in the staining protocol. Preparations were viewed with an Olympus BH-2 microscope equipped with green (G) and blue (B) filters. Cells infected with influenza A virus (fluorescein isothiocyanate conjugate) characteristically fluoresced green when viewed with the B filter, and cells infected with influenza B virus or RSV (TXRD) fluoresced red with the G filter; background emission was dark with both filters. There were no cross-reactions between the reagents used for influenza A and B viruses and the reagents used for influenza A virus and RSV.

Antibody mixtures (IgG1-IgG2b) for influenza A or B virus, antibody mixtures (IgG1-IgG2a-IgG3) for influenza A virus or RSV, and corresponding conjugate mixtures (fluorescein isothiocyanate-TXRD) were subsequently prepared so that the final dilution of each reagent was the same as the optimum dilution obtained in the block titration of the homologous combinations. The antibody and conjugate mixtures were then tested in the indirect immunofluorescence format against antigen preparations consisting of mixtures of influenza A virus- and B virus-infected cells and mixtures of influenza A virus- and RSV-infected cells. A viewing field was examined consecutively with B and G filters. Cells infected with influenza A or B virus and cells infected with influenza A virus or RSV could be readily discerned from each other in the same viewing field by changing the filter (Fig. 1); control preparations consisted of influenza A virus- or B virus-infected or RSV-infected cells stained with the homologous reagents. The differential set for influenza A and B viruses was next tested against 56 clinical specimens for influenza A and B viruses; the differential set for influenza A virus and RSV was tested against 112 clinical specimens for influenza A virus and RSV. The specimens were nasopharyngeal washes that had been prepared for DIF and frozen at 2708C for less than 1 year. The specimens were selected by an individual not involved in the study and were read blindly by two other technologists. In the original diagnostic evaluation, the specimens had been inoculated into MRC-5, PRMK, and HEp-2 cell cultures and had been evaluated for influenza A and B viruses, RSV, and parainfluenza viruses 1, 2, and 3 by DIF. The majority of specimens that were positive for RSV by DIF were not cultured, according to the operational policy of the laboratory.

A total of 56 specimens were examined for influenza A and B viruses by the mixed-isotype test. Twenty-two of 23 specimens positive for influenza A virus and 4 of 4 specimens positive for influenza B virus by conventional DIF were also positive in the mixed-isotype test (Fig. 2 and 3). Fourteen specimens positive for RSV by DIF, 1 specimen positive for parainfluenza virus type 3 by DIF and culture, and 14 specimens negative for all viruses by DIF and culture were also negative in the mixed-isotype test. Influenza A virus was isolated in cell culture from 23 of the 26 specimens positive by DIF in the comparison with influenza B virus and RSV; influenza B virus was isolated from the 4 specimens positive by DIF.

All of the influenza A viruses were influenza A/Beijing (H3N2) virus, and the influenza B isolates were influenza B/Panama virus. A total of 112 specimens were examined for influenza A

virus and RSV by the mixed-isotype method. Twenty-four of 26 specimens positive for influenza A virus by conventional DIF were also positive in the mixed-isotype test. Twenty-five of 27 specimens positive for RSV by conventional DIF were positive by the mixed-isotype test; 1 specimen was positive by the mixed-isotype test and negative by the conventional DIF test.

One dual infection (influenza A virus and RSV) was identified in the same viewing field by the mixed-isotype method. Fiftyeight specimens were negative by both immunofluorescence procedures; two parainfluenza type 3 viruses and one influenza B virus were identified by isolation in culture and DIF. Overall, the mixed-isotype test compared favorably with conventional DIF (Table 1).

While requirements for laboratories to offer specific and rapid testing directed at treatable virus infections are increas- ing, economic considerations favor the least costly diagnostic approach. Focusing on one virus in a diagnostic test, however, rather than employing a differential approach may not identify the causative agent and will not identify dual infections.

Instances of viruses, such as influenza A and B viruses, that cause similar clinical presentations although only one virus is treatable illustrate the need for a clinically relevant diagnosis.

Additionally, a rapid differential diagnosis may be important because two potential pathogens, such as RSV and influenza A virus, may be treated with different antiviral agents. Rapid testing by DIF for more than one virus in a clinical specimen is the best available and most economical approach to these problems but may be compromised by an insufficient number of cells in a specimen, particularly for infants and patients for whom only one attempt at specimen collection is feasible. This study demonstrated that isotype differences between MAbs can be utilized to target relevant viruses that may be present in a specimen and that a diagnosis can be obtained by viewing a single field of a DIF preparation.

Infection and replication

Host cell invasion and replication by the influenza virus.

Symptoms and diagnosis

In humans, influenza's effects are much more severe and last longer than those of the common cold. Recovery takes about one to two weeks. Influenza, however, can be deadly, especially for the weak, old or chronically ill. The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure. Smoking is another risk factor associated with more serious disease and increased mortality from influenza.

Symptoms

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures as high as 39 °C (approximately 103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of influenza may include:

· Body aches, especially joints and throat

· Coughing and sneezing

· Extreme coldness and fever

· Fatigue

· Headache

· Irritated watering eyes

· Nasal congestion

· Reddened eyes, skin (especially face), mouth, throat and nose

· Abdominal pain (in children with influenza B)

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections, but usually the symptoms of the flu are more severe than their common cold equivalents. Research on signs and symptoms of influenza found that the best findings for excluding the diagnosis of influenza were:

Highest sensitive individual findings for diagnosing influenza
Finding:	sensitivity	specificity
Fever	86%	25%
Cough	98%	23%
Nasal congestion	70–90%	20–40%

Notes to table:

· Sensitivity is the proportion of people who tested positive of all the positive people tested. In this case, being positive or negative is having influenza or not, and being tested positive or negative is having the symptom or not. For instance, 86% of those with influenza had fever.

· Specificity is the proportion of people who tested negative of all the negative people tested. In this case, the ones without fever only constitute 25% of those without influenza. In other words, the majority of people with fever do not have influenza.

· All three findings, especially fever, were less sensitive in patients over 60 years of age.

Since anti-viral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of findings below can improve diagnostic accuracy. Unfortunately, even combinations of findings are imperfect. However, Bayes Theorem can combine pretest probability with clinical findings to adequately diagnose or exclude influenza in some patients. The pretest probability has a strong seasonal variation; the current prevalence of influenza among patients in the United States receiving sentinel testing is available at the CDC.^[55] Using the CDC data, the following table shows how the likelihood of influenza varies with prevalence:

Combinations of findings for diagnosing influenza
Combinations of findings	Sensitivity	Specificity	As reported in study^[53] and projected during local outbreaks (prevalence=66%)		Projected during influenza season (prevalence=25%)		Projected in off-season (prevalence=2%)
			PPV	NPV	PPV	NPV	PPV	NPV
Fever and cough	64%	67%	79%	49%	39%	15%	4%	1%
Fever and cough and sore throat	56	71	79	45	39	17	4	2
Fever and cough and nasal congestion	59	74	81	48	43	16	4	1

Two decision analysis studies suggest that during local outbreaks of influenza, the prevalence will be over 70%, and thus patients with any of the above combinations of symptoms may be treated with neuramidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.

Most people who get influenza will recover in one to two weeks, but others will develop life-threatening complications (such as pneumonia). According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the world-wide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness." Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.

Common symptoms of the flu such as fever, headaches, and fatigue come from the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells. In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.

Laboratory tests

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.^[62] According to the CDC, rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% when compared with viral culture. These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season (prevalence=10%^[57]).

Epidemiology

Seasonal variations

Cumulative Confirmed Human Cases of H5N1. The regression curve for deaths is shown extended through the end of April 2007.

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.

It is not completely clear why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Another is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus may also survive longer on exposed surfaces (doorknobs, countertops, etc.) in colder temperatures. Increased travel due to the Northern Hemisphere winter holiday season may also play a role. A contributing factor is that aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low humidity. However, seasonal changes in infection rates also occur in tropical regions, and these peaks of infection are seen mainly during the rainy season. Seasonal changes in contact rates from school terms, which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles. H5N1 exhibits seasonality in both humans and birds.

An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus. This idea was first proposed by Robert Edgar Hope-Simpson in 1965. He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.

Epidemic and pandemic spread

Antigenic drift creates influenza viruses with slightly modified antigens, while antigenic shift generates viruses with entirely novel antigens.

How antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out while others create epidemics, while yet another strain can cause a pandemic.

Prevention

Vaccination and infection control

Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly. Influenza vaccines can be produced in several ways; the most common method is to grow the virus in fertilized hen eggs. After purification, the virus is inactivated (for example, by treatment with detergent) to produce an inactivated-virus vaccine. Alternatively, the virus can be grown in eggs until it loses virulence and the avirulent virus given as a live vaccine. The effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year, allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains. Vaccines have also been developed to protect poultry from avian influenza. These vaccines can be effective against multiple strains and are used either as part of a preventative strategy, or combined with culling in attempts to eradicate outbreaks.

It is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific flu strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003–2004 flu season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.

The 2006–2007 season was the first in which the CDC had recommended that children younger than 59 months receive the annual influenza vaccine. Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous side-effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.

U.S. Navy personnel receiving influenza vaccination

Good personal health and hygiene habits are reasonably effective in avoiding and minimizing influenza. People who contract influenza are most infective between the second and third days after infection and infectivity lasts for around ten days. Children are notably more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.

Since influenza spreads through aerosols and contact with contaminated surfaces, it is important to persuade people to cover their mouths while sneezing and to wash their hands regularly. Surface sanitizing is recommended in areas where influenza may be present on surfaces. Alcohol is an effective sanitizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol to increase the duration of the sanitizing action. In hospitals, quaternary ammonium compounds and halogen-releasing agents such as sodium hypochlorite are commonly used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms. During past pandemics, closing schools, churches and theaters slowed the spread of the virus but did not have a large effect on the overall death rate.

Treatment

People with the flu are advised to get plenty of rest, drink a lot of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as paracetamol (acetaminophen) to relieve the fever and muscle aches associated with the flu. Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye's syndrome, a rare but potentially fatal disease of the liver. Since influenza is caused by a virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia, they may lead to resistant bacteria. Antiviral medication is sometimes effective, but viruses can develop resistance to the standard antiviral drugs.

The two classes of anti-virals are neuraminidase inhibitors and M2 inhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections. The CDC recommended against using M2 inhibitors during the 2005–06 influenza season.

Neuraminidase inhibitors Antiviral drugs such as oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza) are neuraminidase inhibitors that are designed to halt the spread of the virus in the body. These drugs are often effective against both influenza A and B. The Cochrane Collaboration reviewed these drugs and concluded that they reduce symptoms and complications. Different strains of influenza viruses have differing degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future pandemic strain might have.

M2 inhibitors (adamantanes) The antiviral drugs amantadine and rimantadine are designed to block a viral ion channel (M2 protein) and prevent the virus from infecting cells. These drugs are sometimes effective against influenza A if given early in the infection but are always ineffective against influenza B.^[91] Measured resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005.

Research

CDC scientist working on influenza under high bio-safety conditions

Research on influenza includes studies on molecular virology, how the virus produces disease (pathogenesis), host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in developing influenza countermeasures; for example, a better understanding of the body's immune system response helps vaccine development, and a detailed picture of how influenza invades cells aids the development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing Project, which is creating a library of influenza sequences; this library should help clarify which factors make one strain more lethal than another, which genes most affect immunogenicity, and how the virus evolves over time.

Research into new vaccines is particularly important, as current vaccines are very slow and expensive to produce and must be reformulated every year. The sequencing of the influenza genome and recombinant DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new antigens into a previously developed vaccine strain. New technologies are also being developed to grow viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity. Research on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2 protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their team and has now successfully concluded Phase I clinical trials.The US government has purchased several million doses of vaccine from Sanofi Pasteur and Chiron Corporation, meant to be used in case of an influenza pandemic of H5N1 avian influenza and is conducting clinical trials with these vaccines.^[101] The UK government is also stockpiling millions of doses of antiviral drugs (oseltamivir (Tamiflu), zanimivir (Relanza)) to give to its citizens in the event of an outbreak; the UK Health Protection Agency has also gathered a limited amount of HPAI H5N1 vaccines for experimental purposes.

Economic impact Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects. Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion. Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.^[111] On November 1, 2005, United States President George W. Bush unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza backed by a request to Congress for $7.1 billion to begin implementing the plan. Internationally, on January 18, 2006, donor nations pledged US$2 billion to combat bird flu at the two-day International Pledging Conference on Avian and Human Influenza held in China. As of 2006, over ten billion dollars have been spent, and over two hundred million birds have been killed to try to contain H5N1 avian influenza.^[118] However, as these efforts have been largely ineffective at controlling the spread of the virus, other approaches are being tried: for example, the Vietnamese government in 2005 adopted a combination of mass poultry vaccination, disinfecting, culling, information campaigns and bans on live poultry in cities. As a result of such measures, the cost of poultry farming has increased, while the cost to consumers has gone down due to demand for poultry falling below supply. This has resulted in devastating losses for many farmers. Poor poultry farmers cannot afford mandated measures which isolate their bird livestock from contact with wild birds (among other measures), thus risking losing their livelihood altogether. Multinational poultry farming is increasingly becoming unprofitable as H5N1 avian influenza becomes endemic in wild birds worldwide.^[120] Financial ruin for poor poultry farmers, which can be as severe as threatening starvation, has caused some to commit suicide and many others to stop cooperating with efforts to deal with this virus—further increasing the human toll, the spread of the disease, and the chances of a pandemic mutation.