Respiratory Airway Infections: Bronchitis and Bronchiolitis

Acute bronchitis causes inflammation of the trachea and bronchi but does not involve the alveoli; it is usually caused by viral agents. Acute bronchitis occurs in patients of all ages but is most common in young and older persons. Chronic bronchitis, which is not discussed here, occurs in adulthood.

Viruses are the most common cause of acute bronchitis. Acute bronchitis can be caused by the following agents.

Manifestations of bronchitis include a cough (which is nonproductive at first but can become mucopurulent), substernal pain, and fever (38.3–38.9°C). Physical findings will reveal an infected pharynx; rhonchi and moist crackles can be heard upon auscultation. Several hours before symptoms of bronchitis develop; the patient will experience malaise, headache, coryza, and sore throat. Chest radiographs do not reveal consolidations or infiltrates, as seen in patients with pneumonia; therefore, a chest radiograph can be helpful in differentiating bronchitis from pneumonia.

Acute bronchitis usually occurs after a previous upper respiratory tract infection with extension of the infection to the bronchial tree.
It is most common in the winter months, similar to most other respiratory diseases.
Air pollution increases the number of cases of bronchitis.
Acute bronchitis is a self-limiting disease in healthy adults and resolves within 7–10 days.
Predisposing factors for the development of acute bronchitis in children include poor nutrition, allergy, deficiencies in IgG2, IgG3, and IgG4 subclasses, and rickets.
Older patients who have emphysema or chronic respiratory disease (e.g., tuberculosis) are more likely to develop acute bronchitis.

Acute bronchitis usually follows a viral upper respiratory tract infection that extends into the trachea, bronchi, and bronchioles and results in a hacking cough and sputum production. The inflammation results in hypersecretion of mucus in the bronchial airways. The cough reflex aids in the elimination of mucous secretions from the airways. In time, bacteria can colonize the damaged airways causing the sputum to be purulent. If the patient is healthy, the viral infection is eliminated and the mucous membranes return to normal within 7–10 days. Mucociliary clearance of the airway may be delayed in patients who smoke or who are exposed to smoke because of excess mucous production and loss of ciliated cells, which leads to a productive cough. These patients are more likely to develop chronic bronchitis.

Diagnosis of acute bronchitis is based on clinical signs and symptoms. Differentiation between bronchitis and pneumonia is nearly impossible to determine based on clinical grounds unless chest radiographs demonstrate infiltrates or consolidation consistent with pneumonia. If the patient's temperature is elevated, a bacterial bronchitis may be present. Healthy persons usually improve with few complications.

Bronchitis in an otherwise healthy person is almost always self-limiting. Supportive therapy with analgesics (e.g., acetaminophen), antipyretics (e.g., ibuprofen), antitussives (e.g., dextromethorphan), and expectorants (e.g., guaifenesin) is recommended. If the patient has bronchitis of greater than 14 days, a fever, and if the sputum becomes purulent, it may be necessary to identify the bacterial pathogen by culturing the sputum and treating the patient with erythromycin or azithromycin.

There are no preventative measures available to treat all of the possible agents that can cause bronchitis. The influenza virus vaccine is available to prevent bronchitis due to this agent.

Bronchiolitis causes inflammation of the bronchial tree as low as the bronchioles but does not involve the alveoli. Because infants have narrower airways, bronchiolitis is usually a disease of infants younger than 1 year of age.

The most common cause of bronchiolitis is respiratory syncytial virus; other causes include human metapneumovirus, parainfluenza viruses, and adenoviruses.

Early symptoms of bronchiolitis are similar to symptoms of a viral upper respiratory tract infection and include mild rhinorrhea, cough, and sometimes a low-grade fever. In some infants and young children, the infection extends downward into the lower respiratory tract causing paroxysmal cough and dyspnea. Other common symptoms include tachypnea, tachycardia, fever (38.5–39°C), diffuse expiratory wheezing, inspiratory crackles, nasal flaring, intercostal retractions, grunting, vomiting (especially posttussive), cyanosis, and hyperinflation of the lungs and depression of the diaphragm.

The incidence of bronchiolitis parallels respiratory infections in older children and adults and is most common during fall and winter months.
Although infection with respiratory syncytial virus may occur at any age, the clinical disease bronchiolitis develops only in infants and young children. About 75% of cases of bronchiolitis occur in children younger than 1 year of age and 95% occur in children younger than 2 years of age, with a peak incidence at 2–8 months of age. The infection is usually self-limiting.
Bronchiolitis is an acute viral infection with a favorable outcome; fatalities rarely occur.
About 95% of children aged 2 have serologic evidence of past infection with respiratory syncytial virus; the presence of antibodies to this virus does not confer immunity.
Risk factors include: age younger than 6 months, bottle feeding, prematurity (born before 37 weeks’ gestation), exposure to cigarette smoke, and crowded living conditions.
The virus is transmitted from person-to-person by direct contact with nasal secretions or by airborne droplets.
The risk of RSV lower respiratory tract infection (bronchiolitis) was 10 times higher for children who had older siblings, high parental educational levels, birth weights of >4 kg, attended day care, and were born between April and September, compared with children without these factors (M.L. Houben et al. Clinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns: Prognostic Birth Cohort Study. 2011. Pediatrics. 127:35-41).

Bronchiolitis is usually a viral infection of the small airways (bronchioles). Infection of the bronchiolar respiratory and ciliated epithelial cells produces increased mucous secretion, cell death, and sloughing, followed by a peribronchiolar lymphocytic infiltrate and submucosal edema. Debris in the bronchioles and edema of the walls of the bronchioles results in critical narrowing and obstruction of these airways. Decreased ventilation of portions of the lung causes ventilation-perfusion mismatching resulting in hypoxia. The expiratory phase of respiration also causes dynamic narrowing of the airways resulting in decreased air flow from the lungs and air trapping. The patient must work harder to breathe, which is due to increased end-expiratory lung volume and decreased lung compliance. The debris present in the bronchioles is cleared by macrophages. The pulmonary epithelial cells regenerate within 3–4 days after the infection clears.

The diagnosis of bronchiolitis involves observation of the patient’s signs and symptoms, chest radiographs, and antigen testing for respiratory syncytial virus in nasal washings. Chest radiographs should include anteroposterior (AP) and lateral views, which may show hyperinflation and patchy infiltrates, air trapping, focal atelectasis, flattened diaphragm, increased anteroposterior diameter and peribronchial cuffing.

Antigen tests of nasal washings provide rapid and accurate detection of respiratory syncytial virus. A positive culture or direct fluorescent antibody test result can confirm the diagnosis of respiratory syncytial virus bronchiolitis. Nasal washings should be obtained from children who are hospitalized and children at risk for severe disease. RT PCR tests are now available and more sensitive than the antigen tests.

Patients with bronchiolitis may require supplemental oxygen and replacement of electrolytes and fluids. Empiric treatment with beta agonists (e.g., albuterol) may be helpful in some cases. Anticholinergics (e.g., ipratropium) inhibit smooth muscle contraction and are useful in patients with severe bronchospasm. Studies on treatment of respiratory syncytial virus with ribavirin are mixed and several studies show no significant effect of this treatment on children with severe bronchiolitis. Currently if used it is recommended only in select patients with severe bronchiolitis.

To prevent bronchiolitis palivizumab (humanized monoclonal antibody reactive with respiratory syncytial virus) can be given to high-risk patients including infants born prematurely, patients with cystic fibrosis, patients who have hemodynamically significant acyanotic or cyanotic congenital heart disease, or patients who are immunodeficient.

To emphasize the importance of this disease, influenza is discussed as a separate topic. Although it is a self-limiting disease, severe complications leading to fatalities are seen in the very young, the elderly, patients with underlying cardiovascular and pulmonary diseases, and women in the third trimester of pregnancy.

The causative agent of influenza (or flu) is the influenza virus; the three different antigenic types of the virus are A, B, and C. Virus types A and B cause most epidemics and sporadic outbreaks of flu worldwide. Type C is usually seen as a mild disease of the very young, and rarely causes a flu epidemic. By age 15, nearly everyone has developed antibodies to the type C virus.

A distinctive terminology is used when discussing influenza A virus— the type of influenza virus, the geographic location where it was first isolated, the month it was first isolated, the year it was first isolated, and the H and N antigens expressed (e.g., A/Ann Arbor/1/86/H1N2—an influenza virus type A, first isolated in Ann Arbor, Michigan, in January of 1986 that is a H1N2 type). Influenza B viruses are identified by type, place first isolated, and the date first isolated but NOT by the H and N types.

Symptoms of influenza include abrupt onset of fever (38.9–40°C), chills, rigors, headache, congested conjunctiva, extreme prostration with myalgia in the back and limbs, nonproductive cough, and injection of the pharynx and conjunctiva. Diarrhea and vomiting can also be present but are usually only seen in children with influenza. Fever usually abates within 3–4 days, and recovery usually is complete within 1 week. Cough and malaise may persist for 2 weeks or longer.

In very young, the elderly, patients with underlying cardiovascular and pulmonary diseases, and women in the third trimester of pregnancy, the condition may worsen with persistent fever, marked prostration, cough with rales, and pneumonia. The pneumonia usually is due to a secondary bacterial infection, which can include Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus pyogenes.

Adults are infectious from 1 day before symptoms begin through approximately 5 days after onset of illness. Severely immunocompromised persons can shed the virus for weeks to months.
Rates of influenza infection are highest among children, but rates of serious illness and death are highest among persons aged 65 or older and persons of any age who have medical conditions that place them at high risk for complications from influenza (e.g., pulmonary or cardiac disease).
Epidemics of influenza usually occur every year during the winter months and are responsible for an average of approximately 36,000 deaths per year in the US.
Epidemic flu is cyclic and is usually caused by virus types A or B. Epidemics of type A occur every 2–3 years. Epidemics of type B occur every 4–6 years. Epidemics usually occur from late autumn to early spring.
The most common complications associated with influenza infection are pneumonia and death. The overall mortality rate is about 1%. Influenza can exacerbate underlying medical conditions and lead to secondary bacterial pneumonia or primary influenza viral pneumonia.
Young children with influenza infection can develop symptoms mimicking bacterial sepsis and have high fevers. Some children hospitalized with influenza may have febrile seizures.
Influenza viruses are spread from person to person primarily by the coughing and sneezing of infected persons. Another way to describe it is as follows: the virus is spread through close contact, which is defined as within six feet of an infected person.

Avian influenza is caused by influenza A virus H5N1 that primarily infects birds.
Outbreaks of H5N1 among poultry have occurred in Africa, East Asia, and the Pacific, South Asia, the Near East, Eurasia, and Europe.
The mortality rate is high, at around 60%. Most patients acquired the infection after direct close contact with infected poultry or contaminated surfaces.
A few rare cases of human-to-human spread of H5N1 virus have occurred, although transmission did not continue beyond one person.

The influenza viruses are segmented single-strand RNA viruses. Influenza types A and B viruses have eight RNA segments, and influenza type C virus has seven RNA segments. The RNA codes for five structural proteins and three nonstructural proteins. Protein M and nucleoprotein NP are used to place the virus into types A, B, and C. The hemagglutinins (H antigen) and the neuraminidases (N antigen) are important in the pathogenesis of influenza—the H antigen is required for binding of the virus to the cell, and the N antigen helps the mature virus escape from the cell.

In addition to the major types of the influenza A virus, there are also subtypes of the virus that are determined by the H and N antigens. There are at least five antigenic types of H antigen (i.e., H1, H2, H3, H5, and H7) and three antigenic types of N antigen (N1, N2, and N9) that infect humans. Antibodies to one type of H or N antigen are not effective in protecting a person from being infected by another type of the H or N antigen.

Influenza viruses can infect other animal hosts (e.g., ducks, swine). Two different influenza A viruses can infect the same animal host cell, and as long as the viruses that result from this dual infection have the right number and kinds of RNA segments, they can cause infection in another host.

If two viruses are circulating in a population of swine (e.g., influenza A H5N2 virus and influenza A H1N1), the viruses can co-infect one animal. Suppose, for example, that one of these two viruses, the influenza A H1N1 virus, infected several persons the previous year. Because of their ability to produce antibodies that inactivate the influenza A H1N1 virus, those who survived the influenza A H1N1 infection would not acquire this viral infection again the following year. However, if influenza A H1N1 virus and influenza A H5N2 virus co-infected a pig and re-assorted their viral RNA segments, an influenza A H5N1 virus could result. The influenza H5N1 virus could cause the next influenza epidemic in humans if they were exposed to the infected pig with the re-assorted virus. These major changes in H or N types are called shifts. The H5N1 Influenza A virus in this example represents an antigenic shift.

Mutations can also occur in the H and N genes that result in slight changes in the H or N antigens. These slight changes are called antigenic drift. Influenza A viruses undergo both shift and drift, whereas influenza B viruses only undergo drift in their H and N antigens.

If a susceptible person inhales droplets containing the influenza virus, the virus attaches to the epithelial cells lining the respiratory airways as well as to the nasal turbinates. The virus replicates in the cells, causing desquamation of ciliated epithelium, hyperplasia of transitorial cells, edema, hyperemia, congestion, and increased secretions. Pneumonic complications without secondary bacterial infections can occur; however, they usually are due to a secondary infection with bacteria (commonly Staphylococcus aureus).

Diagnosis of influenza is difficult in that there are no pathognomonic signs and the infection can be easily confused with other respiratory tract infections. Influenza can be differentiated from the common cold because the flu results in a high fever but the common cold is an afebrile disease. Differentiating influenza pneumonia from atypical pneumonia may be difficult however; the onset of atypical pneumonia is usually insidious whereas influenza is rapid in onset.

Definitive diagnosis requires laboratory testing. There are several tests available and include direct antigen detection tests, virus isolation in cell culture, or detection of influenza-specific RNA by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR). Rapid influenza diagnostic tests (RIDTs) are available and they detect the viral nucleoprotein antigen.

RIDTs can detect viral antigen in patient samples within 30 minutes or less and are referred to as “point-of-care” tests since CLIA-waived (Clinical Laboratory Improvement Amendments) the requirement that skilled medical technicians need to perform these tests. RIDTs can i) detect and distinguish between influenza A and B viruses; ii) detect both influenza A and B but not distinguish between influenza A and B viruses; or, iii) detect only influenza A viruses. RIDTs have low to moderate sensitivity compared to viral culture or RT-PCR. The sensitivities of RIDTs to detect influenza B viruses are lower than for detection of influenza A viruses. Sensitivities of RIDTs are higher in samples taken from children than in samples taken from adults.

In uncomplicated cases of influenza, recovery is usually complete, with no residual effects. Supportive care is recommended for patients with healthy immune systems. Antipyretics and analgesics can provide relief for fever and muscle pain. The antiviral drugs described below are only effective in reducing illness severity and shortening duration of illness if given within the first two days of influenza symptoms.

Antiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. Four licensed influenza antiviral agents are available in the U.S.: amantadine, rimantadine, zanamivir, oseltamivir and peramivir. Amantadine and rimantadine are effective against influenza A viruses but NOT against influenza B viruses. Amantadine and rimantadine can be used in chemoprophylaxis and in the treatment of influenza A viral infections in adults. Only amantadine can be used in the treatment of influenza A viral infections and chemoprophylaxis in children aged 1 year or older. Rimantadine can only be used for chemoprophylaxis in children.

Zanamivir, oseltamivir and paramivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both drugs are approved for treating uncomplicated influenza infections. Zanamivir is approved for treating persons aged 7 years or older and for chemoprophylaxis of influenza among persons aged 5 years or older. Oseltamivir is approved for treatment and for chemoprophylaxis of influenza among persons aged 1 years or older. Oseltamivir resistance was widespread in the influenza A H1N1 strains during the 2008/2009 flu epidemic. Treatment with zanamivir or a combination of oseltamivir and rimantadine or amantadine is now recommended in situations where the influenza subtype is likely to be H1 or unknown.

The seasonal influenza vaccination contains three different influenza viruses (two As and one B). Vaccination and chemoprophylaxis with amantadine, rimantadine, or oseltamivir are useful for the prevention of seasonal influenza disease in high-risk groups. Use of antiviral medications for postexposure chemoprophylaxis should be reserved for persons at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza. An emphasis on early treatment once a patient has developed symptoms, rather than chemoprophylaxis, should reduce opportunities for development of oseltamivir resistance. Chemoprophylaxis should not be used for prevention of illness among healthy persons after exposures in community settings.

NEW DRUG CLASS; FDA approved in October 24, 2018 single dose of baloxavir marboxil significantly reduced the duration of flu symptoms, duration of fever, length of time of viral shedding, and levels of virus in the nose and throat compared with placebo. This first-in-class drug inhibits the production of the cap-dependent endonuclease protein within the flu virus. This viral protein is essential for viral replication.

Vaccination campaigns begin in mid-August and end in mid-November. Vaccination is recommended for all persons over 6 months of age. The 2019-2020 trivalent vaccines will contain the following: A/Brisbane/02/2018 (H1N1)pdm09-like virus (updated), A/Kansas/14/2017 (H3N2)-like virus (updated), B/Colorado/06/2017-like (Victoria lineage) virus. Quadrivalent vaccines will contain these three viruses and B/Phuket/3073/2013-like virus (Yamagata lineage).

Pertussis (also known as whooping cough) was once a rare disease but is now becoming more common in the US. The word pertussis means cough, and the pathognomonic whoop following a paroxysmal coughing episode aids greatly in diagnosis. In the US., Bordetella pertussis causes about 95% of cases of pertussis, and Bordetella parapertussis causes the other 5% of cases.

Pertussis is a coughing illness that lasts at least 2 weeks and has one of the following manifestations: paroxysms of coughing, inspiratory “whoop,” or posttussis vomiting without any other apparent cause. The incubation period for pertussis is 7–10 days, which is followed by the catarrhal phase. During the catarrhal phase, the disease is indistinguishable from an upper respiratory tract infection. The person is most infectious during this phase, which is characterized by the insidious onset of coryza, sneezing, low-grade fever, and a mild occasional cough similar to the cough of the common cold. The cough gradually becomes more severe and after 1–2 weeks, the second, or paroxysmal, stage begins.

The paroxysmal phase begins with episodic, sudden coughing and generally lasts 2–4 weeks. The cough is so severe that patients are unable to sleep or eat. The whoop, if present, results from inspiratory stridor and is pathognomonic. The patient has paroxysms of numerous, rapid coughs. When paroxysm ends, a long inspiratory effort is usually accompanied by a pathognomonic high-pitched whoop. During such an attack, the patient may become cyanotic. Vomiting and exhaustion commonly follow the episode. The patient usually appears normal between attacks. Paroxysmal coughing attacks occur more frequently at night, with an average of 15 attacks per 24 hours. Severe cases result in hemoptysis, subconjunctival hemorrhages, hernias, seizures, and death.

Adults with pertussis infection may complain of chronic cough. They may be asymptomatic or they may present with an illness that ranges from a mild cough to classic pertussis, with persistent cough lasting more than 7 days. Inspiratory whoop is uncommon.

B pertussis is inhaled on respiratory droplets and attaches to the ciliated epithelium in the trachea. The pertussis toxin causes almost all of the tissue damage in the trachea. The pertussis toxin is an enzyme that ribosylates guanine–nucleotide-binding protein with adenosine diphosphate, affecting regulatory mechanisms in the ciliated cells that line the host’s trachea. This causes death and sloughing of the ciliated cells. Other products of importance are the tracheal cytotoxin and a filamentous hemagglutinin. The cytotoxin kills the cells that line the trachea, and the filamentous hemagglutinin is important in the attachment of B pertussis to the ciliated cells. Large amounts of mucus are produced in response to the infection and cause the patient to cough. The neurologic effects of infection are associated with hypoxia, lymphocyte plugging, and intracerebral hemorrhage.

The presence of the whoop is pathognomonic for pertussis. Laboratory procedures necessary for diagnosis include nasopharyngeal aspirates plated on Bordet-Gengou medium, immunofluorescent staining of nasal secretions for B pertussis, and serologic testing (ELISA) with acute and convalescent sera. An elevated white blood cell count with a lymphocytosis is usually present in children, which is unusual for a bacterial infection. Most bacterial infections result in an increase in neutrophils rather than an increase in lymphocytes.

Antibiotics are ineffective in shortening the course of pertussis infection once the patient has entered the paroxysmal stage. If antibiotics are given, erythromycin is the drug of choice and will eradicate the organism from secretions and decrease spread of the infection to others and, if initiated early, may modify the course of the illness.

Supportive care is essential in the prevention of hypoxia and pulmonary complications. An antibiotic effective against pertussis (e.g., azithromycin, erythromycin, or trimethoprim-sulfamethoxazole) should be administered to all close contacts of persons with pertussis, regardless of age and vaccination status.

The best means of preventing pertussis is vaccination. The most commonly used vaccine is the acellular pertussis vaccine (DTaP), which is mixed with diphtheria and tetanus toxoids and is given to children aged 6 weeks to 6 years. Herd immunity does not seem to completely protect unvaccinated children from pertussis (Glanz JM, McClure DL, Magid DJ, et. al. 2009. Parental Refusal of Pertussis Vaccination is Associated with Increased Risk of Pertussis infection in Children. Pediatrics 123(6):1446-51). One in 20 children whose parents do not get them vaccinated against pertussis will get this disease whereas only 1 in 500 children who were vaccinated developed pertussis.

Because of the waning immunity of adolescents and adults to pertussis and asymptomatic infections that spread from asymptomatic adolescents and adults to unprotected infants, vaccine recommendations have been expanded to give persons older than 10 years of age the tetanus-diphtheria-acellular pertussis vaccine rather than the tetanus-diphtheria vaccine for their scheduled booster shot. Vaccine coverage rates in adolescents and adults are currently around 41% (2008 data).

RESPIRATORY AIRWAY INFECTIONS

Bronchitis, Bronchiolitis, Influenza and Pertussis

I. Acute Bronchitis