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Acute Bronchiolitis

Acute bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities is primarily a pediatric respiratory condition caused by inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the bronchioles Bronchioles The small airways branching off the tertiary bronchi. Terminal bronchioles lead into several orders of respiratory bronchioles which in turn lead into alveolar ducts and then into pulmonary alveoli. Bronchial Tree: Anatomy in response to a viral infection. The condition is a common cause of hospitalization Hospitalization The confinement of a patient in a hospital. Delirium in children in the United States, with the majority of cases caused by respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus ( RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus). Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship usually present with upper respiratory symptoms, such as cough and congestion, and later develop lower respiratory signs, including dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, crackles, and hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage, for up to 10 days. Diagnosis is clinical and treatment is directed at improving oxygenation and hydration. As the disease course is self-limiting Self-Limiting Meningitis in Children, acute bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities has good prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas with appropriate management.

Last updated: May 22, 2023

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Acute bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities is a clinical constellation of respiratory symptoms (increased work of breathing Work of breathing Respiratory muscle contraction during inhalation. The work is accomplished in three phases: lung compliance work, that required to expand the lungs against its elastic forces; tissue resistance work, that required to overcome the viscosity of the lung and chest wall structures; and airway resistance work, that required to overcome airway resistance during the movement of air into the lungs. Work of breathing does not refer to expiration, which is entirely a passive process caused by elastic recoil of the lung and chest cage. Pulmonary Examination, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, and crackles) caused by acute inflammation Acute Inflammation Inflammation of the small airways (small bronchi Bronchi The larger air passages of the lungs arising from the terminal bifurcation of the trachea. They include the largest two primary bronchi which branch out into secondary bronchi, and tertiary bronchi which extend into bronchioles and pulmonary alveoli. Bronchial Tree: Anatomy and bronchioles Bronchioles The small airways branching off the tertiary bronchi. Terminal bronchioles lead into several orders of respiratory bronchioles which in turn lead into alveolar ducts and then into pulmonary alveoli. Bronchial Tree: Anatomy), typically secondary to viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.

Epidemiology

  • Population statistics:
    • Peak incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency between 2 and 6 months of age
    • Leading cause of hospitalization Hospitalization The confinement of a patient in a hospital. Delirium of infants in the United States
  • Seasonal preference ( respiratory syncytial virus Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus ( RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus)–related): fall and winter Winter Pityriasis Rosea 
  • Risk factors for severe disease:
Seasonal behaviour of bronchiolitis

The annual distribution (%) of pathogens that cause bronchiolitis. “Bronchiolitis season” starts around October and finishes around May in the Northern Hemisphere.

Image by Lecturio.

Etiology

  • Viral infection:
    • RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus: ⅓ of cases
    • Rhinovirus Rhinovirus Rhinovirus is an acid-labile, positive-sense RNA virus of the Picornavirus family. The virus, which causes the common cold, is most often acquired through the airway via the inhalation of aerosols containing rhinovirus and fomites. Rhinovirus
    • Less common:
      • Parainfluenza virus Parainfluenza virus Human parainfluenza viruses (HPIVs) are single-stranded, linear, negative-sense RNA viruses of the family Paramyxoviridae and the genus Paramyxovirus. Human parainfluenza viruses are the 2nd most common cause of lower respiratory disease in children, after the respiratory syncytial virus. Parainfluenza Virus
      • Human metapneumovirus
      • Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology
      • Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
      • Mycoplasma pneumoniae Mycoplasma pneumoniae Short filamentous organism of the genus mycoplasma, which binds firmly to the cells of the respiratory epithelium. It is one of the etiologic agents of non-viral primary atypical pneumonia in man. Mycoplasma 
      • Pertussis Pertussis Pertussis, or whooping cough, is a potentially life-threatening highly contagious bacterial infection of the respiratory tract caused by Bordetella pertussis. The disease has 3 clinical stages, the second and third of which are characterized by an intense paroxysmal cough, an inspiratory whoop, and post-tussive vomiting. Pertussis (Whooping Cough)
Causes of bronchiolitis

Seasonal variations in the number of cases that can be attributed to the respiratory syncytial virus (RSV): At its peak, RSV accounts for about 1/3 of bronchiolitis cases.

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Pathophysiology and Clinical Presentation

Pathophysiology

Pathologic changes are noted within 24 hours of contact with a pathogen:

  • Virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology enters epithelial cells of terminal bronchioles Bronchioles The small airways branching off the tertiary bronchi. Terminal bronchioles lead into several orders of respiratory bronchioles which in turn lead into alveolar ducts and then into pulmonary alveoli. Bronchial Tree: Anatomy.
  • Inoculation causes inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, mucus secretion Secretion Coagulation Studies, and epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium: Histology sloughing
  • Sloughing and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema → narrowing and obstruction of small airways
  • Narrowing results in atelectasis Atelectasis Atelectasis is the partial or complete collapse of a part of the lung. Atelectasis is almost always a secondary phenomenon from conditions causing bronchial obstruction, external compression, surfactant deficiency, or scarring. Atelectasis and symptoms begin to appear.

Clinical presentation

Symptoms are on a spectrum based on the severity of the disease:

  • Initial 1–3 days (upper respiratory tract symptoms):
  • Peaks on day 3–5, lasting up to 10 days (lower respiratory tract symptoms):
    • Wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing and diffuse crackles on lung exam
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Severe cases:

Diagnosis and Management

Diagnosis

  • Diagnosis based on clinical suspicion:
    • Characteristic lower respiratory tract symptoms
    • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 2 years
    • Presenting during the fall and winter Winter Pityriasis Rosea seasons
  • Further investigation:
    • High fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Severe presentation 
    • History of comorbidities Comorbidities The presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival. St. Louis Encephalitis Virus
  • Routine testing of any kind is discouraged, as it provides no additional therapeutic value.
  • Investigation in severe cases to evaluate comorbid conditions or superimposed infection:
    • Complete blood count (CBC): leukocytosis Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus 
    • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests: hyperinflation Hyperinflation Imaging of the Lungs and Pleura with atelectasis Atelectasis Atelectasis is the partial or complete collapse of a part of the lung. Atelectasis is almost always a secondary phenomenon from conditions causing bronchial obstruction, external compression, surfactant deficiency, or scarring. Atelectasis 
    • RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus testing on aspirate

Management

Management depends on severity:

  • Mild-to-moderate cases → supportive:
    • Caregiver education on upright positioning during sleeping and feeds
    • Use of cool-mist humidifier and antipyretic Antipyretic Acetaminophen
    • Bulb suctioning of oral and nasal secretions
    • Maintain hydration and feeding
    • Follow-up if patient worsens
  • Severe (< 28 days old, apnea, respiratory distress, lethargic):
    • Admit for inpatient care
    • Humidified oxygen and nebulized hypertonic saline Hypertonic saline Hypertonic sodium chloride solution. A solution having an osmotic pressure greater than that of physiologic salt solution (0. 9 g NaCl in 100 ml purified water). Hyponatremia
    • Suctioning of secretions
    • IV hydration Iv Hydration Crush Syndrome
    • No evidence to support use of albuterol Albuterol A short-acting beta-2 adrenergic agonist that is primarily used as a bronchodilator agent to treat asthma. Sympathomimetic Drugs, epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs, or corticosteroids Corticosteroids Chorioretinitis
  • Complications, such as pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure, can occur and must be managed accordingly.

Prevention and Prognosis

Prevention

  • Encourage breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding.
  • Stop exposure to second-hand smoke.
  • Hand hygiene Hand hygiene Practices involved in preventing the transmission of diseases by hand. Surgical Infections 
  • Palivizumab Palivizumab A humanized monoclonal antibody and antiviral agent that is used to prevent respiratory syncytial virus infections in high risk pediatric patients. Respiratory Syncytial Virus (monoclonal antibody) in high-risk patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship:
    • Meeting American Academy of Pediatrics (AAP) criteria for neonatal chronic lung disease:
    • > 1 year old at onset of RSV RSV Respiratory syncytial virus (RSV) is an enveloped, single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae and the genus Orthopneumovirus. Two subtypes (A and B) are present in outbreaks, but type A causes more severe disease. Respiratory syncytial virus causes infections of the lungs and respiratory tract. Respiratory Syncytial Virus season OR >2 years old but requiring medication for neonatal chronic lung disease

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Differential Diagnosis

  • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma: an inflammatory airway Airway ABCDE Assessment disease that leads to bronchial luminal narrowing and thus obstruction of airflow. Characterized by cough, wheezes, and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma is usually diagnosed after the age of 2 and has known triggers, with reversibility of symptoms with bronchodilator use in all cases, differentiating this condition from bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities.
  • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: infection of the lower respiratory tract that results in symptoms very similar to bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities in infants. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities may develop atypical pneumonia Atypical pneumonia Mycoplasma due to superimposed bacterial infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease or worsened viral infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease. Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests findings typically lag behind presentation in these cases, so the diagnosis is made when a patient has sustained hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage with increased oxygen supplementation, consolidations on lung exam, and increased work of breathing Work of breathing Respiratory muscle contraction during inhalation. The work is accomplished in three phases: lung compliance work, that required to expand the lungs against its elastic forces; tissue resistance work, that required to overcome the viscosity of the lung and chest wall structures; and airway resistance work, that required to overcome airway resistance during the movement of air into the lungs. Work of breathing does not refer to expiration, which is entirely a passive process caused by elastic recoil of the lung and chest cage. Pulmonary Examination.
  • Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD) ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD)): Acid reflux into the esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus: Anatomy in infancy and childhood may present with intermittent cough and wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing. May also be accompanied by a lack of weight gain and increased irritability. Gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (GERD) can be differentiated from bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities if symptoms correlate to feeding routine and not seasonality. Bronchiolitis Bronchiolitis Inflammation of the bronchioles. Pediatric Chest Abnormalities usually presents with a history of upper respiratory symptoms prior to wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing.

References

  1. Teshome, Getachew, M.D., M.P.H., Gattu, R., M.D., & Brown, R., M.D. (2013). Acute bronchiolitis. Pediatric Clinics of North America, 60(5), 1019-1034. doi://dx.doi.org/10.1016/j.pcl.2013.06.005
  2. Kliegman, R. M. et al. (2020). Wheezing, bronchiolitis, and bronchitis. In R. M. Kliegman MD et al., Nelson textbook of pediatrics (pp. 221–2221.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501004181
  3. Justice NA, Le JK. Bronchiolitis. (2020). Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK441959/

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