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Pediatric chronic wet cough:What are we missing?
Luke Wall, MDAssistant Clinical Professor of Pediatrics
Section of Allergy/ImmunologyLSU HSC New Orleans
Pediatrics Grand RoundsDecember 18, 2013
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BACKGROUND AND BURDENOF
CHRONIC COUGH
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Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
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Burden of Chronic Cough
• Survey of 165 school children– Australia and Nigeria– Average 8% with persistent cough (>3 weeks)
Faniran, Adeola O., Jennifer K. Peat, and Ann J. Woolcock. "Measuring Persistent Cough in Children in Epidemiological StudiesDevelopment of a Questionnaire and Assessment of Prevalence in Two Countries." CHEST Journal 115.2 (1999): 434-439.
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Burden of Chronic Cough
• Children referred for chronic cough– 53%: >10 visits– 20%: >20 visits– Significantly higher
parental stress
Marchant, Julie M., et al. "What is the burden of chronic cough for families?." CHEST Journal 134.2 (2008): 303-309.
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Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
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Cough Due to Asthma• Features
– Episodic– Expiratory wheeze and/or exertional dyspnea– Obstructive pattern on spirometry
• Reversible– May have
• Exertional cough• Atopy
Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
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Allergic Rhinitis• Evidence of postnasal drip as cause of
cough is weak– Coexisting upper airway disease
• Aeroallergen identification and avoidance• Treatment with intranasal corticosteroid• No proven benefit of antihistamines in
children• Option of allergen immunotherapy
Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
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GERD• Controversy: Cause vs Effect• Red flags: Seek GI consultation
– Choking, vomiting– Failure to thrive
• Cease ineffective PPI therapy • Avoid fundoplication
Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
Arch int med 137.9 (1977): 1186.
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Protracted Bacterial Bronchitis
• Recognized by multiple thoracic societies• Clinical Diagnosis of Childhood
– Chronic wet cough• > 4 weeks
– Complete resolution with antibiotics– Absence of other specific cause
• Growth from bronchoalveolar lavage (BAL) makes a definitive diagnosis (not required)
Mehr, Sam. "The Immunological Investigation of a Child with Chronic Wet Cough." Paediatric Respiratory Reviews 13.3 (2012): 144-149.
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Protracted Bacterial Bronchitis
• Factors to Consider: PBB– May masquerade as asthma
• Cough worse at night– Postural
• Exercise intolerance• Exacerbations with viral URI
– May have concomitant bronchospasm• Concurrent wheezing• Partial response to inhaled beta-agonist
Craven, Vanessa, and Mark L. Everard. "Protracted bacterial bronchitis: reinventing an old disease." Archives of disease in childhood 98.1 (2013): 72-76.
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Protracted Bacterial Bronchitis
• How to differentiate from other conditions?– Nature of cough
• Wet• Lasting > 4 weeks
– Lower airway sounds• Wheeze is rare• Rattle / ruttle is common
– Coarse, non-musical noise– Mucous in larger airways
1. Donnelly, Deirdre, Anita Critchlow, and Mark L. Everard. "Outcomes in children treated for persistent bacterial bronchitis." Thorax 62.1 (2007): 80-84.
2. Craven, Vanessa, and Mark L. Everard. "Protracted bacterial bronchitis: reinventing an old disease." Archives of disease in childhood 98.1 (2013): 72-76.
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Nelson Pediatrics. 19th ed. 2011
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HOW COMMON IS PROTRACTED BACTERIAL BRONCHITIS?
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• Large Pulmonary group in Australia• 108 children over 2 year period
– Referred by primary care– Chronic wet cough > 3 weeks duration
• Applied diagnostic algorithm to determine cause
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• Findings: Wet cough > 3 weeks– ≤ 10% Asthma – ≤ 10% Upper airway cough syndrome (UACS)– 15% GERD– 33% Airway malacia– 40% Protracted Bacterial Bronchitis (PBB)
• 22% Definite PBB• 18% Probable PBB
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Working Diagnosis prior to evaluation
Asthma 50%
Bronchitis 2%
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Working Diagnosis prior to evaluation
Findings
Asthma 50% 4%
Bronchitis 2% 40%
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CAUSES OF PROTRACTED BACTERIAL BRONCHITIS?
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• Retrospective review– University of Iowa Pulmonary 1999-2009– Children <5 yrs old
• Cough, wheeze, noisy breathing– ≥ 1 month
• Positive bacterial growth from BAL• Excluded asthma, other known causes
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Results
• Organisms– S. pneumoniae– M. catarrhalis– H. influenzae
• Cause– Airway malacia in 74%– No cause reported in 26%
Kompare, Michelle, and Miles Weinberger. "Protracted bacterial bronchitis in young children: association with airway malacia." The Journal of pediatrics 160.1 (2012): 88-92.
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Boiling Down the Problem
Kompare, Michelle, and Miles Weinberger. "Protracted bacterial bronchitis in young children: association with airway malacia." The Journal of pediatrics 160.1 (2012): 88-92.
• On the contrary, a child with PIDD might not develop a life threatening infection for many years, in this era of vaccination and antibiotic usage in developed countries.
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NATURAL PROGRESSION?
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Natural Progression
Chang, A. B., G. J. Redding, and M. L. Everard. "Chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis." Pediatric pulmonology 43.6 (2008): 519-531.
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Natural Progression
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SIGNIFICANCE OFBRONCHIECTASIS
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Bronchiectasis
• Radiographic diagnosis• Irreversible bronchial dilatation• Key features
– One or more “dilated” bronchi• Diameter of airway exceeding that of adjacent vessel• Non-tapering of bronchi• Visible bronchi in distal lung fields
• Primary Immunodeficiency accounts for 25% of non-CF bronchiectasis.
1. Chang, A. B., C. A. Byrnes, and M. L. Everard. "Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis." Paediatric respiratory reviews 12.2 (2011): 97-103.
2. Mehr, Sam. "The Immunological Investigation of a Child with Chronic Wet Cough." PaediatricRespiratory Reviews 13.3 (2012): 144-149.
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Bronchiectasis
• 25% Primary Immunodeficiency• 50% Idiopathic
• What do we mean by “Idiopathic?”– There is no underlying cause?– Current medical knowledge falls short of
determining a cause?
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Chronic Suppurative Lung Disease
• Precursor to bronchiectasis • Identical symptoms (no dilated bronchi)
– Prolonged productive cough– Exertional dyspnea– Growth failure– Recurrent chest infections– Clubbing– Chest wall deformity / hyperinflation
Chang, A. B., C. A. Byrnes, and M. L. Everard. "Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis." Paediatric respiratory reviews 12.2 (2011): 97-103.
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Vicious Circle Hypothesis
ImpairedHost Defense
BacterialInfection/
Colonization
AirwayInflammation
ImpairedMucociliaryClearance
HostDefect
ProgressiveLung
Damage Wall, Luke MD
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Bronchiectasis:Diagnostic Dilemma
• CT criteria for bronchiectasis based on adult data– Bronchial lumen : artery ratio (>1)– Used by radiologists despite age
• Ratio influenced by age• Infant normal ratio is 0.4-0.5• May explain CSLD in children
Chang, A. B., C. A. Byrnes, and M. L. Everard. "Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis." Paediatric respiratory reviews 12.2 (2011): 97-103.
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When does chronic cough of bronchiectasis begin?
King, Paul T., et al. "Phenotypes of adult bronchiectasis: onset of productive cough in childhood and adulthood." COPD: Journal of Chronic Obstructive Pulmonary Disease 6.2 (2009): 130-136.
• 60-80% of adults with newly diagnosed bronchiectasis have had chronic wet cough since childhood
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When does chronic cough of
bronchiectasis begin?
King, Paul T., et al. "Phenotypes of adult bronchiectasis: onset of productive cough in childhood and adulthood." COPD: Journal of Chronic Obstructive Pulmonary Disease 6.2 (2009): 130-136.
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RESPIRATORY INFECTIONS:
THE CONTROVERSY
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• Highlights risks of antibiotic use– Antimicrobial resistance– C. difficile diarrhea– Side effects and reactions
• Focused on three most common URI’s– Acute otitis media– Acute bacterial sinusitis– Group A streptococcal (GAS) pharyngitis
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• Principles– Applying stringent clinical criteria for diagnosis– Weighing benefits and harms of antibiotics– Implementing judicious prescribing strategies
• In summary: Reduce overuse and ensure appropriate agents are prescribed
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• ju·di·cious
– having, exercising, or characterized by sound judgment
merriam-webster.com
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WHY DO WE CARE?
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Recent Case
• 11 year old boy• Ill from September- March annually• Frequent asthma exacerbations
– Cough is predominant symptom– Antibiotics given >75% of episodes
• Resolution of symptoms– Oral steroids 2-3x annually
• Wheeze with exercise• Recurrent otitis media and sinusitis
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Recent Case
• IgG 493 mg/dL [595-1275] L• IgA 22.3 mg/dL [43.2-207.5] L• IgM 69.9 mg/dL [28.1-184.3]• IgE 90.1 IU/mL [0-195]
• Previous evaluation: – Normal immunoglobulins
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Photo source: http://babies-dangerous-wild-animals.blogspot.com/2011/06/baby-zebra.html
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ROLE OF IMMUNITY
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The Lungs: Basic Defense
• Surface area of tennis court• Air volume: 10,000 L/day• Extremely thin membrane• Barrier defense mechanisms
– Filtration: nasopharynx, conducting airways– Sneezing and coughing– Mucociliary clearance
1. Wright, Jo Rae. "Immunoregulatory functions of surfactant proteins." Nature Reviews Immunology 5.1 (2005): 58-68.
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Pulmonary Immunity
• Innate Immunity– Toll-like receptors
• TLR2: S. pneumoniae– Adapter molecules
• IRAK4,MyD88: • S. pneumoniae, S. aureus
– Transcription factors• NF-kB: E. coli, S.
pneumoniae, multiple others– Central mediator of multiple
immune mechanisms1. Branger, Judith, et al. "Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice." Infection
and immunity 72.2 (2004): 788-794.2. Picard, Capucine, Jean-Laurent Casanova, and Anne Puel. "Infectious diseases in patients with IRAK-4, MyD88,
NEMO, or IκBα deficiency." Clinical microbiology reviews 24.3 (2011): 490-497.
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Pulmonary Immunity
• Innate Immunity– Mannose-binding lectin (MBL)
• Collectin protein family• Activation of lectin complement pathway• Most substantiated clinical role:
– Coexistent primary or secondary immune deficiency
1. Cedzynski, M., et al. "Mannan‐binding lectin insufficiency in children with recurrent infections of the respiratory system." Clinical & Experimental Immunology 136.2 (2004): 304-311.
2. Wright, Jo Rae. "Immunoregulatory functions of surfactant proteins." Nature Reviews Immunology 5.1 (2005): 58-68.
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Pulmonary Immunity
• Innate Immunity– Surfactant proteins
• SP-A and SP-D– Collectin protein family– Opsonize bacterial pathogens– Activate signaling cascades (TLR2, TLR4)
• Absent SP-D in BAL (limited data)– Associated with PBB– Increased frequency of pneumonia
1. Wright, Jo Rae. "Immunoregulatory functions of surfactant proteins." Nature Reviews Immunology 5.1 (2005): 58-68.2. Griese, M., et al. "Children with absent surfactant protein D in bronchoalveolar lavage have more frequently pneumonia."
Pediatric Allergy and Immunology 19.7 (2008): 639-647.
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Pulmonary Immunity
• Adaptive Immunity– Immunoglobulins
• Hypogammaglobulinemia and bronchiectasis– XLA, CVID, others
– IgG Subclasses• Concomitant role with other defects
– SAD, Selective IgA Deficiency
Mehr, Sam. "The Immunological Investigation of a Child with Chronic Wet Cough." Paediatric Respiratory Reviews 13.3 (2012): 144-149.
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Pulmonary Immunity• Adaptive Immunity
– Specific Antibody Deficiency (SAD)• Associated with recurrent respiratory infections• Documented in bronchiectasis (4% of cases)• Never investigated in PBB
– Memory B Cells• Deficiency associated with CVID, SAD• Associated with recurrent respiratory infections• Never investigated in PBB
1. Mehr, Sam. "The Immunological Investigation of a Child with Chronic Wet Cough." Paediatric Respiratory Reviews 13.3 (2012): 144-149.2. Leiva, Lily E., Hanh Monjure, and Ricardo U. Sorensen. "Recurrent Respiratory Infections, Specific Antibody Deficiencies, and Memory B
Cells." Journal of clinical immunology 33.1 (2013): 57-61.3. Chang, A. B., et al. "Non‐CF bronchiectasis: clinical and HRCT evaluation." Pediatric pulmonology 35.6 (2003): 477-483.4. Pasteur, Mark C., et al. "An investigation into causative factors in patients with bronchiectasis." American Journal of Respiratory and
Critical Care Medicine 162.4 (2000): 1277-1284.
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BACK TO THE BASICS
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Potential Pitfalls: Every Child Coughs
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Don’t Miss the Forest• Wet cough responding to antibiotics
– Common:• Sinusitis• Pneumonia
– Zebras:• Primary Immunodeficiency (1:1000)• Tuberculosis or atypical infection• Cystic fibrosis• Primary ciliary dyskinesia• Structural anomaly• Aspirated foreign body
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Diagnosing PBB: Old Methods• History:
– Young child, wet cough >4 weeks• Parental report of “wet cough” is accurate
– Complete resolution with antibiotics• Poor response to other therapies
• Physical Exam:– Chest ruttle (rattle) in most– Wheeze may be present
• Not the primary symptom1. Donnelly, Deirdre, Anita Critchlow, and Mark L. Everard. "Outcomes in children treated for persistent bacterial
bronchitis." Thorax 62.1 (2007): 80-84.2. Craven, Vanessa, and Mark L. Everard. "Protracted bacterial bronchitis: reinventing an old disease." Archives of
disease in childhood 98.1 (2013): 72-76.3. Chang, Anne B., et al. "Cough quality in children: a comparison of subjective vs. bronchoscopic findings." Respir
Res 6.3 (2005).
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Recommendations
• Approach to PBB– Antibiotics
• 2 week course• Cover common respiratory pathogens• Amoxicillin / clavulanic acid
– Two-thirds: recurrence– Half: symptom free following 2 courses
1. Donnelly, Deirdre, Anita Critchlow, and Mark L. Everard. "Outcomes in children treated for persistent bacterial bronchitis." Thorax 62.1 (2007): 80-84.
2. Kompare, Michelle, and Miles Weinberger. "Protracted bacterial bronchitis in young children: association with airway malacia." The Journal of pediatrics 160.1 (2012): 88-92.
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Recommendations
• Referral and evaluation:– Other concomitant infections– ≥ 2 episodes PBB in one year
• Allergy/Immunology and Pulmonology
Chang, A. B., G. J. Redding, and M. L. Everard. "Chronic wet cough: protracted bronchitis, chronic suppurative lung disease and bronchiectasis." Pediatric pulmonology43.6 (2008): 519-531.
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Recommendations
• Suggested Immunologic Workup– Complete Blood Count with differential– IgG, IgA, IgM, and IgE– Pneumococcal antibody titers
Mehr, Sam. "The Immunological Investigation of a Child with Chronic Wet Cough." Paediatric Respiratory Reviews 13.3 (2012): 144-149.
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Pediatric Wet Cough
RhinitisViral LRTI+/- RAD GERD
Wet Cough >4weeks
Resolved with antibiotics
(PBB)
RecurrenceOR
Other RedFlags
ZEBRAZONEWall, Luke MD
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FINAL THOUGHTS
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Info4PI.org
Arrows: indicators which may represent permanent morbidity or late findings
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Nelson Pediatrics. 18th ed. 2007
Arrows: indicators which may represent permanent morbidity or late findings
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Gibson, Peter G., Anne B. Chang, and Andrew S. Kemp. "CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement." Medical Journal of Australia 192.11 (2010): 672.
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Final Thoughts
• 12 year delay in diagnosis of PIDD• 32% with PIDD have permanent lung
impairment at time of diagnosis• 60-80% of adults with newly diagnosed
bronchiectasis: Wet cough since childhood
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Special Thanks• LSU Faculty and Children’s Staff
– Teaching me all things Pediatrics• Section of Allergy Immunology
– Teaching me all things A/I• A/I Fellows
– Showing me what I don’t know• Dr. Ricardo Sorensen
– Teaching me how to chase zebras• Dr. Derek Pepiak
– Keeping me from getting lost on the zebra chase• Wife and children, for their love, support and patience