Topic 3: Differential diagnosis of hereditary, congenital, and chronic disease of the
bronchopulmonary system in children.
Thematic chapter: Differential diagnosis of the most common respiratory tract diseases in
childhood. Emergency care in common emergency conditions.
Academic hours: 6
Self-education: 4
1. SIGNIFICANCE
Congenital and chronic disease of bronchial tree usually manifest in infancy or in childhood.
Some of them produce debilitating condition that potentially can be prevented in case of making
timely diagnosis. That is why it is important to remember that the most common case of cough
may not be only frequent respiratory viral infections or asthma, but illnesses with specific
organic structural changes in the broncho-pulmonary tree, much rare, including bronchomalacia
and tracheomalacia, α1-antitrypsin deficiency and emphysema, pulmonary hypoplasia,
pulmonary sequestration, bronchogenic cysts, lung hernia, pulmonary hemosiderosis, congenital
pulmonary lymphangiectasia.
However, the most prevalent cause of chronic pulmonary disease in children, after bronchial
asthma, is cystic fibrosis (CF). It takes a significant proportion of children who require long-term
support on the part of medical personnel, a large among of antibiotics and other treatments and
health related costs involved. The diagnosis of the disease can be easily obscured by a number of
CF like disease, that is why it is important to the student to familiarize with clinical and
laboratory presentation of the disease, make a clear differential diagnosis, and be aware of the
contemporary treatment protocols for CF.
2. PREREQUISITES
The skills listed below will not be taught in this lesson but are necessary to perform physical
examination of the patient practical training. Therefore, before beginning this lesson, one has to
be sure of the ability to:
 Inspect the thorax and its respiratory movements and note rate, rhythm, depth, and effort of
breathing;
 Inspect for retractions of the supraclavicular areas of contractions of the sternomastoid
muscles on respiration;
 Observe shape of child`s chest;
 Auscultate child`s breathing for increased white noise and wheezes;
 Palpate the chest for respiratory expansion, tactile fremitus;
 Percuss the chest in the standard areas, comparing one side with the other at each level;
 Auscultate the chest with stethoscope in order to evaluate breath sounds and not any
adventitious sounds.
3. EDUCATIONAL OBJECTIVES
Student should know:
- know the way of differential diagnosis between bronchomalacia and tracheomalacia, α1antitrypsin deficiency and emphysema, pulmonary hypoplasia, pulmonary sequestration,
bronchogenic cysts, lung hernia, pulmonary hemosiderosis, congenital pulmonary
lymphangiectasia, CF and other chronic bronchopulmonary diseases in infants and children.
Student should be able:
- to identify the child with bronchomalacia and tracheomalacia, α1-antitrypsin deficiency
and emphysema, pulmonary hypoplasia, pulmonary sequestration, bronchogenic cysts, lung
hernia, pulmonary hemosiderosis, congenital pulmonary lymphangiectasia, make correct
decisions during physical examination of the patient with given conditions, take appropriate
actions based on those decisions, demonstrate skills to develop management and follow up
measures.
4. INTERDISCIPLINARY INTEGRATION
Discipline
Normal anatomy,
Physiology
Student should know
Anatomic and physiologic
features of the respiratory
system in children of different
age groups
Biochemistry
Pathology
Pathologic physiology
Microbiology
Propedeutics of pediatric
diseases
Imaging studies
Intensive care
Student should be able to
Use knowledge of anatomic and
physiologic features of the
respiratory system in children
for evaluation of clinical
findings
Normal ranges for the routine
Assess blood biochemistry and
biochemical blood analysis
comment on deviations from
normal in a clinical context
Histologic and histochemical
Use knowledge of histologic
presentation of the respiratory
and histochemical presentation
tract illnesses in children
of the respiratory tract illnesses
in children for evaluation of
clinical findings
Pathophysiologic mechanisms of Recognize symptom and signs
the respiratory failure
of respiratory failure
Sampling of sputum, pleural
Assess microbiologic findings
excudate, blood for bacterial
in clinical context
cultures
Physical examination of the
Perform physical examination
respiratory system in children.
of the respiratory system (gross
Correct performance of
inspection, palpation,
pulmonary tests.
percussion, auscultation),
Assess the results of pulmonary
tests
Indications and methods of
Assess radiologic examination
imaging studies in respiratory
of the chest
tract illnesses
Symptoms and signs of
Recognize respiratory failure,
respiratory failure of different
assess its severity, provide
stages, its etiology, and
emergency care
principles of intensive care
5. ABSTRACT FOR PRE-WORKSHOP SELF-EDUCATION
1. Diffrenential diagnosis of chronic and inherited anomalies of pulmonary system
Bronchomalacia and
tracheomalacia
Primary tracheomalacia and bronchomalacia are principally disorders of
infants, with a male: female ratio of 2: 1.
The dominant finding, low-pitched monophonic wheezing, is most
prominent over the central airways.
Parents often describe persistent respiratory congestion even in the
absence of a viral respiratory infection.
When the lesion involves only one main bronchus (more commonly the
left), the wheezing is louder on that side.
In cases of tracheomalacia, the wheeze is loudest over the trachea.
Hyperinflation and/or subcostal retractions do not occur unless the patient
also has asthma or another cause of small airways obstruction.
In the absence of asthma, patients with tracheomalacia and
bronchomalacia are not helped by administration of a bronchodilator.
Acquired tracheomalacia and bronchomalacia are seen in association with
vascular rings (and may persist after surgical correction),
tracheoesophageal fistula, and cardiomegaly, and after lung
transplantation.
The definitive diagnosis of tracheomalacia and bronchomalacia is
established by flexible or rigid bronchoscopy.
Other important diagnostic modalities include MRI and CT scanning.
MRI is especially useful when there is a possibility of vascular ring and
should be performed when a right aortic arch is seen on plain film
radiography.
Cystic fibrosis
Α1-Antitrypsin
Deficiency and
Emphysema
See below
Little or no detectable pulmonary disease during childhood.
A few have early onset of chronic pulmonary symptoms, including
dyspnea, wheezing, and cough, and panacinar emphysema
It is probable that these findings occur secondarily to infection, causing
inflammation with consequent early disease.
Smoking greatly increases the risk of emphysema developing in mutant Pi
types.
Physical examination in childhood is usually normal.
It very rarely reveals growth failure, an increased anteroposterior diameter
of the chest with a hyperresonant percussion note, crackles if there is
active infection, and clubbing.
Severe emphysema can depress the diaphragm, making the liver and
spleen more easily palpable.
Serum immunoassay measures low levels of α1-antitrypsin; normal serum
levels are 180–280 mg/dL.
Serum electrophoresis reveals the phenotype, and genotype is determined
by polymerase chain reaction
Chest CT may show more hyperexpansion in the lower lung zones, with
occasional bronchiectasis.
Pulmonary
hypoplasia
Secondary to other intrauterine disorders that produce an impairment of
normal lung development
Deformities of the thoracic spine and rib cage (thoracic dystrophy),
pleural effusions with fetal hydrops, cystic adenomatoid malformation,
and congenital diaphragmatic hernia physically constrain the developing
lung.
Any condition that produces oligohydramnios (fetal renal insufficiency or
prolonged premature rupture of membranes) can also lead to diminished
lung growth.
Pulmonary hypoplasia involves a decrease in both the number of alveoli
and the number of airway generations.
The hypoplasia may be bilateral because of the presence of bilateral lung
constraint, as occurs in oligohydramnios or thoracic dystrophy.
Pulmonary hypoplasia is usually recognized in the newborn period due to
either the respiratory insufficiency or the presentation of persistent
pulmonary hypertension.
Later presentation (tachypnea) with stress or respiratory viral infection
can be seen in infants with mild pulmonary hypoplasia.
Pulmonary
sequestration
Area of dullness to percussion and decreased breath sounds over the
lesion.
During infection, crackles may also be present.
A continuous or purely systolic murmur may be heard over the back. If
findings on routine chest radiographs are consistent with the diagnosis,
further delineation is indicated before surgical intervention
CT with contrast can demonstrate both the extent of the lesion and its
vascular supply.
Magnetic resonance angiography (MRA) is also useful.
Ultrasonography can help rule out a diaphragmatic hernia and
demonstrate the systemic artery.
Surgical removal is recommended.
Intrapulmonary sequestration is generally found in a lower lobe
Patients usually present with infection.
In older patients, hemoptysis is common.
A chest radiograph during a period when there is no active infection
reveals a mass lesion; an air-fluid level may be present.
During infection, the margins of the lesion may be blurred.
Bronchogenic cysts
Fever, chest pain, and productive cough are the most common presenting
symptoms.
Dysphagia may be present; some bronchogenic cysts are asymptomatic.
A chest radiograph reveals the cyst, which may contain an air-fluid level
CT scan or MRI is obtained in most cases to better demonstrate anatomy
and extent of lesion before surgical resection.
Treatment of symptomatic cysts is surgical excision after appropriate
antibiotic management.
Symptomatic cysts are generally excised in view of the high rate of
infection
Lung hernia
Cervical hernia (“Sibson hernia”) is usually a neck mass noticed while
straining or coughing.
Some lesions are asymptomatic and detected only when a chest film is
taken for another reason.
Findings on physical examination are normal except during Valsalva
maneuver, when a soft bulge may be noticed in the neck. In most cases,
no treatment is necessary.
These hernias may cause problems, however, during attempts to place a
central venous catheter through the jugular or subclavian veins.
Spontaneous resolution can occur.
Paravertebral or parasternal hernias are usually associated with rib
anomalies.
Intercostal hernias usually occur parasternally, where the external
intercostal muscle is absent
Straining, coughing, or playing a musical instrument may have a role in
causing intercostal hernias, but in most cases, there is probably a preexisting defect in the thoracic wall.
Pulmonary
hemosiderosis
Hemorrhage may be significant without remarkable symptomatology.
Hemoptysis may not occur.
Bleeding may occasionally be recognized by the presence of alveolar
infiltrates on a chest radiograph.
It should be noted that the absence of an infiltrate does not rule out an
ongoing hemorrhagic process.
Wheezing, cough, dyspnea, and alterations in gas exchange, reflecting
bronchospasm, edema, mucous plugging, and inflammation.
On physical examination, the patient may be pale with tachycardia and
tachypnea.
During an acute exacerbation, children are frequently febrile.
Examination of the chest may reveal retractions and differential or
decreased aeration, with crackles or wheezes.
The patient may present in shock with respiratory failure from massive
hemoptysis.
Children in particular may present with symptoms of chronic anemia,
such as failure to thrive.
Pulmonary hemorrhage is associated with a decrease in hemoglobin and
hematocrit. The classic finding is a microcytic, hypochromic anemia. The
reticulocyte count is elevated
White blood count and differential should be evaluated for evidence of
infection and eosinophilia.
A stool specimen can be heme-positive secondary to swallowed blood.
Renal and liver function should be reviewed. A urinalysis should be
obtained to assess for evidence of nephritis.
A coagulation profile, quantitative immunoglobulins (including IgE), and
complement studies are recommended.
Testing for antinuclear antibody (ANA), anti–double stranded DNA,
rheumatoid factor, antiphospholipid antibody, and anti–glomerular
basement membrane antibody (antiGBM) evaluates for a number of
primary and secondary etiologies of DAH.
Sputum or pulmonary secretions should be analyzed for significant
evidence of blood or hemosiderin-laden macrophages (HLM).
Congenital
pulmonary
lymphangiectasia
Children with pulmonary venous obstruction or severe pulmonary
lymphangiectasia present with dyspnea and cyanosis in the newborn
period.
Chest radiographs reveal diffuse, dense, reticular densities with
prominence of Kerley B lines.
If the lung is not completely involved, the spared areas appear
hyperlucent.
Respiration is compromised because of impaired diffusion and decreased
pulmonary compliance.
The diagnosis can be suggested by CT scan and cardiac catheterization;
definitive diagnosis requires lung biopsy (either thoracoscopic or open).
2. Cystic fibrosis.
Abnormal CFTR gene in 1:of 25 individuals in the Caucasian population. Incidence of
cystic fibrosis 1:2500 in Caucasian population. 1:17,000 in African-American population (rarely
seen in African blacks and Asians).
Etiology.
 The most common severe inherited disease in the Caucasian population (autosomal recessive
in inheritance).
 Cystic fibrosis transmembrane regulator (CFTR): functions as a cyclic AMP-activated
 chloride channel, which allows for the transport of chloride out of the cell. It is accompanied
by the passive passage of water, which keeps secretions well hydrated.
 In cystic fibrosis, an abnormality in CFTR blocks chloride transport and inadequate
hydration of the cell surface results in thick secretions and organ damage.
 The CFTR gene is 250,000 base pairs long and located on the long arm of chromosome
7.The most common deletion is three base pairs, which results in the absence of phenylalanine
at codon 508 (seen in over 70% of the cystic fibrosis population in North America).
Clinical presentation.
Symptoms.
 Chronic cough, recurrent pneumonia, bronchorrhea, nasal polyps, and chronic pansinusitis.
 Pancreatic insufficiency: occurs in 85% of patients. Fat malabsorption may lead to failure to
thrive or pancreatitis.
 Rectal prolapse: occurs in 2% of the patients.
 Meconium ileus: 15%–20% of patients present with this symptom.
 Distal obstruction: of the large intestine may be seen in older children.
 Hyponatremic dehydration.
 Hypochloremic metabolic alkalosis.
Signs.
 Cough (frequently productive of mucopurulent sputum), rhonchi, rales, hyper-resonance to
percussion, nasal polyps, and cyanosis (in later stages).
 Digital clubbing, hepatosplenomegaly in patients with cirrhosis, growth retardation,
hypertrophic osteoarthropathy, and delayed puberty, amenorrhea, irregular menstrual periods
(in teenage patients).
Laboratory work-out.

Sweat test: “gold standard” for the diagnosis of cystic fibrosis (CF). Sweat chloride >60
mEq/L is considered abnormal. False positives are seen in severe malnutrition, ectodermal
dysplasia, adrenal insufficiency, nephrogenic diabetes insipidus, hypothyroidism,
hypoparathyroidism, mucopolysaccharidoses. False negatives are seen in patients with edema
and hypoproteinemia.

Genetic testing: over 600 identified CF genotypes, but only 20–70 of the most common are
tested; thus, the lack of a positive genotype reduces (but does not eliminate) the possibility that
a CF sample can be obtained from blood or buccal cell scraping. Sputum cultures: frequent
pathogens include Staphylococcus aureus, Pseudomonas aeruginosa (mucoid and nonmucoid),
Burkholderia cepacia.

Pulmonary function tests: usually reveal obstructive lung disease.

Pancreatic function tests: 72-hour fecal fat measurement, measurement of serum paraaminobenzoic acid (PABA) levels, stool trypsin levels, serum immunore-active trypsin (IRT).

Chest radiography: typical features include hyperinflation, peribronchial thickening,
atelectasis, cystic lesions filled with mucus, and bronchiectasis.

Sinus radiography: typically shows pansinusitis.
Complications.
 Respiratory: recurrent bronchitis and pneumonia, chronic sinusitis, pneumothorax,
hemoptysis
 Gastrointestinal: include pancreatic insufficiency; patients usually have steatorrhea;
decreased levels of vitamins A, D, E and K; poor growth and failure to thrive; meconium ileus
equivalent; rectal prolapse; and clinically significant hepatobiliary disease (cirrhosis of the
liver, esophageal varices and splenomegaly).


Reproductive: include sterility in 98% of males and 75% of females.
Endocrine: abnormal glucose tolerance; diabetes mellitus.
Differential diagnosis.
 Pulmonary: recurrent pneumonia, chronic bronchitis, immotile cilia syndrome, severe
asthma, aspiration pneumonia.
 Gastrointestinal: gastroesophageal reflux, celiac sprue, protein-losing enteropathy.
 Other: Failure to thrive (secondary to neglect, poor caloric intake or feeding problems).
Immune deficiency syndromes. Nasal polyposis. Male infertility. Hyponatremic dehydration.
Treatment aims
 To maintain good nutritional status (good nutrition is associated with a better prognosis).
 To slow pulmonary deterioration as much as possible.
 To maintain a normal lifestyle.
Treatment.
High calorie diet with nutritional supplements (given orally, via nasogastric tube feedings or
through gastrostomy tube feeding). Vitamin supplements: multivitamins and fat soluble vitamin
replacement (usually E and K).
Pancreatic enzyme-replacement therapy can be used in patients who are pancreatic
insufficient. Dosage is adjusted for the frequency and character of the stools and for growth
pattern.
Stool softeners treat constipation or meconium ileus equivalent and include mineral oil, oral
N-acetylcysteine, lactulose, enemas.
Pharmacologic treatment.
 Antibiotic therapy (based on sputum culture results). Oral antibiotics: cephalexin, cefaclor,
trimethoprim-sulfamethoxazole, chloram-phenicol, ciprofloxacin. Intravenous antibiotics
(given for 2–3-week course): Staphylococcus aureus: oxacillin, nafcillin; Pseudomonas
aeruginosa or Burkholderia cepacia: semisynthetic penicillin (ticarcillin, piperacillin) or a
cephalosporin (ceftazidime) plus an aminoglycoside (gentamicin, tobramycin, or amikacin) to
obtain synergistic action.
 Aerosolized bronchodilator therapy: albuterol
 Mucolytic agents: N-acetyl-cysteine, recombinant DNase.
 Chest physiotherapy with postural drainage.
Prognosis
 Long-term prognosis is poor.
 The course of the illness is variable; it is impossible to predict the course of
 the disease in a specific person.
 The current mean life span is 29 years.
 Due to new antibiotics, enzyme-replacement therapy, and maintenance of good pulmonary
toilet with chest physiotherapy and bronchodilators, the mean age of survival has been
increasing for the past three decades.
Follow-up and management
• Routine care should be at a Cystic Fibrosis Center.
• Frequency of visits is dependent on severity of illness: usually every 2–4 m.
• Usually lifelong nutritional support is required.
• Duration of antibiotic therapy is controversial. Chronic use is eventually required as the
patient’s pulmonary function deteriorates.
• All siblings should have a sweat test
6. MATERIALS FOR METHODOLOGICAL BACKGROUND OF THE WORKSHOP
6.1. Quiz
1. What is the diagnosis and differential diagnosis for bronchomalacia and tracheomalacia?
2. What is the diagnosis and differential diagnosis for α1-antitrypsin deficiency and
emphysema?
3. What is the diagnosis and differential diagnosis for pulmonary hypoplasia?
4. What is the diagnosis and differential diagnosis for pulmonary sequestration?
5. What is the diagnosis and differential diagnosis for bronchogenic cysts?
6. What is the diagnosis and differential diagnosis for lung hernia?
7. What is the diagnosis and differential diagnosis for pulmonary hemosiderosis?
8. What is the diagnosis and differential diagnosis for congenital pulmonary
lymphangiectasia?
9. Define CF
10. What is the epidemiology of the disease?
11. In which population one may encounter the most severe cases of CF?
12. What is disorder seen in CF patients?
13. What is pathophysiology of the disease?
14. Why does the mucus become dense in CF?
15. What does CFTR gene represent?
16. What pulmonary changes are seen in CF?
17. What are the symptoms in CF?
18. What are the signs of pancreatic insufficiency in children with CF?
19. What is the clinical presentation of meconium ileus?
20. How will you treat hyponatremic dehydration in patient with CF?
21. How will you treat hypochloremic metabolic alkalosis in a patient with CF?
22. What are the signs of pulmonary involvement in CF?
23. What findings can be expected after the examination of the abdominal cavity of the
patient with CF?
24. What is the gold laboratory standard for making the diagnosis of CF?.
25. Which level of sweat chloride we consider as pathologic?
26. In which clinical circumstances we may expect false positive results of sweat chloride
test?
27. In which clinical circumstances we may expect false negative results of sweat chloride
test?
28. Which pathegens are most commonly cultered from the sputum?
29. What do pulmonary tests usually reveal in CF?
30. What are the laboratory tests to check pancreatic function?
31. What are the findings on X-ray in CF patients?
32. What are respiratory complications of CF?
33. What are gastrointertinal complications of cystic fibrosis
34. What is the differencial diagnosis in CF?
35. What are the treatment aims in CF?
36. Describe diet therapy in CF?
37. List pancreatic enzymes preparations you would employ in CF?
38. What stool softeners do you knwp?
39. What is antibiotic therapy in CF?
40. What is the prognosis in CF?
6.2. Multi-choice questions
A 14 year old girl was complaining on decreased exercise tolerance during sport classes and
intermittent breathlessness. Chest radiography showed a homogenous soft tissue mass at right
lower lobe of the lung. Thoracic echocardiography showed normal cardiac structure. As the
mother mentioned that the family is positive for hereditary hemorrhagic teleangiectasia, doctor
directly send a girl for computer tomography pulmonary angiogram. What is the most common
finding in this case?
1.
2.
3.
4.
5.
Pulmonary sequestration
Bronchogenic cyst
Pulmonary arteriovenous malformation*
Pulmonary embolism
Pnumonia
6.3. Sample case report
A 6 years old female child from a poor socioeconomic status family, born of a non
consanguineous marriage presented with cough, respiratory difficulty, recurrent hemoptysis and
pallor with easy fatigability beginning at the age of four years. There was no history of recurrent
fever, skin lesions, bleeding from any other site, arthritis, bone pain, significant drug intake or
prolong exposure to toxin. Her appetite, bladder & bowel habits were normal. She had received
antibiotics, bronchodilators treatment along with iron prophylaxis and total six blood
transfusions. At the time of admission the child had marked pallor, respiratory distress,
tachypnea (respiratory rate = 46/min) and tachycardia (pulse = 120/min). Other vital parameters
were normal. Her weight was 15 kg and height was 105.5 cm. Examination of chest revealed
crepitations bilaterally. Other examination findings were normal. On investigation hemoglobin
was 4.6gm% with hypochromic microcytic anemia, total leukocyte count was 8700/cumm
(polymorph 58%, lymphocyte 30%, eosinophil 07%, monocyte 03%), platelets were adequate,
serum ferritin level was low (4mg/l), total iron binding capacity was 500 mg/dl (Normal = 250400 mg/dl) suggestive of iron deficiency anemia. Clotting time, prothombin time, activated
partial thromboplastin time, liver function test, renal function test were normal. Antinuclear
antibody (ANA), anti neutrophil cytoplasmic antibody (ANCA) and Mantoux test were negative.
Chest radiograph revealed bilateral pulmonary infiltrate. CT scan sowed bilateral ground glass
opacity. Bronchoalveolar lavage demonstrated significant number of hemosiderin-loaded
macrophages. As no cause was identified the child was diagnosed as idiopathic pulmonary
hemosiderosis. The patient was given blood transfusion and oral prednisolone in the dose of 2
mg/kg along with iron. Her condition improved after 7 days of therapy. After 1 month of
treatment, chest radiograph was clear and there was no further hemoptysis for last 6 months.
1. What is the diagnosis?
2. What is the differential diagnosis?
3. What are the characteristic laboratory tests?
Suggested reading
1. James W. Shroeder Jr. and Lauren D. Holinger. Congenital anomalies of the larynx,
trachea, and bronchi / in Nelson Textbook of Pediatrics, 2-Volume Set, 20th ed. by
Kliegman R.M., Bonita M.D. Stanton MD, Geme J.S., Nina F Schor MD / Elsevier Inc.,
2016. P. 2036-2039.
2. Joshua A. Blatter and Jonathan D. Finder. Congenital disorders of the lung / in Nelson
Textbook of Pediatrics, 2-Volume Set, 20th ed. by Kliegman R.M., Bonita M.D. Stanton
MD, Geme J.S., Nina F Schor MD / Elsevier Inc., 2016. P. 2057-2061.
3. Anne G. Griffiths and Thomas P. Green. Chronic or reccurent respiratory sympthoms / in
Nelson Textbook of Pediatrics, 2-Volume Set, 20th ed. by Kliegman R.M., Bonita M.D.
Stanton MD, Geme J.S., Nina F Schor MD / Elsevier Inc., 2016. P. 2027-2031.
4. Susanna A. McColley. Extrapulmonary diseases with pulmonary manifestations / in
Nelson Textbook of Pediatrics, 2-Volume Set, 20th ed. by Kliegman R.M., Bonita M.D.
Stanton MD, Geme J.S., Nina F Schor MD / Elsevier Inc., 2016. P. 2055-2057.
Additional reading
1. Brenda B. Poindexter, Alan H. Jobe et.al. The diagnostic Conundrum of
Bronchopulmonary Dysplasia // The Journal of Pediatrics, Vol. 167, Issue 3,(2014) p517518.
2. Tom Watson, Catherine M. Owens et.al. Computer tomography in children with lung
disease, How, when and why? Myths and mystery unraveled // Pediatrics and Child
Health, Vol. 23, Issue 3, (2013) p125-132.
3. Diana L. Diesen, Steve Megison et.al. Congenital Diaphragmatic Hernia with Associated
Pulmonary Sequestration // The Journal of Pediatrics, Vol. 167, Issue 3,(2014) p517-518.