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a r t i c l e i n f o a b s t r a c t
Article history: The Japanese Guideline for the Diagnosis and Treatment of Allergic Diseases 2017 (JAGL 2017) includes a
Received 6 September 2016 minor revision of the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012
Available online 18 January 2017 (JPGL 2012) by the Japanese Society of Pediatric Allergy and Clinical Immunology. The section on child
asthma in JAGL 2017 provides information on how to diagnose asthma between infancy and adolescence
Keywords: (0e15 years of age). It makes recommendations for best practices in the management of childhood
Acute exacerbation
asthma, including management of acute exacerbations and non-pharmacological and pharmacological
Anti-inflammatory drugs
management. This guideline will be of interest to non-specialist physicians involved in the care of
Childhood asthma
Guideline
children with asthma. JAGL differs from the Global Initiative for Asthma Guideline in that JAGL em-
Long-term management phasizes diagnosis and early intervention of children with asthma at <2 years or 2e5 years of age. The
first choice of treatment depends on the severity and frequency of symptoms. Pharmacological man-
agement, including step-up or step-down of drugs used for long-term management based on the status
of asthma control levels, is easy to understand; thus, this guideline is suitable for the routine medical
care of children with asthma. JAGL also recommends using a control test in children, so that the physician
aims for complete control by avoiding exacerbating factors and appropriately using anti-inflammatory
drugs (for example, inhaled corticosteroids and leukotriene receptor antagonists).
Copyright © 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Definition and pathophysiology of childhood asthma asthma, childhood asthma is pathologically characterized by
(Fig. 1) chronic airway inflammation1,2 and airway wall remodeling.3e7
Childhood asthma causes recurrent dyspnea accompanied by Chronic airway inflammation is caused by the activation of eo-
paroxysmal whistling/wheezing. The dyspnea is spontaneously or sinophils, mast cells, and lymphocytes and by airway mucosal
therapeutically remitted or cured and rarely lethal. Like adult damage. The viewpoint that asthma is a condition of chronic
inflammation has an important implication for asthma treatment
and management. It is fundamental to understand the necessity of
*
anti-inflammatory drugs for basic treatment of persistent asthma.
This article is an updated version of “Japanese guideline for childhood
asthma 2014” published in Allergol Int 2014:63:335e56. Many aspects of airway wall remodeling, which may influence the
* Corresponding author. Department of Pediatrics, Gunma University Graduate prognosis of asthma, are still unknown, including its causes, onset
School of Medicine, 39-22 Showa-machi 3-chome, Maebashi, Gunma 371-8511, time, and effects of anti-inflammatory treatment. Airway hyper-
Japan. responsiveness, which is a clinical characteristic of asthma, is
E-mail address: harakawa@gunma-u.ac.jp (H. Arakawa).
intensified by airway epithelial damage due to airway
Peer review under responsibility of Japanese Society of Allergology.
http://dx.doi.org/10.1016/j.alit.2016.11.003
1323-8930/Copyright © 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
H. Arakawa et al. / Allergology International 66 (2017) 190e204 191
mine or methacholine. Exercise-induced asthma (EIA) is also 1. Respiratory functions: spirogram, flow volume curve, peak flow (PER) rate,
associated with airway hyper-responsiveness. and reactivity and reversibility for b2 stimulants
2. Airway hyper-responsiveness test: acetylcholine and histamine thresholds
and exercise stress test
3. Data indicating airway inflammation: eosinophils, mast cells (basophils) in
2. Diagnosis and differential diagnosis of childhood asthma rhinorrhea and sputum, and concentration of nitric oxide (FeNO) in exhaled
The typical symptoms of asthma are dyspnea accompanied by breath
whistling/wheezing, coughing, and chest tightness. Expiratory 4. IgE: total serum IgE level, specific IgE antibody, immediate skin response, and
dyspnea occurs mainly during asthma exacerbation. As symptoms antigen inhalation test
5. Family and patients' past histories of allergic diseases
progress, however, inspiratory dyspnea may coexist. If such
symptoms recur, it is reasonable to diagnose symptomatic asthma.
However, some patients present with misleading symptoms.
Table 1 summarizes the physiological and immunological exami- Table 2
nations and allergy tests that may support the accuracy of Differential diagnosis.
diagnosis. Anomalies Others
Chest vascular malformation Hypersensitive pneumonitis
Congenital heart diseases Bronchial foreign bodies
2.1. Differential diagnosis Anomalies of airway Psychogenic cough
Laryngomalacia Vocal cord dysfunction
The differential diagnosis of asthma in children is shown in
Bronchomalacia Compression of airway
Table 2. Children with wheezing symptoms, particularly those with Tracheomalacia Pulmonary edema
acute wheezing, must be differentially diagnosed. In infants, an Immotile cilia syndrome Allergic bronchopulmonary
accumulation of secretion in the lower respiratory tract resulting Infection aspergillosis
from conditions such as bronchitis, bronchiolitis, or pneumonia Nasopharyngitis, sinusitis Cystic fibrosis
Croop (acute laryngitis) Sarcoidosis
may cause recurrent episodes of wheezing. In addition, recurrent Pulmonary embolism
Bronchitis
wheezing can be seen in children with complications of underlying
Bronchiolitis
conditions such as congenital anomalies (for example, vascular Pneumonia
ring), immotile cilia syndrome, gastroesophageal reflux disease, Bronchiectasis
and congenital heart disease. Pulmonary tuberculosis
Table 3
Asthma prevalence rate in Japan.
children with a family history of allergic diseases. Children with a Sixty percent of children who have had wheezing before age 6
higher body mass index (>90th percentile) have a higher preva- experience no more wheezing after 6 years of age. On the other
lence of asthma from infancy to adolescence.12 The prevalence of hand, it was demonstrated that 52e72% of children diagnosed as
childhood asthma in Japan is ranked at the middle of various asthmatic at the age of 6 have asthma symptoms at 22 years of
countries throughout the world. age.14,15
Table 4
Intensity of asthma exacerbation.
Daily life Speech Pause after one sentence Pause after phrases Pause after one word Impossible
Feeding Almost normal Slightly difficult Difficult Impossible
Sleep Can sleep Occasionally wake up Disturbed Disturbed
There are several criteria. It is not required that all criteria be met.
As intensity of exacerbation increases, infants present with seesaw breathing, not shoulder breathing. During expiration and inspiration, distention and depression of the chest
and abdomen repeat like a seesaw. Exclude intentional abdominal breathing.
y
Difficult to determine during tachypnea. During severe exacerbation, the expiratory phase is at least twice longer than the inspiratory phase.
and excessive dependence on pressurized metered-dose inhalers failure. It is based on the degree of impairment of respiratory
(pMDI) of short-acting b2 agonists of the severity of exacerbation status and the activities of daily life such as eating, speaking,
can also lead to death. sleeping, and exercising (Table 4). Because infants cannot
To reduce the number of deaths from asthma, early and accurate complain of dyspnea themselves, the intensity of exacerbation in
diagnosis and treatment is necessary, and patients should be thor- them is determined on the basis of objective findings. Ill-temper,
oughly educated. Instructions about the appropriate use of pMDI of vomiting, screaming, and difficulty sleeping unless held by the
short-acting b2 agonists against acute exacerbation, early and com- mother are important interview items for identifying severe
plete anti-inflammatory therapy with inhaled corticosteroids, and exacerbation (Table 5).
adherence to asthma management are particularly important. Supportive indications of the intensity are determined by oxy-
gen saturation (SpO2) measured using a pulse oximeter and peak
4. Management of acute asthma exacerbation expiratory flow (PEF) measured using a spirometer. However,
4.1. Intensity of asthma exacerbation because SpO2 varies widely among infants compared with school
The intensity of asthma exacerbation is classified into four children, caution is needed in the use of SpO2 to evaluate the in-
stages: mild, moderate, and severe exacerbations and respiratory tensity of exacerbation in infants.
194 H. Arakawa et al. / Allergology International 66 (2017) 190e204
Table 5 receive the inhalation again 20e30 min later. Inhalation can be
Symptoms during severe exacerbation in infantile asthma. repeated up to three times. When a favorable response is obtained
1. Severe cough (with occasional 8. Inability to sleep after the initial treatment, the patient should be observed for an
vomiting) 9. Cyanosis additional hour. If asymptomatic then, the patient is given in-
2. Marked wheezing (occasionally 10. Moaning structions about future treatment and allowed to go home. If no
reduced) 11. Tachycardia
3. Depression of suprasternal space 12. Ill-temper
remission is achieved after two or more inhaled b2 agonists, an
and supraclavicular fossa and be- 13. Scream additional treatment will be conducted. Infants should be treated
tween ribs 14. Lowered level of consciousness after hospitalization. Additional treatment for moderate exacer-
4. Tachypnea bation includes a steroid and/or aminophylline administration,
5. Nasal alar breathing
although aminophylline should be used with caution to prevent
6. Seesaw breathing
7. Comfort when held upright adverse effects. If additional treatment results in an unfavorable
(orthopnea) response or exacerbates symptoms, the patient should be treated
after hospitalization.
(1) Steroids are administered via an intravenous or oral route
(see Table 6 for initial and maintenance doses). Even in pa-
4.2. History taking in the outpatient department tients with moderate exacerbation, an intravenous steroid
In the outpatient department, the intensity, duration, and cause should be considered for early treatment if they are patients
of exacerbation must be assessed. The patient's previous history of (i) at step 3 or above for stepwise management, (ii) with a
exacerbation and medical treatment on such occasions should also history of hospitalization owing to asthma exacerbation
be evaluated before a treatment plan is determined. within the past year, or (iii) with a history of endotracheal
intubation for the treatment of extremely severe asthma
exacerbation.
4.3. Treatment of acute exacerbation in outpatient
(2) Aminophylline is not recommended for the patients shown
departments (Fig. 4)
in Table 7, because unequivocal indications for aminophylline
Treatment strategies of mild exacerbation. An inhaled b2 agonist
treatment are difficult to secure.
(salbutamol or procaterol: 0.1e0.3 mL to infants or 0.3e0.5 mL to
school children or adolescents, diluted in 2 mL of physiological
saline or disodium cromoglycate inhalant solution; 1
ampule ¼ 2 mL) can be administered using a nebulizer. When 4.4. In-hospital treatments and procedures
cough and wheezing disappear, and SpO2 or PEF rates become Criteria for in-hospital treatment are shown in Table 8.
97% or 80% of predicted values and/or personal best, respec- Treatment strategies of severe exacerbation. An inhaled b2 agonist
tively, 15e30 min after the inhalation, the patient can go home. If a is administered with a nebulizer along with oxygen inhalation. An
mild cough and wheezing remain even after the inhalation, an initial transfusion is performed along with intravenous steroid
additional inhaled b2 agonist is administered 20e30 min later. If administration (Table 6). Aminophylline can be administered
there is an inadequate response or even exacerbation of symptoms concomitantly. However, caution should be used in patients aged
in response to the b2 agonist, an additional treatment should be 0e2 years (Table 9). If symptoms markedly improve, the patient is
conducted equivalent to that for moderate exacerbation. observed every 4e6 h while receiving inhaled b2 agonists and
Treatment strategies of moderate exacerbation. An inhaled b2 maintenance transfusion. If needed, repeated glucocorticosteroid
agonist can be administered using a nebulizer driven by oxygen in administration and continuous intravenous aminophylline infusion
patients with <95% SpO2. Patients with an insufficient response can are concomitantly conducted. If exacerbation does not show any
Fig. 4. Treatment for acute exacerbation in hospital (2e15 years old). Weak exacerbation usually responds to b2 inhalation at home.
H. Arakawa et al. / Allergology International 66 (2017) 190e204 195
Table 6 Table 10
Formulas for glucocorticosteroids. Continuous inhalation therapy with b2 agonist.
Table 7
Patients with moderate exacerbation for whom aminophylline administration is not
advisable (2e15 years old).
improvement at 30 min after the start of treatment, additional
treatments are considered. Continuous isoproterenol (e.g., Asthpul)
1. Patients with a history of convulsions or with complications of CNS disease.
inhalation can be conducted.17e19 During this treatment, parame-
2. Caution should be taken in treatment of the following patients whose serum
theophylline levels cannot be quickly measured. ters such as blood pressure, heart rate, respiratory rate, and SpO2
(a) Patients with a history of adverse effects caused by aminophylline or should be monitored. The continuous inhalation is usually very
theophylline. effective, and effects can be observed within 30 min. Intravenous
(b) Patients periodically receiving sustained-release theophylline, with serum glucocorticosteroid administration is carried out periodically
theophylline level maintained at >15 mg/mL.
(Table 6) and can be stopped within several days after recovery
(c) Patients for whom it is difficult to determine the safety of intravenous
aminophylline infusion, because of above, or the use status of theophylline (Table 10).
is unclear.
4.5. Treatment of respiratory failure
Patients with respiratory failure require intensive care with the
Table 8 assistance of emergency specialists and anesthesiologists. Respi-
Indications for hospital admission. ratory failure results in the alleviation and disappearance of
1. Severe exacerbation and respiratory failure wheezing and causes severe cyanosis. In addition, it may be
2. Moderate exacerbation accompanied by urinary and fecal incontinence and unconscious-
- Past history of severe exacerbation ness. Arterial blood gas analysis is needed to assess respiration
- Not improved by ambulatory treatment for about 2 h
- Moderate exacerbation, continuing from the previous day and accompanied
status, and the presence of complications (such as subcutaneous
by sleep disturbance emphysema, mediastinal emphysema, atelectasis, pneumonia, and
(Hospitalize patients who are younger than 2 years old) pneumothorax) to preclude treatment has to be carefully assessed.
3. Complications Although there is no definite indication for artificial respiratory
- Pneumonia, atelectasis, mediastinal emphysema, subcutaneous
management, it should be considered when one or more of the
emphysema, pneumothorax, etc.
following signs are apparent: (1) reduced respiratory sounds and
wheezing in the presence of cyanosis, (2) impaired consciousness
resulting in somnolence or coma; (3) <60 mmHg PaO2 (<90% SpO2)
even after sufficient oxygen inhalation; and (4) elevated PaCO2
(65 mmHg or 5 mmHg/h).
Table 9
Cautions against aminophylline administration for patients younger than 2 years
The usefulness of noninvasive positive ventilation is still under
old. investigation for childhood asthma.
1. If b2 stimulants or steroids are not effective for severe exacerbation or
respiratory failure, theophylline should be prescribed by a specialist. 4.6. Complications with acute asthma exacerbation
2. Do not prescribe theophylline for the patients with convulsive disorders, such Air leak syndromes such as mediastinal emphysema, subcu-
as febrile convulsions and epilepsy. taneous emphysema, and pneumothorax are major complications
3. If there is fever, carefully refer to indications.
with acute exacerbation. Patients with pneumothorax complain of
4. Determine dosage based on 10 mg/mL of serum level. Monitor serum level as
needed. Adjust dosage as needed, with an upper limit of 15 mg/mL. chest pain that worsens with exertion and deep respiration. Cough
5. Theophylline clearance is reduced by fever, viral infection, foods, concomitant and dyspnea are often observed. Leaked air is usually absorbed
drugs, etc. In some cases, serum levels are elevated. spontaneously. In acute asthma exacerbation, airway obstruction
often occurs with airway constriction, mucus hypersecretion and
196 H. Arakawa et al. / Allergology International 66 (2017) 190e204
Mild persistent Cough and/or mild wheezing; more than 1/ 5.3. Control level
month, less than 1/week
Control levels are determined by symptoms, interference with
Sometimes dyspnea also, but it does not
continue for long enough to disturb daily life daily activities, and frequency of using inhaled b2 agonists
(Table 14).
Moderate persistent Cough and/or mild wheezing; more than 1/
week, but not everyday
Sometimes progresses to moderate to severe 5.4. Control of asthma
exacerbation, and disturbs daily life This guideline intends to help non-specialist physicians to aim
Severe persistent Cough and/or mild wheezing occurs everyday at reaching the level of complete control in asthma treatment and
Moderate to severe exacerbation occurs 1e2/ management. Important factors to attain this goal are appropriate
week, disturbing daily life and sleep
use of anti-inflammatory drugs, elimination of environmental risk
Most severe persistent (sub- Asthma symptoms continue despite the factors, and educational and enlightening activities for patients
group of severe persistent) treatment for severe persistent asthma.
and caregivers regarding adequate asthma management in daily
Frequent asthma exacerbation requiring
treatment at ER and hospitalization.
life. The first factor is the most efficient and effective strategy
Daily life is disturbed to a large extent. along with the recent development of anti-inflammatory drugs for
chronic airway inflammation. Favorable control can be achieved
by selecting an appropriate step based on asthma severity.
However, insufficient treatment, inappropriate drugs, and un-
avoidable exacerbation factors result in poor control. The asthma
submucosal edema, resulting in pulmonary atelectasis in bronchi
control test was devised for the evaluation of control levels, which
and alveoli of the lung. Atelectasis is most often observed in the
would help to adjust treatment and management toward favor-
right middle lobe as a silhouette sign on chest radiography. A
able control.
computed tomography scan is more helpful for diagnosis. Treat-
ment of asthma exacerbation is the highest priority. Postural
drainage, physical therapy, and administration of expectorants may 5.5. Evaluation methods of asthma control levels
be helpful. (1) Asthma diary. A diary kept by a patient would be useful for
doctors to gain access to the information pointing to asthma
control through the patient's own description of respiratory
5. Basics of long-term management of childhood asthma symptoms and daily activities such as sleeping, eating, and
5.1. Severity determination exercising. The information about drug use and the values of
Asthma severity is classified into four levels: intermittent, mild peak flow meter monitoring would also be important for the
persistent, moderate persistent, and severe persistent, including evaluation of control. In addition, assessment of respiratory
most severe persistent as a subgroup. functions using a spirometer is important.
The severity of disease in patients not taking long-term man- (2) Childhood Asthma Control Test (C-ACT).20 The C-ACT is used in
agement drugs is shown in Table 11. If long-term management many countries for children aged 4e11 years. The test con-
drugs are already administered, the “true” severity is determined sists of seven questions, the first four of which are answered
under consideration of the present treatment step (Table 12). For by the children with asthma and the remaining three
example, if the “apparent” severity in a patient being treated at step answered by their parents. The first four questions use a
2 is mild persistent, the “true” severity is determined as their faces scale to allow children to answer them easily. Scoring is
intersection point, i.e., moderate persistent asthma. In patients with as follows: 27, 20, and <20 points indicate complete,
symptoms not controlled at step 4, whose “apparent” severity is favorable, and poor control, respectively. For children aged
moderate or severe persistent, the “true” severity is determined as 12 years, the Asthma Control Test (ACT) for adults can be
the most severe persistent asthma. used.
Comparison of asthma severity between children and adults (3) Japanese Pediatric Asthma Control Program (JPAC).21 Severity
demonstrates one-level differences; intermittent, mild persistent, and control status can be assessed using the JPAC program. It
and moderate persistent in adults correspond to mild persistent, allows the selection of treatment step according to this
moderate persistent, and severe persistent in children, respectively. guideline. Step-up and step-down may also be determined.
Table 12
How to determine true asthma severity in patients under treatment with anti-asthma drugs.
Intermittent asthma Intermittent asthma Mild persistent Moderate persistent Severe persistent
Mild persistent asthma Mild persistent Moderate persistent Severe persistent Severe persistent
Moderate persistent asthma Moderate persistent Severe persistent Severe persistent Most severe persistent
Severe persistent asthma Severe persistent Severe persistent Severe persistent Most severe persistent
H. Arakawa et al. / Allergology International 66 (2017) 190e204 197
Table 13 Table 15
Treatment goal of childhood bronchial asthma. Points for improvement in environmental conditions.
Although final goal is remission or cure, the aims of daily control are: Bedding Use anti-mite sheets and covers; wash bedding frequently
1. Complete control of asthma symptoms and hang it outdoors to dry in the sun
Reduced or no need for b2 stimulants in exacerbation. Mattress Do not use mattresses; wooden floors are preferable
No symptoms day and night. Sofa Use sofas made of leather or artificial leather; no fabric-
2. Normal respiratory functions made sofas
Stable PEF rate. Stable pulmonary function tests. Stuffed toys Do not use stuffed toys; use washable ones if necessary
Improved airway hyper-responsiveness (no symptom aggravation after Furniture Use easily cleanable furniture only
exercise, cold air inhalation, etc.). Drapes Use window shades instead of curtains; washable curtains
3. Improved QOL if necessary
Normal daily life, including sports. No absence from school. Pet animals Do not keep mammals and/or birds inside rooms
No side effects associated with drug therapies. Vacuum cleaner Use one equipped with 2-layered dust bag
Potted plants Do not grow plants inside rooms
Laundry Do not hang the laundry inside rooms
Heating appliances Exhaust gas must be ducted outdoors if kerosene or gas
Table 14 heater is used
Asthma control levels. Materials for Eliminate architectural materials containing volatile
building houses chemicals such as aldehyde and phenol
Component of control Classification of asthma control Tobacco-smoking Persuade family members to discontinue smoking inside
Well- Partially Poorly rooms
controlled controlled controlled
Control levels are evaluated by conditions during the recent 4 weeks. 5.9. Instructions for smoking cessation
Mild symptoms indicate transient cough and/or wheezing induced by exercise, Active or passive smoking is an important exacerbation factor
laughing and crying. Also included are short periods of coughing at the time of for asthma. Smoking by pregnant mothers affects the respiratory
awakening and during sleep.
function of their children after birth.22 Parents with smoking habits
Apparent symptoms indicate continuous coughing and wheezing with dyspnea and
chest tightness. must be instructed about the need for smoking cessation as a vital
>80% of predicted/personal best in PEF and/or FEV1. 0%, <20% of circadian changes component of childhood asthma treatment. If children themselves
in PEF, and <12% of FEV increase by b2 stimulant inhalation are preferable as well- are smokers, they should be educated about the adverse influences
controlled conditions. on treatment and smoking cessation therapy.
At the time of assessment, hospital admission due to severe exacerbation, use of oral
glucocorticosteroid for symptom control, and seasonal exacerbation in recent 12
months should be considered. 6. Long-term management by medication
6.1. Formulations and characteristics of long-term
management drugs (controllers)
Scoring is as follows: 15, 12e14, and 11 points show com- Long-term management drugs (controllers) are continuously
plete, favorable (but still insufficient), and poor control, used to reduce and eliminate asthma symptoms, improve QOL, and
respectively. Full scores in both the C-ACT and JPAC corre- normalize and maintain respiratory function. Controllers with anti-
spond to a well-controlled state in JAGL 2017. inflammatory effects include inhaled corticosteroids (ICSs), leuko-
triene receptor antagonists (LTRAs), and theophylline. Oral steroid
administration for long-term management should be limited to the
5.6. Avoidance of exacerbation factors most severe cases because of systemic side effects. ICSs are
Most patients with childhood asthma have atopic diathesis and routinely used for patients with a level of severity that is higher
produce specific IgE antibodies to house dust mites. Tests are than mild persistent, because ICSs have strong anti-inflammatory
needed to determine the specific IgE antibodies to house dust mites effects with relatively low systemic adverse effects. Long-acting
and other possible allergens, and the elimination of these allergens b2 agonists (LABAs) are concomitantly used with ICSs for long-
from the patient's living environment is necessary. term management. LABAs should not be used alone.23
Inhaled corticosteroids potently suppress airway inflammation
5.7. Allergy tests and assessment and play an important role in long-term asthma control. The
Total serum IgE values vary with age. High values are those that amelioration of airway inflammation by ICSs leads to improvement
exceed the mean þ 2 standard deviations. The first step to identify in subjective symptoms, respiratory function, and airway hyper-
the allergens of children with asthma is to take carefully past his- responsiveness. Hospitalization owing to acute exacerbation and
tory of episodic symptoms after a particular antigen exposure. deaths from asthma also decrease.24e26 However, no evidence has
Routine examinations include skin tests and measurement of spe- been obtained regarding alteration in the natural history of asthma
cific IgE antibodies in serum. However, the results of positive skin resulting from the persistent use of ICSs for long periods.27,28 A
test or positive specific IgE do not mean that allergen is causing combination of the drugs ICS and LABA can be used for children
symptoms. aged 5 years. An adequate drug formulary should be selected
depending on the patient's age and/or inhalation techniques to
5.8. Instructions for environmental improvement (Table 15) maximize the efficiency of drug inhalation.
Cleaning rooms with a vacuum cleaner is an important measure Leukotriene receptor antagonists inhibit bronchoconstriction and
against mite antigens. Using a wood or cushioned floor as a flooring airway inflammation,29 and are effective for long-term
198 H. Arakawa et al. / Allergology International 66 (2017) 190e204
Table 16
Asthma management in children under 2 years of age.
Basal therapy SABA as needed LTRA and/or ICS ICS (high dose) possibly add
DSCG (medium dose) LTRA
Additional therapy LTRA and/or DSCG ICS (low dose) LTRA LABA (p.o. or adhesive skin patch)
LABA (p.o. or adhesive skin patch) Theophylline (maintain at 5e10 mg/mL
in blood conc.) can be considered
LTRA, leukotriene receptor antagonist; ICS, inhaled corticosteroid; DSCG, disodium cromoglycate; LABA, long-acting beta agonist.
LABA is discontinued when good control level is achieved. LABA (p.o.) is defined as the b2 stimulants prescribed as twice a day.
Theophylline is not used for patients under 6 months of age. Theophylline is not recommended for patients with history of convulsion. Prescription of theophylline for patients
with fever should be with caution.
Strongly recommend that uncontrollable patients with step 3 or step 4 management strategy be referred to experts in treating severe childhood asthma.
Table 17
Asthma management in children 2e5 years of age.
Basal therapy SABA as needed LTRA and/or DSCG and/or ICS ICS (medium dose) ICS (high dose) þ (possibly add one or more
(low dose) of the following drugs)
LTRA
Theophylline
LABA or SFC
LTRA, leukotriene receptor antagonist; ICS, inhaled corticosteroid; DSCG, disodium cromoglycate; LABA, long-acting beta agonist; SFC, salmeterol/fluticazone combined drug.
LABA is discontinued when good control level is achieved. When SFC is started, oral and percutaneous LABA should be discontinued.
Addition of SFC to ICS is acceptable; however, total dose of steroid is limited within the dose of basal therapy. SFC should be used for patients 5 years or more of age.
Uncontrollable patients with step 3-management strategy are recommended to be referred to experts in treating severe childhood asthma.
As an additional therapy at step 4, an increase of ICS/SFC to higher doses or p.o. steroid therapy or long-term admission management is considered. Patients should be
controlled under experts in treating severe childhood asthma.
Table 18
Asthma management in children 6e15 years of age.
Basal therapy SABA as needed ICS (low dose) and/or ICS (medium dose) ICS (high dose) þ (possibly add one or more
LTRA and/or DSCG of the following drugs)
LTRA
Theophylline
LABA or SFC
Additional therapy LTRA and/or DSCG Theophylline (consider) LTRA Consider the following:
Theophylline Increase ICS/SFC to higher doses or p.o. steroid
LABA or SFC
LTRA, leukotriene receptor antagonist; ICS, inhaled corticosteroid; DSCG, disodium cromoglycate; LABA, long-acting beta agonist; SFC, salmeterol/fluticasone combined drug.
LABA is discontinued when good control level is achieved. When SFC is started, oral and percutaneous LABA should be discontinued. Addition of SFC to ICS is acceptable;
however, total steroid dose is limited within the dose of basal therapy.
It is recommended that uncontrollable patients with step 3-management strategy be referred to experts in treating severe childhood asthma.
As an additional therapy at step 4, an increase of ICS/SFC to higher doses or p.o. steroid therapy or long-term admission management is considered. Patients should be
controlled under experts in treating severe childhood asthma.
management. In many cases, LTRAs improve respiratory function Long-acting b2 agonists may be used concomitantly with ICSs or
and reduce the frequency of exacerbations within 1e2 weeks after other anti-inflammatory drugs, because b2 agonists have no
administration of LTRAs. In patients with mild persistent asthma, inhibitory effects on airway inflammation. Besides inhaled LABAs,
LTRAs are as effective as ICSs.30,31 Efficacy of LTRAs as add-on transdermal patches36,37 and per oral medicines are available as
therapy to ICSs has also been demonstrated.32e34 LABAs in Japan. The serum tulobuterol level is maintained at a
Sustained-release theophylline (SRT) has a bronchodilator action therapeutic range for 24 h after application of a transdermal tulo-
and an anti-inflammatory effect and is used as a controller. The buterol patch.
dosage of theophylline is determined by factors that influence
metabolism such as individual differences, infections, meal con- 6.2. Long-term management plan
tents, and concomitant drugs. It should be noticed that fever during In a pharmacotherapy plan for long-term control of asthma, a
a viral infection causes an elevated serum theophylline level owing long-term management drug for the treatment step determined by
to decreased clearance. An intractable convulsion associated with the severity should be selected (Table 12). The severity is deter-
theophylline administration can occur as a severe side effect mined on the basis of symptoms and their frequency during the
particularly in infants.35 most recent month (see Table 11). The pharmacological stepwise
H. Arakawa et al. / Allergology International 66 (2017) 190e204 199
Fig. 5. Strategy of long-term management of asthma. yAt the assessment of patient asthma control, it is important to check drug-adherence, inhalation techniques, and envi-
ronmental controls for eliminating aggravating factors. zKeep treatment regimen at least 3 months till patient's control levels are well maintained. xIt is preferable to step-up
treatment regimen when patient's control levels stay at the partially controlled level for 3 months. ¶In cases where patient's control level is expected to improve through education
(y), treatment regimen can be maintained at the same step.
200 H. Arakawa et al. / Allergology International 66 (2017) 190e204
Table 21 (1) A nebulizer can be used regardless of age if a mask is used. Jet
Combination of inhalation device and aiding tools. nebulizers are the most widely used for inhalation therapy of
Age Drug Inhalation devices and aiding tools asthma. Mesh nebulizers, a subtype of ultrasonic nebulizers,
are lightweight, save power, and have a high vaporizing ca-
Baby Solution Nebulizer þ mask pacity. Ordinary ultrasonic nebulizers are unsuitable for
pMDI Spacer with mask
inhaling anti-asthma drugs because of thermal denaturation
Infant Solution Nebulizer þ mask or mouth piece and concentration changes of drugs in the reserve tank.39
pMDI Spacer with mask or mouth piece
School children Solution Nebulizer þ mouth piece When children use nebulizers, they should inhale at a resting
pMDI Spacer with mouth piece
respiratory rate in a sitting position. In children old enough to
DPI ()
breathe orally, soluble drugs are inhaled with a mouth piece
attached to the nozzle of the nebulizer. In infants, a nebulizer is
Table 22 used with a face mask attached to the nozzle, to cover the mouth
Check list of inhalation therapy. and nose. Adhesion of the mask to the patient's face is important to
optimize inhalation efficiency, which is reduced by nasal inhalation
Nebulizer
Bite mouth piece firmly or crying.40,41
Expectorate salivary fluid without reversing from time to time (2) Both pMDIs and DPIs are available. In pMDIs, spray and
Can ventilate through mouth inhalation need to be synchronized. Even in infants for
Adhere mask tightly on the face whom spray and inhalation cannot be synchronized, a pMDI
Can ventilate without crying
Wipe away solution on the face after inhalation
can be employed by using a spacer with a face mask. When
pMDI using a DPI, a patient inhales a drug through self-respiration.
Can synchronize actuation and inhalation School children or adolescents can use DPIs because they can
Can ventilate through mouth generate the certain amount of inspiratory force required.
Can ventilate slow and deep
Can hold breath for certain periods of time
pMDI þ spacer
When using mouth piece, can bite mouth piece firmly 8.2. Spacers
When using mask, can adhere mask tightly on the face A spacer is an indispensable aiding instrument for pMDIs in in-
Inhale at every actuation fants who cannot accurately perform the procedures for the syn-
Can ventilate without crying
Can hold breath for certain periods of time
chronization of spray and inhalation. Concomitant use of a spacer
DPI allows inhalation at a normal respiratory rhythm even without
Keep device in appropriate position synchronizing spray and inhalation, thus increasing inhalation effi-
Do not blow away drug-powder before inhalation ciency. In addition, a spacer is useful in adsorbing large particles
Can ventilate with strong inspiration
(5 mm) onto the inner wall of the spacer to prevent deposition of
Can ventilate deep
Can hold breath for certain periods of time excess drugs in the oral cavity and reduce adverse effects. In infants
Other points who cannot breathe through the mouth, the nose and mouth are
Gargle or drink water after inhalation (in the case of using ICS) covered with a face mask without leakage to maintain inhalation
efficiency and maximize the benefit from a spacer.
Many types of spacers are available. A spacer with data assuring
7.2. Treatment of persistent cough aerodynamic properties, clinical usefulness, and safety should be
The fundamental strategy for the treatment of persistent cough selected. The effectiveness of a spacer is greatly influenced by
is to first determine the underlying mechanisms. If the underlying concomitant agents and procedures as well as its shape, structure,
mechanism of persistent cough is asthma, the patient can be and physical properties.
treated according to the asthma guideline. In the case of poor Technical mastery in the adequate use of inhalation devices and
control, stepping-up of the treatment level, elimination of exacer- aiding accessories is essential to obtain maximal efficacy of inha-
bation factors from the patient's environment, and educating the lation drugs (Table 22).
patient about asthma control should be considered.
9. Patient education
To perform asthma treatment effectively, patients and their
8. Inhalers and spacers caregivers need to be educated and actively involved in the
Inhalation therapy is critical and effective for the daily man- treatment.42,43
agement and treatment of asthma exacerbation in children, (1) The caregivers must ensure that infants do not experience
including infants. A good understanding of the characteristics of discomfort during treatment. The caregivers should also help
inhalers is important for the selection of an appropriate inhaler the infant to be interested in the treatment and stay moti-
based on the child's status. vated. They should encourage and compliment them on their
good performance in inhalation and habituate them to the
8.1. Inhalers treatment gradually.
Inhalers are classified into nebulizers and metered-dose in- (2) School-age children should have the pathophysiology of
halers. Three types of nebulizers are available based on their drive asthma explained to them, using simple terms and meta-
systems: jet, ultrasonic, and mesh. Metered-dose inhalers include phors, to understand the need for treatment. They should be
the pMDI and the dry powder inhaler (DPI). In Table 21, combina- cheerfully instructed about the abdominal breathing tech-
tions of nebulizers or spacers with and without a face mask and nique, PEF measurement, and other matters as if they were
inhaled drugs for different age groups are demonstrated. The playing some kind of game.
appropriate combination can be selected by assessing various (3) Prepubertal children should be instructed about the need for
conditions such as efficiency of inhalation, compliance, patient continuing treatment without interruption. According to
preference, and financial matters. their level of understanding, they should be educated about
H. Arakawa et al. / Allergology International 66 (2017) 190e204 201
the pathophysiology of asthma and its treatment. Because it pathophysiology.47,48 Increased airway temperature after exercise
is difficult to make such young patients take charge of the may also be involved.49
part of treatment and management that their parents had If coughing, wheezing, and dyspnea occur during or after exer-
been taking care of, compliment them on their efforts to cise, a diagnosis of EIA may be easily made. An exercise stress test is
achieve self-fulfillment and eventually self-management. conducted to quantitate the EIA.50,51 If the maximal percent de-
(4) Children in puberty are more likely to disobey their parents creases of the forced expiratory volume in 1 s (FEV1) and PEF are
because of parentechild conflicts during puberty. Treatment larger than 15% and 20%, respectively, a diagnosis of EIA is
and management will be interrupted if the education and confirmed. The maximum decrease in the rate of FEV1 after exer-
instruction are insufficient, which results in poor control and cise is higher in patients with more severe asthma. This serves as a
increased risk of death from asthma. Children are directly parameter in the determination of the severity of asthma.52
instructed at their consultation. As it is often the case that not Because EIA is also associated with airway hyper-responsiveness,
enough time may be taken in outpatient departments, it is the patient's history with respect to EIA provides clues as to
far more effective to hospitalize children with severe whether the current treatment step is appropriate.
persistent asthma for education and instruction during a To prevent EIA, the appropriate treatment step should be
summer vacation or when they can take time off from selected based on severity. If in fact EIA has occurred, the proced-
schoolwork without difficulty. ures shown in Table 24 may prevent its repetition.
(5) Pubertal and adolescent patients have problems such as low Exercise does not have to be restricted because it otherwise
compliance, remodeling, and death from asthma.44 Under- benefits the child's growth in various ways. Parents, teachers,
standing the characteristics and problems of pubertal school officials, school physicians, and attending physicians should
asthma on the patient's part is important for treatment and collaborate to take measures so that children with asthma can
management (Fig. 6). Points of management and treatment safely participate in exercise at preschools and schools.
for pubertal asthma are demonstrated in Table 23.
Table 23 Table 24
Countermeasures for adolescent asthma. Prophylaxis of exercise-induced asthma (EIA).
11.6. Considerations for surgery 7. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC,
Prins JB. Airway inflammation is present during clinical remission of atopic
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to the management of physical conditions before and during sur- flow variability, methacholine responsiveness and atopy as markers for
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946e52.
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