Acute and Chronic Bronchitis in Childhood: Cystic Fibrosis

Abstract

The chapter discusses the problems of clinical diagnosis, treatment, and follow-up of children with acute and chronic bronchitis. All clinical types of acute bronchitis are covered. Special focus is paid on cystic fibrosis—diagnosis, clinical features, and treatment. Affecting the lower respiratory tract (bronchi and bronchioles) is a very common phenomenon in childhood, most often with a viral etiology, sometimes bacterial, atypical, allergic, etc. Children’s bronchi have a small amount of cartilaginous tissue, mainly smooth muscle tissue, and react to various triggers with bronchial spasm and increased mucus secretion. A significant part of pediatric pathology in early childhood is acute inflammatory diseases of the lower respiratory tract.

1. Introduction

Affecting the lower respiratory tract (bronchi and bronchioles) is a very common phenomenon in childhood, most often with viral etiology, sometimes bacterial, atypical, allergic, etc.

Children’s bronchi have a small amount of cartilaginous tissue, mainly smooth muscle tissue, and react to various triggers with bronchial spasm and increased mucus secretion. A significant part of pediatric pathology in early childhood is acute inflammatory diseases of the lower respiratory tract.

2. Acute bronchiolitis

Acute bronchiolitis (AB) is a viral infectious disease of the lower respiratory tract that involves bronchioles (airways with a diameter of less than 2 mm) and is most often caused by respiratory syncytial virus (RSV) or human metapneumovirus (HMPV) [1, 2, 3, 4, 5, 6, 7, 8, 9], as well as by other viral agents [10, 11, 12, 13, 14]. It mainly affects ages 1–24 months, with an age prevalence between 3 and 6 months [15].

Acute bronchiolitis is the most common lower respiratory tract infection in the first year of life. There is an autumn-winter prevalence of the disease, which depends on the peak incidence of RSV, but is most often in the period from October to March [16, 17]. Boys get sick more often [18, 19].

There is still a high rate of hospitalization in these patients and a wide variability in clinical behavior and treatment approaches worldwide.

Children at increased risk of RSV infection or severe disease are [15]:

• Premature, low birth weight infants

• Groups with low socioeconomic status

• Parental smoking

• Broncho-pulmonary dysplasia as an underlying disease

• Severe congenital or acquired neurological diseases.

• Congenital heart defects with pulmonary hypertension

• Immune deficiencies

• Abnormalities of the respiratory tract

• Age under 3 months

• Hypotrophy, malabsorption, rickets

Acute bronchiolitis (AB), according to a WHO bulletin, has a significant impact on respiratory pathology worldwide with approximately 150 million cases per year, of which 7–13% are severe and require hospital treatment [15, 18, 19].

AB is essentially a self-limiting disease. Its treatment is supportive and includes oxygenation, adequate hydration, and temperature control. With early diagnosis and treatment, the prognosis is very good. The duration of the illness is usually 7–10 days, and most children recover without consequences. In some children, AB leads to recurrent “wheezing.”

The clinical onset is most often atypical—irritability, decreased appetite, low temperature, and nasal discharge. In adults and in older children, RSV infection in 60% remains in the upper respiratory tract. After the incubation period of 2–5 days at a young age, RSV infection progressively affects the small airways with the development of cough, dyspnea, “wheezing,” and difficulty feeding. Severe cases lead to manifestations of RDS with tachypnea, nasal breathing, dyspnea, and cyanosis [20].

The objective examination reveals tachypnea, expiratory dyspnea, tachycardia, fever, and diffuse “wheezing.” Hypoxemia is the most accurate predictor of disease severity and correlates with the degree of tachypnea (over 50 bpm) [21].

Extrapulmonary manifestations include otitis media, myocarditis, arrhythmias, impaired secretion of ADH, etc. Acute bronchiolitis can be complicated by ARDS, bronchiolitis obliterans, congestive heart failure, myocarditis, secondary bacterial infection, and development of asthma [22, 23, 24, 25, 26]. Neurological complications with seizures and encephalopathy are rare.

Diagnosis of acute bronchiolitis is based on a well-taken history (most often patients with acute respiratory infections in the family), clinical presentation, the age of the child, the season of the disease, and the physical examination.

Laboratory studies tend to exclude other pathology. They include rapid RSV test from nasopharyngeal secretions, blood gas analysis or pulse oximetry, CBC, CRP, chest X-ray, etc. [27]. Usually, leukocytes are normal or slightly elevated with neutrophilia, which can be explained by a stress reaction [28].

X-ray of the lungs shows hyperinflation, and it is possible to observe lobular infiltrates, atelectasis, flat and low diaphragmatic cupola, and thickened bronchial walls. Atelectasis is a common finding and can cause arterial desaturation in these patients. An ECG is performed if there is evidence of arrhythmia or cardiomegaly from the lung X-ray [29, 30].

Pulse oximetry is an important method for determining the severity of AB and indications for hospital treatment. Patients with persistent TcSaO2 below 92% need hospital treatment and observation [31, 32, 33].

2.1 Treatment of acute bronchiolitis

The treatment of acute bronchiolitis is supportive, symptomatic, aiming rehydration and good oxygenation. The literature data on the issue of drug therapy in AB indicates very contradictory data. Only adequate oxygenation is surely effective and shortens the hospital stay [27, 30, 31, 32]. It can be performed with a nasal cannula, mask, tent, or mechanical ventilation.

The use of a bronchodilator has no proven effect and should be reserved only for patients with clinical improvement. It can be included orally or inhaled with a nebulizer or volume chamber [34, 35].

Regardless of their powerful anti-inflammatory effect and frequent application, corticosteroids (CS) do not lead to a significant improvement in the clinical status of patients and should be used only in severe cases [30, 36]. In cases of apnea, hypercapnia, and extreme hypoxemia, mechanical ventilation is required.

The application of oxygen—a helium mixture—Heliox is also important. In recent years, both in outpatient settings and as hospital treatment, the use of hypertonic 3% sodium chloride solution for the treatment of AB has been promoted as a safe, effective, and inexpensive way of treatment [37]. Chest physiotherapy is not recommended in the AB treatment plan.

Differences in therapeutic practices around the world are huge and lead in 2006 developing from the American Academy of Pediatrics (AAP) a Consensus for behavior in acute Bronchiolitis [30]:

• The diagnosis and the severity of the disease are determined by the clinical examination and history, not based on laboratory or imaging studies. Assessment of risk factors helps to decide for or against hospitalization.

• Bronchodilators should not be used routinely, but only when a clinical effect has been established [38].

• CS and antiviral medications should not be used routinely.

• Antibiotics are prescribed only when there is evidence of bacterial infection.

• Adequate hydration is very important.

• Oxygen therapy is carried out at oxygen saturation below 90% (or 92%).

• Palivizumab prophylaxis should only be used in certain groups.

• A very important element is the disinfection of staff’s hands to prevent the transmission of infection in hospital wards.

• Parents should avoid smoking.

• Breastfeeding sick children is recommended.

After the implementation of the AAR recommendations in the USA, there was a decrease in hospitalizations (29%), length of stay (17%), RSV testing of nasopharyngeal swabs (52%), chest X-rays in AB in hospital, and outpatient cases [27, 30].

The criteria for hospitalization include [30]:

• Persistently measured oxygen saturation below 92% when breathing atmospheric air before beta 2 agonist administration.

• Significant tachypnea (>70–80 breaths/min)

• Expiratory dyspnea and intercostal retractions, signs of respiratory distress

• Desaturation when stopping the supply of 40% oxygen (3–4 L/min), cyanosis.

• Chronic lung disease

• Congenital cardiac malformation is especially associated with cyanosis and pulmonary hypertension.

• Prematurity

• Age under 3 months with an expected more severe course of the disease

• Impossible to perform oral rehydration in patients under 6 months of age.

• Difficulty feeding because of RDS.

• Social factor—parents who cannot take care of their children at home.

The prevention of RSV infection is essential for the general practitioner and for the narrow specialist—pulmonologist. Since 1967 attempts have been made to create and administer a formalin-inactivated RSV virus vaccine, still not been used for a massive vaccination. The use of the RSV-specific monoclonal antibody Palivizumab i.m. at a dose of 15 mg/kg/dose every 30 days from October to March significantly reduced the incidence of AB and the need for hospital treatment [39].

Acute bronchitis (AB) is an inflammatory disease of the large airways with a leading symptom—cough. In childhood, it is mainly associated with viral infections, most often descending upper respiratory airway infection, but it can be also connected to mechanical (dust, gas), chemical, or allergic inflammation of the respiratory tract. Clinically, it presents with a wet and productive cough with sputum discharge, sometimes with retrosternal pain when breathing or when coughing. It most often occurs as a self-limiting disease with complete recovery in 7–14 days (maximum 28 days) [15, 18].

Chronic bronchitis is defined as a recurrent inflammation and degeneration of the bronchial wall. In chronic bronchitis, increased mucus production is observed either due to increased secretion or due to impaired clearance. Defining chronic bronchitis in childhood, as well as its distribution, is very difficult due to overlapping clinical diagnoses.

For adults, it is defined as diffuse and non-specific inflammation of the bronchi, manifestation of cough, and daily expectoration within 3 months for 2 consecutive years. Some authors apply this definition to children as well or define chronic bronchitis as a productive cough lasting more than 4 weeks regardless of treatment, with expectoration and an auscultation finding of wheezing and variable wet crackles bilaterally.

2.2 Etiology

Acute bronchitis (AB) has a viral etiology in 90%, and a bacterial etiology in 10%, rarely others. Viral agents include adenoviruses, influenza, parainfluenza, rhinovirus, RSV, coxsackievirus, HSV, etc. Secondary bacterial infection can be observed from Str. pneumoniae, M. catarrhalis, Chlamydia pneumonia, H. influenzae, M. pneumoniae [40]. Both active and passive smoking can increase the risk of recurrent bronchitis. Less common causes are GERD, fungal infections, etc. The seasonal prevalence of acute bronchitis is mainly during autumn and winter season.

• Pathoanatomic forms: catarrhal, fibrinous, purulent, and necrotizing.

• By localization of the inflammatory process: diffuse or limited.

• By course: primary or secondary (within another disease)

• According to the presence or absence of bronchospasm: obstructive or non-obstructive

The clinical course could be:

2.2.1 Acute bronchitis, acute tracheobronchitis

It is defined as an inflammation of the epithelium of the trachea and large and medium bronchi. It appears with a preserved general condition, normal or low-grade temperature, and cough, which can be mainly dry, painful (typical for tracheitis), or wet with expectoration.

Physically, diminished or more aggravated vesicular breathing with/without dry wheezing sounds, and large and medium wet crackles, often of a transient nature is found.

Normal laboratory values are observed, lung X-ray is not necessary—if done it is normal or shows thickened pulmonary roots and peribronchial changes [29].

It passes with symptomatic therapy for 8–10 days, which includes a home regime, mucolytics, inhalations, antipyretic when needed, and very rarely the inclusion of antibiotic treatment.

2.2.2 Bronchitis obstructiva, asthmatiformis

It is most often caused by RSV, Parainfluenzavirus, etc. It starts as an upper respiratory tract infection and gradually develops tachypnea, expiratory dyspnea, nasal breathing, etc.

Physically, a hypersonic percussive tone is observed, diminished vesicular breathing with prolonged expiration, and dry wheezing noises bilaterally are established.

Pulmonography demonstrates evidence of hyperinflation of the lung parenchyma—emphysema [29]. Laboratory parameters are normal, and eosinophilia is possible. The treatment is the same as for acute bronchitis with the addition of bronchodilators, with/without corticosteroids [27].

• Bronchiolitis acuta (see above)

• Bronchiolitis obliterans

Acute bronchiolitis, even with a protracted course, improves in 2 weeks. If the symptoms of respiratory failure, obstruction, and hypoxemia persist, the development of bronchiolitis obliterans is possible.

Radiologically, it is demonstrated with ultra-transparency of the lung parenchyma, reduced vascular pattern, peribronchial thickening, and the development of bronchiectasis [29].

Etiologically, it is most often associated with adenovirus, influenza virus, and mycoplasma infection, but not with RSV [10, 11]. It leads to the development of chronic respiratory failure and cor pulmonale.

A rare form, but potentially fatal, is the so-called plastic bronchitis—the formation of solid casts of the tracheobronchial tree. For unexplained reasons, this type of bronchitis is seen more often in patients with congenital cardiac defects and Fontan operations. It is believed that pathogenetically this bronchitis is associated with high thoracic lymphatic pressure.

Acute and chronic bronchitis are the main reason for a doctor’s consultation on a global aspect, and their probable incidence is about 20% in school age. In acute bronchitis, gender dependence is not established, in chronic bronchitis the male gender is prevalent.

2.2.3 Bronchitis chronica (chronic bronchitis)

According to the definition of WHO: “chronic bronchitis is a diffuse and non-specific inflammation of the bronchi, which is manifested by cough and mucopurulent expectoration with autumn-winter seasonality for at least 3 months in two or three consecutive years.”

About 2–3 times more often affects the male sex, more typical for smokers (5×), and increases in frequency with age [15, 18, 19].

Chronic inflammation occurs due to the disruption of natural defense mechanisms, the damaging role of exogenous factors: moisture, dust, cold, steam, gases, smoking, etc., in combination with endogenous factors (kyphoscoliosis, diabetes, heart failure, immune deficiency, etc.)

Pathogenetically, there is chronic hypoxemia, which leads to an increase in pulmonary vascular resistance, metabolic acidosis, and polycythemia, followed by the development of cor pulmonale and pulmonary hypertension.

Pathoanatomically, hyperemia is found, as well as edema, and lymphocytic infiltration of the bronchial wall, followed by mucosal atrophy, and reduction of secretory glands and elastic fibers.

The clinic is represented by three main symptoms:

• Cough

• Expectoration—mucopurulent

• Shortness of breath, with/without chest or abdominal pain

Physically, sonorous, or hyper sonorous percussive tone is found, reduced respiratory mobility, and diffuse dry crackles are detected.

Pulmonography shows low standing of the diaphragmatic cupola, the presence of pulmonary emphysema, and fibrosis [29].

Chronic bronchitis occurs with episodes of exacerbation and remission. Complications include recurrent pneumonias, bronchiectasis, pulmonary emphysema and COPD, and the development of cor pulmonale.

In terms of differential diagnosis, the following are discussed: cystic fibrosis, asthma, PCD, TB, foreign body in the respiratory tract, aspiration, immune deficiency, etc.

In periods of exacerbation, antibiotic treatment is carried out according to the antibiogram of the pathogenic flora from sputum (throat secretion), secretolytic, and bronchodilator therapy [34, 35]. Physiotherapy—postural drainage, ultrasound of the chest, and magnetotherapy are also widely used.

Recurrent episodes of acute and chronic bronchitis are atypical for childhood and should prompt the pediatrician to look for childhood asthma. In such children, the presence of family burden and personal atopic characteristics increases the risk of childhood asthma [21, 22, 23, 24, 25, 26].

The presence of recurrent bronchitis points to the search for immune deficiency—IgA or IgG transient or subclasses.

In addition to chronic bronchitis, one of the most common reasons for chronic bronchitis in childhood is cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic multisystem disease affecting Caucasians with autosomal recessive inheritance. The disease has an average incidence among Caucasians of 1 in 2000 to 2500 live births. The carrier frequency is 4–5% in the population [41, 42].

The cystic fibrosis gene is located on the long arm of the 7th chromosome, locus 7q31.2, and was mapped in 1989. The cystic fibrosis protein called cystic fibrosis transmembrane conductance regulator (CFTR) is a transmembrane transport protein with a complex configuration [43]. More than 1600 mutations in the CFTR gene are currently known, of which delta F508 is the most common. Mutations are divided into 6 classes [42, 44].

CF is a congenital genetic disease. The phenotype manifestation of the disease can begin at different ages. As a rule, class I and class II mutations cause earlier and more severe clinical symptoms, while those of the other classes underlie milder cases [43]. The phenotype–genotype correlation is more demonstrative for symptoms from the digestive and reproductive systems and less pronounced for pulmonary manifestations [45].

Clinical diagnosis: In 5–10% of children with CF, presentation is in the neonatal period with meconium ileus. This is a reason for early diagnosis of the disease. Sick children are born with healthy lungs.

Typical neonatal and infant clinical manifestations of the disease include cough with different characteristics—dry or more moist and productive, sometimes—pertussis-like with painful expectoration, manifestations of bronchospasm with difficulty resolved bronchial obstruction by conventional treatment, recurrent broncho-pulmonary infections in infancy with frequent detection of S. aures from throat secretions (or sputum).

In this period, manifestations of GER, cholestatic jaundice, chronic diarrhea with malabsorption, bulky and greasy stools, and lack of weight gain are common. The last symptom is of leading importance in infancy for an active search for the diagnosis. Infants have a preserved, even increased appetite, in the absence of weight gain. The “salty kiss” symptom is also positive in infancy. A special clinical form characterized by generalized hypoproteinemic edema and anemic syndrome is the so-called edematous-anemic form of the disease, which is observed mainly in the age up to 1 year [45, 46].

In early childhood, the clinical symptoms are presented with: chronic cough with/without sputum discharge, recurrent infections of the respiratory tract, colonization with a wider range of microorganisms: S. aureus, H. influenzae, Pseudomonas aeruginoza, S. maltofila, etc., chronic diarrhea, manifestations of hypovitaminosis for fat-soluble vitamins. Manifestations of rectal prolapse and distal intestinal pseudo-obstruction syndrome (DIOS) are more common. Initial bronchiectasis is detected more often in chest X-rays in patients with more marked pulmonary symptoms. Changes begin on the nails and fingers with clubbing and “drumstick” nail types. At this age, changes in the rheology of the bile also occur—“thick bile syndrome” with possible gall bladder calculus and hepatic steatosis. During the summer months, electrolyte disturbances and a tendency to dehydration are observed [45, 46].

At school age, the manifestations of chronic respiratory failure dominate with changes in the chest, which becomes emphysematous with an increased anterior–posterior diameter. The auscultation phenomena are most often represented by a hypersonic percussion tone, weakened vesicular breathing with a rich exudative finding of moist rhonchi and crepitations, maybe a localized finding of lung inflammation or bronchiectasis, broncho-obstructive symptoms are also common.

With the development of pulmonary hypertension, ECG changes and accentuated cardiac T2 may be detected [45, 46].

At this age, colonization with Pseudomonas aeruginosa (PA) is of leading importance for the evolution of the disease. When it is first established, an eradication course is recommended. In chronic PA infection, pulmonary exacerbations are treated. Pulmonary complications are observed: atelectasis, bronchiectasis, pneumothorax, pulmonary bleeding, etc. With poor therapeutic control of the disease, children have an asthenic and cachectic appearance, and reduced subcutaneous fat tissue. It is not uncommon to involve the upper respiratory tract with the development of chronic rhinosinusitis and nasal polyposis. It is the cause of difficult nasal breathing and bacterial colonization of nasal secretions by Staphylococcus aureus. Advanced involvement of the endocrine pancreas leads to manifestations of diabetes mellitus, which necessitates additional insulin treatment. Changes in bone density are observed with the development of osteoporosis. In puberty, mental and emotional problems intensify, which complicate the treatment of the disease.

In patients of reproductive age, reduced fertility in women and azoospermia and sterility in men have been observed.

Laboratory diagnosis of the disease has several steps:

1. Related to the diagnosis of the disease:

   • Possible performance of neonatal screening—carried out in some countries—USA, Australia, some European countries—immunoreactive trypsinogen is examined and only in case of deviation a sweat test is carried out.

   • Sweat test—“gold standard”—positive result above 60 mmol/l (mEq/l), at least 2 positive tests are required, in 1% of patients the sweat test is normal.

   • Fecal elastase 1, steatorrhea, coprocitogramm

   • Genetic DNA analysis with determination of the type of mutation, prenatal diagnosis in the case of another pregnancy in the family

   • Determination of nasal or rectal transepithelial potential difference (NTP)

2. Related to monitoring of diagnosed patients:

   • Blood gas analysis demonstrating metabolic alkalosis, hypoxemia with/without hypercapnia

   • Changes in electrolytes—hypochloremia, hyponatremia

   • Determination of the fraction of exhaled nitric oxide (FeNO)—(reduced in patients with CF)

   • Carrying out pulmonary function test (PFT)—most often indicates a mixed ventilatory defect with a reduction of VC and dynamic indicators

   • Chest X-ray depending on the involvement of the lung, can demonstrate a very rich image “picture,” in the terminal stages we talk about the so-called “honeycomb”: pulmonary emphysema and fibrosis, bronchiectasis, sites of old and fresh inflammatory changes, asthenic chest, prominent arch of the pulmonary artery, possible atelectasis, etc. [41, 42].

   • Liver enzymes—most often they are increased with a dominant change in cholestatic indicators, coagulation factors, total protein and serum albumins also change dynamically.

   • Blood analysis: accelerated ESR, leukocytosis and neutrophilia in bacterial infection, data on hemoconcentration in dehydration and chronic hypoxemia

   • Abdominal ultrasound

   • Blood glucose, blood glucose profile, oral glucose tolerance test—OGTT

   • Wrist X-ray for assessing the bone age

2.3 Follow-up of CF patients

CF is currently an incurable disease. In recent decades, a significant improvement in the duration and quality of life of these patients has been observed. The effect of therapy is complex and is based on self-control and training of patients, close cooperation with a team of professionals, new medications and recommendations for treatment [47].

Around the world, the monitoring and control of these patients is most often carried out in the so-called “Cystic Fibrosis Centers” (CFCs), most of which are affiliated with university hospitals or outpatient follow-up clinics. CFCs teams include a pulmonologist, gastroenterologist, nutritionist, physical therapist, social worker, psychologist, trained nurses, microbiologist, and more.

In outpatient care (outpatient care): patients are followed up every 1–3 months, and newly diagnosed patients—every month. Each visit includes a routine physical examination, measurement of height, weight, BMI, pulse oximetry, functional respiratory testing, and microbiological analysis of sputum or deep throat secretions. At each visit, the treatment plan and any changes to it are discussed in detail. Patients with positive P. aeruginosa or B. cepacia must be separated from the others [47].

In case of in-patient care, beds are provided for immediate admission, separate rooms for 1 child each, and strict control of infectious transmission is observed—hand hygiene, use of disinfectants, and clear antibiotic treatment protocols. Smooth transition into the age of 16–18 years from a pediatric team to a team of internists.

A CF patient’s annual protocol includes the following:

• History of events since the last examination, previous illnesses, and treatment.

• Immunizations, annual flu vaccine.

• Detailed clinical examination: anthropometric data: height, weight, head circumference, BMI, growth curves

• Review by a physiotherapist of drainage techniques used, frequency of sessions, and use of respiratory therapy (bronchodilators, nebulized antibiotics, rhDNase). Overview of inhaler used and cleaning technique.

• Spirometry in patients older than 5 years.

• Dietary reassessment and commentary on diet, knowledge and dosage of pancreatic enzymes, vitamin therapy, additional calorie foods

• Time to work with a social worker and a psychologist

• Blood collection for: CBC and smear, C-reactive protein, IgG, serum electrolytes, blood glucose, kidney and liver samples, fat-soluble vitamins: A, D, E, K, prothrombin time, IgE, antibodies against Aspergillus fumigatus—RAST or skin test, antibodies against P. aeruginosa

• Fecal test for pancreatic elastase 1, steatorrhea

• X-ray of the lungs, abdominal ultrasound, microbiology of sputum/deep throat secretion [47].

2.4 Treatment of patients with CF

Outpatient treatment for children with cystic fibrosis has several aspects:

• Regarding nutrition and pancreatic replacement therapy: recommendations for 3 main meals, intermediate meals [18, 19], intake of more salt in the summer months, fluids, intake of high-calorie food, fat-soluble vitamins (Aquadeks), pancreatic enzymes—Kreon 25,000 E (dose 500–2000 E lipase/kg/dose at the beginning of the meal, without disturbing the integrity of the microsomes in the capsules). The main criterion for enzyme sufficiency is weight gain and the number of bowel movements per day. Good nutritional status is directly related to FEV1 and lung function in children with CF. There are affordable caloric foods: Fresubin, Nutrinidrink, and Infatrini, which help weight gain in case of malnutrition.

• Regarding the lung, the therapy is inhaled, antibiotic, mucolytic, and enzymatic.

Inhalation therapy consists of daily inhalations with 0.9% sodium chloride and hypertonic sodium chloride solution—1.5%, 3%, 4.5–7%. The side effect of hypertonic solutions could be possibly bronchospasm. Mannitol is also inhaled in some countries. The aim is to facilitate secretions and improve mucociliary clearance.

Mucolytics—Mistabron, N-Acetylcystein, Fluimucil, are mainly administered orally, and the dose is increased in case of pulmonary exacerbation.

Enzyme therapy: Pulmozyme/Rh-Dornase Alpha/—recombinant human deoxyribonuclease (rhDNase). It is administered by inhalation 1× daily (1 ampule of 2 ml, 2500E/, from 5 years of age.

Prophylactic long-term treatment with inhaled antibiotics when chronic P. aeruginosa infection is proven—TOBI 300 mg/5 ml 2×/day, 1 amp each, Arikase 1×/day, Colistin 2000000E 2×/day, etc. They are applied with aerosol inhalers or powder inhalers, 1-2×/day in cycles of 28 days on, 28 days off. Their role is to suppress chronic pseudomonas infection and improve lung function.

Pulmonary exacerbations usually require hospital treatment and parenteral administration of combinations of broad-spectrum antibiotics according to an antibiogram in maximum dosage and maximum duration of 14–21 days. Oral courses with combined penicillins, cephalosporins, macrolides, and quinolones are administered in outpatient settings [48].

• Physiotherapy—daily, parents are trained in various techniques—mechanical percussion, postural bronchial drainage, autogenous drainage, breathing with a flutter, breathing against positive expiratory pressure (PEP mask), breathing with oral high-frequency oscillation, the so-called vest—device, etc.

• Gene therapy and CFTR modifiers—this is a therapy of the future for CF, there are many studies proving a good effect of the latter in some mutations, still with a high economic cost.

• Lung transplantation—the last choice for the so-called end–stage CF – has more experience in the USA, and few transplant centers in Europe.

The future is open to new therapeutic methods for children with CF, for the last decades, the life expectancy for most countries has increased many times. The result of the treatment is a complex of measures and methods concerning training, self-control, nutrition, physiotherapy, and inhalation therapy, to be well monitored by qualified specialists in this serious disease [46].