Bronchiectasis In Children Research Articles

Childhood bronchiectasis around the world

Childhood bronchiectasis around the world

Non-cystic fibrosis bronchiectasis: review and recent advances

Bronchiectasis is an abnormal dilatation of bronchi and bronchioles associated with repeated cycles of airway infection and inflammation. This review will focus on non-cystic fibrosis bronchiectasis in children, with regard to etiology, diagnosis, treatment options, and recent advances.

Association between MucoidPseudomonasInfection and Bronchiectasis in Children with Cystic Fibrosis

To correlate the severity of bronchiectasis in children with cystic fibrosis with clinical and microbiologic variables in order to clarify risk factors for the development of irreversible lung disease. After institutional review board approval and parental informed consents were obtained, a HIPAA-compliant longitudinal epidemiologic evaluation was performed in patients with cystic fibrosis who were enrolled in the Wisconsin trial of newborn screening from 1985 to 2009. Thin-section chest computed tomography (CT) was used in a prospective cross-sectional design to study patients ranging in age from 6.6 to 17.6 years (mean, 11.5 years). Thin-section CT scores were determined objectively on coded images by multiple raters in a standardized fashion. Microbiologic data were obtained by means of culture of respiratory secretions by using methods for differentiation of Pseudomonas aeruginosa (PA) as either nonmucoid or mucoid. Eighty-three percent of patients (68 of 82) showed bronchiectasis of varying severity. Of 12 potential risk factors, only respiratory infection with mucoid PA correlated significantly with bronchiectasis (P = .041). The severity of bronchiectasis in children with cystic fibrosis is significantly related to respiratory infection with mucoid PA; attempts to prevent bronchiectasis should include reducing exposure to and early eradication of PA.

Bronchiectasis secondary to primary immunodeficiency in children: Longitudinal changes in structure and function

Primary immunodeficiency is a common cause of bronchiectasis in children. The term bronchiectasis suggests an irreversible process; however, disease progression following treatment is controversial. The aim of this study was to evaluate the progression of bronchiectasis in children with primary immunodeficiency after institution of treatment. A retrospective review of case notes of children with primary immunodeficiency was undertaken to identify patients with confirmed bronchiectasis. Children who had two high-resolution computed tomography scans of the chest (HRCT chest) with an interval of at least 2 years were identified. The HRCT-chest scans at diagnosis and follow up were scored using a Bhalla score. Spirometry results (FEV1, FVC, and FEV1:FVC ratios) were related to HRCT-chest scores, where available. Statistical analysis was by Wilcoxon signed rank test and Spearman's rank order correlation. Eighteen subjects were studied. The diagnosis of primary immunodeficiency was established at median (range) age 3.4 (1-13) years, and bronchiectasis at 9.3 (3.1-13.8) years. There was no significant difference between baseline and follow-up median (range) HRCT-chest scores (6 [1-13] and 7.5 [0-15], P = 0.21) respectively. The follow-up FEV1 and FVC percent predicted median (range) were significantly higher than baseline (86% [49-124%] vs. 75% [36-93%], P < 0.005, and 86% [47-112%] vs. 78% [31-96%], P < 0.05), respectively; there was no significant difference between baseline and follow-up FEV(1):FVC ratios. There was no significant correlation between HRCT-chest score changes and FEV1 or FVC changes. Bronchiectasis secondary to primary immunodeficiency in childhood is not always a progressive condition, suggesting a potential to slow or prevent disease progression with appropriate treatment.

Association between Mucoid Pseudomonas Infection and Bronchiectasis in Children with Cystic Fibrosis

Association between Mucoid Pseudomonas Infection and Bronchiectasis in Children with Cystic Fibrosis

Thoracoscopic Pneumonectomy for Severe Bronchiectasis in a 9-Year-Old Female

Thoracoscopic total pneumonectomy has not been previously described in the pediatric surgical literature. In this paper, we describe a case of pneumonectomy performed through a minimally invasive approach in a 9-year-old female with Down's syndrome and gastroesophageal reflux disease. The patient suffered from multiple recurrent aspiration pneumonias, which progressed to bronchiectasis of the entire left lung. As a result, the patient was hypoxemic and required continuous supplemental oxygen. Preoperative perfusion scans showed diminished perfusion of the left lung. Thoracoscopy was performed by using 3-5 mm trocars and one 12-mm trocar. Insufflation pressure was maintained at 5 mm Hg. Dissection was performed at the hilum by using hook electrocautery and the LigaSure device (ValleyLab, Boulder, CO). The pulmonary artery, veins, and left mainstem bronchus were sequentially divided by using a 35-mm ENDO GIA vascular stapler (Ethicon Endo-Surgery, Cincinnati, OH). There were no intraoperative complications. Eight months following surgery, her health is improved and she no longer requires supplemental oxygen. Thoracoscopic pneumonectomy is a safe, technically feasible approach for severe bronchiectasis in children.

Lung resection for bronchiectasis in children.

Twenty children with bronchiectasis underwent pulmonary resections during an 8-year period. All patients suffered from significant symptoms that did not respond to medical treatment and had localised disease. In 7 patients bronchiectasis developed following foreign body aspiration and in two the aetiology was cystic fibrosis and immune deficiency, respectively. The lower lobes were most commonly involved. Atelectasis of the remaining ipsilateral lung was the most common postoperative complication occurring in four patients. One patient required reoperation for recurrent symptoms. Fifteen out of 18 patients who underwent curative resections were asymptomatic in the longterm follow-up. It is concluded that for children with significant symptoms due to localised bronchiectasis that fails to respond to medical treatment, resection of the affected lobes is indicated.

Aerosolized Antibiotics for Non-Cystic Fibrosis Bronchiectasis

There are strong data supporting using the use of aerosolized antibiotics for the treatment of Gram-negative infections in patients with cystic fibrosis (CF). The regular use of aerosol tobramycin or colistin can decrease exacerbations of lung disease, decrease bacteria counts, and improve pulmonary function in persons with CF and Pseudomonas aeruginosa airway infection. Bronchiectasis is caused by reoccurring or continuous presence of bacteria in association with airway obstruction. Although CF is the most common cause of childhood bronchiectasis, there are many other causes. Because secretions in the bronchiectasis airway are similar to the pus found in the CF airway, and because pulmonary complications and progression of disease in non-CF bronchiectasis is similar to CF bronchiectasis, many centers treat patients with bronchiectasis using aerosolized tobramycin solution for inhalation (TSI). There have been only a few small studies of aerosolized antibiotics to treat pseudomonas infection in subjects with non-CF bronchiectasis. Unlike the CF experience, there does not seem to be an improvement of pulmonary function after treatment with aerosol tobramycin in this population despite a decreased sputum bacterial density and a trend toward a decrease in risk of hospitalization. Furthermore, the risk of adverse events such as bronchospasm may be more common in adults with non-CF bronchiectasis than reported in the CF population.

Indikacije i rezultati resekcionih hirurskih postupaka u lokalizovanom obliku bronhiektazija

Although the prevalence of bronchiectasis decreased significantly in developed countries, in less developed and in developing countries, it still represents a significant cause of morbidity and mortality. The localised form of bronchiectasis is the indication for surgical treatment if recurrent respiratory infections make normal life and professional activity impossible. Less frequently, the operation is necessary independently on the symptoms duration, if massive hemoptysis are life threatening for the patient. Compared with the period 10-15 years ago, the diagnostics of bronchiectasis changed in terms that bronchography has been replaced by high resolution CT scan. Owing to angiographic studies performed on sufficient number of patients, the patophysiology of bronchiectasis is furtherly highlited, but without significant changes in the process of patient selection. In the text, particular accent was given to situations that usually represent practical problems: billateral bronchiectasis, hemoptysis, bronchiectasis after pleural empyema, abscending bronchiectasis and bronchiectasis in children. The outcome of the surgical treatment is good in 90% patients, with operative mortality thatis comparable to that after lung resections for other indications.

Bronchiectasis in Children with Recurrent Pneumonia: An Immunopathological Damage Associated with Secondary Ciliary Dysmotility

The aim of this study is to assess ciliary motion patterns in children with bronchiectasis unrelated to cystic fibrosis or primary ciliary dyskinesia. In 51 children with recurrent pneumonia, high resolution computed tomography (HRCT) was carried out to detect and score bronchiectasis. Moreover, ciliary ultrastructure, beat frequency and motion pattern were evaluated and compared to those observed in 30 healthy children. Bronchiectasis at HRCT was found in 31/51 children. Ciliary dysmotility was found in 20/31 children with bronchiectasis (64.5%). Overall, ciliary dysmotility was found in 39/51 patients (76.5%). Ciliary dysmotility showed a significant correlation with the HRCT score (p=0.02). Absent motion in some fields was found in 44/51 patients (86.3%) and this also showed significant correlation with the HRCT score (p=0.005). The specificity and sensitivity of ciliary dysmotility as an indicator of bronchiectasis was 74.3% and 83.3% respectively. The positive predictive value was 93.5%, and negative predictive value was 50%. Ciliary dysmotility, in children with recurrent airways infections, correlates with the presence and severity of bronchiectasis. Whether ciliary dysmotility is a cause or a consequence of anatomical lesion is a matter of speculation. Very likely there is an amplification and self-maintaining mechanism between the two events which may lead to more serious disease.

The role of TAP1 and TAP2 gene polymorphism in idiopathic bronchiectasis in children

Bronchiectasis is characterized by permanent changes in the structure and function of the airways. Its cause cannot be identified in some cases. A genetic disease can predispose to bronchiectasis in our country, where consanguinity of parents is common. Transporter associated with antigen presentation (TAP) deficiency syndrome is characterized by recurrent bacterial lower respiratory tract infections, which cause bronchiectasis. Our aim was to document the relationship between idiopathic bronchiectasis and TAP gene polymorphisms. Forty-four patients with idiopathic bronchiectasis and 100 healthy individuals as the control group were included. DNA was extracted and gene polymorphisms for TAP1 and TAP2 were studied. When compared to healthy controls, in the patient group, Ile/Ile genotype was decreased and Ile/Val genotype was increased in TAP1-333 polymorphism analysis; Asp/Asp and Gly/Gly genotypes were decreased and Asp/Gly frequency was increased in TAP1-637 polymorphism analysis; Ile/Val genotype was increased and Ile/Ile genotype was decreased in TAP2-379 polymorphism analysis; and Thr/Thr genotype frequency was decreased and Thr/Ala and Ala/Ala genotypes were increased in TAP2-665 polymorphism analysis. No statistically significant difference between patient and control groups was noted only in TAP2-565 polymorphism analysis. These results indicate that TAP gene polymorphisms may have had a role in the development of bronchiectasis in our patient group. Therefore, TAP deficiency syndrome should be considered in children with idiopathic diagnosis, since early diagnosis of the disease will improve life quality and survival.

Surgical management of bronchiectasis in childhood

Though there is a gradual decrease in the prevalence of bronchiectasis, it is still a cause of mortality and morbidity among children in developing countries such as Turkey. We reviewed the morbidity and mortality rates and the outcome of surgical treatment for childhood bronchiectasis. Age, sex, etiological factors, symptoms, radiological examinations, surgical procedures, postoperative morbidity and mortality in patients aged 16 years and younger, operated for bronchiectasis between January 1991 and April 2006 in the Thoracic Surgery Clinic of Atatürk Training and Research Hospital for Chest Disease and Chest Surgery were reviewed retrospectively. Between January 1991 and April 2006, 176 cases aged 16 and younger were operated for bronchiectasis. There were 95 females (54%) and 81 males (46%), with a mean age of 12.3 years (range: 3.4-16 years). The most common cause of bronchiectasis was lung infection (n: 87, 49.4%). Main symptoms were coughing (n: 167, 94.9%), sputum (n: 139, 79%), hemoptysis (n: 78, 44.3%), and fever (n: 77, 43.7%). Mean duration of the symptoms in patients who were operated was 3.8 years (range: 0-7.6 years). Cases underwent a total of 201 operations: 19 cases had bilateral surgical resection and 6 cases had completion pneumonectomy. Majority of cases had complete resection (n: 165, 93.75%) while only 11 cases (6.25%) had incomplete resection. Mean duration of hospitalization was 8.9 days (range: 5-39 days). The outcome, based on the responses of patients postoperatively, was 'perfect' in 129 cases (73.3%), 'improved' in 41 cases (23.3%), and 'no changes' in 6 cases (3.4%). The mean follow-up after surgery was 4.3 years (range: 14 months to 7.2 years), mortality was 0% and morbidity was 13% (n: 23). With acceptable mortality and morbidity rates and high chance of cure after complete resection, surgical treatment is a successful and reliable method of treatment in childhood bronchiectasis that yields marked improvement in the quality of life.

Non-Cystic-Fibrosis Bronchiectasis in Children: A Persisting Problem in Developing Countries

Background: Non-cystic-fibrosis (non-CF) bronchiectasis in childhood is still one of the most common causes of childhood morbidity in developing countries. The management of these patients remains problematic, and there are few studies of long-term outcome. Objective: The aim of this retrospective study was to define the general characteristics, underlying causative factors and long-term follow-up results of non-CF bronchiectasis patients. Methods: One hundred and eleven consecutive children, diagnosed with non-CF bronchiectasis were included in the study. General characteristics and underlying causes were recorded from the medical records. Clinical outcomes were evaluated in terms of lung function tests, annual exacerbation rates and patient/parent perception of health status. Results: Mean age of the patients was 7.4 ± 3.7 years at presentation, and patients had been followed 4.7 ± 2.7 years on average. In 62.2% of the patients, an underlying etiology was identified, whereas postinfectious bronchiectasis was the most common (29.7%). In spite of intensive medical treatment, 23.4% of the patients required surgery. The annual lower respiratory infection rate has decreased from a mean of 6.6 ± 4.0 to 2.9 ± 2.9 during follow-up (p < 0.0001). Lung function tests were also found to be improved (mean FEV₁% 63.3 ± 21.0 vs. 73.9 ± 27.9; p = 0.01; mean FVC% 68.1 ± 22.2 vs. 74.0 ± 24.8; p = 0.04). There was clinical improvement in both the surgical (73%) and medical (70.1%) groups (p > 0.05). Conclusion: In conclusion, bronchiectasis remains a disease of concern to pediatricians, particularly in developing countries. Infections are still important causes of bronchiectasis, and clinical improvement can be achieved by appropriate treatment. Although medical treatment is the mainstay of management, surgery should be considered in selected patients.

Tomografía computarizada pulmonar en niños con fibrosis quística en Asturias

The advent of computed tomography (CT) has allowed the early detection of pathological changes in patients with cystic fibrosis (CF). Description of the early pathological changes and distribution of bronchiectasis in children with CF is limited, because most studies have been performed in older children and adults with well-established lung disease. The aim of this study was to describe the distribution pattern of this disease in Asturius. We performed a retrospective study of the medical records and CT scans of patients followed up in our Cystic Fibrosis Unit. CT scans were scored by two radiologists according to Bhalla and Nathanson scores. Pathological changes were analyzed and correlated with clinical data and pulmonary function tests. The 41 CT reviewed contained between 10 and 47 slices, with a median of 16. The total number of slices was 758, of which 606 (79.95%) were considered acceptable and 152 were considered unacceptable by the radiologists. The most frequent lesions found were bronchiectasis (78.38%), followed by mucous plugs (37.84%). The most frequently affected bronchopulmonary segments were S1 and S2 in the right lung. Statistically significant correlations were found between Bhalla and Nathanson scores and disease duration. No statistically significant correlations were found between Bhalla and Nathanson scores and pulmonary function tests. The most frequent lesions in our environment were bronchiectasis followed by mucous plugs. The upper right lobe was the first to be affected, which correlates with findings in most published studies.

Bronchiectasis: the Consequence of Late Diagnosis in Chronic Respiratory Symptoms

Bronchiectasis is still common among some developing countries like Turkey. The aim of this study was to document the number of children with non-cystic fibrosis (CF) bronchiectasis, to evaluate the risk factors and to emphasize early diagnosis and treatment. All children, except those diagnosed with CF, with bronchiectasis established by chest radiogram, bronchography and/or computed tomography or biopsy material, were retrospectively reviewed. They were tested for serum total eosinophil count, nasal smear, serum levels of immunoglobulins A, G, M, E, and serum alpha-1 antitrypsin level. Pulmonary function tests, rigid bronchoscopy, nasal biopsy, lung scintigraphy, and echocardiogram were also performed. There were 204 patients whose most common presenting symptoms were cough, sputum expectoration, and dyspnea. Bronchiectasis was present mostly in the left lower lobe. The cause could not be determined in 49 per cent of patients. Among the identified causes, infection was present in most patients, followed by asthma, primary ciliary dyskinesia, congenital immune deficiency, and foreign body aspiration. It is possible to prevent bronchiectasis in children with vaccinations and improved nutrition in developing countries. Early diagnosis and treatment will increase the quality of life and survival of patients with bronchiectasis, which has irreversible and progressive complications if untreated.

Nebulised gentamicin—suitable for childhood bronchiectasis

Nebulised antibiotic therapy is an established, safe and effective therapy for cystic fibrosis with chronic pseudomonas infection resulting in improved pulmonary function and reduced hospitalisation. Despite similar respiratory disease, this therapy has not been evaluated in children with non cystic fibrosis bronchiectasis. This study evaluates the suitability of a gentamicin solution and nebuliser combination for use in this population. Materials and methods: Four millilitres of gentamicin (80 mg) in saline delivered by a PARI LC plus ® nebuliser and PARI Turboboy N ® compressor was used. The pH, osmolarity, chloride concentration and aerosol particle size was determined. Ten children with non cystic fibrosis bronchiectasis received nebulised antibiotic and had peak gentamicin concentrations measured in sputum and serum. Pulmonary function was measured pre and post nebulisation. Results: The solution had an osmolarity of 199 mOsm/l, pH of 4.1, chloride concentration of 75 mmol/l and the aerosol a mass median aerodynamic diameter of 3.3 μm. Nebulisation was well tolerated, with no significant change in FEV1. Peak serum levels were at the threshold of detectability (0.3 mg/l). Sputum concentrations had a mean of 624 mg/g and lower 95th confidence interval 25 times the minimum inhibitory concentration for the predominant infecting organism, Haemophilus influenzae. Conclusion: Nebulisation of 80 mg of gentamicin in saline achieved bactericidal concentrations in sputum, was well tolerated and had negligible systemic absorption making it a suitable choice for this population.

Surgical treatment of bronchiectasis in children

Background purpose Surgical treatment of childhood bronchiectasis has not been discussed extensively because of decline in prevalence and experience with this disease. It remains controversial as to which children would benefit from surgery and surgical points that may affect the outcome. Therefore, a retrospective series was prepared to evaluate the results of surgical treatment of bronchiectasis in children. Methods The records of 54 children who underwent surgery for bronchiectasis between 1991 and 2002 were analyzed retrospectively for age; sex; clinical features; radiologic examinations; details of surgery including type of resection, operative morbidity, and mortality; and outcome. Results Fifty-four patients underwent 58 pulmonary resections during the study period. The mean ages at diagnosis of bronchiectasis and at the time of surgery were 7.80 ± 3.70 years (range, 1 to 15 years) and 9.25 ± 3.92 years (range, 1.5 to 17 years), respectively, with a male to female ratio of 5:4. The causes of bronchiectasis were lung infection (n = 39), hereditary and inborn diseases (n = 14), and foreign body aspiration (n = 1). Chest X-rays, bronchography (n = 12) or chest computed tomography (n = 43), and ventilation-perfusion scintigraphy (n = 13) were used, and pulmonary function tests (n = 21) and bronchoscopy (n = 54) were performed. The types of resections were lobectomy (63%), pneumonectomy (18.5%), lobectomy with segmentectomy (11.1%), segmentectomy (3.7%), and bilobectomy (3.7%). Four patients required a second operation. Forty-one patients (76%) had complete resection, and 13 patients (24%) had incomplete resection. Intraoperative and postoperative complications were encountered in 4 (7.4%) and 4 patients (7.4%), respectively. The course after surgery was well in 23 (42.5%), improved in 23 (42.5%), and unchanged or worse in 5 patients (9.4%). The mortality rate was 5.6%. Conclusions The decision for bronchiectasis surgery should be made in cooperation with the chest diseases unit. Anatomic localization of the disease should be mapped clearly by radiologic and scintigraphic investigations. The morbidity and mortality rates of bronchiectasis surgery are within acceptable ranges. Most of the children benefit from surgery, especially when total excision is accomplished. Pneumonectomy is well tolerated in children without increase in morbidity and mortality. Therefore, pneumonectomy may be preferred instead of leaving residual disease when bronchiectasis is unilateral.

Surgical management of childhood bronchiectasis due to infectious disease

Background The purpose of this study was to estimate operative risk and to identify indicators of adverse prognosis in patients undergoing resection for childhood bronchiectasis. Methods From January 1985 to February 2001, patients undergoing resection for bronchiectasis were studied. The indications for operation were failure of medical therapy in 33 patients (94.2%) and hemoptysis in 2 (5.7%). The mean duration of symptoms was 4.2 years (range, 1-9 years). Surgical treatment included lobectomy in 17 patients (48.5%), pneumonectomy in 7 (20%), lobectomy plus segmentectomy in 5 (14.2%), bilobectomy in 2 (5.7%), and segmentectomy in 4 (11.4%). Results The operative mortality rate was 2.8%, and the morbidity rate was 17.6%. The mean follow-up in 34 patients was 5.4 years (range, 1-12 years). Overall, 22 patients (64.7%) were asymptomatic after surgery. Clinical improvement was noticed in 8 patients (23.5%), and no improvement was noticed in 4 (11.7%). Complete resection resulted in a significantly better clinical outcome than incomplete resection ( P < .05). Conclusions Surgery for childhood bronchiectasis can be performed with low mortality and morbidity. Complete resection should be performed when possible.

Early radiographic and clinical features associated with bronchiectasis in children.

Bronchiectasis among children living in developing regions is associated with respiratory infections during early childhood, but specific risk factors that precede childhood bronchiectasis are not fully characterized. We hypothesized that severe respiratory syncytial viral (RSV) infection in infancy would increase the risk of bronchiectasis among Alaska Native children in rural Alaska. This was a follow-up cohort study of a 1993-1996 case-control study of RSV-hospitalized case patients and their controls. For each 5-8-year-old former case-patient and control subject, we reviewed medical records, interviewed parents, performed physical examinations and spirometry, collected sera, and analyzed all historical chest radiographs. Ten (11%) RSV cases and 10 (9%) controls had radiographic evidence of bronchiectasis. The mean age at radiographic diagnosis of bronchiectasis was 3.3 years (range, 1.2-6.1 years). Children were more likely to develop bronchiectasis if their chest radiographs, when they were < 2 years of age, showed lung parenchymal densities (RR = 3.9, P < 0.013), persistent parenchymal densities > 6 months' duration (RR = 3.0, P = 0.02), or infiltrates on multiple episodes (test for trend, P = 0.003). Radiographic features of hyperinflation and atelectasis among children < 2 years old were not associated with eventual bronchiectasis. A single severe infection with RSV alone did not predispose Alaska Native infants to bronchiectasis. Childhood bronchiectasis was associated with lung and hence airway injury, manifested on radiographs by parenchymal densities or "pneumonia" rather than by hyperinflation or atelectasis.

Retrospective review of children presenting with non cystic fibrosis bronchiectasis: HRCT features and clinical relationships

Non cystic fibrosis (CF) bronchiectasis in children presents with a spectrum of disease severity. Our aims were to document the extent and severity of disease in children with non-CF bronchiectasis, to review the inter- and intraobserver agreement for the high-resolution computed tomography (HRCT) features examined, and to assess correlations between HRCT features and clinical measures of severity. We performed a retrospective review of 56 children from the Starship Children's Hospital. HRCT scans were scored by a modified Bhalla system, and the chest X-rays using the Brasfield score. Scores were correlated with demographics, number of hospitalizations, disease duration, pulmonary function, clinical examination, and chronic sputum infection. The bronchiectasis seen was widespread and severe, particularly in Maori and Pacific Island children. The kappa coefficient for intraobserver agreement was better than that for interobserver agreement. Comparisons between HRCT scan and lung function parameters showed that the strongest relationships were between forced expiratory volume in 1 sec (FEV(1)) and forced expiratory flow between 25-75% of forced vital capacity (FEF(25-75)) with the extent of bronchiectasis, bronchial wall thickening, and air trapping. Children with digital clubbing and chest deformity showed significantly higher scores for extent of bronchiectasis, bronchial wall dilatation and thickness, and overall computed tomography (CT) score. No relationship was demonstrated between chronic sputum infection and CT score. The HRCT score demonstrated a stronger correlation between the extent and severity of bronchiectasis, and spirometry values, than the chest X-ray score. In conclusion, pediatric non-CF bronchiectasis in Auckland is extensive and severe. The good intraobserver ratings mean that consistency of scoring is possible on repeated scans. This study cannot comment on the relationships of CT and less severe disease.