The pathology of cystic fibrosis

doi:10.1054/cdip.2001.0088

Current Diagnostic Pathology

Volume 8, Issue 1, February 2002, Pages 50-59

https://doi.org/10.1054/cdip.2001.0088 Get rights and content

Abstract

Cystic fibrosis (CF) is one of the commonest lethal inherited conditions among Caucasians. It affects multiple organ systems and exhibits a range of clinical problems of varying severity. Life expectancy has improved in recent years as treatment regimes have become more intensive, but current treatments are expensive, often time consuming and may affect quality of life. New treatments for the pulmonary disease are under clinical trial and include antiproteases, amiloride, a sodium channel blocker, DNase and gene therapy. The gene for cystic fibrosis was identified in 1989 and this together with the emerging technology of gene therapy heralded a new dawn for the treatment of genetic disease. The lung is considered an ideal organ to target due to ease of access, but subsequent research has shown that the airway surface provides an efficient barrier to topically applied gene transfer agents. A number of Phase I clinical safety trials were carried out through the 1990s and provided proof of concept evidence that delivery of DNA by either viral or non-viral means was safe though not clinically efficacious. Current research is now focusing more on the barriers faced by delivery agents, with the aim that more efficient gene delivery will lead to a gene therapy for cystic fibrosis. The histopathologist is rarely called upon to make the initial diagnosis as cystic fibrosis is usually diagnosed clinically, being characterized by chronic bronchopulmonary infection, malabsorption due to pancreatic insufficiency and a high sweat-sodium concentration on sweat testing. Most information concerning both macroscopic and microscopic findings in cystic fibrosis has come from autopsy studies, so the pathological features are often extreme. However, with increasing survival of patients with cystic fibrosis, we are seeing more subtle changes in other organs and in addition, more aggressive drug therapy, gene therapy and lung transplantation are bringing with them new disease entities and complications.

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Experiment proves that the pro-inflammatory cytokines IL-1β directly regulates the initiation of acute and chronic inflammation making it a valuable target of IPF [88]. Cystic fibrosis is characterized as a most common autosomal recessive genetic disorder caused by the mutation in CFTR gene (transmembrane protein gene-cystic fibrosis transmembrane conductance receptor) [89]. Pathology of the disease involves bronchiolitis, obstruction of pathways, endobronchiolar infection, impaired ciliary actions, atelectasis finally leading to secondary alveolar injury.
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Cystic fibrosis (CF) is a genetic rare disease caused by mutations in the gene coding the CF trans-membrane conductance regulator protein leading to viscous mucus presence in the airways (Moskowitz et al., 2005; Sheppard and Nicholson, 2002).
The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy.
For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD.
An in vivo study in healthy human volunteers showed that 3–6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device.
The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy.
Vitamin E status and its determinants in patients with cystic fibrosis
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The membrane protein is a product of CFTR gene transcription and functions as an ion channel for sodium, chloride and water [3]. Dysfunctional protein leads to the accumulation of mucus on epithelial surfaces in many organs of respiratory, digestive and reproduction systems [4]. Accordingly, pancreatic insufficiency is one of the many consequences occurring in 85–90% CF patients and leads to fat-soluble vitamins deficiency (A, D, E, K) [5,6].
The risk of vitamin E deficiency is of primary concern in cystic fibrosis patients. However, early diagnosis and routine vitamin E supplementation can lead to its normal or even high levels. In the present study, we assessed vitamin E status in a large group of cystic fibrosis patients. Moreover, we also aimed to establish determinants of its body resources in cystic fibrosis patients.
The study group comprised 211 cystic fibrosis patients aged from 1 month to 48 years. In all of them serum α-tocopherol concentration was analyzed using high-performance liquid chromatography.
Median vitamin E concentration was 9.9 μg/ml (1st–3rd quartile: 7.5–13.5). Vitamin E deficiency was found in 17 (8.0%) and high levels were documented in 24 (11.4%) participants. Patients with and without vitamin E deficiency did not differ significantly with respect to age, standardized body weight and height, FEV1, albumin concentration and vitamin E supplementation dose. However, vitamin E deficiency appeared more frequently in participants without vitamin E supplementation. Moreover, in multiple linear regression analysis pancreatic insufficiency, severe CFTR gene mutation and vitamin E dose, were potentially defined as determinants of vitamin E concentration.
Vitamin E deficiency in cystic fibrosis patients is rather rare nowadays. Excessive vitamin E levels seem to be more frequent. Vitamin E status wasn’t documented to be strictly related to clinical determinants. Beyond vitamin E supplementation, exocrine pancreatic function and CFTR gene mutations may have had an impact on the vitamin E body resources in cystic fibrosis patients.
Inhalable DNase I microparticles engineered with biologically active excipients
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Cystic fibrosis (CF) is the most common autosomal, recessive, life-span shortening disease in Caucasians. Development of chronic pulmonary diseases is the main cause of mortality in CF patients [1]. Currently, DNase I (Mw 33 KDa) is delivered as a nebulising solution.
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Cystic fibrosis (CF) is a common autosomal recessive disorder in the Caucasian population, affecting 1 in 2000 of live births (Sheppard and Nicholson, 2002).
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^f1: Correspondence to: MNS. E-mail: [email protected]

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ReviewThe pathology of cystic fibrosis

Abstract

J Paediatr

J Allergy Clin Immunol

Hum Pathol

Hum Pathol

J Pediatr

Transplan Proc

Lancet

Hum Pathol

Hum Pathol

J Pediatr Surg

J Urol

Fertil Steril

J Pediatr

Ann Diagn Pathol

J Urol

The diagnosis of cystic fibrosis

N Eng J Med

Clinical presentation of exclusive cystic fibrosis lung disease

Thorax

Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis

Pediatrics

Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations

Hum Genet

Cystic fibrosis mutation associated with mild lung disease

N Engl J Med

HLA class II polymorphism in cystic fibrosis—a possible modifier of pulmonary phenotype

Am J Respir Crit Care Med

Genotype and phenotype in cystic fibrosis

Respiration

Upper respiratory tract in cystic fibrosis. Ear–nose–throat survey in children

Arch Dis Child

Pathogenesis of lung disease in cystic fibrosis

Respiration

Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis

Br Med J

Microbiology of lung infections in cystic fibrosis patients

Acta Paediatr Scand Suppl

Pseudomonas cepacia in the sputum of cystic fibrosis patients

Pathology

Non-tuberculous mycobacteria in cystic fibrosis

Thorax

Chlamydia pneumoniae infection in patients with cystic fibrosis

Clin Infect Dis

Three cases of pulmonary aspergilloma in adult patients with cystic fibrosis

Thorax

Allergic bronchopulmonary aspergillosis

Annu Rev Med

Fatal invasive aspergillosis in an adolescent with cystic fibrosis

Pediatr Pulmonol

The pathogenesis of fibrocystic disease of the pancreas. A study of 36 cases with special reference to pulmonary lesions

Pediatrics

Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis

Am J Med Genet

Bronchial obstruction with lobar atelectasis and emphysema in cystic fibrosis of the pancreas

Pediatrics

Bronchiolitis obliterans organizing pneumonia: a distinct pulmonary complication in cystic fibrosis

Respiration

Pneumothorax in cystic fibrosis

JAMA

Review
The pathology of cystic fibrosis