Diffuse Interstitial Pulmonary Fibrosis Research Articles

Safety of Lumason® (SonoVue®) in special populations and critically ill patients.

Evidence for the safe use of Lumason® (SonoVue®), an ultrasound enhancing agent (UEA), in special patient populations is critical to enable healthcare professionals to make informed decisions concerning its use in such patients. Herein, we provide insight on the safety and tolerability of Lumason® in special patient populations. Findings are presented from clinical pharmacology studies conducted in patients with compromised cardiopulmonary conditions, from a retrospective study performed in critically ill patients, and from post-marketing surveillance data from over 20 years of market use of Lumason® (SonoVue®). No detrimental effects of Lumason® on cardiac electrophysiology were observed in patients with coronary artery disease (CAD), and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure. Similarly, no effects on several assessments of pulmonary function (e.g., FVC) were observed in patients with chronic obstructive pulmonary disease (COPD), and no clinically meaningful changes in O2 saturation or other safety parameters were observed after administration of Lumason® to patients with diffuse interstitial pulmonary fibrosis (DIPF). The retrospective study of critically ill patients revealed no significant difference for in-hospital mortality between patients administered Lumason® for echocardiography versus those who had undergone echocardiography without contrast agent. Post-marketing surveillance revealed very low reporting rates (RR) for non-serious and serious adverse events and that serious hypersensitivity reactions were rare. These findings confirm that Lumason® is a safe and well tolerated UEA for use in special populations and critically ill patients.

Update in Diagnosis of Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormality

최신 국제 임상진료지침을 기반으로 한 특발폐섬유증의 진단은 부합하는 임상 소견과 함께 고해상 CT에서 전형적인 상용간질폐렴 소견을 보일 때 조직학적 폐 생검 없이 진단 가능하다. 영상 검사는 특발폐섬유증의 평가 및 진단에 중추적인 역할을 하며, 정확한 진단을 위하여 임상적, 영상의학적 및 병리학적 소견에 대한 다학제 검토의 중요성이 강조된다. 간질성 폐이상(interstitial lung abnormality)은 우연히 발견된 영상의학적 이상 소견을 지칭하며, 간질성폐이상과 임상적으로 의미 있는 간질폐질환에 대한 구분은 적절한 임상 평가를 기반으로 이루어져야 한다. 저자들은 이번 종설을 통하여 특발폐섬유증 진단의 최신 지견 및 간질성폐이상에 대한 이해를 도움으로써 미만성 간질폐섬유증 환자의 정확한 진단과 치료 및 예후 증진에 도움이 되고자 한다.

Radiologic Diagnosis of Asbestosis in Korea.

Asbestosis is the most important change noted in the lung parenchyma after environmental and occupational exposure to asbestos fibers. It is characterized by diffuse interstitial pulmonary fibrosis. In Korea, the incidence of asbestosis will continue to increase for many years to come and the government enacted the Asbestos Damage Relief Law in 2011 to provide compensation to those suffering from asbestos-related diseases. Radiologic evaluation is necessary for diagnosis of asbestosis, and radiologists play a key role in this process. Therefore, it is important for radiologists to be aware of the various imaging features of asbestosis.

Angelica sinensis is effective in treating diffuse interstitial pulmonary fibrosis in rats

The aim of this study was to investigate the therapeutic effect of Angelica sinensis on a rat model of diffuse interstitial pulmonary fibrosis induced by bleomycin A5. The mechanism by which A. sinensis exerts its effect is also discussed. A diffuse interstitial pulmonary fibrosis model was established in 36 male Wistar rats by an endotracheal injection of bleomycin A5 (5 mg/kg). Then, these rats were randomly divided into the model group (n = 18) and the treatment group (treated with A. sinensis after modelling, n = 18). Control rats (n = 6) received an equal volume of saline. Hematoxylin–eosin (HE) staining was performed to analyse alveolitis and Masson staining, to observe pulmonary fibrosis. Collagen content was determined by hydroxyproline assay. Nuclear factor kappa B (NF-κB) activity was measured by electrophoretic mobility shift assay. Transforming growth factor-β (TGF-β) expression at mRNA level was detected by northern blotting and at protein level by enzyme-linked immunosorbent assay. The results obtained showed that the alveolitis and pulmonary fibrosis of the rats treated with A. sinensis was significantly alleviated compared with that of the rats in the model group. Treatment with A. sinensis also lowered the content of collagen, decreased NF-κB activity in alveolar macrophages and reduced the TGF-β expression at the mRNA and protein level. These results indicated that A. sinensis is effective in treating and alleviating interstitial pulmonary fibrosis, possibly by lowering collagen, inhibiting the activity of NF-κB and reducing the TGF-β expression.

Case 3 - Congestive Heart Failure in Male with Systemic Sclerosis

71 year-old Caucasian male, resident of Campinas - SP, diagnosed with diffuse systemic sclerosis, with clinical condition initiated by skin stiffening in lower limbs for seven months, which spread three months ago to the upper limbs (hands and forearms) and, one month ago, to chest and abdomen; in addition to confirmatory laboratory exams, such as the research of anti-nuclear factor reagent in 1:640 titration with dense fine speckled pattern and anti-topoisomerase antibodies I (Anti-Scl 70) also reagent, was under outpatient follow-up at the service rheumatology sector. The patient had no other comorbities or relevant medical history. In the occasion, he sought medical care and had progressive dyspnea during minor efforts, edema on lower limbs and dry cough. This clinical condition began five months earlier. Physical exam showed good general state, with 92bpm heart rate and 80/60mmHg blood pressure, 60o jugular turgidity and peripheral perfusion unchanged. When examining the lungs, vesicular breath sounds was significantly reduced, with velcro-type rales in both bases. Precordium and abdomen exams showed no changes. There was a severe skin tightening on hands and forearms, with limited movements, contracture flexion and tendon retraction, giving the appearance of claw and digital ulcers. Lower limbs showed the same skin severity level, also with movements limitation and edema ++/+4 on the distal 2/3. On the skin we noticed several pigmentary changes on hands, forearms, chest and abdomen. However, skin biopsy was not performed. Chest computed tomography showed diffuse interstitial pulmonary fibrosis, characteristic of usual interstitial pneumonia with subpleural involvement and regions with ground glass appearance, in addition to distortion signs of the pulmonary parenchyma, with reticulate and images that suggest bronchiectasis, specially in lower limbs (Figure 1). On the mediastinal window there was a suggestive image of pericardial thickening, in addition to a small amount of fluid (Figure 2). Figure 1 Chest CT showing a diffuse interstitial pulmonary fibrosis, with subpleural involvement, honeycombing and bronchiectasis, characteristics of a usual pattern of interstitial pneumonia. Figure 2 Chest CT demonstrating pericardial thickening and a small amount of fluid. In the electrocardiogram there was an atrial fibrillation rhythm, without further changes. Echocardiogram measures are described on Table 1. This exam also identified a mild mitral insufficiency, severe tricuspid insufficiency and signs of severe pulmonary hypertension, being the systolic pressure in pulmonary artery (SPPA) underestimated due to severe tricuspid reflux, with RV - RA gradient of 20mmHg.No changes on pericardium were shown. Table 1 Measures obtained through echocardiogram, showing a moderate dilation on the left atrium After 40 days of hospitalization, he showed a worsening clinical condition and a relevant hemodynamic impairment, which resulted in cardiogenic shock and death. (Dr. Mariana Bittar Lopes; Academician Caio Bosquiero Zanetti)

The effect of octreotide, an analog of somatostatin, on bleomycin-induced interstitial pulmonary fibrosis in rats

In this study, octreotide (OCT), a synthetic somatostatin analog, was tested for its beneficial effects in the prevention of interstitial pulmonary fibrosis (IPF) induced by bleomycin (BLM) in rats by histological examination and by evaluating tissue OH-proline levels. Thirty male Wistar rats were divided randomly into three groups: group I: intratracheal (i.t.) BLM (7.5 mg/kg, single dose) + saline solution [0.9% NaCl, subcutaneously (s.c.), once-daily for 7 days]; group II: i.t. BLM (7.5 mg/kg, single dose) + OCT acetate (82.5 µg/kg, s.c., once-daily for 7 days); and the control group. At the end of the 7 days, lung tissues were excised and examined by histopathological methods. Levels of tissue hydroxyproline (OH-proline) were determined. BLM administration resulted in prominent histopathologic findings, such as diffuse alveolar damage and interstitial pulmonary fibrosis, as well as a significant increase in OH-proline level, as compared to controls. OCT application explicitly attenuated the histopathologic changes to a significant extent. OCT decreased paranchymal fibrosis and structural deformities in BLM-induced lung fibrosis. These results suggest that OCT administration to rats with BLM-induced IPF has a protective effect. Further studies are necessary to reveal the molecular mechanism(s) of OCT-induced protective effect.

Methotrexate-induced pulmonary toxicity in psoriatic arthritis (PsA): case presentation and literature review

A 45-year-old female with a 4-week history of psoriatic arthritis developed cough, fever, and progressive shortness of breath 2 weeks following initiation of methotrexate therapy. High resolution CT of chest revealed bilateral basal interstitial involvement and diffuse ground glass opacities. Patient, though, died despite immediate discontinuation of methotrexate and initiation of treatment with IV methylprednisolone and cyclophosphamide. Post-mortem examination showed diffuse interstitial pulmonary fibrosis. Methotrexate-induced pulmonary toxicity is a serious event, unpredictable, and unusual, especially in patients with psoriatic arthritis, and although reversible, it may be fatal.

Drug-induced pneumonitis

Drug can cause various types of lung damages, with drug-induced pneumonitis (including acute interstitial pneumonia, usual interstitial pneumonia, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, bronchiolitis obliterans with organizing pneumonia, eosinophilic pneumonia and hypersensitivity pneumonitis) being the most important among them. The incidence and the causative agents of drug induced pneumonitis have varied over time. Before 1980, anticancer agents and gold salts were the main drugs, and the number of causative drugs (61) and case reports was small. Recently, pneumonitis has increasingly been caused by Chinese herbal medicines, antibiotics, chemotherapy agents, anti-inflammatory drugs, analgesics, cytokines, and gold salts, and the number of case reports and drugs involved (177) has increased. Drug-induced pneumonitis has characteristics that depend on the causative agent. Review of our patients and reports in Japan revealed the following. Pneumonitis caused by anti-inflammatory drugs, analgesics, and antibiotics generally develops at 1-2 weeks after starting administration, and bronchoalveolar lavage and histologic examination of lung biopsies reveals the features of eosinophilic pneumonia. Such pneumonitis is associated with a high frequency of a positive drug lymphocyte stimulation test (DLST), and has a good outcome. Conversely, with pneumonitis caused by anticancer and immunosuppressive agents, the onset is often delayed and the disease has features of diffuse interstitial pneumonia and pulmonary fibrosis. The frequency of a positive DLST is low, and the outcome is generally poor. Pneumonitis induced by Chinese herbal medicines, gold salts, and antituberculosis agents has intermediate features between the above two types :i.e., it develops after 2-3 months or six months (gold salts), and resembles either eosinophilic pneumonia, BOOP or interstitial pneumonia. For in vitro identification of causative drugs, the DLST and the leukocyte migration inhibition test (LMIT) are generally used. The latter test is superior in sensitivity, suggesting that the mechanism of this test involves cytokines such as IL-1 alpha, IL-1 beta, IL-2, TNF-alpha, and IL-8.

Asbestos fiber content of lungs with diffuse interstitial fibrosis: An analytical scanning electron microscopic analysis of 249 cases.

Abstract Context.—Asbestosis is one of many forms of diffuse interstitial pulmonary fibrosis. Its histologic diagnosis rests on the pattern of fibrosis and the presence of asbestos bodies by light microscopy in lung biopsies. Objective.—To determine the asbestos fiber burden in patients with diffuse pulmonary fibrosis (DPF) who had a history of asbestos exposure, but whose biopsies did not meet established criteria for asbestosis, and compare it with the fiber burden in confirmed asbestosis cases. Design.—Fiber burden analysis was performed using scanning electron microscopy and energy-dispersive x-ray analysis of lung parenchyma from 86 patients with DPF and 163 patients with asbestosis. The correlation of the number of asbestos fibers found for a quantitative degree of fibrosis was analyzed. Results.—The fibrosis scores of the asbestosis cases correlated best with the number of uncoated commercial amphibole fibers. Seven DPF cases fell within the 95% interval of asbestos body count by light microscopy a...

Asbestos Fiber Content of Lungs With Diffuse Interstitial Fibrosis: An Analytical Scanning Electron Microscopic Analysis of 249 Cases

Asbestosis is one of many forms of diffuse interstitial pulmonary fibrosis. Its histologic diagnosis rests on the pattern of fibrosis and the presence of asbestos bodies by light microscopy in lung biopsies. To determine the asbestos fiber burden in patients with diffuse pulmonary fibrosis (DPF) who had a history of asbestos exposure, but whose biopsies did not meet established criteria for asbestosis, and compare it with the fiber burden in confirmed asbestosis cases. Fiber burden analysis was performed using scanning electron microscopy and energy-dispersive x-ray analysis of lung parenchyma from 86 patients with DPF and 163 patients with asbestosis. The correlation of the number of asbestos fibers found for a quantitative degree of fibrosis was analyzed. The fibrosis scores of the asbestosis cases correlated best with the number of uncoated commercial amphibole fibers. Seven DPF cases fell within the 95% interval of asbestos body count by light microscopy and 3 cases within that of the total commercial amphibole fiber count. Strict histologic criteria are useful for positive identification of asbestosis among cases of advanced pulmonary fibrosis. Few DPF patients with history of asbestos exposure whose biopsies did not meet the criteria for asbestosis may have asbestos fiber counts in the range seen in asbestosis, and fiber type identification by scanning electron microscopy with energy-dispersive x-ray analysis should be considered in these rare instances to avoid false-positive and false-negative diagnoses of asbestosis.

Pulmonary alveolar microlithiasis with calcified pleural plaques

Pulmonary alveolar microlithiasis (PAM) is a rare disease. Herein we report a case of pulmonary alveolar microlithiasis who was suspected to have the disease on chest X-ray and was confirmed on high resolution CT and transbronchial lung biopsy. These investigations showed characteristic features of pulmonary alveolar microlithiasis with diffuse interstitial pulmonary fibrosis.

Computed Tomographic Features of Idiopathic Fibrosing Interstitial Pneumonia

To compare the computed tomographic (CT) features of idiopathic fibrosing interstitial pneumonia with those of pulmonary fibrosis related to collagen vascular disease (CVD). We reviewed the CT scans of 177 patients with diffuse interstitial pulmonary fibrosis, of which 97 had idiopathic fibrosing interstitial pneumonia and 80 had CVD. The CT images were systematically scored for the presence and extent of pulmonary and extrapulmonary abnormalities. Computed tomographic diagnosis of usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) was assigned. A CT pattern of UIP was identified in 59 (60.8%) of patients with idiopathic fibrosing interstitial pneumonia compared with 15 (18.7%) of those patients with CVD; conversely, the CT diagnosis of NSIP was made in 51 (64%) of patients with CVD compared with 36 (37%) of patients with idiopathic disease (P < 0.01). In 113 patients who had lung biopsy, the CT diagnoses of UIP and NSIP were concordant with the histologic diagnoses in 36 of 50 patients and 34 of 41 patients, respectively. Pleural effusions, esophageal dilation, and pericardial abnormalities were more frequent in patients with CVD than in patients with idiopathic fibrosing interstitial pneumonia. Compared with patients with CVD, those patients with an idiopathic fibrosing interstitial pneumonia showed a higher prevalence of a UIP pattern and lower prevalence of an NSIP pattern as determined by CT. Identification of coexisting extrapulmonary abnormalities on CT can support a diagnosis of CVD.

Imaging Diagnosis of Asbestosis

Asbestosis is diffuse interstitial pulmonary fibrosis associated with asbestos fiber inhalation. The typical chest radiographic findings in asbestosis are small irregular or reticular opacities, predominating at the lung bases. Honeycombing is evident in more advanced diseases. But chest radiograph is relatively insensitive in detecting the presence of asbestosis. HRCT is more sensitive than simple chest radiograph for diagnosis of asbestosis, especially the early change of asbestosis. The early findings of asbestosis on HRCT are subpleural dotlike opacities and curvilinear opacities. As progression of fibrosis, intralobular interstitial thickening and interlobular septal thickening are presented. In advanced diseases, parenchymal bands, traction bronchiectasis or bronchiolectasis, and honeycombing are noted. These findings are typically located in lower posterior subpleural portions with bilateral symmetric patterns. Imaging findings that are compatible with asbestosis, rale, and a reduced diffusing capacity can increase confidence of diagnosis of asbestosis.

Asbestosis

Asbestosis is a diffuse interstitial pulmonary fibrosis, secondary to the inhalation of asbestos fibres. There is a dose-response relationship between exposure to asbestos and the risk of developing asbestosis, in such a way that the greater the exposure, the greater the risk of developing the disease. The time of clinical latency is inversely proportional to the level of exposure. Dyspnoea upon exertion and a dry cough together with end-inspiratory crackles are the most frequent symptoms and signs. Chest radiography is a basic tool in identifying the disease, however high resolution CAT has added greater sensitivity. Tests of the respiratory function show alterations and restrictive ventilations with a reduction of pulmonary spread. Determination of asbestos bodies in BAL is an indicator of exposure, although their absence does not rule out the disease. A histopathological diagnosis is the most reliable, although in the majority of cases the diagnosis is established on the basis of the existence of an antecedent of exposure to asbestos together with suggestive clinical, radiological and functional findings, and a suitable time of latency, without having recourse to a pulmonary biopsy.

Rapid onset of pergolide-induced pulmonary fibrosis in a patient with corticobasal degeneration

A 66-year-old man presented with gradually increasing dyspnoea and reduced exercise tolerance. There was no chest pain or any other respiratory symptoms, he had never smoked and there was no occupational exposure to dusts, toxins or asbestos. He also complained of a dull pain and numbness in his left forearm, unrelated to exertion. Previous medical history included ischaemic heart disease and parkinsonism which was unresponsive to escalating therapy. Medication on presentation included aspirin 75 mg, pergolide 1 mg three times daily and two Sinemet plus three times daily. He was apyrexial and tachypnoeic (respiratory rate 32/min), oxygen saturation 89% on air, the peak expiratory flow rate was 140 litre/min, heart rate 82 beats/minute and bloot pressure 143/66 mmHg. The jugular venous pressure was not raised and there was poor lung expansion with florid, bibasal, late inspiratory crackles to the midzones. He was bradykinetic with a marked coarse, jerky resting tremor in the left upper limb with quasi-purposeful involuntary movements and marked apraxia. There was greatly increased axial tone. No limb weakness was demonstrated, reflexes were unremarkable and the plantar response was flexor. There was sensory impairment in the left arm and leg to all modalities. His gait was bradykinetic and shuffling with retropulsion on stopping. He had a full range of eye movements with unrestricted vertical gaze. Full blood count, urea and electrolytes, liver function tests, calcium and creatine kinase were all normal. His C-reactive protein level was 63 mg/litre and erythrocyte sedimentation rate was 45mm/hr. Arterial blood gas analysis on air revealed; partial pressure of arterial oxygen (PaO2) 7.2 Kpa, partial pressure of arterial carbon dioxide (PaCO2) 2.6 Kpa, pH 7.52, base excess 2, bicarbonate 26 mmol. An electrocardiogram showed sinus rhythm with Q waves in III and aVf. Chest X-ray showed bilateral extensive subpleural interstitial changes and honeycombing with loss of volume particularly in the right lung (Figure 1). High resolution computed tomography of the thorax demonstrated widespread bilateral reticular shadowing suggestive of fibrosis, honeycomb changes and associated basilar traction bronchiectasis. Lung function tests demonstrated a forced expiratory volume in 1 second (FEV1) 1.41 litres (52% of predicted), forced vital capacity (FVC) 1.45 litres (43% of predicted), FEV1/FVC 97% and gas transfer factor (DLCO) 17.4 (70% of predicted). He was treated with oxygen and antibiotics. Transbronchial biopsy with histology demonstrated diffuse fibrous tissue, with no evidence of infection, tuberculosis or malignancy. Bronchoalveolar lavage revealed a neutrophilia. Microbiology cultures were negative. His antinuclear antibody, complement levels, classical antineutrophil cytoplasmic antibody, rheumatoid factors, Scl-70 and Jo-1 antibodies were normal. Reviewing his medication with pharmacy led to the discontinuation of pergolide since it has been reported to cause diffuse interstitial pulmonary fibrosis. A consultant neurological review was sought and a diagnosis of corticobasal degeneration made. He was discharged on home oxygen. After 1 month of discontinuing pergolide, the patient subjectively noticed improvement in his dyspnoea, reflected in an increase in DLCO (82% predicted).

Pharyngeal and Pharyngolaryngeal Bands: Report of An Unusual Combination of Congenital Anomalies

Multiple abnormal pharyngeal and pharyngolaryngeal bands were present in a child presenting with diffuse interstitial pulmonary fibrosis. The soft palate was fused to the posterior pharyngeal wall. Instead of there being facial pillars, a muscular band on either side extended from the base of the tongue to the lateral pharyngeal walls. There was neither tonsil nor adenoid tissue present. The epiglottis was tethered to the posterior pharyngeal wall by bands from its lateral aspects. The right arytenoid mound was tethered to the posterior wall of the hypopharynx. It is postulated that these arose from a failure of development of the second branchial pouch.

The Role of HRCT in the Follow-Up Evaluation of Diffuse Interstitial Pulmonary Fibrosis

Background: Because of the power of HRCT to detect the minute changes in lung parenchyme and the advantage of noninvasiveness, it may be the ideal method of follow-up evaluation of the patients with diffuse interstitial pulmonary fibrosis. So the aim of the study is to find out whether the change of HRCT during the course of the disease can represent the change in symptom and pulmonary function test. Method: Thirteen patients with diagnosis of diffuse interstitial pulmonary fibrosis who had more than two times of HRCT during the course of disease were studied. The extent of the disease in HRCT was measured at three levels using image analyzer. The ralationship between the percent change in the disease extent in HRCT, symptom score, and pulmonary function tests were analysed. Results: The change of disease extent in HRCT has good correlation with the change in dyspnea and diffusion capacity(r=0.716, p=0.0012). But there was no correlation between the change of HRCT and FVC or TLC. Also significant inverse correlation was noted between the change in dyspnea and diffusion capacity(r=-0.707, p=0.0047). Conclusion: These data suggest that HRCT may be a good method of follow-up in diffuse interstitial pulmonary fibrosis.

Endomyocardial biopsy finding in two patients with idiopathic dilated cardiomyopathy receiving long-term treatment with amiodarone

Amiodarone, a highly effective antiarrhythmic agent, accumulates in different tissues, causing a variety of adverse effects.1–3 Long-term amiodarone treatment may cause diffuse interstitial pulmonary fibrosis and inflammation, with accumulation of cytoplasmic bodies containing electron-dense lamellas in pneumyocytes and alveolar macrophages 1,2. Similar bodies have been described in liver, lymph nodes, blood leukocytes, cornea, endothelial cells of skin, colonie mucosa, 3 and Schwann cells. Such bodies also have been found in cardiac myocytes of experimental animals treated with multiple doses of this drug 4,5; however, to our knowledge, they have not been reported in the myocardium of patients treated with amiodarone. This report describes ultrastructural changes in the myocardium of 2 patients with idiopathic dilated cardiomyopathy who had received long-term amiodarone treatment.

Tracheobronchomegaly Associated with Interstitial Pulmonary Fibrosis

Tracheobronchomegaly (TBM) is the syndrome of enlarged trachea and main bronchi associated with recurrent and chronic respiratory tract infections. A 42-year-old man with TBM and diffuse interstitial pulmonary fibrosis is described. The possible relationship between the two entities is discussed and the etiology, pathogenesis, clinical manifestations, prognosis and treatment of TBM are reviewed.

Asbestos-related benign disease and cancer

Long lasting occupational exposure to asbestos dust may cause skin corns, benign pleural effusion, hyaline plaques of the parietal pleura, diffuse thickening of the pulmonary pleura, and asbestosis, i.e. diffuse interstitial pulmonary fibrosis. Malignant disorders include lung cancer and mesothelioma of the pleura, peritoneum and pericardium. In general, many years elapse from first exposure to the appearance of symptoms. Almost all these diseases are the result of dusty working conditions more than 20 years ago. In spite of the fact that the general public is invariably exposed to small amounts of the material, asbestos is not a public health problem. Even living in a building containing sprayed asbestos is calculated to produce a lifetime risk of death which is negligible. There is no evidence to indicate that ingested asbestos fibres represent a major health problem.