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Small airways in fibrosing alveolitis.

Pulmonary function, including lung elastic recoil, was measured in 9 subjects with fibrosing alveolitis. Closing volume and upstream conductance were studied to assess small airway function. Lung volumes, diffusing capacity, and transfer coefficient were decreased. Peak expiratory flow and the ratio of 1-sec forced expiratory volume to forced vital capacity were normal, whereas total lung resistance was low, suggesting that large airways were not narrowed. Lung elastic recoil was increased, but the changes could be accounted for by the loss of lung volume. Closing volume and closing capacity were increased when expressed as a percentage of vital capacity and total lung capacity, respectively; but again, this could be accounted for by the decrease in lung volume, because the absolute lung volume at which airway closure occurred was normal. Upstream conductance was not reduced. We conclude that there is no evidence of narrowing of functional small airways in ventilated parts of the lung. The mechanical findings are compatible with the patchy involvement seen pathologically in fibrosing alveolitis.

Adult↗

Interstitial vascularity in fibrosing alveolitis.

The aim of this study was to evaluate interstitial vascularity in cryptogenic fibrosing alveolitis (CFA) and in fibrosing alveolitis associated with systemic sclerosis (FASSc). Open lung biopsies from eight patients with CFA, nine patients with FASSc, and normal lung from 12 patients undergoing surgery for lung cancer were studied. Markers for endothelial cells (CD34) and cell proliferation (proliferating cell nuclear antigen) were localized by sequential immunohistochemistry and quantified using computer-assisted analysis. Vascular distribution was evaluated at increasing distances (up to 160 microm) from the airspaces. Vessel density was markedly reduced in both FASSc (3.9%) and in CFA (4.5%) compared with control samples (20.4%, p < 0.0001). The percentage of tissue occupied by vessels decreased with increasing distance from alveoli in control samples but not in CFA or FASSc samples. Endothelial cell proliferation indices were increased in FASSc but not in CFA, compared with control samples (p = 0.006). In conclusion, there is net vascular ablation and redistribution of blood vessels in areas of interstitial thickening in both CFA and FASSc, which may contribute to gas exchange impairment.

Adult↗

Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis.

Systemic sclerosis (SSc), a multisystem immunologic disease of unknown etiology, is commonly manifested in the lung as fibrosing alveolitis (FASSc). There is evidence to support the role of genetic factors in the predisposition to pulmonary fibrosis in SSc (HLA DR3/DR52a). This association is not complete and other candidate genes are likely involved. Of these, fibronectin is a growth factor known to play a crucial role in lung fibrosis. Our study investigated whether polymorphisms of the fibronectin gene are associated with lung fibrosis in SSc. Using the polymerase chain reaction and the restriction enzymes HaeIII, MspI, HindIII, and TaqI, we assessed the restriction fragment length polymorphisms (RFLPs) in 161 patients with SSc and 253 healthy control subjects from the United Kingdom. For each restriction enzyme, three genotypes were possible corresponding to the presence of the cutting site on neither, one, or both chromosomes (HaeIII AA, AB, BB; MspI CC, CD, DD; HindIII EE, EF, FF; TaqI GG, GH, HH). There was a significant decrease of genotype BB (FASSc: 17%, control: 34%; Pcorr = 0.006) with a reciprocal increase of genotype AB (FASSc: 62%, control: 46%; Pcorr = 0.022) in FASSc with the HaeIII RFLP. A significant decrease of genotype DD was observed in FASSc (FASSc: 28%, control: 41%; Pcorr = 0.038) with the MspI RFLP. The coassociation of genotypes AB (HaeIII RFLP) and CD (MspI RFLP) was present in 45% of the FASSc group (P = 0.0059), with an increased relative risk of developing fibrosing alveolitis of 1.988. We conclude that genotypes of the fibronectin gene are useful prognostic factors in SSc, helping to predict individuals likely to develop pulmonary fibrosis.

Adult↗

Fibrosing granulomas in the equine liver and peritoneum: a retrospective morphologic study.

Fibrosing granulomas were found in the liver and occasionally on the intestinal and diaphragmatic serosae and in the lung of 11 horses submitted for necropsy. Although these granulomas were considered incidental findings in most of the horses, they had caused liver failure in 1 horse. The granulomas typically were characterized by a dense collagenous core that frequently was mineralized. The periphery contained a rim of inflammatory cells. Only in 1 of the 11 horses was there evidence of an egg shell suggestive of schistosomes. Schistosomal eggs were not detected in the feces of the horses. The typical architecture of the granulomas combined with the occasional finding of a residual egg led to the circumstantial conclusion that the fibrosing granulomas were the result of chronic schistosomiasis of undeterminable origin.

Animals↗

Peripheral blood neutrophils are hyperresponsive to IL-8 and Gro-alpha in cryptogenic fibrosing alveolitis.

Cryptogenic fibrosing alveolitis (CFA) is characterized by increased pulmonary recruitment of peripheral blood neutrophils (PBNs) by interleukin (IL)-8 and other chemotactic mediators. This study investigated whether, in CFA, the PBN motility response is primed by IL-8 and growth-related oncogene (Gro)-alpha, as demonstrated in other neutrophilic inflammatory diseases, and whether the motility response of PBNs to IL-8 and Gro-alpha can be abrogated using a selective antagonist for the neutrophil receptor for IL-8 and Gro-alpha, CXCR2. The percentage of PBNs to undergo shape change (%SC), spontaneously and in response to IL-8 and Gro-alpha, was measured in patients with CFA (n=10) and controls (n=10), and the effect of the CXCR2 antagonist SB272844 studied. Plasma levels of IL-8, and Gro-alpha were measured using an enzyme-linked immunosorbent assay (ELISA). The %SC of unstimulated PBNs and the potency of Gro-alpha and IL-8 to produce neutrophil polarization was greater in CFA than in controls; dose which produces 50% of maximal effect (EC50) of IL-8 was 3.6 +/- 0.7 nM for CFA versus 6.3 +/- 1.0 nM for controls; p<0.05. SB272844 inhibited Gro-alpha induced but not IL-8 induced neutrophil shape change (equilibrium constant (KD) 123 +/- 18 nM). Plasma concentrations of Gro-alpha were increased in patients with CFA. PBNs are spontaneously activated and undergo a greater motility response to IL-8 and Gro-alpha in CFA. Interleukin-8 and growth-related oncogene-alpha, circulating in substimulatory amounts in cryptogenic fibrosing alveolitis, may prime the peripheral blood neutrophils motility response, thus increasing their capacity for migration to the lung. Selective CXCR2 antagonists may be useful to block the Gro-alpha-induced priming response whilst preserving neutrophil functions mediated by CXCR1, the alternative neutrophil receptor for interleukin-8.

Aged↗

Resting energy expenditure in cryptogenic fibrosing alveolitis.

A proportion of patients with chronic airflow limitation appear to have a raised resting energy expenditure (REE). This has been suggested as the reason for weight loss which may occur in these patients. A previous study found an increased REE in patients with interstitial lung disease of mixed aetiology. We were interested in studying REE in a more homogeneous group, with cryptogenic fibrosing alveolitis (CFA). Twenty patients with CFA were studied. They were compared with 18 controls matched for age, sex, weight and height. REE was measured by indirect calorimetry. Fat-free mass (FFM), was estimated by anthropometry. Patients had respiratory function tests performed, disability related to breathlessness was assessed by the activity section of the St George's Respiratory Questionnaire. Mean REE in the CFA group was not different from the control group: 5.20 (0.56) versus 5.12 (0.51) kj x h(-1) x kgFFM(-1). REE was elevated to greater than 110% of the value predicted by the Harris-Benedict equation in one CFA patient and in no control subjects. There was no correlation of REE with weight, pulmonary function tests, arterial oxygen saturation or activity score. The prevalence of a raised resting energy expenditure in cryptogenic fibrosing alveolitis patients with low transfer factor and relatively preserved vital capacity is low, and is less than that reported previously in a group of patients with interstitial lung disease of mixed aetiology.

Adult↗

Alpha1-antitrypsin phenotypes in patients with cryptogenic fibrosing alveolitis: a case-control study.

Cryptogenic fibrosing alveolitis (CFA) is an interstitial lung disease, which by definition is of unknown aetiology. Recent evidence has suggested that smoking and occupational exposure to dusts may be environmental risk factors for the disease, but there has been little research into potential host risk factors. One previous study has suggested that the prevalence of abnormal alpha1-antitrypsin phenotypes may be increased in patients with CFA. Since alpha1-antitrypsin is important in regulating inflammation within the lung in response to environmental exposures, such abnormalities may be of aetiological importance in this disease. We have compared the alpha1-antitrypsin phenotypes of 189 patients with CFA with 189 age-, sex-, and community-matched controls. This sample size was sufficient to provide more than 95% power to detect an odds ratio (OR) of 2.5. Alpha1-antitrypsin phenotype was established by isoelectric focusing, and the prevalence of abnormal phenotypes in cases and controls was compared by conditional logistic regression. Personal smoking histories were obtained by postal questionnaire. The prevalence of abnormal alpha1-antitrypsin phenotypes was similar in cases and controls (12.7 versus 15.3%; OR 0.88; 95% confidence interval 0.49-1.57; p=0.66). No interaction was found between the presence of abnormal alpha1-antitrypsin phenotypes and a history of smoking. We conclude that cryptogenic fibrosing alveolitis is not associated with abnormal alpha1-antitrypsin phenotypes.

Adult↗

Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus.

Nephrogenic fibrosing dermopathy (NFD) is a novel fibrosing disorder of the skin with characteristic histopathology. It affects patients with impaired renal function and appears to be independent from the type of kidney disease. Its aetiopathology is unknown and presently no standard therapy exists. We report a patient with systemic lupus erythematosus (SLE) and glomerulonephritis who developed diffuse indurated erythematous plaques covering nearly the entire legs and trunk. She had never received dialysis. The second patient suffered from SLE and antiphospholipid syndrome related thrombotic glomerulopathy. After 10 weeks of haemodialysis she developed the same skin condition. To the best of our knowledge, these are the first reports of NFD occurring in patients with SLE.

Antiphospholipid Syndrome↗

Fibrosing pseudotumor of the sella and parasellar area producing hypopituitarism and multiple cranial nerve palsies.

We present an unusual patient with a medical history of a fibrosing pseudotumor of the left orbit that had been stable for 8 years who presented with acute anterior hypophyseal failure. During the next 10-month period, sequential magnetic resonance scans showed a rapid growth of a plaque-like sellar and parasellar mass extending into the right cavernous sinus, right Meckel's cave, along the dural surfaces of the clivus, dens, and body of the second cervical vertebra. A transsphenoidal biopsy revealed sphenoid and intrasellar pseudotumor that invaded the adenohypophysis and had microscopic features identical to those of the previously excised orbital pseudotumor. Rapid growth of the pseudotumor continued despite a course of radiotherapy. Palsies of cranial nerves V and VI and of the sensory root of the cranial nerve VII developed on the right side. Steroid therapy was associated with improvement of the cranial nerve palsies. This is the first report of the sellar fibrosing pseudotumor producing not only anterior hypophyseal failure, but also cranial nerve dysfunction secondary to plaque-like extension into the cavernous sinus, Meckel's cave, and cranial base dura. This intracranial plaque-like extension of a fibrous pseudotumor corresponds to a hypertrophic intracranial pachymeningitis, which is a rare, previously described phenomenon associated to the syndrome of multifocal fibrosclerosis.

Biopsy↗

Crackles in interstitial lung disease. Comparison of sarcoidosis and fibrosing alveolitis.

STUDY OBJECTIVE: Determine why crackles on chest auscultation are characteristic of most interstitial lung diseases, but may not be heard in sarcoidosis. DESIGN: All patients with sarcoidosis or cryptogenic fibrosing alveolitis seen during a four-week period were studied. In a second study to relate ausculatory findings to anatomy, patients with fibrotic changes on their chest roentgenogram were studied. SETTING: Patients were recruited from outpatient clinics. PATIENTS: In the first part, all patients seen over the course of one month were studied. In the second study, patients with pulmonary fibrosis seen on chest roentgenograms were studied. INTERVENTIONS: For the first study, two independent observers performed auscultation on five sites for crackles and reviewed four roentgenogram quadrants for changes. For the second study, patients underwent VC measurements, auscultation, and high resolution computer tomography scans. MEASUREMENTS AND RESULTS: For the first study, crackles were noted at greater than 2 sites in all 11 CFA patients, but only one of 17 SARC patients (p less than 0.001). Roentgenogram changes were seen in greater than 2 quadrants in nine of 11 CFA patients and eight of 17 SARC patients (p = ns). In the second study, the VC was similar in the two groups: SARC: 1.96 +/- .90 L (means +/- SD), 58 +/- 20.4 percent predicted; CFA: 1.81 +/- .33 L, 59 +/- 9.2 percent predicted). Only two of 14 SARC patients had crackles in greater than 1 area, while all 14 CFA patients had crackles at greater than 2 sites. The HRCT studies were read by a radiologist unaware of the diagnosis. The presence and degree (0 to 3 scale) of subpleural and peribronchial fibrosis were scored. Twelve SARC patients had peribronchial changes (mean score 1.9 +/- 1.08), while only eight had subpleural fibrosis (mean score .6 +/- .52). There was a significantly different pattern in the CFA patients, where eight had peribronchial fibrosis (mean score = .9 +/- .78, p less than 0.05) and all 14 had subpleural fibrosis (mean score = 1.6 +/- .73, p less than 0.01). CONCLUSIONS: We conclude that crackles are more frequent in fibrosing alveolitis than in sarcoidosis; this difference may be due to the distribution of parenchymal fibrosis.

Auscultation↗

Fibrosing alveolitis responsive to corticosteroids following Legionnaires' disease pneumonia.

Two male patients ages 54 and 58 years had persisting pneumonia with dry cough, dyspnea, weight loss, and fever up to 39 degrees C that did not respond to erythromycin treatment. There was extensive restrictive impairment of ventilation and loss of diffusing capacity for carbon monoxide. Histologic examination of the basal pulmonary infiltrates showed fibrosing alveolitis. Serologic titers indicated that the patients had suffered from Legionella pneumophila infection. We believe that Legionella had caused the fibrosing alveolitis since there was absence of any other causative agents or factors. Both patients responded to corticosteroid treatment with rapid clinical improvement but delayed radiologic regression.

Humans↗

Exhaled nitric oxide is increased in active fibrosing alveolitis.

STUDY OBJECTIVES: Interstitial inflammation is a major aggravating factor in fibrosing lung disease associated with scleroderma (FASSc) and cryptogenic fibrosing alveolitis (CFA). Exhaled nitric oxide (NO) production is increased in asthma and bronchiectasis and reflects the degree of inflammation. We investigated whether measuring levels of exhaled NO is valuable in assessing disease activity in patients with CFA and patients with FASSc. MEASUREMENTS AND RESULTS: NO levels were measured in 11 patients with CFA (mean age +/- SEM, 58 +/- 12 years old; 5 were male) and 17 patients with FASSc (mean age, 48 +/- 9 years old; 5 were male), and they were compared to BAL cell counts and lung function. Patients with CFA and FASSe had elevated NO levels (11.2 +/-1.0 parts per billion [ppb] and 9.8 +/- 1.0 ppb, respectively; p > 0.05), whereas in a group of 13 nonsmoking normal subjects, the NO levels were not elevated (6.9 +/- 0.5 ppb; p < 0.05). Patients with FASSc (n = 8) who had active BAL (defined as either lymphocytes > 14%, neutrophils > 4%, or eosinophils > 3%) had significantly higher NO levels (13.2 +/- 1.8 ppb), and neutrophil (16.5 +/- 4.0%) and lymphocyte (26.8 +/- 3.4%) BAL cell counts than did patients with FASSc who had inactive BAL (6.7 +/- 1.2 ppb; 1.3 +/- 1.0% and 7.5 +/- 1.3%, respectively; p < 0.05). There was a significant correlation between exhaled NO and lymphocyte cell count in patients with FASSc (r = 0.58; p < 0.05). All patients with CFA had active BAL; however, those treated with corticosteroids (12.9 +/- 1.0% ppb, p < 0.05) had lower NO levels (9.0 +/- 1 ppb) and higher BAL lymphocyte cell couits (16.6 +/- 2.0%) than did those not treated with corticosteroids (7.2 +/- 1.7%; p < 0.05). CONCLUSIONS: We conclude that exhaled NO may be a useful addition to BAL cell counts in disease monitoring.

Breath Tests↗

Expiratory lung crackles in patients with fibrosing alveolitis.

Inspiratory lung crackles are a diagnostic feature of interstitial pulmonary fibrosis, but expiratory crackles are not well documented. In a phonopneumographic study of 13 patients with fibrosing alveolitis, expiratory crackles were audible with the stethoscope in 12. Phonopneumographic analysis of these 12 patients showed the crackles to be fine with the initial wave deflection of the expiratory and inspiratory crackles in opposite directions. They were few in number, occurred predominantly in mid- and late expiration, and were not affected by varying the volume history or by breath holding maneuvers. These observations support the theory that some crackles are produced by vibration of the walls of peripheral airways. In addition, this group of patients showed a significant correlation between the number of expiratory crackles and the reduction in predicted transfer factor, suggesting that expiratory crackles may be a clinical indicator of the severity of disease in fibrosing alveolitis.

Aged↗

Increases in HLA-DQ, DP, DR, and transferrin receptors on alveolar macrophages in sarcoidosis and allergic alveolitis compared with fibrosing alveolitis.

We have used flow cytometric methods to detect and quantify HLA-DR, DQ, and DP antigens and transferrin receptors on alveolar macrophages in lavage samples from 36 patients with granulomatous lung diseases (extrinsic allergic alveolitis [EAA], n = 13; sarcoidosis, n = 23), and 12 patients having fibrosing alveolitis (FA) (cryptogenic fibrosing alveolitis, n = 3; FA and scleroderma, n = 8; FA and primary biliary cirrhosis, n = 1). HLA-DR, DQ, and DP antigens were expressed on the majority of alveolar macrophages in all the patients, and the percentages of positive cells were similar to those in control subjects without lung disease. However, the amounts expressed were higher in those with EAA and sarcoidosis than in the FA group or control subjects, the most significant differences being in HLA-DQ and HLA-DP expression. Transferrin receptor expression was also higher in the granulomatous lung diseases. In sarcoidosis, higher levels of HLA-DQ correlated with lower lung function measurements (Dco p less than 0.025, FVC p less than 0.025, FEV1 p less than 0.005), suggesting this may be a marker of disease activity. HLA-DP levels also showed a trend (p less than 0.1) of inverse correlation with lung function. Levels of HLA-DQ (p less than 0.005) and HLA-DP (p less than 0.001) correlated more closely than HLA-DR with numbers of lymphocytes in the lavage fluids, and HLA-DQ levels correlated with increasing proportions of lymphocytes in proliferation (p less than 0.05). We suggest that high levels of HLA-DQ and DP on alveolar macrophages may be more relevant than HLA-DR to the enhanced antigen-presenting function of these cells in sarcoidosis, and possibly also in EAA.

Adult↗

Radioimmunoassay of main urinary metabolite of prostaglandin F2alpha in patients with diffuse interstitial fibrosing pneumonitis (DIFP) and other respiratory diseases.

Radioimmunoassay of 5alpha, 7alpha-dihydroxy-11-keto-tetra-norprosta-1,16-dioic acid, main urinary metabolite of prostaglandin F2alpha (PGF2alpha-MUM), was performed in patients with various respiratory diseases including diffuse interstitial fibrosing pneumonitis (DIFP, fibrosing alveolitis). Twenty-four hr excretion of PGF2alpha-MUM in patients with primary lung cancer, pulmonary fibrosis secondary to collagen diseases and stationary DIFP was normal. On the other hand, 24 hr excretion of PGF2alpha-MUM in patients with carcinomatous pleuritis was high and that in patients with aggravating DIFP was markedly high. There was no correlation between serum LDH levels and 24 hr excretion of PGF2alpha-MUM.

Collagen Diseases↗

Fibrosing cholestatic hepatitis in hepatitis C virus-infected renal transplant recipients.

Severe hepatitis C virus (HCV)-related fibrosing cholestatic hepatitis leading to early liver failure has been reported only exceptionally. Of 259 HCV-infected renal transplant (RT) patients in one hospital unit, four (1.5%) are described, representing the first series of this particular post-RT disease. Patient mean age was 55.7 yr. Three were men. All had pretransplant, hepatitis B surface antigen-negative and were anti-HCV antibodies positive. Three of them showed pretransplant mild liver enzyme abnormalities, and all received kidneys from HCV-negative donors. All were on steroids, cyclosporine, and azathioprine (AZA). The clinical pattern appeared early after RT (mean, 11.5 mo). In three patients, hyperbilirubinemia (6.5 to 20 mg/dl) and high alkaline phosphatase levels (428 to 859 IU/L) were observed. Also, in all subjects, high gamma glutamyl transpeptidase levels (639 to 4270 IU/L), mild aspartate aminotransferase and alanine aminotransferase abnormalities, and serum HCV RNA were observed. Liver biopsy revealed diffuse fibrosis, leukocyte infiltrates, and different degrees of cholestasis, with typical signs of HCV hepatitis in only one patient. Two patients developed subfulminant liver failure and died 2 and 3 mo after biopsy, respectively. One patient also suffered hepatic failure, receiving a liver transplant. The fourth is alive on dialysis awaiting a combined kidney and liver transplant. It is concluded that fibrosing cholestatic hepatitis is a new, early, and severe complication after RT in HCV(+) patients, which appears in patients with ongoing HCV infection under AZA therapy, despite a nonaggressive immunosuppressive protocol. Both HCV and AZA could play a concurrent role in the pathogenesis of this severe complication after RT.

Adult↗

Nephrogenic fibrosing dermopathy: a comprehensive review for the dermatologist.

Nephrogenic fibrosing dermopathy (NFD) is an acquired, idiopathic, chronic, progressive eruption of the skin sometimes accompanied by systemic fibrosis that occurs in the context of renal failure. The age of patients with NFD ranges from 8 to 87 years at the time of onset, with a mean age of 46.4 years. Most cases have been reported in the US and Europe, but recently cases have also been reported in India. About 175 cases have been noted in a registry established for NFD patients. Even in the setting of renal disease, NFD still occurs rarely and its cause is unknown. Patients present with hard, indurated, sometimes peau d'orange plaques. They often show a distinctive physical appearance, with elbows and knees angled inward, and most patients complain of a loss of range of motion. Histology demonstrates thickened collagen bundles with surrounding clefts, mucin, and a proliferation of fibroblasts and elastic fibers, sometimes with reticular, dermal, large epithelioid or stellate spindle cells. Fibrosis of NFD can affect the internal organs and thus the term nephrogenic systemic fibrosis has been used by some analysts to describe this fibrosing process. The fibrosis of NFD appears to be due to the effects of a cell referred to as the circulating fibrocyte. Rare cases of partial-to-complete spontaneous resolution have been reported in the absence of specific therapy. Treatments yield inconsistent results and include restoration of renal function, extracorporeal photopheresis, photodynamic therapy, high-dose intravenous immunoglobulin, and other immunosuppressive therapies.

Fibrosis↗

[A case of idiopathic fibrosing mediastinitis presented with bilateral pleural effusion].

A case is reported of a 56-year-old male who presented with bilateral pleural effusion as an initial manifestation of idiopathic fibrosing mediastinitis. The patient showed shortness of breath with severe loss of vital capacity and weight loss. A mediastinal mass surrounding the thoracic aorta and bilateral pleuritis was identified by the chest CT scan. The mass extended, along the abdominal aorta, to the upper portion of retroperitoneum. Laboratory data showed elevated levels of C-reactive protein (CRP), erythrocyte sedimentation ratio (ESR), and IgG. Biopsy of the mediastinal and the pleural mass showed adipose tissue and fibrosis with mild perivascular inflammatory infiltration. A diagnosis of idiopathic fibrosing mediastinitis was made, and 40 mg/day of prednisolone was administered. Although CRP and ESR was normalized, the mass size and vital capacity were almost unchanged.

Humans↗