[Diffuse interstitial lung disease of possible occupational origin treated at the Navarra Health Service. Navarra, Spain, 2017-2022]. / Enfermedad pulmonar intersticial difusa de posible origen laboral atendida en el Servicio Navarro de Salud. Navarra, España, 2017-2022.

INTRODUCTION: Diffuse interstitial lung disease (ILD) describes a broad group of pulmonary inflammatory and fibrosis disorders. Asbestosis and silicosis are the main causes linked to occupational exposure. The aim of this study was to estimate the proportion of cases with possible occupational origin and describe their exposure, clinical, and occupational status. METHOD: We conducted a retrospective longitudinal study of ILD cases between 2017 - 2022 at the University Hospital of Navarra was conducted. Information was supplemented with interviews of cases with possible occupational origin. The occupational proportion was calculated, labor and clinical characteristics analyzed, by statistical comparison of percentages and means. RESULTS: Out of 1067 ILD cases, 56 had a possible occupational origin 5,2% (95% CI 3,9-6,6%). 36 (64,3%) corresponded to asbestosis, 15 (26,8%) to silicosis, and 5 (8,9%) to unspecified pneumoconiosis. The most frequent activities in silicosis were "stone cutting-carving" and in asbestosis "manufacture of iron products". The average age of asbestosis cases was higher than that of silicosis cases (78,2 vs. 67,3 years), as well as their clinical manifestation. Five cases (8,9%) had been recognized as occupational diseases. CONCLUSIONS: The implementation of a computer tool in medical records has made it possible to estimate the magnitude and assess the evolution of occupational ILD treated in the Public Health Service. Economic activities reflect the economic risk structure of the region. However, there is a lack of recognition of these diseases as occupational illnesses and they represent a preventable burden of respiratory disease.

Introducción: La enfermedad pulmonar intersticial difusa (EPID) describe un amplio grupo de trastornos con inflamación y fibrosis pulmonar. La asbestosis y la silicosis son las principales causas por exposición laboral. El objetivo de este trabajo fue estimar la proporción de casos de posible origen laboral y describir la exposición, situación clínica y laboral.  Método: Estudio longitudinal retrospectivo de los casos de EPID, en el período 2017-2022 en el Hospital Universitario de Navarra. Se completó la información con entrevista a los casos de posible origen laboral.  Resultados: De un total de 1067 casos de EPID, 56 tuvieron un posible origen laboral, 5,2% (3,9-6,6 IC 95%) 36 (64,3%) correspondieron a asbestosis, 15 (26,8%) a silicosis y 5 (8,9%) a neumoconiosis no especificada. Las actividades más frecuentes en silicosis fueron "corte-tallado de piedra" y para asbestosis "fabricación productos hierro". La media de edad de los casos de asbestosis fue superior a los de silicosis (78,2 vs. 67,3 años), así como su afectación clínica. Cinco casos (8,9%) habían sido reconocidos como enfermedad profesional  Conclusiones: La implementación de una herramienta informática en historia clínica ha hecho posible estimar la magnitud y valorar la evolución de las EPID laborales atendidas en el servicio nacional de salud. Las actividades económicas reflejan la estructura económica de riesgo de la región. Sin embargo, existe una falta de su reconocimiento como enfermedad profesional y suponen una carga de enfermedad respiratoria evitable.

Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial.

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL [SD 329]) and the rituximab group (97 mL [234]); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was -40 mL (95% CI -153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 [95% CI 0·11 to 1·68]). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group. INTERPRETATION: Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy. FUNDING: Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).

Prognostic impact of home oxygen therapy on patients with resected non-small-cell lung cancer with interstitial lung disease.

PURPOSE: Non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) have a poor prognosis. The present study evaluated the prognostic impact of home oxygen therapy (HOT) in NSCLC patients with ILD. METHODS: Overall, 3099 consecutive patients underwent complete resection of stage IA to IIIA NSCLC at our institution between 2002 and 2016. ILD was diagnosed and categorized based on high-resolution computed tomography. The criteria for HOT included less than 90% resting oxygen saturation in the peripheral arteries and severe exertional dyspnea. We retrospectively compared the overall survival between ILD patients with and without HOT. RESULTS: ILD was observed in 150 (5%) patients. Seventeen (11%) patients needed HOT at discharge. The incidences of usual interstitial pneumonia (UIP) pattern (p = 0.03) and blood loss (p < 0.01) were significantly higher in the patients requiring HOT than in those without HOT. Significantly more patients developed complications (p = 0.04) in the HOT group than in the non-HOT group, with three (18%) having acute exacerbations. The 3-year overall survival rate was significantly lower in the HOT patients than in those without HOT (28% vs. 63%, p = 0.03). CONCLUSIONS: Patients requiring postoperative HOT showed a significantly poorer prognosis after complete resection than those without HOT. Therefore, the indication for surgery should be investigated cautiously in order to prevent the need for postoperative HOT.

Combined mutations of NKX2-1 and surfactant protein C genes for refractory low oxyhemoglobin saturation and interstitial pneumonia: A case report.

RATIONALE: Mutations of the NKX2-1 gene are associated with brain-lung-thyroid syndrome, which is characterized by benign hereditary chorea, hypothyroidism, and pulmonary disease with variable presentation. Surfactant protein C (SFTPC) gene mutations result in chronic interstitial lung disease in adults or severe neonatal respiratory distress syndrome. PATIENT CONCERNS: Recurrent hypoxemia was observed shortly after birth in a baby at a gestational age of 40 weeks and birth weight of 3150 g. The need for respiratory support gradually increased. He had hypothyroidism and experienced feeding difficulties and irritability. DIAGNOSIS: Genetic examination of the peripheral blood revealed combined mutations of the NKX2-1 and SFTPC genes. INTERVENTIONS: The patient was administered respiratory support, antibiotics, low-dose dexamethasone, supplementary thyroxine, venous nutrition, and other supportive measures. OUTCOMES: The patient's guardian stopped treatment 3 months after commencement of treatment, due to the seriousness of his condition and the patient died. LESSONS: Combined mutations of NKX2-1 and SFTPC genes are very rare. Thus, idiopathic interstitial pneumonia with hypothyroidism and neurological disorders require special attention.

Management issues in rheumatoid arthritis-associated interstitial lung disease.

PURPOSE OF REVIEW: Summarize recent evidence on the identification and management of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). RECENT FINDINGS: Clinical and subclinical interstitial lung disease (ILD) are frequent extra-articular manifestations of rheumatoid arthritis (RA). Better means of identifying and treating RA-ILD are needed to improve the prognosis, with a median survival of only 3-7 years after diagnosis. Several serum biomarkers are currently being evaluated for their ability to detect RA-ILD. Thorough evaluation and multidisciplinary discussion remains the gold standard for establishing the diagnosis of RA-ILD. Management is challenging with most RA disease-modifying antirheumatic drugs (DMARDs) linked to pneumonitis. Methotrexate is typically avoided in clinically significant ILD, although alternative therapies including leflunomide and biologic DMARDs also carry risks in RA-ILD. Antifibrotics appear to slow the progression of ILD, and a large phase II trial exclusively in RA-ILD is underway. In addition, smoking cessation, pulmonary rehabilitation, oxygen therapy, managing comorbidities, and lung transplantation evaluation are vital to improving patient outcomes in RA-ILD. SUMMARY: With little high-quality evidence to guide the management of RA-ILD, multidisciplinary teams with expertise in RA-ILD are highly valuable for diagnosing and treating RA-ILD. Clinical and translational research in RA-ILD is needed to fill the many evidence gaps.

Antifibrotics in interstitial lung disease related to connective tissue diseases - a paradigm shift in treatment and outcome.

Interstitial lung disease (ILD) is one of the major causes of morbidity and mortality in patients with connective tissue disease (CTD) and the treatments available until nowadays are in most cases unable to halt disease progression. CTD-ILD pathogenesis includes an initial inflammatory phase, followed by a fibrotic phase, in which extracellular matrix proteins are produced and fibrotic scaring tissue within the lung develops. Steroids and immunosuppressants are the weapons we currently have to treat CTD-ILD. However, mortality rates remain high and identification of new therapeutic targets is crucial. Antifibrotic drugs, which include nintedanib and pirfenidone, have been approved for the treatment of idiopathic pulmonary fibrosis (IPF) and due to similar pathogenesis between IPF and CTD-ILD, their use seems attractive in patients with CTD-IL. We report 3 cases of patients with different CTDs, with predominantly fibrotic changes in high resolution computed tomography that progressed despite immunosuppression, and who have attained disease stability after introduction of antifibrotic drugs.

Interstitial pneumonia and pulmonary hypertension associated with suspected ehrlichiosis in a dog.

BACKGROUND: In dogs with canine monocytic ehrlichiosis (CME), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. However, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known. Pulmonary hypertension (PH) is classified based on the underlying disease and its treatment is aimed at reducing the clinical signs and, if possible, addressing the primary disease process. PH is often irreversible, but can be reversible if it is secondary to a treatable underlying etiology. CME is currently not generally recognized as one of the possible diseases leading to interstitial pneumonia and secondary PH in dogs. Only one case of PH associated with CME has been reported worldwide. CASE PRESENTATION: A seven-year-old, male intact, mixed breed dog was presented with 2 weeks history of lethargy and dyspnea. The dog previously lived in the Cape Verdean islands. Physical examination showed signs of right-sided congestive heart failure and poor peripheral perfusion. Thoracic radiography showed moderate right-sided cardiomegaly with dilation of the main pulmonary artery and a mild diffuse interstitial lung pattern with peribronchial cuffing. Echocardiography showed severe pulmonary hypertension with an estimated pressure gradient of 136 mm Hg. On arterial blood gas analysis, severe hypoxemia was found and complete blood count revealed moderate regenerative anemia and severe thrombocytopenia. A severe gamma hyperglobulinemia was also documented. Serology for Ehrlichia canis was highly positive. Treatment with oxygen supplementation, a typed packed red blood cell transfusion and medical therapy with doxycycline, pimobendan and sildenafil was initiated and the dog improved clinically. Approximately 2 weeks later, there was complete resolution of all clinical signs and marked improvement of the PH. CONCLUSION: This report illustrates that CME might be associated with significant pulmonary disease and should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. This is important because CME is a treatable disease and its secondary lung and cardiac manifestations may be completely reversible.

Diffuse parenchymal diseases associated with aluminum use and primary aluminum production.

Aluminum use and primary aluminum production results in the generation of various particles, fumes, gases, and airborne materials with the potential for inducing a wide range of lung pathology. Nevertheless, the presence of diffuse parenchymal or interstitial lung disease related to these processes remains controversial. The relatively uncommon occurrence of interstitial lung diseases in aluminum-exposed workers--despite the extensive industrial use of aluminum--the potential for concurrent exposure to other fibrogenic fibers, and the previous use of inhaled aluminum powder for the prevention of silicosis without apparent adverse respiratory effects are some of the reasons for this continuing controversy. Specific aluminum-induced parenchymal diseases described in the literature, including existing evidence of interstitial lung diseases, associated with primary aluminum production are reviewed.

Supportive care for patients with pulmonary complications of connective tissue disease.

Patients with connective tissue disease often suffer from pulmonary complications, including interstitial lung disease and pulmonary hypertension. Supportive care for these patients aims to relieve symptoms and improve activity level and quality of life. A holistic approach to the management of patients with advanced connective tissue disease-associated pulmonary disorders includes a full assessment of patient symptoms as well as a careful search for side effects of treatment and treatable comorbidities. This article addresses supportive measures such as supplemental oxygen and pulmonary rehabilitation. Issues related to quality of life, sleep disturbances, and identification of mood disorders are discussed. In addition, we review significant comorbidities, including cardiovascular disease, glucocorticoid-induced osteoporosis, and gastroesophageal reflux disease. Essential facets of advanced lung disease, including mechanical ventilation, lung transplantation, end-of-life care, and hospice, are covered.

Successful treatment for conventional treatment-resistant dermatomyositis-associated interstitial lung disease with adalimumab.

Dermatomyositis (DM) is a systemic autoimmune disorder characterized by the inflammation of skeletal muscles and pathognomonic skin rashes, namely heliotrope rash and Gottron's papules and involvement of other organs. Interstitial lung disease (ILD) seems to be one of the most characteristic manifestations of the lung and associated with increased morbidity and mortality in patients with DM. Despite DM-associated ILD requires aggressive therapy with cytotoxic agents, the efficacy is questionable in some cases, and more effective and less toxic therapies are needed. Recently, although there have been several reports of successful treatment of refractory case of PM and DM with the TNF-α antagonists, including infliximab and etanercept, there was no enough evidence for DM-associated ILD. We described herein a patient with DM-associated ILD who had poor response to conventional therapies and successfully treated with adalimumab.

[A case of diffusely infiltrating rectal cancer with pulmonary lymphangitis carcinomatosa successfully treated with mFOLFOX6 chemotherapy as salvage].

We report a case of diffusely infiltrating rectal cancer with pulmonary lymphangitis carcinomatosa that responded to mFOLFOX6 chemotherapy and enabled survival for 19 months. A 68-year-old man was admitted to our hospital for a dry cough and dyspnea. Chest X-ray and CT examination revealed prominent pulmonary markings and abnormal infiltrating shadows. Interstitial pneumonia was suspected, and we started treatment with steroid medication, but this had no effect. A colonoscopy and barium enema revealed diffusely infiltrating rectal cancer. Abdominal CT and PET showed lymphangitis carcinomatosa of the lung, paraaortic lymph node swelling, and left hydronephrosis due to rectal cancer. The patient was diagnosed with stage IV rectal cancer. Thus, a curative operation was deemed impossible. Because of subileus, we performed a decompression loop colostomy in the transverse colon, and started treatment with mFOLFOX6 chemotherapy as salvage in spite of the patient's poor respiratory condition. Though the patient's tumor markers were very high (CEA 107 ng/mL, CA19-9 7,940 U/mL) prior to chemotherapy, they decreased dramatically (CEA 49.7 ng/mL, CA19-9 772 U/mL), and subjective symptoms (dry cough and dyspnea) also improved after 2 courses. After 3 courses of treatment the patient was discharged. After 7 courses, pulmonary markings and abnormal infiltrating shadows had disappeared on chest X-ray and CT. This condition was maintained for 19 months by ambulant chemotherapy without sacrificing high quality of life. Thus, mFOLFOX6 chemotherapy could be an effective salvage regimen in cases of diffusely infiltrating rectal cancer with pulmonary lymphangitis carcinomatosa.

Management of interstitial lung disease in systemic sclerosis: lessons from SLS and FAST.

Interstitial lung disease (ILD) is a leading cause of death in systemic sclerosis (SSc). Two randomized controlled trials recently demonstrated the modest effects of cyclophosphamide on lung physiology (forced vital capacity) and extrapulmonary outcomes (dyspnea, function, quality of life, and skin thickening). Recommendations can now be made about the short-term management for SSc-ILD. However, many questions remain unanswered, including how long to treat with cyclophosphamide; whether patients should take maintenance therapy after the initial or induction phase; whether there are alternative therapies; how to treat patients with ILD and pulmonary hypertension; and how to treat patients with severe ILD.

[Therapeutic management of systemic sclerosis]. / Prise en charge thérapeutique de la sclérodermie systémique.

UNLABELLED: Improved understanding of the pathophysiology of systemic sclerosis (SSc) opens new therapeutic avenues in its treatment. The efficacy of disease-modifying agents remains limited however, and none has yet demonstrated its ability to improve survival in a prospective randomized trial. RESULTS: of traditional antifibrotic agents such as colchicine and D-penicillamine are disappointing. Cyclophosphamide (CYC) seems to be beneficial in interstitial lung disease associated with SSc. Organ-specific therapies may produce dramatic benefits. Examples include angiotensin-converting enzyme inhibitors for renal failure and epoprostenol for primary pulmonary hypertension. Several new therapeutic approaches are currently under evaluation, including high-dose CYC followed by peripheral stem cell transplantation, vasodilators, and antiinflammatory and antifibrotic agents. Physical therapy and rehabilitation may help to treat disability and loss of function in SSc patients.

Febrile-range hyperthermia augments pulmonary neutrophil recruitment and amplifies pulmonary oxygen toxicity.

Febrile-range hyperthermia (FRH) improves survival in experimental infections by accelerating pathogen clearance, but may also increase collateral tissue injury. We hypothesized that FRH would worsen the outcome of inflammation stimulated by a non-replicating agonist and tested this hypothesis in a murine model of pulmonary oxygen toxicity. Using a conscious, temperature-controlled mouse model, we showed that maintaining a core temperature at FRH (39 degrees C to 40 degrees C) rather than at euthermic levels (36.5 degrees C to 37 degrees C) during hyperoxia exposure accelerated lethal pulmonary vascular endothelial injury, reduced the inspired oxygen threshold for lethality, induced expression of granulocyte-colony stimulating factor, and expanded the circulating neutrophil pool. In these same mice, FRH augmented pulmonary expression of the ELR(+) CXC chemokines, KC and LPS-induced CXC chemokine, enhanced recruitment of neutrophils, and changed the histological pattern of lung injury to a neutrophilic interstitial pneumonitis. Immunoblockade of CXC receptor-2 abrogated neutrophil recruitment, reduced pulmonary vascular injury, and delayed death. These combined data demonstrate that FRH may enlist distinct mediators and effector cells to profoundly shift the host response to a defined injurious stimulus, in part by augmenting delivery of neutrophils to sites of inflammation, such as may occur in infections. In certain conditions, such as in the hyperoxic lung, this process may be deleterious.

[Metastatic pulmonary calcification: a rare cause of interstitial lung disease]. / Calcificación pulmonar metastásica: una rara causa de enfermedad pulmonar intersticial.

We report the case of a 58-year-old woman with metastatic pulmonary calcinosis who presented with bronchial hyperreactivity. She was receiving calcium and vitamin D supplementation following total bilateral thyroidectomy with parathyroidectomy and had a history of episodes of symptomatic hypercalcemia secondary to exogenous administration. Lung function testing showed slight obstruction that was reversed by bronchodilators. Images showed a bilateral micronodular pattern mainly in the upper fields (x-ray and high resolution computed tomography of the thorax) and abnormal calcium deposition in the lungs (bone scintigraphy). The diagnosis was established by transbronchial biopsy. The clinical course was favorable. Metastatic pulmonary calcinosis is rare and usually asymptomatic and evolution is good. This entity should be taken into account in the differential diagnosis of interstitial lung diseases involving micronodular infiltrates in patients at risk.

Pulmonary complications after hepatic artery chemoembolization or infusion via the inferior phrenic artery for primary liver cancer.

PURPOSE: The purpose of this study was to determine the frequency, patterns of disease, and risk factors for development of pulmonary complications after liver chemoembolization via the inferior phrenic artery (IPA). MATERIALS AND METHODS: Forty-four selective transcatheter hepatic chemoembolization (THCE) procedures via the IPA were performed in patients with primary liver cancers with use of a mixture of anticancer agents and iodized oil (Lipiodol) with or without transcatheter arterial embolization. The grades of pulmonary complications were assessed on triphasic helical computed tomographic (CT) images after THCE and were correlated with angiographic findings of the IPA, infused dosages of Adriamycin and Lipiodol, and hepatic venous tumor thrombus on triphasic CT images before THCE. RESULTS: THCE via the IPA frequently resulted in lung CT changes: Lipiodol accumulation in the lung field (52%), consolidation (68%), and pleural effusion (41%). Among 44 patients, two (5%) developed respiratory symptoms. An excellent correlation was shown between Lipiodol accumulation and the presence of angiographic abnormalities of the IPA (P <.005). A significant correlation was also shown between the grades of pulmonary complications and the numbers of angiographic abnormalities (P <.01). The grades of pulmonary complications increased according to the infused dosage of Adriamycin and Lipiodol (P <.05). CONCLUSIONS: Angiographic abnormalities such as arteriovenous shunts, dilated anastomotic branches, and dense pleural staining are important risk factors for pulmonary complications of THCE via the IPA. Embolization for shunts may be required to prevent such complications, especially in cases with shunts to pulmonary vessels or hepatic veins.

Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma.

Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.

Inhibition of exhaled nitric oxide production during sepsis does not prevent lung inflammation.

OBJECTIVES: Increases in exhaled nitric oxide have been demonstrated to originate from the lungs of rats after septic lung injury. The aim of this study was to investigate whether treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) would prevent lipopolysaccharide (LPS)-induced increases in exhaled nitric oxide and whether this would have an effect on septic lung inflammation. DESIGN: Prospective, randomized, placebo-controlled animal laboratory investigation. SETTING: University laboratory. SUBJECTS: Male, anesthetized, paralyzed, and mechanically ventilated Sprague-Dawley rats (n = 27). INTERVENTIONS: Rats were mechanically ventilated with air filtered to remove nitric oxide (expiratory rate 40 breaths/min, tidal volume 3 mL, positive end-expiratory pressure 0, FIO2 0.21). They were then randomized to receive intravenous injections of either L-NAME (25 mg/kg/hr x 4 hrs) (n = 11) or saline (n = 10). Both groups were again randomized to receive either LPS (Salmonella typhosa: 20 mg/kg i.v. x 1 dose) or an equal volume of saline 5 mins later. Thereafter, exhaled gas was collected in polyethylene bags for measurements of nitric oxide concentration. After 4 hrs, the rats were killed and the lungs were preserved and examined histologically. To examine the effect of L-NAME and LPS on mean arterial blood pressure, six additional rats underwent the same ventilation protocol with cannulation of the right internal carotid artery so that systemic arterial pressures could be measured. MEASUREMENTS AND MAIN RESULTS: Exhaled gas was collected and measurements of NO concentrations were made using chemiluminescence every 20 mins for 240 mins during ventilation. A total lung injury score was calculated by determining the extent of cellular infiltrate, exudate and hemorrhage. Mean arterial pressure was recorded every 5 mins for 20 mins and then at 20-min periods for 120 mins. Exhaled nitric oxide concentrations increased in all the LPS-treated rats that did not receive L-NAME by 120 mins; a plateau was reached by 190 mins that was approximately 4 times greater than control rats not treated with LPS (p < .001). In contrast, rats treated with L-NAME and LPS did not show an increase in exhaled NO. Administration of L-NAME induced a 10-min nonsustained increase in mean arterial pressure in two rats treated with L-NAME followed by LPS. This increase in mean arterial pressure was not seen in two placebo and two LPS-treated rats that did not receive L-NAME. Lung inflammation was significantly worse in the two groups of rats which received LPS compared with the two that did not. L-NAME did not cause lung inflammation in rats that did not receive LPS; however, LPS-treated rats that received L-NAME had more inflammatory interstitial infiltrate (p < .05) and a trend toward worse lung injury than did LPS-treated rats that did not receive L-NAME. CONCLUSION: We conclude that L-NAME can inhibit the increase in exhaled NO from the lungs of septic rats, but that this inhibition does not reduce lung inflammation, and may worsen it.

[Interstitial pneumonia associated with human adjuvant disease which developed 30 years after silicone augmentation mammoplasty].

A 51-year-old woman was admitted to our hospital with exertional dyspnea, swelling and stiffness in her fingers. Raynaud's phenomenon and mammary and axillary lymphadenopathy. She had received silicone augmentation mammoplasty 30 years ago, and had since noticed bilateral mammary and axillary lymphadenopathy that was stable in size. In the 2 years before admittance she had become aware of an exacerbation of the lymphadenopathy had begun to experience and exertional dyspnea several months before admission suggesting a connective tissue disease. Physical examination revealed symmetrical weakness of the proximal limb muscles and fine crackles in the base of both lungs. Elevated myogenic enzymes, inflammatory reactions, and positive anti-SSA antibody were noted. Based upon these findings, muscle and lip biopsy results, myogenic EMG, and an apple tree appearance on sialography, a differential diagnosis of polymypositis or sjögren's syndrome was made. Axillary lymph node biopsy findings were consistent with silicone lymphadenitis. In addition, chest roentgenogram and HRCT (which revealed decreased lung volumes and interstitial opacities with no honeycombing, present predominatly in the subpleural space), pulmonary function tests (decreased VC and DLco), bronchoalveolar lavage (elevated total cell count and neutrophil and eosinophil fractions), and transbronchial lung biopsy specimens (unevently distributed alveolitis with fibrosis) indicated concurrent interstitial pneumonia. The clinical correlation between exacerbation of silicone lymphadenopathy and the development of connective tissue disease with accompanying interstitial pneumonia strongly suggested human adjuvant disease (HAD) as the pathogenesis. To our knowledge, interstitial pneumonia associated with HAD is rare.