Christian Domingo

LATE-ONSET CONGENITAL CYSTIC ADENOMATOID MALFORMATION OF THE LUNG

Background: Congenital cystic adenomatoid malformation of the lung (CCAM) is an embryonic developmental anomaly of an unknown etiology usually diagnosed antenatally by imaging techniques. A minority of cases may not be identified by prenatal imaging techniques and may go unnoticed for the first 6 months of their extrauterine life. Due to its rarity, physicians are unlikely to suspect the condition. Objectives: To highlight the embryology, clinical symptomatology, diagnostic procedures, therapeutic approach and clinical follow-up of a series of 12 patients with late-onset CCAM. Methods: An observational study which offers the description of the clinical presentation, diagnostic methods, treatment and follow-up of 12 patients with late-onset CCAM. Setting: A 600-bed teaching hospital in a reference area of 350,000 inhabitants. Patients: 12 patients from 1983 to 1999. Results: Twelve diagnosed cases of late-onset CCAM. Mean age at diagnosis: 6.7 years (range: 6 months to 23 years). Clinical presentation: 9 out of 12 (75%) with repeated lung infections, 2 out of 12 (16%) chance finding, and 1 case (8%) with pneumothorax. On pathological examination, 7 were found to be CCAM type I and 4 CCAM type II according to Stocker’s classification; 1 patient is currently awaiting surgery. The diagnostic method of choice nowadays is a computed tomography (CT) scan performed in the 7 more recent cases; in the former 5 cases an isotopic lung scan was done (and in 2 of them a bronchography was also performed). Treatment: 11 patients were operated: 8 lobectomies, 2 segmentectomies and 1 localized resection. Mean follow-up: 8 years (range: 6 months to 16 years). Complications: One reintervention due to a reappearance of the lesion in the patient who underwent localized resection of the CCAM. No cases of malignancy were found. Conclusions: Late-onset CCAM is an infrequent illness which requires a high level of clinical suspicion. It usually presents in the form of repeated infections. The most frequent pathological forms are type I and II (Stocker). The diagnostic method of choice is the CT scan. The recommended treatment is radical surgery of the lesion once diagnosis has been established. Malignancy and relapses are very infrequent when radical surgery is not postponed.

Pulmonary Nocardiosis: Clinical Experience in Ten Cases

Background: Pulmonary nocardiosis is an infrequent infection whose incidence seems to be increasing due to a higher degree of clinical suspicion and the increasing number of immunosuppressive factors. Objective: To study the predisposing factors, clinical characteristics, diagnostic procedures, treatment and progress of pulmonary nocardiosis (PN). Methods: Review of 10 patients (9 male, 1 female, mean age 61) with PN in a 600-bed teaching hospital, diagnosed from 1992 to 1999. Results: Associated diseases observed were chronic obstructive pulmonary disease (COPD) in 6 patients, human immunodeficiency virus (HIV) infection in 3 and polymyalgia rheumatica in 1. Four patients had received oral corticotherapy for COPD for over a year (mean dose 13 mg/day of prednisone or equivalent). The main reason for consultation was an increase in dyspnea in the patients with COPD (6/6) and fever in those with HIV (3/3). Mean time between onset of symptoms and diagnosis was 5 weeks. In 8 patients, the infection occurred outside the hospital setting. The infection was restricted to the lung in 9/10; in the remaining case, the central nervous system (CNS) and subcutaneous tissue were affected. Lobar or multilobar consolidation was the most frequent radiographic pattern found (6/10). Sputum culture was positive when performed (8 cases). Diagnosis was made or confirmed by bronchoscopy (bronchoaspirate or protected specimen brush) in 5 patients. Germs isolated were: Nocardia asteroides (8/10), Nocardia farcinica (1/10), Nocardia otitidiscaviarum (1/10). Cotrimoxazole was the most used empirical treatment (6/10). Resolution was achieved in 5 cases. Four subjects died: 1 HIV patient with disseminated nocardiosis, and 3 COPD patients, 2 of whom had received long-term corticotherapy. Illness recurred in only 1 case, due to failure to comply with treatment. Conclusions: (1) In our geographical setting Nocardia presents as a subacute or chronic pulmonary infection, mainly outside the hospital. (2) It tends to affect only the lung. (3) Diagnosis requires a high clinical suspicion, and can be made on the basis of a sputum culture. (4) Nocardia tends to attack patients with underlying COPD, or immunodepressed patients treated with glucocorticoids, or patients with HIV infection. (5) Mortality is high in both COPD and HIV patients. (6) In our area, cotrimoxazole seems to be the most commonly prescribed treatment.

Pulmonary Capillary Hemangiomatosis: Report of a Case and Review of the Literature

We describe a case of pulmonary capillary hemangiomatosis in a 60-year-old woman with a 1-year history of progressive exertional dyspnea. Four years before admission a diagnosis of breast cancer was made, and she underwent mastectomy plus radiation therapy and treatment with oral antiestrogens. The chest X-ray showed bilateral interstitial infiltrates. Pulmonary function studies revealed a severe restrictive pattern. Abundant red blood cells were found in the bronchoalveolar lavage fluid. On the basis of open lung biopsy, interstitial fibrosis was diagnosed. Cardiac catheterization revealed pulmonary hypertension. Steroids were prescribed, but the patients condition continued to deteriorate and she died approximately 3 years after presentation. The identification of proliferating and invasive capillaries, which are unique to pulmonary capillary hemangiomatosis, led to the correct diagnosis at autopsy.

Long-term Efficacy and Safety of Mepolizumab in Patients With Severe Eosinophilic Asthma: A Multi-center, Open-label, Phase IIIb Study

PURPOSE Patients with severe eosinophilic asthma often experience recurrent asthma exacerbations despite intensive inhaled corticosteroid therapy. In 2 previous double-blind studies (MENSA [NCT01691521] and SIRIUS [NCT01691508]), treatment with intravenous or subcutaneous mepolizumab was associated with significantly reduced annualized exacerbation rates and oral corticosteroid (OCS) requirements compared with placebo. The purpose of this study was to assess the long-term safety and efficacy of subcutaneous mepolizumab treatment in patients with severe eosinophilic asthma. METHODS COSMOS was a 52-week, open-label extension study in patients who received mepolizumab or placebo in MENSA or SIRIUS. Patients received subcutaneous mepolizumab regardless of prior treatment allocation and continued to receive appropriate standard-of-care asthma therapy throughout. The primary objective was to assess the long-term safety of mepolizumab; end points included adverse events (AEs) and serious AEs (SAEs). Efficacy assessments included the annualized exacerbation rate and durability of response (defined as the exacerbation rate and OCS dose reduction when combined with MENSA and SIRIUS data, respectively). FINDINGS In total, 558 (86%; previous mepolizumab: 358; previous placebo: 200) and 94 (14%; previous mepolizumab: 58, previous placebo: 36) patients experienced on-treatment AEs and SAEs, respectively. No fatal AEs were reported. Totals of 13 (2%) and 29 (4%) patients experienced systemic and local site reactions, respectively. There were no reports of mepolizumab-related anaphylaxis. Mepolizumab treatment was shown to exert a durable response, with patients who previously received mepolizumab in MENSA or SIRIUS maintaining reductions in exacerbation rate and OCS dosing throughout COSMOS. Patients who previously received placebo in MENSA or SIRIUS demonstrated improvements in these end points following treatment with mepolizumab in COSMOS. IMPLICATIONS These data demonstrate a favorable safety profile of mepolizumab and indicate a durable and stable effect over time, supporting long-term treatment in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT01842607.

Treatment of Legionnaires’ Disease

SummaryLegionnaires’ disease is a relatively common cause of community-acquired pneumonia and of some outbreaks of hospital-acquired pneumonia. Moreover, Legionella pneumophila is frequently involved in the aetiology of the subset of pneumonias that is characterised by severe clinical course and high mortality. No sure clinical, radiographical or analytical features are useful in differentiating Legionella infection from other aetiologies of pneumonia.On the basis of these data, a rational initial therapeutic approach to community-acquired pneumonia, as well as to nosocomial pneumonia in certain circumstances, has to include an antimicrobial agent that is clinically effective against Legionella spp. Clinical studies have provided evidence that erythromycin is the first-line treatment. An intravenous dosage of 1g every 6 hours as initial therapy will be effective in most cases. Parenteral treatment may be switched to oral administration only after clinical response is observed. In vitro susceptibilities and preliminary experimental and clinical results suggest that clarithromycin will most likely become the preferred treatment once an intravenous preparation is available worldwide. However, orally administered clarithromycin at the dosage of 500mg every 12 hours may be recommended in those developing countries in which health systems cannot afford the costs of intravenous therapy.In the case of clinically severe illness or in seriously immunosuppressed hosts with confirmed legionellosis, a combined therapeutic approach is warranted. Rifampicin 600mg every 12 hours intravenously or orally has to be added to the usual dosage of erythromycin. Other alternative therapies, but with less distinct clinical efficacy, that can be combined with erythromycin are doxycycline 100mg every 12 hours intravenously or orally, and intravenous ciprofloxacin 200mg every 6 hours.

Omalizumab in the management of oral corticosteroid-dependent IGE-mediated asthma patients

Abstract Background: Several studies have demonstrated the beneficial effects of omalizumab in asthma patients. Here we describe the drug’s tolerance and oral corticosteroid sparing capacity in a long-term observational study. Methods: Thirty-two patients aged ≥18 years with obstructive airway disease and FEV1 reversibility ≥12% and 200 mL, with an oral steroid requirement ≥7.5 mg per day of prednisolone during a period of ≥1 year, a positive prick test or in vitro reactivity (RAST) to at least one perennial aeroallergen and a baseline immunoglobulin E level ranking between 30–700 IU/mL were prospectively followed for 17.2 ± 8.5 months. Patients were visited once or twice a month, depending on their schedule for omalizumab administration. Intervention: blood analysis every six months; spirometry and nitric oxide measurement at every visit. Results: One patient who dropped out early was excluded. Follow-up period: the treatment benefited 83.9% (26/31) of the cohort; oral corticosteroids were reduced from 7.19 ± 11.1 to 3.29 ± 11.03 mg (p < 0.002) and withdrawn in 74.2% of patients. FEV1 (percent predicted) was 64.4 ± 22.7 at the beginning and 62.9 ± 24.3 at the end. IgE at entry was 322.2 ± 334.2 IU/mL and increased 2.34-fold. Respiratory function and NO did not present statistically significant changes. We identified three groups of patients: the first (n = 17) receiving oral steroid at entry in whom the accumulated dose of oral steroids progressively decreased; another (n = 10) including patients who had quit oral steroids before starting omalizumab although they had not been instructed to do so and whose oral steroid dose at the end of follow-up was zero; and a third group (n = 4) that did not benefit from omalizumab treatment. The only relevant side effect was a flu-like syndrome which required discontinuation of treatment in one patient. Conclusion: In our series, a substantial, safe decrease in oral corticosteroid requirements was observed due, at least to some extent, to omalizumab therapy. Oral corticosteroids were withdrawn in three-quarters of the patients. We were unable to identify a factor able to predict which patients would benefit most from omalizumab treatment.

Omalizumab for Severe Asthma: Efficacy Beyond the Atopic Patient?

Several years ago, omalizumab became commercially available for the treatment of severe asthma. It remains the only monoclonal antibody to be marketed for this purpose. Since then, many studies have been published endorsing its efficacy and effectiveness. Concomitantly, evidence of an overlap between atopic and non-atopic severe asthma has emerged. However, there also appears to be some disagreement regarding the value of omalizumab in the management of non-atopic disease, as some studies have failed to show any benefit in these patients. The recent literature has also sought to identify appropriate prognostic biomarkers for the use of omalizumab, other than immunoglobulin (IgE) levels. This article briefly summarizes the evolution of asthma treatment, the pathophysiology of the condition, and the method of action of omalizumab. The author describes the controlled and uncontrolled studies (also named “real-life studies”) published in adult and pediatric populations in different countries and expresses his view on the current place of the drug in the management of severe allergic asthma. He offers a personal perspective on the recent evidence for the use of omalizumab in non-atopic patients, highlighting the implications for current clinical practice and the gaps in our knowledge. The author justifies his belief that omalizumab is not only an IgE-blocking drug and should be considered as a disease-modifying therapy because of its multiple effects on different biologic pathways. Finally, some areas for future research are indicated.

Twelve years’ experience with methotrexate for GINA treatment step 5 asthma patients

ABSTRACT Background: Certain studies have shown the beneficial effects of methotrexate (MTX) in asthma patients. Here we describe the drugs tolerance and oral corticosteroid sparing capacity in a long-term observational study. Methods: Forty-four patients with steroid-dependent asthma treated with 10 mg per week of oral MTX were prospectively followed for 91.3 ± 39.5 months. Intervention: blood analysis each 3 months; spirometry monthly during the first 3 months and then every 3–6 months; liver ultrasound when an accumulated dose of 1500 mg was reached or whenever hepatic function was altered. Results: Two patients who dropped out early were excluded. Mean accumulated dose of MTX was 3.499 ± 2.207 mg. Corticosteroid use was reduced from 15.1 ± 8.2 to 2.64 ± 5.35 mg (p < 0.008) and was withdrawn in 25 patients. In the remaining 17 patients, the dose was reduced from 17.1 ± 9.1 mg to 6.5 ± 6.8 mg. FEV1 (% predicted) was 66.2 ± 19.7 at the beginning and 65.7 ± 19.1 at the end. Haematology was normal and only a mild increase in hepatic enzymes was observed in four patients, which normalized after treatment discontinuation. Hair loss was observed in one case. Conclusions: In our series, a substantial, safe decrease in oral corticosteroid requirements was observed, probably due, to some extent, to MTX therapy. Oral corticosteroids were withdrawn completely in 59% of patients. Liver function was impaired in some patients; however, it recovered after MTX withdrawal and MTX could be safely reintroduced. The association of oral corticosteroids and MTX did not increase the number of side-effects and immunity was not affected. We were unable to identify a factor that could predict which patients would benefit most from MTX treatment. Some limitations of the study include the lack of control of asthma exacerbations and the lack of booster courses of corticosteroids.

Oropharyngeal Examination to Predict Sleep Apnea Severity

OBJECTIVE To evaluate the usefulness of the examination of the upper airway, paying special attention to the Friedman tongue position (FTP), to confirm obstructive sleep apnea syndrome (OSAS) and its severity. DESIGN Prospective, single-center, cross-sectional study. SETTING Sleep disorders unit of a community hospital. PATIENTS A total of 301 consecutive patients admitted to the sleep disorders unit due to suspicion of OSAS. Assessments included body mass index calculated as weight in kilograms divided by height in meters squared (BMI); neck perimeter measurement; oropharyngeal examination; fiberendoscopy; rhinomanometry; and a sleep study. MAIN OUTCOME MEASURES Apnea-hypopnoea index (AHI), FTP, the uvula size, and certain complementary examinations (sex, age, BMI, cervical perimeter, nasal flow) whose importance has not been clearly established, and to explore their potential value as predictors of the AHI. RESULTS Findings included the following: the mean (SD) age of the patients was 51 (12) years; 71.1% were male; the mean (SD) BMI was 29.8 (4.6); and the mean (SD) cervical perimeter, 40.5 (3.7) cm. In 94.0% of the patients the AHI value was at least 5.0/hour. Patients with FTP scores of 2 and 3 accounted for 74.1% of the whole cohort: 14.3% had an FTP score of 1, and only 11.6% had a score of 4. Of the 6.0% of cases with a normal AHI, 16 patients were classified as having FTP scores of 1, and 2 as having a score of 2. Tonsil size score (P = .005), uvula score (P = .003), BMI (P < .001), cervical perimeter (P < .001), nasal flow at 150 Pa (P = .02), and age (P = .007) were related to OSAS severity. Curiously, AHI in patients who had undergone tonsillectomy was higher than in the TS1 group (tonsils inside the tonsillar fossa) and quite similar to the TS 2 group (tonsils that extend beyond the tonsillar pillars). In the multiple regression model, only the FTP score showed a relevant relationship to OSAS severity. CONCLUSIONS First, since the FTP score is almost the only parameter related to OSAS severity, a simple oropharyngeal examination can provide key information on this issue. Second, tonsillectomy does not seem to protect against development of OSAS.

The Relevance of IgE in the Pathogenesis of Allergy: The Effect of an Anti-IgE Drug in Asthma and Other Diseases

The frequency of allergic diseases has increased in recent decades. Asthma is one of the most prevalent conditions and a leading cause of morbidity. It affects 3-4% of the population in our geographical setting and extrinsic allergens are detected as the diseases etiological agent in around half of these cases. IgE is one of the molecules involved in the allergic process. Most of the time and resources at asthma units are devoted to corticosteroid-dependent patients. International guidelines for asthma treatment recommend a stepwise therapeutic approach; in the last step, the use of oral corticosteroids is advised when control is not achieved with long-acting beta-2-agonists and high doses of inhaled corticosteroids. No alternatives or complements to oral corticosteroids had been proposed until November 2006, when the latest GINA update included the IgE blocker omalizumab in the last step of asthma treatment. In this paper we discuss the pathogenesis of the allergic reaction and the key importance of IgE in this process in order to highlight the beneficial effects of a drug able to block the circulation of the free form of this immunoglobulin. We also review the most important studies and patents for the efficacy and effectiveness of the drug in the treatment of adults and pediatric patients with asthma and other diseases.