Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Once daily ledipasvir/sofosbuvir fixed-dose combination with ribavirin in patients with inherited bleeding disorders and hepatitis C genotype 1 infection.

AIM: People with inherited bleeding disorders have been disproportionally affected by HCV. We assessed the fixed-dose combination of the NS5A inhibitor ledipasvir (LDV) with the NS5B polymerase inhibitor sofosbuvir (SOF) with ribavirin (RBV) in patients with genotype 1 HCV and inherited bleeding disorders. METHODS: To be eligible, patients had to be over 18 years of age and have an inherited bleeding disorder. HCV treatment-naïve and -experienced patients could enrol. All patients received LDV 90 mg per SOF 400 mg once daily and weight-based RBV in a divided dose for 12 weeks. The primary efficacy endpoint was sustained virologic response (SVR), defined as HCV RNA below the limit of detection (15 IU mL-1 ) 12 weeks after the end of treatment (SVR12). RESULTS: Of the 14 patients enrolled, 8 (57%) had haemophilia A, 3 (21%) had haemophilia B and 2 (14%) had von Willebrand disease, and 1 (7%) had factor XIII deficiency. All 14 patients (100%, 95% CI: 77-100%) achieved SVR12. Treatment was well tolerated: all patients completed therapy, with mostly mild adverse events. No specific safety concerns associated with the patient's underlying bleeding disorders were noted. CONCLUSION: These results appear to suggest that people with HCV and inherited bleeding disorders can be safely and effectively treated with 12 weeks of LDV/SOF plus RBV.

Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy.

Clinical phase II/III studies of the nucleotide analogue HCV NS5B inhibitor sofosbuvir (SOF) have demonstrated high efficacy in HCV-infected patients in combination therapy. To date, resistance to SOF (S282T in NS5B) has rarely been detected in patients. In this study, we investigated the evolution of S282T viral variants detected in one HCV genotype 2b-infected patient who relapsed following 12 weeks of SOF monotherapy. Deep sequencing of the NS5B gene was performed on longitudinal plasma samples at baseline, days 2 and 3 on SOF, and longitudinal samples post-SOF treatment through week 48. Intrapatient HCV evolution was analysed by maximum-likelihood phylogenetic analysis. Deep sequencing analysis revealed a low level pre-existence of S282T at 0.05% of viral sequences (4/7755 reads) at baseline and 0.03% (6/23 415 reads) at day 2 on SOF. Viral relapse was detected at week 4 post-treatment where 99.8% of the viral population harboured S282T. Follow-up analysis determined that S282T levels diminished post-treatment reaching undetectable levels 24-48 weeks post-SOF. Phylogenetic analysis together with the persistence of unique post-treatment mutations in all post-SOF samples suggested that growth of wild type resulted from reversion of the S282T mutant to a wild type and not outgrowth of the baseline wild-type population. Our data suggest that a very low level of pre-existing S282T at baseline in this patient was enriched and transiently detected following SOF monotherapy. Despite relapse with drug resistance to SOF, this patient was successfully retreated with SOF plus ribavirin for 12 weeks and is now cured from HCV infection.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Tumor-associated peripheral eosinophilia: two unusual cases.

Peripheral eosinophilia is a rare but recognized accompaniment of malignant disease. Two unusual cases, one with a histiocytic lymphoma and the other with cervical carcinoma, are described. In the first patient, pulmonary infiltrates developed at the height of the eosinophilia and in the second, the peripheral eosinophilia heralded the onset of disseminated disease. Tumor-associated peripheral eosinophilia is reviewed, and it is concluded that peripheral eosinophilia associated with a malignant setting is a marker of extensive disease and is thus associated with a poor prognosis.

The role of the cysteine-rich region of the beta2 integrin subunit in the leukocyte function-associated antigen-1 (LFA-1, alphaLbeta2, CD11a/CD18) heterodimer formation and ligand binding.

The cysteine-rich region (CRR) of the beta2 integrin subunit was replaced by that of beta1 to give the chimera beta2NV1. Beta2NV1 can combine with alphaL to form a variant leukocyte-function-associated antigen (LFA)-1 on COS cell surface, suggesting that the specificity of the beta2 interaction with alphaL does not lie in the CRR. Unlike those expressing wild-type LFA-1, COS cells expressing alphaL beta2NV1 are constitutively active in intercellular adhesion molecule (ICAM)-1 adhesion. These results suggest that activation of LFA-1 involves the release of an intramolecular constraint, which is maintained, in part, by the authentic beta2 CRR.

Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature.

In a retrospective review of 116 consecutive allogeneic bone marrow transplants (BMT), severe obstructive airways disease was identified in 11 patients. Lung pathology demonstrated bronchiolitis in 9 patients and physiologic studies showed small-airways disease consistent with bronchiolitis in the other 2. None of the 5 patients with associated infection survived, while 3 of the 6 patients without an identified pathogen stabilized or improved. Analysis of the 11 cases presented and all 25 cases reported in the literature (1982 to 1985) supports the conclusion that graft-versus-host disease is a major risk factor for bronchiolitis in BMT recipients. Among the proposed mechanisms for the development of bronchiolitis after allogeneic BMT, the 2 most likely are graft-versus-host disease directly causing bronchiolitis, and increased immunosuppressive therapy given for graft-versus-host disease predisposing to viral bronchiolitis. The available evidence would suggest that it is prudent to obtain serial pulmonary function tests even in asymptomatic patients post-BMT, and particularly in those with chronic graft-versus-host disease, in the hope that early detection will allow for early intervention that will arrest or reverse the progression of the obstructive airways disease.

Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation.

In a retrospective analysis (July 1979 to March 1984) of 120 allogeneic adult bone marrow transplant recipients, we identified seven patients with small-airway disease for whom no microbiologic agent was detected. Six had pulmonary function studies demonstrating air flow obstruction. Five of the seven patients had an open-lung biopsy showing pathologic changes within small airways; these varied from early bronchiolar wall damage to bronchiolitis obliterans. The inflammatory cell infiltrate was peribronchiolar, and consisted of polymorphonuclear leukocytes and lymphocytes in varying proportions. Three of the seven patients recovered following increased immunosuppressive therapy; the other four died. Because all seven patients had acute and chronic graft-versus-host disease, in the absence of any identifiable pathogen, we postulate that small-airway damage represents one of the facets of graft-versus host-disease. An additional analysis of 26 patients with respiratory symptomatology and available histologic material supports the hypothesis that small-airway disease in bone marrow transplant patients represents a risk factor for the subsequent development of respiratory opportunistic infections.

Chimeras of the integrin beta subunit mid-region reveal regions required for heterodimer formation and for activation.

A central region of the beta2 integrin subunit, RN (residues D300 to C459), was replaced by the equivalent sequences from beta1 and beta7 to give the chimeras beta2RN1 and beta2RN7. Whilst the former construct failed to form heterodimer at the cell surface with alphaL, the later of these could be expressed together with the alphaL subunit to form a variant LFA-1. Based on recent modelling work, the RN region consists of two parts, one is the C-terminal end of the putative A-domain (RB, residues D300 to A359), and the other the mid-region (BN, residues Y360 to C459). Chimeras exchanging the two component regions were made. Of the four resultant chimeras, only the beta2RB1 chimera failed to support LFA-1 expression. Thus the beta1 specific residues of this region affect the interaction with the alphaL subunit. Whereas the alphaL/beta2RB7 LFA-1 variant is wildtype like with respect to ICAM-1 adhesion, the alphaLbeta2BN1 and alphaLbeta2BN7, as well as the alphaLbeta2RN7, variants are more adhesive than the wildtype. These results suggest that an authentic beta2 mid-region is, in part, required for maintaining the LFA-1 in a resting state.

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).

Hereditary Hemorrhagic Telangiectasia (HHT) is easily recognized in individuals displaying the classical triad of epistaxis, telangiectasia, and a suitable family history, but the disease is more difficult to diagnosis in many patients. Serious consequences may result if visceral arteriovenous malformations, particularly in the pulmonary circulation, are unrecognized and left untreated. In spite of the identification of two of the disease-causing genes (endoglin and ALK-1), only a clinical diagnosis of HHT can be provided for the majority of individuals. On behalf of the Scientific Advisory Board of the HHT Foundation International, Inc., we present consensus clinical diagnostic criteria. The four criteria (epistaxes, telangiectasia, visceral lesions and an appropriate family history) are carefully delineated. The HHT diagnosis is definite if three criteria are present. A diagnosis of HHT cannot be established in patients with only two criteria, but should be recorded as possible or suspected to maintain a high index of clinical suspicion. If fewer than two criteria are present, HHT is unlikely, although children of affected individuals should be considered at risk in view of age-related penetration in this disorder. These criteria may be refined as molecular diagnostic tests become available in the next few years.

Toxic shock syndrome as the AIDS-defining diagnosis.

Toxic shock syndrome (TSS) has been infrequently reported as a complication of AIDS. We present the case of a 24-year-old man, previously unknown to be positive for the human immunodeficiency virus, presenting in septic shock. The literature on TSS in AIDS is reviewed and the association between the two diseases is presented.

Diphenylhydantoin-induced lymphocytic interstitial pneumonia.

A patient developed diffuse lymphocytic interstitial pneumonia after receiving diphenylhydantoin therapy for 14 months. Withdrawal of medication resulted in reversal of the disease process. This case illustrates the value of combined transbronchial biopsy and bronchoalveolar lavage sampling in establishing a diagnosis, and the utility of serial bronchoalveolar lavage in monitoring disease evolution.

Spirometry and dyspnea in patients with COPD. When small differences mean little.

OBJECTIVE: To determine when a difference in FEV1 is sufficiently large to be associated with a noticeable difference in dyspnea symptoms for patients with chronic lung disease. DESIGN: Cross-sectional analysis of 15 groups (n = 112 patients, 832 contrasts). SETTING: Respiratory rehabilitation program. PATIENTS: Patients with COPD (mean FEV1 = 35% predicted). MEASURES: Patients' perspectives assessed through subjective comparison ratings of dyspnea and of overall health. Relation between the FEV1 and patients' perspectives determined the smallest difference in spirometry that was associated with a noticeable difference in patients' symptoms. RESULTS: The FEV1 was moderately correlated with patients' ratings of dyspnea (r = 0.29; 95% confidence interval (CI), 0.22 to 0.35). In contrast, the FEV1 was minimally correlated with patients' ratings of overall health (r = 0.10; 95% CI, 0.03 to 0.17). The FEV1 needed to differ by 4% predicted for the average patient to stop rating his or her dyspnea as "about the same" and start rating his or her dyspnea as either "a little bit better" or "a little bit worse" relative to other patients (95% CI, 1.5 to 6.5). This was equivalent to the average patient's FEV1 increasing by 112 mL (starting from 975 mL and ending at 1,087 mL). CONCLUSIONS: Some statistically significant differences in the FEV1 are so small that they may not represent important differences in symptoms for the average patient with severe COPD; an awareness of the smallest difference in FEV1 that is noticeable to patients can help clinicians interpret the effectiveness of symptomatic treatments.

Cyclosporine as possible prophylaxis for obstructive airways disease after allogeneic bone marrow transplantation.

The objective of this study was to evaluate the impact of cyclosporine (cyclosporin A; CyA) prophylaxis for graft-versus-host disease (GVHD) on the development of obstructive airways disease (OAD) after allogeneic bone marrow transplantation (BMT) in leukemic patients. Patients with normal pulmonary function tests (PFTs) prior to BMT were followed with serial PFTs for the development of OAD. Follow-up PFTs were performed at 3, 6, 9, and 12 months, and thereafter at consecutive yearly intervals. Obstructive airways disease was defined as FEV1 less than 80 percent, ratio of FEV1 over the forced vital capacity (FEV1/FVC) less than 80 percent of predicted, maximal midexpiratory flow rate at 50 percent vital capacity less than 65 percent of predicted, or residual volume greater than 120 percent of predicted. In the period prior to CyA prophylaxis for GVHD development (March 1983 to September 1986), 17 (39 percent) of the 44 patients undergoing BMT developed OAD, compared with 2 (4 percent) of 45 in the post-CyA period (September 1986 to March 1990) (chi 2 = 17; p < 0.00005). Age, sex, type of leukemia, severity of GVHD, histocompatibility status, presence of acute GVHD, and sex mismatch between donor and recipient were not associated with development of OAD. Although chronic GVHD was associated with OAD in univariate analysis, a multivariate logistic regression analysis showed that the only significant independent predictor for OAD was the use of CyA. We conclude that CyA is protective against the development of OAD after BMT in leukemic patients.

The malignancy-sarcoidosis syndrome.

In a retrospective review of six patients with malignancy preceding sarcoidosis, we found four cases of malignant lymphoproliferative disease (LD) and one case each of ovarian cancer and breast cancer. The median interval from onset or relapse of malignancy to sarcoidosis was nine months. Of the four patients with LD, sarcoidosis appeared within six months of termination of chemotherapy for three of the patients and 15 months after allogeneic bone marrow transplantation for the fourth patient. At the time of diagnosis of sarcoidosis, there was no clinical or pathologic evidence of malignancy in the chest. We conclude that in contradistinction to the previously described syndrome of sarcoidosis preceding LD, there exists a syndrome of sarcoidosis following malignancy with or without chemotherapy.

Prevention of acute pulmonary edema after bone marrow transplantation.

In a retrospective review of 21 bone marrow transplantation procedures (BMT), we identified ten episodes of acute pulmonary edema coinciding with significant weight gain in the second week after BMT. When we prospectively observed nine consecutive BMT recipients, six patients developed acute pulmonary edema associated with significant (p less than 0.05) weight gain and an increase in echocardiographically determined left ventricular end diastolic diameter. These findings led to a prospective prophylactic intervention study of 30 consecutive BMT patients. Prophylactic intervention consisting of reduced fluid volume of parenteral alimentation, and diuretic therapy was instituted at any clinical sign of fluid overload. No episode of pulmonary edema occurred. The dramatic difference--acute pulmonary edema occurred in 16/30 untreated vs 0/30 treated cases--suggests that this post-BMT complication is critically related to fluid balance and can be prevented by careful clinical examination, close monitoring of weight change, avoidance of fluid overload and the appropriate use of diuretic therapy.

Diffuse pulmonary arteriovenous malformations: characteristics and prognosis.

OBJECTIVE: To study the clinical characteristics and prognosis of patients with diffuse pulmonary arteriovenous malformations (AVMs). DESIGN: Retrospective chart review of all patients (n = 16) with diffuse pulmonary AVMs seen at Yale New Haven Hospital, Johns Hopkins Hospital, and St. Michael's Hospital. Up-to-date follow-up information was obtained in all living patients. RESULTS: All patients were severely hypoxic. Neurologic complications (stroke or brain abscess) had occurred in 70% of patients by the time of diagnosis. During the follow-up period (mean, 6 years), three patients died and two others developed new neurologic complications. One of the deaths occurred perioperatively during lung transplantation. All patients underwent transcatheter embolotherapy of any large pulmonary AVMs. A selected group underwent pulmonary flow redistribution, a novel technique. Oxygenation did not improve significantly with embolotherapy of the larger AVMs, but there was a small significant improvement in those patients who underwent pulmonary flow redistribution. The majority (85%) of the living patients are currently working or studying full-time. CONCLUSIONS: Patients with diffuse pulmonary AVMs are at increased risk of neurologic complications. Transcatheter embolotherapy does not significantly improve the profound hypoxia, but it may reduce the risk of neurologic complications. Antibiotic prophylaxis is recommended for bacteremic procedures to prevent brain abscess. These patients can live for many years and lead productive lives. We do not recommend lung transplantation because survival with disease is difficult to predict and we have observed a perioperative transplant death.

Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of hypoxemia.

STUDY OBJECTIVES: To determine (1) the prevalence of pulmonary hypertension and cardiac dysfunction in adult cystic fibrosis (CF) patients with severe lung disease, (2) the relationship between these cardiovascular abnormalities and hypoxemia, and (3) the impact of subclinical pulmonary hypertension on survival. DESIGN: Single-blind, cross-sectional study. SETTING: Ambulatory clinic of the Adult CF program at a tertiary-level hospital. PATIENTS: Clinically stable patients with severe lung disease (FEV1 < 40% of predicted normal value) who were not receiving supplemental oxygen. A second cohort of patients in stable condition with less severe lung disease (FEV1 40 to 65% predicted) was also recruited to enable multivariate analysis for the determinants of pulmonary hypertension. MEASUREMENTS AND RESULTS: Eighteen patients with severe lung disease (FEV1 28 +/- 7% of predicted normal value) were initially studied. Each patient had overnight polysomnography, pulmonary function tests, and Doppler echocardiography. Arterial oxygen saturation (SaO2) was reduced during wakefulness (87.1 +/- 6.1%) and fell during sleep (84.0 +/- 6.6%) while transcutaneous PCO2 was normal during wakefulness (41.1 +/- 6.9 mm Hg) and increased during sleep (46.6 +/- 4.7 mm Hg). Left ventricular size, systolic function, and diastolic function were normal except in one patient who had had a previous silent myocardial infarction due to coronary artery disease. Qualitative assessment of right ventricular function was normal in all patients. Pulmonary artery systolic pressure (PASP) was increased (> 35 mm Hg) in seven patients without clinical evidence of cor pulmonale. Regression analysis was performed by combining these data with data from an additional 15 CF patients with moderately severe lung disease (FEV1 56.3 +/- 8.9% predicted normal) who were recruited to a modified study protocol that included overnight oximetry, pulmonary function tests, and Doppler echocardiography. None of these patients had evidence of hypoxemia and only three had mild elevation of PASP (36, 37, and 39 mm Hg). Linear regression analysis revealed that PASP was significantly correlated with FEV1 (r = -0.44; p = 0.013), and SaO2 during wakefulness (r =-0.60; p = 0.0003), during sleep (r = -0.56; p = 0.0008), and after 6 min of exercise (r = -0.75; p < 0.0001). Multivariate analysis revealed that awake SaO2 was a significantly better predictor of PASP than FEV1 (p = 0.0104). Clinical follow-up of the original cohort for up to 5 years revealed that mortality was significantly higher in those with pulmonary hypertension than those without pulmonary hypertension (p = 0.0129). CONCLUSIONS: In adult CF patients with severe stable lung disease, left and right ventricular function is well maintained in the absence of significant coronary artery disease; pulmonary hypertension develops in a significant proportion of patients and is strongly correlated with oxygen status, independent of lung function; and subclinical pulmonary hypertension is associated with an increased mortality.

Evaluation of the single-breath diffusing capacity in asthma and cystic fibrosis.

To explain why the single-breath carbon monoxide diffusing capacity (Dsb) was, on the average, elevated in 163 asthmatic subjects and 175 patients with cystic fibrosis, we simulated this elevation in ten normal subjects by having them perform the test for Dsb through an inspiratory obstruction. This resulted in an 18 percent increase in Dsb corrected for pulmonary volume. Inhalation of a bronchodilator drug was associated with relief of obstruction and a fall in the corrected Dsb in 31 asthmatic subjects but did not change either the obstruction or the corrected Dsb in 17 patients with cystic fibrosis. We suggest that elevated Dsb in asthma and cystic fibrosis is partly due to maximal inspiration against obstructed airways. This requires abnormally negative intrathoracic pressures, increasing the pulmonary capillary blood volume, and, thereby, increasing the Dsb.

Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy.

STUDY OBJECTIVES: To determine if transcatheter embolotherapy is safe and effective for the treatment of pulmonary arteriovenous malformations during pregnancy. DESIGN: Prospective study. SETTING: Specialized hereditary hemorrhagic telangiectasia centers at Yale University School of Medicine and St. Michael's Hospital, University of Toronto. PATIENTS: Seven pregnant women (age range, 24 to 34 years; gestational age range, 16 to 36 weeks) undergoing transcatheter embolotherapy. INTERVENTIONS: Transcatheter embolotherapy in all patients. MEASUREMENTS AND RESULTS: Thirteen pulmonary arteriovenous malformations in seven patients were embolized with detachable silicone balloons and/or stainless steel coils without incident. The estimated fetal radiation dose ranged from < 50 to 220 mrad. No complications of pulmonary arteriovenous malformations occurred in any of the patients after transcatheter embolotherapy. The mothers went on to deliver healthy babies in all cases. CONCLUSIONS: Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations performed by an experienced radiologist appears to be safe and effective after 16 weeks of gestational age.