A Man with a Pruritic Rash

Posted by Carla Rothaus • June 24th, 2016

2016-06-17_12-33-39Although human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus, it seems to induce a precancerous state that can lead to adult T-cell leukemia–lymphoma (a subtype of cutaneous T-cell lymphoma), instead of being directly carcinogenic. HTLV-1 is associated with a long latency period, and most affected patients are exposed to the virus early in life. The four clinical variants of adult T-cell leukemia–lymphoma — acute, lymphomatous, chronic, and smoldering — affect the clinical presentation and prognosis.

A 65-year-old man with end-stage renal disease and a history of syphilis presented with a leg injury and a diffuse pruritic rash. A recent serologic test had been positive for human T-lymphotropic virus type 1. A diagnostic procedure was performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some general features of cutaneous T-cell lymphoma?

Cutaneous T-cell lymphoma can be manifested by pruritic scaly plaques and papules that usually occur on the buttocks and other nonphotodistributed areas and appear gradually. There are many types of cutaneous T-cell lymphoma. Mycosis fungoides accounts for the majority of cases of T-cell lymphoma with cutaneous involvement (approximately 65%), whereas adult T-cell leukemia–lymphoma accounts for less than 1% of cases. Mycosis fungoides can be manifested by a patch, plaque, or tumor and may also progress to involve the lymph nodes and viscera.

Clinical Pearl

• HTLV-1–associated adult T-cell lymphoma–leukemia occurs most commonly in patients living in what geographic regions?

HTLV-1–associated adult T-cell leukemia–lymphoma occurs most frequently in patients who live in areas where HTLV-1 is endemic, such as the Caribbean basin, southwestern Japan, and parts of South American and central Africa, but it can also be identified in the United States.

Figure 1. Clinical Photographs.

Figure 2. Skin-Biopsy Specimen (Hematoxylin and Eosin).

Morning Report Questions

Q: Is adult T-cell leukemia–lymphoma difficult to distinguish from mycosis fungoides?

A: The diagnosis of adult T-cell leukemia–lymphoma with cutaneous involvement is challenging because it mimics other forms of T-cell lymphoma with cutaneous involvement, particularly mycosis fungoides. Skin biopsies from patients with adult T-cell leukemia–lymphoma often initially lead to a diagnosis of mycosis fungoides. Findings that suggest that cutaneous patches or plaques are caused by adult T-cell leukemia–lymphoma instead of mycosis fungoides include increased expression of CD25 and distribution of the patches or plaques in photodistributed areas. Among patients who live in areas where HTLV-1 is endemic, serologic testing for HTLV-1 may be positive both in those with adult T-cell leukemia–lymphoma and in those with mycosis fungoides. Thus, in a patient who has HTLV-1 infection, the accurate diagnosis of adult T-cell leukemia–lymphoma requires evidence of proviral DNA integration, obtained by means of direct polymerase-chain-reaction testing of skin lesions.

Figure 3. Skin-Biopsy Specimen (Immunoperoxidase).

Table 2. Features of Mycosis Fungoides and Adult T-Cell Leukemia–Lymphoma.

Q: What is the prognostic implication of cutaneous involvement in adult T-cell leukemia–lymphoma?

A: Approximately 50% of patients with adult T-cell leukemia–lymphoma have some form of cutaneous involvement, such as patches, plaques, papules, nodules, tumors, erythroderma, or purpura. The type of skin lesion is of prognostic importance, since the survival rate is lower among patients with erythroderma or tumors than among patients with only patches or plaques. Among patients with acute or lymphomatous adult T-cell leukemia–lymphoma, cutaneous involvement has been associated with a decreased survival rate.

Body-Mass Index in Adolescents

Posted by Carla Rothaus • June 24th, 2016

2016-06-17_10-36-07Overweight and obesity in adolescents have increased substantially in recent decades and affect a third of the adolescent population in some developed countries. Twig et al. assessed the risk of fatal cardiovascular events in adulthood according to the body-mass index range during adolescence, using a national database of 2.3 million Israeli adolescents in whom height and weight were measured between 1967 and 2010.

In this study, a range of values for body-mass index that were well within the accepted normal range in adolescence predicted increased cardiovascular and all-cause mortality during 40 years of follow-up. A new Original Article summarizes.

Clinical Pearl

• In developed countries, how do trends in cardiovascular mortality among young adults compare to those among older age groups?

In contrast to the steep decline in the rate of death from cardiovascular causes among older age groups, cardiovascular mortality among young adults has not decreased or the decline has slowed in several developed countries.

Clinical Pearl

• Is the association between body-mass index and increased risk of subsequent cardiovascular mortality limited to those who are overweight or obese?

Some, although not all, studies suggest that a BMI that falls within the upper-normal range in adolescence is associated with an increased risk of death from cardiovascular causes, although a determination of the BMI threshold that is associated with such an increased risk remains uncertain.

Morning Report Questions

Q: Is there evidence of an association between an adolescent BMI in the mid-normal range and an increased risk of subsequent cardiovascular mortality?

A: The large size of the study by Twig et al., which incorporated more than 42 million person-years of follow-up, provided adequate statistical power to assess the associations within the currently accepted normal range of BMI values. Excess all-cause mortality (including cardiovascular mortality) starting at the 50th percentile of adolescent BMI values confirmed the findings of an earlier study on a portion of this cohort. Thus, the classification of BMI according to the accepted normal range (i.e., the 5th to 84th percentiles and a BMI ranging from 18.5 to 25.0) may underestimate the risk associated with being overweight in adolescence. This inference is supported by findings of the current study of Twig et al. that there is a graded increase in the risk of death starting at the mid-normal range of adolescent BMI (50th to 74th percentiles) and that the high-normal BMI range (75th to 84th percentiles) was associated with hazard ratios of 2.2 for coronary heart disease and 1.8 for total cardiovascular causes.

Table 2. Duration of Follow-up and Cause of Death, According to Percentile of BMI during Adolescence.

Table 3. Hazard Ratios for Cause of Death, According to Percentile of BMI during Adolescence.

Figure 2. Body-Mass Index (BMI) during Adolescence and Subsequent Cardiovascular Mortality.

Q: Does the association between cardiovascular mortality and increased BMI in adolescence take decades to become evident?

A: Twig et al. found that, in calculations of the risk of death from total cardiovascular causes at different follow-up times and 10-year intervals, the association between cardiovascular mortality and increased BMI was evident by 10 years of follow-up (hazard ratio, 2.0; 95% CI, 1.1 to 3.9) and was more pronounced during the follow-up period from 30 to 40 years (hazard ratio, 4.1; 95% CI, 3.1 to 5.4).

Sudden Cardiac Death in the Young

Posted by James Yeh, M.D. M.P.H. • June 22nd, 2016

2016-06-22_10-01-53Fatal heart conditions are shocking and tragic when they are sudden and unexpected, and especially when they occur in the young. Occasionally the public is reminded of this via a news story of a high school or professional athlete who collapses suddenly and dies during a sporting event. Often, the first manifestation of a serious heart condition in the young is also the last.

What are common causes of sudden cardiac death in the young?  

A number of structural and arrhythmogenic heart conditions are associated with sudden cardiac death.  The list includes hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, myocarditis, congenital long-QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.  Most of these conditions have a genetic basis.

What is this study about?

In this week’s issue of NEJM, Bagnall and colleagues present their findings from a prospective population-based observational study evaluating the incidence and cause of sudden cardiac death in individuals ages 1-35 years in Australia and New Zealand during a 2-year period from 2010 to 2012.  The investigators collected autopsy information, demographic information, and clinical data, including genetic and laboratory information, about the deceased.

How is sudden cardiac death defined?

Various criteria have been used to define sudden cardiac death in the medical literature.  However, the investigators defined sudden cardiac death as a sudden unexpected death in an otherwise healthy person within one hour of symptom onset, or within 24 hours of being seen well by others. Sudden unexplained death was defined as sudden cardiac death without clear cause of death identified after a complete and comprehensive autopsy examination.

What did they find?

Four hundred ninety sudden cardiac death cases were identified.  The mean age was 24 years with a male predominance of slightly greater than 70% of the cases.  Nearly 40% of the individuals died during sleep.  The annual incidence was 1.3 per 100,000 persons aged 1-35 years.  The age group at highest risk for sudden cardiac death was those in the 31-35 years group (3.2 per 100,000).

Forty percent of the cases had structurally normal hearts and were designated sudden unexplained deaths. The most common explained causes of sudden cardiac death were coronary artery disease (24%) and inherited cardiomyopathies (16%).   For all age subgroups, unexplained death was the most common finding except for those 31-35 years, where coronary artery disease was most common.

In nearly 30% of the sudden unexplained death cases, a clinically relevant cardiac gene mutation was identified.  During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 12% of the families.

What is my take-away?

Unexplained sudden cardiac deaths in the young account for 40% of the cases.  While we often think about coronary artery disease as a disease occurring in the older population, nearly 25% of the cases in this study had coronary artery disease leading to sudden cardiac deaths with the highest risk in those in the older age group (31-35).  Genetic testing was able to identify a clinically relevant cardiac gene mutation for nearly one-third of the sudden unexplained death cases and increased the likelihood of identifying a possible cause of death in individuals over autopsy alone. According to NEJM Deputy Editor Dr. John Jarcho, “This study suggests that genetic testing is a useful addition to standard autopsy procedures in cases of sudden cardiac death in the young. However, there still remain many such cases for which no cause can be found.”

Announcing NEJM Resident 360

Posted by Jennifer Zeis • June 21st, 2016

res360_logoNo one said residency would be easy. But it doesn’t have to be quite so hard. NEJM Resident 360, a new website and discussion platform from NEJM Group, gives residents the information, resources, and support they need to approach each rotation with confidence.

  • Rotation Prep helps residents solidify their foundational medical knowledge with materials that have been written and curated by a team of physician experts, fellows and residents, and are mapped to 14 common residency rotations in internal medicine. Each rotation includes brief topic overviews, links to landmark trials, and review articles from NEJM and other highly respected sources, and a selection of questions from NEJM Knowledge+.
  • Learning Lab provides further educational and interactive tools that explain the medical literature, demonstrate procedures, and hone diagnostic skills.
  • Resident Lounge and Career sections feature resources that address social pressures and aim to inspire and assist with professional growth, including podcasts, blog posts, and professional articles.
  • Discussions engage residents with experts and one another on a variety of clinical, career, and resident life topics.

Residents are encouraged to register with NEJM Resident 360 by creating a personal profile, which enables participation in discussions. Access to Rotation Prep is a benefit of any institutional or individual subscription to an NEJM Group product: the New England Journal of Medicine, NEJM Journal Watch, or NEJM Knowledge+.

For more information, visit resident360.nejm.org.


A Woman with a Pleural Effusion

Posted by Carla Rothaus • June 16th, 2016


A 52-year-old woman presented with a unilateral pleural effusion. Several weeks later, uterine bleeding, pelvic fullness, and bloating developed. Magnetic resonance imaging revealed a large pelvic mass. Diagnostic procedures were performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common benign solid ovarian tumor?

Although only 4% of all ovarian masses are ovarian fibromas, they are the most common benign solid ovarian tumor.

Clinical Pearl

• What is the ovarian cancer symptom index?

A pelvic mass in a postmenopausal woman always raises concerns about ovarian cancer. The ovarian cancer symptom index is a tool used to predict or screen for ovarian cancer. According to this index, additional diagnostic testing for possible ovarian cancer is indicated in the presence of at least one of the following symptoms: abdominal pain; urinary frequency, urinary urgency, or both; and increased abdominal size, bloating, early satiety, or a combination thereof. The symptoms must be frequent and have occurred for less than a year. This index is 90% specific among women older than 50 years of age and 79.5% sensitive for advanced-stage disease.

Morning Report Questions

Q: Ovarian fibromas are associated with what syndromes?

A: Large fibromas (>10 cm in greatest diameter) are associated with ascites in 10 to 15% of cases and associated with ascites and a pleural effusion (the Demons–Meigs syndrome) in 1% of cases. In rare cases, fibromas may be part of the nevoid basal-cell carcinoma syndrome (Gorlin’s syndrome), which is characterized by the presence of multiple basal-cell carcinomas, keratocysts of the jaws, tumors of the central nervous system, fibromas, and skeletal malformations; in patients with this syndrome, ovarian fibromas are typically bilateral, multinodular, and associated with calcifications.

Figure 2. Imaging Studies of the Pelvis.

Figure 3. Resection Specimen.

Q: What are some of the features of the Demons–Meigs syndrome?

A: In 1887, Demons first described a syndrome in which various benign ovarian diseases were associated with the development of a pleural effusion. The description of this syndrome was further refined in a report of seven cases of ovarian fibroma with pleural effusion (usually unilateral and often on the right side) and pelvic fluid or ascites. Only 1 to 2% of patients with ovarian fibromas present with the Demons–Meigs syndrome. In such patients, the CA-125 level is often elevated, and thus it can be difficult to distinguish the Demons–Meigs syndrome from cancer. The hallmark of this syndrome is that removal of the ovarian mass results in permanent resolution of the pleural effusion.

Upper Gastrointestinal Bleeding

Posted by Carla Rothaus • June 16th, 2016

2016-06-14_13-45-23Peptic ulcers, which are primarily due to Helicobacter pylori infection or the use of nonsteroidal antiinflammatory drugs (NSAIDs), occur in the stomach or duodenum and are the most frequent cause of upper gastrointestinal bleeding. Most patients who are hospitalized with upper gastrointestinal bleeding should undergo endoscopy within 24 hours, after appropriate resuscitation and transfusion to a hemoglobin level greater than 7 g per deciliter.

Peptic ulcers, often due to Helicobacter pylori or the use of nonsteroidal antiinflammatory drugs (NSAIDs), commonly cause upper gastrointestinal bleeding. Endoscopic therapy, proton-pump inhibitors, therapy for H. pylori infection, and nonuse of NSAIDs are described. A new Clinical Practice summarizes.

Clinical Pearl

• When is endoscopic therapy indicated for a bleeding peptic ulcer?

Endoscopic features of ulcers are key in predicting risk and determining management strategies. Rates of further bleeding are highest among patients with active bleeding and nonbleeding visible vessels. Endoscopic therapy with injection (e.g., of epinephrine or alcohol), thermal devices (such as bipolar electrocoagulation probes or heater probes), or clips is performed in patients who have ulcers with active bleeding or a nonbleeding visible vessel. Endoscopic therapy may be considered for ulcers with adherent clots, for which randomized trials show heterogeneous results. Flat, pigmented spots and clean-base ulcers, which are detected at endoscopy in approximately 70% of patients with ulcer bleeding, are associated with low rates of serious rebleeding (5.6% and 0.5%, respectively, in a pooled analysis).

Figure 1. Initial Treatment of Patients with Ulcer Bleeding, According to the Endoscopic Features of the Ulcer.

Figure 2. Endoscopic Hemostatic Therapies.

Clinical Pearl

• How should a patient with recurrent bleeding after endoscopic therapy be managed?

If bleeding recurs, endoscopic therapy should be repeated. A randomized trial involving patients with rebleeding after endoscopic therapy showed that surgery was avoided in 73% of cases and adverse events were significantly less common with endoscopic therapy than with surgical therapy. Transcatheter arterial embolization or surgery is performed if repeat endoscopic therapy fails. Complications of bleeding or perforation occur in approximately 0.5% of patients who undergo endoscopic therapy.

Morning Report Questions

Q: What is the recommended approach to the diagnosis and treatment of H. pylori infection in a patient with a bleeding peptic ulcer? 

A: In patients with ulcers or erosions, biopsy specimens should be obtained from lesion-free areas of the gastric body and antral mucosa for assessment of H. pylori infection. If this testing is negative for H. pylori, subsequent retesting (e.g., with a stool test or breath test) has been recommended because some observational studies suggest decreased sensitivity of testing during acute upper gastrointestinal bleeding. Patients with H. pylori infection should receive therapy to eradicate the bacteria. A meta-analysis of randomized trials of such therapy showed significantly less rebleeding in patients who received this therapy than in patients who did not receive treatment for H. pylori infection and in those who received maintenance antisecretory therapy. Eradication of H. pylori should be confirmed after therapy with a breath test, a stool test, or, if repeat endoscopy is performed for another reason, gastric biopsy. Patients must not receive bismuth or antibiotics for at least 4 weeks and should not receive proton-pump inhibitors for at least 2 weeks before testing to avoid false negative results; histamine H2-receptor antagonists are permissible. In a systematic review of studies with a mean follow-up of 11 to 53 months, the incidence of rebleeding was only 1.3% among patients with confirmed eradication of H. pylori.

Q: What alternative therapy is recommended for patients who have bleeding ulcers while taking NSAIDs? 

A: Patients who have bleeding ulcers while taking NSAIDs should discontinue NSAIDs permanently, if possible. If NSAIDs must be resumed, a combination of a cyclooxygenase-2 (COX-2)–selective NSAID and a proton-pump inhibitor is recommended. Studies have shown rates of rebleeding of 4 to 6% within 6 months among patients who had a bleeding ulcer and were subsequently treated with COX-2–selective NSAIDs alone or traditional NSAIDs plus a proton-pump inhibitor. A 12-month double-blind trial showed significantly less ulcer rebleeding with a COX-2–selective NSAID plus a proton-pump inhibitor than with a COX-2–selective NSAID alone (0 vs. 9%).

Figure 3. Long-Term Treatment of Patients with Bleeding Ulcers, According to the Cause of the Ulcer.

Is It Time to Be Dis-ENCHANTED with Low Dose Alteplase in Acute Ischemic Stroke?

Posted by Bhavna Seth, M.D. • June 15th, 2016

2016-06-13_13-00-21Ms. M, is hustled in to your emergency room, a septuagenarian with a history of hypertension. She was last noted to be well and playing with her grandchildren 1 hour ago, when her family noticed she began to slur her words, her face drooped to the left and she felt a heaviness & inability to lift her left arm. You activate the stroke team and in minutes a stat head CT rules out a cerebral hemorrhage. With evidence of an acute ischemic stroke a decision for thrombolysis with intravenous alteplase is made. However, with her co-morbidities, and the risk of hemorrhage, one pauses to consider low-dose alteplase as a therapeutic avenue: Would a lower dose 0.6mg/kg intravenous alteplase be more beneficial compared to the standard 0.9mg/kg dose? How would it impact her immediate and eventual risk for death and disability?

Despite the lack of high quality evidence, many Asian centers have adopted low-dose alteplase as a therapeutic alternative to limit the risks of intracranial hemorrhage. The Enhanced Control of Hypertension and Thrombolysis Stroke (ENCHANTED) takes on this complex problem and through a well-designed trial endeavors to fulfill this gap.

The study, published in this week’s NEJM, was designed as a non-inferiority trial, with the goal to prove that the low-dose alternative was no worse than the standard regimen. It recruited 3310 eligible stroke patients from 111 clinical centers in 13 countries. Patients were randomly assigned to receive either the standard regimen or the low-dose alteplase, within 4.5 hours of suffering from stroke. The primary outcome was to determine death or disability at 90 days based on the modified Rankin scale (scores 2-6). Secondary outcomes included any intracranial hemorrhage, a shift (‘improvement’) in function across mRS scores, separately on death and disability, early neurological deterioration, health-related quality of life, length of hospital stay, need for permanent residential care, and serious adverse events.

The study failed to show non-inferiority of the low-dose strategy as the primary outcome was observed in 53.2% of the low-dose recipients, and 51.1% of those who received the standard dose regimen (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.95 – 1.25). The non-inferiority margin was set at  1.14; and the P value for non-inferiority was 0.51). This outcome was consistent across all sub-group analyses, thus this study did not establish that low-dose is non-inferior to standard dose and perhaps suggests that it is not the time to make seismic shifts in treatment guidelines in favor of the low-dose strategy.

The authors note possible limitations of their study to be interobserver variability for the administration of the modified Rankin scale via telephone, the high percentage of Asian participants and a concurrent intensive blood pressure control arm precluding generalizability. Additionally, compared to other stroke trials, patients in this trial included those with mild neurological impairment who were treated at a later time point than symptom onset compared to other stroke trials, thus, leading to an element of selection bias.

However, the study did have some interesting findings, which may affect clinical decision-making. Patients in the low-dose group suffered from significantly fewer major, symptomatic intracranial hemorrhages, at 1% with low-dose vs. 2.1% with standard dose (OR 0.48, 95% CI 0.27-0.86, p= 0.01). Although in an accompanying editorial, it is noted the rates of hemorrhage in both arms were low. This trial does however provide some evidence in support of the low-dose strategy to treat patients of acute ischemic stroke who may have elevated risk of suffering from intracranial hemorrhage.

As this trial failed to demonstrate non-inferiority based on the authors’ pre-specified criterion, the results of ENCHANTED are unlikely to change current clinical practice. However, it does open the debate about considering a lower dose regimen in certain risk groups but future research would be necessary to determine whether low-dose alteplase is preferable in some patients.

Apply to Be an NEJM Editorial Fellow

Posted by Jennifer Zeis • June 14th, 2016

The NEJM invites applications for three one-year, full-time, paid editorial fellowships beginning in July 2017 from medical professionals at any career stage. Applications are due by August 15, 2016.

The editorial fellows review and edit Images in Clinical Medicine submissions, organize the Clinical Decisions series, and write the Quick Takes under the supervision of senior editors. The fellows also moderate commenting at NEJM.org, review topic tagging for the NEJM website, write Insights posts for the Now@NEJM blog, and contribute to other Journal work according to their skills and inclinations. We would like one fellow with an interest in medical education to take the lead on managing NEJM Resident 360, a new website and discussion platform for residents — keeping the Rotation Prep current, facilitating discussions, and working with an editorial team to generate new ideas and content as needed. The fellows also participate in the day-to-day editorial activities of the Journal, including attending the editorial meetings.

We are looking for candidates who have good medical judgment, can communicate that judgment in good written English, and can work independently. Applicants are not required to be U.S. citizens, but successful candidates must reside in the Boston area for the duration of the fellowship. To apply, please send curriculum vitae and a letter of interest to Pam Miller, 10 Shattuck St., Boston, MA 02115 or editorial@nejm.org by August 15, 2016.

For more insight on the NEJM fellowship experience, see the article by Dr. Terry Schraeder, a former NEJM fellow, “NEJM Fellowship: The Ultimate Journal Club,” in Science Editor. Although written 10 years ago, it remains applicable to today’s fellowship.

A Woman with Dyspnea

Posted by Carla Rothaus • June 10th, 2016

2016-06-03_12-11-02Bronchiolitis is a disease of the small airways, which are defined as airways less than 2 mm in diameter and without cartilage. The bronchioles are especially vulnerable to infectious or inhalational insults because of their narrow diameter.
A 60-year-old woman was seen in a pulmonary clinic because of increasing dyspnea. Chest imaging revealed bronchiectasis and mild, diffuse bronchial-wall thickening. A diagnostic procedure was performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some of the general characteristics of bronchiolitis?

The primary symptoms of bronchiolitis are cough and dyspnea. Pulmonary-function testing reveals a nonreversible obstructive ventilatory defect and hyperinflation and often reveals diffusion impairment. Bronchiolitis may occur as a distinct clinical entity, such as acute bronchiolitis or obliterative bronchiolitis, or as part of an interstitial lung disease with bronchiolar involvement, such as respiratory bronchiolitis–associated interstitial lung disease. High-resolution computed tomography (CT) of the chest is the imaging study of choice, and characteristic findings include areas of gas trapping, bronchial-wall thickening, and centrilobular nodules.

Clinical Pearl

• What is obliterative bronchiolitis?

Obliterative bronchiolitis, the histopathological equivalent of constrictive bronchiolitis, is a condition in which the airway lumen of the bronchioles becomes narrowed. Patients present with cough, dyspnea, and nonreversible airway obstruction. Obliterative bronchiolitis is progressive and can result in respiratory failure, because the bronchioles may ultimately become obliterated. As this disease advances, both bronchiectasis and diffusion abnormalities may develop. High-resolution CT reveals mosaic attenuation (i.e., areas of differing attenuation) and gas trapping.

Figure 1. Axial CT Scans of the Chest.

Figure 2. Lung-Biopsy Specimen.

Morning Report Questions

Q: What diseases or exposures are associated with obliterative bronchiolitis?

A: Obliterative bronchiolitis is rarely postinfectious. It has been described in conjunction with exposure to certain medications, including penicillamine and gold, and exposure to certain toxins, such as sulfur dioxide, sulfur mustard, nitrogen oxides, and the food flavoring diacetyl. The bronchiolitis obliterans syndrome refers to obliterative bronchiolitis that occurs during the post-transplantation period, specifically after allogeneic hematopoietic stem-cell transplantation and lung transplantation. Like many of the other types of bronchiolitis, obliterative bronchiolitis can be seen in patients with inflammatory bowel diseases and connective-tissue diseases; on rare occasions, it is idiopathic. Rheumatoid arthritis is the connective-tissue disease most frequently associated with bronchiolitis. It is important to note that, in some patients, the development of connective-tissue disease–associated lung disease can precede the development of the connective-tissue disease itself.

Q: What are some of the other types of bronchiolitis?

A: Acute bronchiolitis is infectious in origin and often caused by respiratory syncytial virus, although it can be seen with influenza, parainfluenza, adenovirus, and mycoplasma. Acute bronchiolitis primarily occurs in children but can occur in adults and is most often self-limiting. Diffuse panbronchiolitis primarily affects middle-aged Japanese men, causing a progressive disease that leads to bronchiectasis, to recurrent infections, and often sinusitis. Respiratory bronchiolitis is primarily seen in smokers and most often detected as an incidental finding on pathological examination of the lungs. Follicular bronchiolitis is also characterized by centrilobular nodules and ground-glass opacities on imaging studies of the chest and is associated with connective-tissue diseases (e.g., rheumatoid arthritis and Sjögren’s syndrome) and immunodeficiency syndromes (e.g., HIV and common variable immunodeficiency). Granulomatous bronchiolitis is a condition that can be seen with inflammatory bowel diseases with pulmonary involvement, interstitial lung diseases (e.g., hypersensitivity pneumonitis, sarcoidosis, and granulomatous–lymphocytic interstitial lung disease), and infectious causes (e.g., tuberculous and nontuberculous mycobacteria).

Ablation for Paroxysmal Atrial Fibrillation

Posted by Carla Rothaus • June 10th, 2016

2016-06-03_12-16-42According to a 2012 expert consensus statement, catheter ablation of drug-refractory paroxysmal atrial fibrillation is a class I level A indication, and pulmonary-vein isolation is the standard approach. Kuck et al. conducted a randomized trial to compare the performance of the rather complex yet well-established approach of radiofrequency ablation with that of the apparently simpler approach of cryoballoon ablation in a larger population of patients with paroxysmal atrial fibrillation.
Over 700 patients with drug-refractory paroxysmal atrial fibrillation were randomly assigned to cryoballoon or radiofrequency ablation. Cryoballoon ablation was noninferior to radiofrequency for the composite of recurrent atrial arrhythmia, use of antiarrhythmic drugs, or repeat ablation. A new Original Article summarizes.

Clinical Pearl

• How do the two commonly used ablation techniques differ?

The two most frequently used ablation technologies for pulmonary-vein isolation differ in the energy source and mode of application. The most common method is the use of radiofrequency current applied in a point-by-point mode, which leads to cellular necrosis by tissue heating; the other method is the use of cryogenic energy applied with a balloon in a single-step mode, which leads to necrosis by freezing.

Figure 1. Catheter Ablation Methods.

Clinical Pearl

• What are the relative advantages of each of these two ablation techniques?

Radiofrequency ablation for atrial fibrillation requires only limited use of fluoroscopy, because catheter guidance is achieved with the use of an electroanatomical mapping system, but the approach demands extensive training. The complexity of radiofrequency ablation technology has restricted ablation therapy for atrial fibrillation to a few specialized centers and has limited the availability of ablation therapy. Cryoablation for atrial fibrillation requires more extensive fluoroscopic guidance to position the balloon catheter at the pulmonary veins. The cryoballoon was developed to create a circular lesion around each pulmonary vein in a relatively simple manner.

Morning Report Questions

Q: Is cryoballoon ablation as effective as radiofrequency ablation for the treatment of paroxysmal atrial fibrillation?

A: In the study by Kuck et al., cryoballoon ablation was found to be noninferior to radiofrequency ablation with regard to the primary efficacy end point, and superiority was not achieved in either group. The primary efficacy end point in a time-to-event analysis was the first documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrythmic drugs, or repeat ablation,) following a 90 day period after the index ablation. In the modified intention-to-treat analysis, after the 90-day blanking period, the primary efficacy end point occurred in 138 patients in the cryoballoon group and in 143 patients in the radiofrequency group (1-year Kaplan–Meier event-rate estimates, 34.6% and 35.9%, respectively; hazard ratio, 0.96; 95% confidence interval [CI], 0.76 to 1.22; P<0.001 for noninferiority). In the per-protocol analysis, the primary efficacy end point occurred in 118 patients in the cryoballoon group and in 131 patients in the radiofrequency group (1-year Kaplan–Meier event-rate estimates, 31.9% and 35.0%, respectively; hazard ratio, 0.91; 95% CI, 0.71 to 1.17; P<0.001 for noninferiority). A prespecified superiority test performed for the primary efficacy end point did not indicate a significant difference between the treatment groups (P=0.74).

Table 2. Efficacy End Points.

Figure 2. Event-free Survival for the Primary Efficacy and Safety End Points in the Modified Intention-to-Treat Cohort.

Q: In the study by Kuck et al. what was the most common safety event in each of the two study groups?

A: Phrenic-nerve injury was the most common safety event in the cryoballoon group, although the 2.7% rate in the trial was substantially lower than the 13.5% rate reported in the Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP AF) trial. The most common safety events in the radiofrequency group were groin-site complications, which were unusually frequent in this trial (4.3%). Serious treatment-related adverse events of atrial arrhythmia occurred in 2.7% of the patients in the radiofrequency group and in 0.8% of the patients in the cryoballoon group (P=0.09). There was no significant difference in the primary safety end point (a composite of death from any cause, stroke or transient ischemic attack from any cause, and serious adverse events) between the radiofrequency group and the cryoballoon group.

Table 3. Safety End Points.