Postmenopausal Osteoporosis

Posted by Carla Rothaus • January 22nd, 2016

1-15-2016 1-53-07 PMOsteoporosis results in 1.5 million fractures per year in the United States, with the vast majority occurring in postmenopausal women. Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of −2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk.

Management of postmenopausal osteoporosis includes nonpharmacologic treatment (e.g., weightbearing exercise and fall-prevention strategies) and pharmacologic treatment. Bisphosphonates are considered first-line treatment in most women. In a new Clinical Practice article, benefits and rare potential risks are discussed.

Clinical Pearl

• What is the Fracture Risk Assessment Tool (FRAX)?

The overriding goal in managing postmenopausal osteoporosis is the prevention of future fractures. Therefore, identifying women at the highest risk is a clinical priority. Low bone mineral density (BMD), particularly at the hip, is a strong risk factor for fracture: for each 1-SD decrement in BMD, the risk of fracture increases by a factor of 2 or 3. However, a more comprehensive assessment of clinical risk factors is helpful to define absolute risk for an individual and to select patients for treatment. The Fracture Risk Assessment Tool (FRAX), which was developed by the World Health Organization on the basis of data from several international cohorts, incorporates established risk factors and BMD at the femoral neck to predict individual 10-year risk of hip or major osteoporotic fracture; its use is endorsed by several professional organizations.

Table 1. Guidelines from Professional Organizations for the Treatment of Osteoporosis.

Clinical Pearl

• What are some of the nonpharmacologic therapies for patients with postmenopausal osteoporosis?

Resistance and weight-bearing exercise can increase muscle mass and can transiently increase BMD. Exercise and balance programs (e.g., yoga and tai chi) may result in improved balance and an increase in muscle tone and may secondarily reduce the risk of falls among some elderly persons. Besides exercise, assessment of the home for hazards, withdrawal of psychotropic medications (when possible), and the use of a multidisciplinary program to assess risk factors are prudent strategies for potentially reducing the risk of falls. Other measures should include counseling about cigarette smoking (which is linked to reduced BMD) and about excess alcohol intake (which can increase the risk of falls).

Morning Report Questions

Q: What class of drug is prescribed most often for the treatment of postmenopausal osteoporosis?

A: The bisphosphonates as a class represent the vast majority of prescriptions for osteoporosis treatment, and all are now available in generic form. Bisphosphonates inhibit bone remodeling. Several oral and intravenous bisphosphonates have been shown in randomized trials to reduce the risk of fractures. FDA-approved oral bisphosphonates include alendronate (the first one approved), risedronate, and ibandronate. Although data from randomized trials and clinical experience indicate that they are generally safe, mild hypocalcemia and muscle pain occur infrequently. Two rare but more serious adverse effects have also been observed. These are atypical femoral fractures (i.e., fractures in the subtrochanteric region that have a transverse orientation and noncomminuted morphologic features, show focal lateral cortical thickening, occur with minimal trauma, and may be bilateral) and osteonecrosis of the jaw, which is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks. Use of bisphosphonates should be limited to persons who have an estimated creatinine clearance greater than 35 ml per minute and normal serum vitamin D levels; symptomatic hypocalcemia can develop in patients with low levels of 25-hydroxyvitamin D who receive concomitant treatment with bisphosphonates. Oral bisphosphonates should not be prescribed for patients with clinically significant esophageal disease (e.g., achalasia). Adherence to oral bisphosphonates is low, and it is estimated that less than 40% of persons who are prescribed oral medications are still taking them after 1 year. Intravenous bisphosphonates (ibandronate and zoledronic acid) are alternatives that do not require frequent patient use.

Table 2. Drugs Approved by the Food and Drug Administration for the Treatment and Prevention of Osteoporosis.

Q: What is the risk-benefit ratio associated with bisphosphonate treatment for postmenopausal osteoporosis?

A: The relative importance of the two rare adverse effects (atypical fractures and osteonecrosis of the jaw) versus the benefits of antiresorptive therapy is uncertain and remains controversial. The concerns of many women regarding these potential adverse effects have increasingly become a substantial barrier to initiation of antiosteoporosis therapy and to treatment adherence. Case–control and cohort studies and a few randomized trials have assessed the risk of atypical femoral fractures; in all the studies, the incidence of these fractures is low, ranging from approximately 1 in 100,000 to 5 in 10,000 among bisphosphonate users. Calculations based on recent reviews and meta-analyses suggest a highly favorable benefit-to-risk ratio associated with treatment for up to 5 years in women with osteoporosis, with fewer than 1 event caused per 100 fractures prevented. The incidence of osteonecrosis of the jaw is similarly very low (estimated at <1 case per 10,000 bisphosphonate users). Given concerns about an increased risk of atypical femur fractures with long-term treatment, the possibility of a drug holiday (temporary discontinuation for up to 5 years) has been suggested, although the preferred timing and duration of drug holidays with bisphosphonate therapy are uncertain. Randomized trials have indicated that with discontinuation of alendronate after 5 years of use or of zoledronic acid after 3 years of use, benefits (as determined primarily by assessment of BMD loss and changes in biochemical markers of bone turnover as compared with those with placebo) are generally retained for up to 5 years. The value of monitoring therapy after discontinuation with the use of biochemical markers of bone turnover or BMD to aid in clinical decision making about restarting bisphosphonates is controversial. These recommendations regarding drug holidays do not apply to risedronate or ibandronate, because these agents have not been systematically evaluated, or to other osteoporosis therapies, whose benefits are quickly lost after cessation.

Eluxadoline for Irritable Bowel Syndrome

Posted by Carla Rothaus • January 22nd, 2016

1-15-2016 1-44-35 PMThe irritable bowel syndrome (IBS) with diarrhea is a common functional gastrointestinal disorder that is characterized by recurring abdominal pain, bloating, and loose, frequent stools in the absence of structural, inflammatory, or biochemical abnormalities. Lembo et al. conducted two phase 3 trials to evaluate the clinical response of patients with IBS with diarrhea to eluxadoline, as compared with placebo, through 26 weeks and to evaluate the safety of eluxadoline up to 52 weeks. The authors randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26.

In these two randomized trials, eluxadoline was more effective than placebo in reducing abdominal pain and improving stool consistency in patients who had irritable bowel syndrome with diarrhea. Pancreatitis developed in 5 of 1666 patients (0.3%) who received eluxadoline.A new Original Article summarizes.

Clinical Pearl

• What treatment options are currently available for IBS with diarrhea?

Current treatment options for IBS with diarrhea are limited. Initial therapies include dietary and lifestyle modifications along with antidiarrheal agents; these therapies are frequently unsuccessful. A subgroup of patients with IBS with diarrhea may have a response to either rifaximin or alosetron. Alosetron has been approved by the Food and Drug Administration only for women with severe IBS with diarrhea who have not had a response to conventional therapy, although subsequent data suggest efficacy in men.

Clinical Pearl

• What is eluxadoline?

Opioid receptors (including μ-opioid receptors, δ-opioid receptors, and κ-opioid receptors) in the enteric circuitry of the gastrointestinal tract play a role in regulating gastrointestinal motility, secretion, and visceral sensation. Eluxadoline is a peripherally acting mixed μ-opioid receptor agonist–δ-opioid receptor antagonist and κ-opioid receptor agonist with minimal oral bioavailability. Nonclinical studies have shown that, unlike selective μ-opioid receptor agonists, eluxadoline reduces visceral hypersensitivity without completely disrupting intestinal motility. These data suggest that peripheral δ-opioid receptor antagonism may reduce μ-opioid receptor–mediated constipation and enhance μ-opioid receptor–mediated peripheral analgesia.

Morning Report Questions

Q: How effective is eluxadoline for the treatment of IBS with diarrhea?

A: In the studies by Lembo et al., eluxadoline was effective in simultaneously relieving the symptoms of abdominal pain and diarrhea. The primary outcome measure required simultaneous improvement in the daily scores for the worst abdominal pain and stool consistency on the same day for at least 50% of the days assessed; this end point is currently one of those recommended by the regulatory agencies in the United States and Europe to show treatment effect in trials involving patients with IBS and diarrhea. More patients who received eluxadoline than who received placebo reported significant improvement in the primary outcome measure over both intervals assessed (absolute differences for the two doses across the two studies ranged from 7 to 13 percentage points for weeks 1 through 12, and from 4 to 13 percentage points for weeks 1 through 26). Eluxadoline also resulted in significant improvements in global assessment scores (on measures of adequate relief of IBS symptoms, global symptoms, and quality of life), particularly at the 100-mg twice-daily dose, with improvements in measure of adequate relief of IBS symptoms that were similar to those reported with alosetron and rifaximin. Treatment with eluxadoline did not result in significantly higher rates than placebo of the prespecified secondary outcome of 30% improvement in the average score for the most severe abdominal pain.

Figure 1. Primary Efficacy End Point in the Eluxadoline and Placebo Groups in Each Trial and in the Pooled Trials.

Figure 2. Percentage of Patients Who Met the Daily Composite Response Criteria over Time.

Table 2. Secondary Efficacy End Points (Weeks 1–12).

Q: Are there any subgroups of patients for whom the use of eluxadoline carries specific risks? 

A: Five cases of pancreatitis (0.3%) and 8 cases of abdominal pain with elevated levels of hepatic enzymes (0.5%) occurred in the study by Lembo et al. Nine of these 13 cases were determined by the adjudication committee to be associated with spasm of the sphincter of Oddi. All the patients with pancreatitis were determined by the adjudication committee to have no organ failure or local or systemic complications. The pancreatitis, which occurred in patients with either biliary disorders (spasm of the sphincter of Oddi and biliary sludge) or alcohol use (3 of 5 cases), resolved within the first week. The presence of only mild cases does not preclude the risk of severe cases in the future, nor do these associations preclude other at-risk populations. Data are lacking from studies to assess whether the risk of pancreatitis can be reduced if treatment is restricted to patients with gallbladders or to those who abstain from excessive alcohol use. Identifying patients with IBS with diarrhea who are at risk for acute pancreatitis because of the absence of a gallbladder or excessive alcohol consumption is important before initiating therapy with eluxadoline. Any benefit will need to be considered in the context of side effects and risks.

Table 3. Common Adverse Events.

CDX2 as a Prognostic Biomarker in Colon Cancer

Posted by Chana Sacks • January 20th, 2016

123A few weeks apart, Mr. Green and Mrs. Brown presented to their primary care doctors with intermittent rectal bleeding.  Both were referred for colonoscopies, and each was found to have a colonic mass.  With great trepidation, they awaited the results of the pathology and the CT scans that followed.  Ultimately, both were diagnosed with stage-II colon cancers, confined to the wall of the colon without evidence of systemic spread.  Filled with anxiety, they awaited their physicians’ recommendations for treatment.

Determining treatment plans for these two patients with stage-II colon cancer is increasingly complicated.  Unlike in patients with stage-I cancers, for whom surgery is sufficient, or those with stage-III cancers, which have spread to regional lymph nodes and clearly benefit from systemic chemotherapy, patients with stage-II cancers face uncertainty:  some seem to do well with surgery alone, but a subset develops recurrent disease that might have benefited from adjuvant chemotherapy.  So far, we have lacked tools to differentiate these subtypes, and researchers are increasingly asking, can the genetics of individual tumors predict prognosis and guide treatment?

Now published in NEJM, a study by Dalerba and colleagues tackles this very question.  The investigators describe a novel approach used to identify a tumor marker called CDX2 that might predict prognosis and determine which patients with stage-II colon cancer might benefit from adjuvant chemotherapy, rather than surgery alone.

Investigators reasoned that tumor cells that closely resemble mature colonic epithelial tissue would be less aggressive; by contrast, those tumors that have characteristics of more immature undifferentiated colonic stem cells might behave more aggressively and result in worse outcomes.  So they set out to find markers of immature colonic tissue present in tumors. Using a novel bioinformatics approach, the researchers mined a database of more than 2,000 human colon gene-expression array experiments and identified a number of candidate genes, ultimately selecting the transcription factor CDX2. CDX2 is expressed in more mature cells and is not expressed in more primitive colon precursor cells.  With this candidate biomarker identified, the investigators conducted a retrospective analysis using about 2200 colon cancer tissue microarrays from different databases to determine if there was an association between CDX2 expression and either survival outcomes or response to chemotherapy.

The results:  the data demonstrate that the absence of CDX2 portends worse outcomes.  In the discovery dataset, for patients with stage-II colon cancer with CDX2-negative tumors, the 5-year disease-free survival was 49%, as compared with 87% for those CDX2-positive tumors (p=0.003).  The validation dataset yielded similar results.  A separate analysis of those with CDX2-negative tumors suggests that treatment with adjuvant chemotherapy was associated with improved disease-free survival.

In an accompanying editorial, Drs. Boland and Goel of Baylor University remind us of the limitations of small, retrospective analyses, and they call for prospective trials to confirm these results.  Still, they describe the fundamental importance of this study:  “This work provides an opportunity for oncologists to move beyond what has been an inadequate method of selecting Stage II colon cancer patients for adjuvant chemotherapy.”

NEJM Deputy Editor Dr. Dan Longo agrees: “While these data might prove important for the treatment of patients with Stage II colon cancer, the implications of this study are broader – as they suggest novel ways that we might harness our improving understanding of tumor biology to personalize treatment and cure disease.”

So, for Mr. Green and Mrs. Brown, further testing to determine whether their tumors express CDX2 might help guide treatment options and might result in very different treatment plans for what was thought to be the same disease.  To be sure, more data are needed, but this study points to the importance of this rapidly developing field of inquiry.  As Boland and Goel conclude, “it is likely that a combination of genetic and epigenetic panels will soon help refine and advance the field of predictive oncology.”

Clinical Collections

Posted by Avery Fang • January 18th, 2016

ClinCol_covers_Bundle-4-193x250Did you know that NEJM Group offers Clinical Collections? These Collections include content from the New England Journal of Medicine and NEJM Journal Watch, curated for relevance by expert clinicians to help you improve your knowledge and patient care. Clinical Collections are offered in a convenient PDF format for instant and easy access.

NEJM Cases in Primary Care

The presentation of interesting cases has a long tradition as an educational tool and contributes to lifelong learning. Discussing the clinical course and management of individual patients enhances our understanding of disease and provides a framework for learning about medical advances. The New England Journal of Medicine publishes several case-based series including Case Records of the Massachusetts General Hospital, Clinical Problem-Solving, and Clinical Practice, plus our online Interactive Medical Cases.


Influenza is not a new concern for clinicians, and medical research has devised strategies to prevent and treat it, but challenges remain. The virus changes and evolves, and our preparedness and response must continue to evolve as well. The threat to life and health of a serious flu season cannot be disregarded. We are now in the U.S. vaccinating against the new season and preparing to care for patients who will get sick with influenza. Are you informed and ready?

Hepatitis C

Over the past 3 years, the care of patients with hepatitis C has undergone a revolution. Recommendations for universal screening and a plethora of new drugs have profoundly affected clinical practice, and clinicians, insurance companies, and public-health specialists are scrambling to adapt to the new landscape. This compilation of articles and other content from the New England Journal of Medicine and NEJM Journal Watch is designed to provide much-needed help to non-hepatologists who may be struggling to keep up with rapid developments in the field.


Are you up-to-date on the newest clinical guidelines for concussion? Do you need help developing a clinical strategy for concussions based on the latest recommendations? This collection of content from the New England Journal of Medicine and NEJM Journal Watch summarizes current guidelines and recommendations on concussion. Comprised of NEJM Perspective articles, NEJM Journal Watch guideline summaries, a Concussion Assessment Tool Kit, and more, this collection will help you develop a clinical strategy for the diagnosis, treatment, and management of concussions in children and adults.

Critical Care

Hospital practice has shifted increasingly from acute care to the critical. The change has been attended by a shift to high-tech medicine and by more focus on the care of the dying patient. The New England Journal of Medicine’s series on critical care focuses on, in the words of an introductory editorial, this “all-encompassing specialty with almost limitless boundaries.”

Vitamin D

The literature is full of studies about (and confusion over) vitamin D supplements – namely, who should get them and under what circumstances. While you as a clinician await the results of the widely anticipated VITAL study – due about 5 years from now – you’ll need information to guide you and share with your patients; this collection of articles from NEJM Group publications is that guidance.

Clinical Collections are also available at a discount as bundled packages of multiple Collections. Browse the available Collections, and contact us to let us know what other Collections you’d like to see in the future.

Prescription-Opioid Abuse and Heroin Abuse

Posted by Carla Rothaus • January 15th, 2016

1-11-2016 10-54-43 AM

The nonmedical use of prescription opioids is a major public health issue in the United States, both because of the overall high prevalence and because of marked increases in associated morbidity and mortality.  A key underlying characteristic of the epidemic is the association between the increasing rate of opioid prescribing and increasing opioid-related morbidity and mortality. In response, federal, state, and other vested interests are implementing a variety of policies and programs aimed at curbing inappropriate prescribing. Coinciding with these efforts to reduce nonmedical prescription-opioid abuse and overdose are reports of increases in the rates of heroin use (including both injection and noninjection routes of administration) and deaths from heroin overdose. Some suggest that the very policies and practices that have been designed to address inappropriate prescribing are now fueling the increases in rates of heroin use and death. A new Review Article summarizes.

Clinical Pearl

• How much has heroin use increased in recent years?

Heroin use has been increasing in the United States for the past 10 years, especially since 2007, an increase that has occurred in the context of broad use of multiple substances. According to national surveillance data, 914,000 people reported heroin use in 2014, a 145% increase since 2007, and mortality due to heroin overdose more than quintupled, from 1842 deaths in 2000 to 10,574 deaths in 2014.

Clinical Pearl

• Have recent efforts to curb inappropriate prescribing of opioids been successful?

Although more rigorous evaluation is needed, there are some indications that initiatives aimed at curbing inappropriate prescribing of opioids are beginning to show some success. A recent study showed that the rate of opioid prescribing in the United States stabilized between 2010 and 2012, with some medical specialties showing declines in the rate of opioid prescribing after consistent increases for a number of years. States and localities that took the most decisive action are seeing a decrease in the availability of prescription opioids coupled with a decline in the rate of deaths from overdose.

Figure 1. Age-Adjusted Rates of Death Related to Prescription Opioids and Heroin Drug Poisoning in the United States, 2000–2014.

Figure 2.Nonmedical Use of Prescription Opioids and Heroin during the Previous Year among Noninstitutionalized Persons 12 Years of Age or Older, 2002–2014.

Morning Report Questions

Q: What are some of the recent trends in heroin use?

A: In addition to the 138.9% increase in heroin use among nonmedical users of prescription opioids between the period of 2002–2004 and the period of 2011–2013, heroin use increased 97.5% among nonmedical users of other prescription drugs (stimulants, tranquilizers, and sedatives), 87.3% among users of cocaine, 57.3% among people who binge drink, and 45.4% among marijuana users. Moreover, heroin users increasingly report abuse of or dependence on other substances. There have also been shifts in the demographic characteristics associated with heroin use; the rate has increased particularly steeply among persons 18 to 25 years of age, and increases have been observed in both large urban areas and other geographic regions, in both sexes but more among women than among men, and in all races and ethnic groups but more among non-Hispanic whites than among others.

Table 1. Annual Average Rates of Heroin Use during the Previous Year, According to Substance-Use Characteristic and Time Period, in the United States, 2002–2013.

Table 2. Demographic and Substance-Use Characteristics Associated with Heroin Abuse or Dependence during the Previous Year in the United States, 2011–2013.

Q: Is there a link between policies aimed at curbing inappropriate prescribing of opioids and increases in the rates of heroin use? 

A: In the opinion of the authors of this review article, although none of the available studies can disprove a potential relationship between policies that are aimed at decreasing the availability of inappropriately prescribed opioids and the motivation for heroin use in some people, the results of these studies consistently suggest that the transition to heroin use was occurring before most of these policies were enacted, and such policies do not appear to have directly led to the overall increases in the rates of heroin use. This observation is supported by data on heroin use reported to U.S. poison control centers that show increases starting in 2006, as well as national surveillance data that show a rise in heroin use starting in 2007. Similarly, a study examining hospitalizations for heroin overdose between 1993 and 2009 showed that the rate of such hospitalizations increased 69% between 1993 and 2006 and then rose more sharply, by 44%, between 2005 and 2009. Furthermore, this study showed that these increases occurred in the context of continued increases in the rate of hospitalization for overdose of prescription opioids. Heroin market forces, including increased accessibility, reduced price, and high purity of heroin appear to be major drivers of the recent increases in rates of heroin use.

A Man with Thrombocytopenia

Posted by Carla Rothaus • January 15th, 2016

1-11-2016 12-00-15 PM

In the latest Case Record of the Massachusetts General Hospital, an 18-year-old man presented with fever, abdominal pain, and thrombocytopenia. Abdominal imaging studies showed nonspecific fluid collection and necrotic lymph nodes, and there were elevated levels of C-reactive protein and ferritin. A diagnostic procedure was performed.

A ferritin level as high as 7000 ng/ml is a marker of macrophage activation and is associated with systemic inflammatory diseases, such as systemic juvenile idiopathic arthritis (Still’s disease), acute or chronic inflammatory disorders, liver or renal failure, hemolytic anemia, hematologic cancers, and a hemophagocytic syndrome.

Clinical Pearl

• What causes hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is caused by an impairment of the cytolytic activity of T cells and natural killer cells and leads to uncontrolled T-cell activation and increased secretion of cytokines, processes that directly activate macrophages. Proliferation and activation of benign macrophages is associated with phagocytosis of hematopoietic elements throughout the reticuloendothelial system. Activated macrophages also secrete ferritin, leading to hyperferritinemia.

Clinical Pearl

• Is hemophagocytosis sensitive or specific for HLH?

Hemophagocytosis is not sensitive for HLH and is reported in 25 to 100% of patients with HLH. It is also not specific for HLH, because hemophagocytosis can occur after blood transfusion, during the postoperative period, and in patients with systemic inflammation, such as sepsis.

Figure 2. Bone Marrow–Biopsy Specimen.

Morning Report Questons

Q: Describe some of the features of HLH.

A: HLH has familial and acquired forms. Although familial HLH mostly occurs during the first year of life, it may occur later in some affected patients. Acquired HLH in adults is usually triggered by infection, cancer (most commonly lymphoma), or autoimmune disease (in which case it is termed the macrophage activation syndrome). Infection, most commonly with Epstein–Barr virus (EBV), triggers most forms of HLH, even in patients with cancer or with familial HLH.

Q: How is HLH diagnosed?

A: HLH is a clinical diagnosis that is based on eight diagnostic criteria. These criteria were developed for the diagnosis of HLH in children and may be less effective in adults. At least five of the following eight criteria must be present for a diagnosis to be established: fever; splenomegaly; cytopenia; fasting triglyceride levels >3 mmol/liter and/or fibrinogen level <1.5 g/liter; ferritin level >500 ng/ml; soluble CD25 level >2400 U/ml; decreased or absent natural killer cell activity; or hemophagocytosis in bone marrow, central nervous system, or lymph nodes. In children younger than 3 years of age, a serum ferritin level higher than 10,000 ng/ml is about 95% sensitive and specific for HLH.

Bariatric Surgery Outcome in Adolescents

Posted by James Yeh, M.D. M.P.H. • January 13th, 2016

1-11-2016 9-04-04 AMYou are seeing Anna Boylston in your adolescent primary care clinic today.  You have been her PCP since she was 10 years-old.  She is now 14 and has a history of severe obesity (current BMI 37 kg/m2). She and her family ask you about bariatric surgery options for teenagers and the long term benefits and risks.  What do you tell them?

Volume of adolescent bariatric surgical cases in the United States has doubled from nearly 800 to 1600 cases during the past decade.  However, prospective data on the efficacy and safety of adolescent bariatric surgery is unknown.  Bariatric surgery in adolescents will likely rise, as nearly 7% of 12 to 17 year olds in the United States have severe obesity, defined as an BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m2.

What are the indications for bariatric surgery in adolescents?

The American Society for Metabolic and Bariatric Surgery recommends a minimum BMI threshold of ≥35 kg/m2 with a severe comorbidity or a BMI ≥40 kg/m2 with minor comorbidities.  These are similar indications to those in adults.

What is this study about?

In this week’s issue of NEJM, Inge and colleagues present their findings from a multi-center prospective observational study called Teen-LABS that evaluated the efficacy and safety outcomes of bariatric procedures in adolescents.

The trial enrolled a cohort of 242 adolescents ages 13 to 19.  161 (66%) received gastric bypass and 67 (28%) underwent sleeve gastrectomy.  14 received adjustable gastric banding, but that cohort was too small to include in the analysis.  The outcomes were changes in body weight, comorbidities, quality of life, micronutrient data, and other abdominal procedures 3 years post-operatively.

Who is in the study?

75% of the patients in the analysis were teenage girls.  At baseline, the mean BMI was 53 kg/m2 (ranges 34-88).  98% of the patients had a BMI > 40 kg/m2.  About 13% had type 2 diabetes and 10%, pre-diabetes. Seventy-six % had dyslipidemia, over 40%, elevated blood pressure, and 17%, abnormal kidney function.

What were the results?

At 3-years post-op, participants on average lost 27% of the baseline weight. Weight reduction from either gastric bypass or vertical gastrectomy was similar (28% versus 26%).  A significant portion of the cohort had remissions of their medical comorbidities (type 2 diabetes, 95%; pre-diabetes, 76%; dyslipidemia, 66%; elevated blood pressure, 74%; and abnormal kidney function, 86%).

Weight-related quality of life metrics also improved at 3-years post-op.

However, patients also experienced increased rates of metabolic abnormalities and additional abdominal procedures. The percentage of patients with low ferritin levels (5% versus 57%) and low vitamin B12 levels (3% versus 16%) increased significantly at 3 years.    About 22% of patients had undergone additional intra-abdominal operations after their initial procedure at 3 years.   Twenty-three % of the patients also went under endoscopic procedures during the 3-years follow-up.   Both rates occurred more frequently in those that had gastric bypass versus those who had sleeve gastrectomy.

Should more adolescents with severe obesity undergo bariatric surgery?

A NEJM editorial by Dr. Caroline Apovian from Boston University School of Medicine states that the study “provides longer-term evidence that bariatric surgery can provide relief from the tremendous physical, social, and psychological burden that severe obesity causes in a growing number of American youth.”  However, she cautions that longer-term (>10 year) follow-up is necessary to determine the persistence of anticipated and unanticipated complications and that primary prevention of severe obesity in adolescents also needs to be part of the solution.

What is my take-away?

Bariatric surgery in adolescents appears to result in weight reduction and a decrease in medical co-morbidities. However, the longer-term efficacy and safety requires assessment.

See a NEJM interactive graphics on the different bariatric procedures.

How does the outcome in adolescents compare with those in adults?  Learn about the STAMPEDE trial comparing bariatric surgery versus conventional medical therapy in adults with type 2 diabetes. 

Join a conversation with the authors of this study on the NEJM Group Open Forum, ongoing through January 20. 

Viral Bronchiolitis

Posted by Carla Rothaus • January 8th, 2016

1-5-2016 11-58-44 AMFew diseases have a greater effect on the health of young children than viral lower respiratory tract illness. Approximately 800,000 children in the United States, or approximately 20% of the annual birth cohort, require outpatient medical attention during the first year of life because of illness caused by respiratory syncytial virus (RSV). This review article on viral bronchiolitis in young children considers the viruses involved, the current understanding of pathogenesis, host genetic factors and the environment, and the role of season, race, and sex on attack rates and subsequent episodes of wheezing.

Clinical Pearl

• Is the course of viral bronchiolitis or the response to treatment influenced by the specific viral etiology?

RSV accounts for 50 to 80% of all hospitalizations for bronchiolitis during seasonal epidemics in North America. Although the clinical features of bronchiolitis due to different viruses are generally indistinguishable, some differences in the severity of disease have been reported. For example, it has been observed that rhinovirus-associated bronchiolitis may result in a shorter length of hospitalization than bronchiolitis that is attributable to RSV. Differences in the response to medical intervention have not been identified consistently among children with bronchiolitis caused by different viruses.

Table 1. Viruses Detected in Nasopharyngeal Secretions

Clinical Pearl

• What is hypothesized to contribute to severe disease in infants with a first episode of RSV bronchiolitis?

The immune response elicited by RSV may be both protective and pathogenic, and there appear to be functional differences between an initial infection in a seronegative infant and reinfection in an older child or adult. At least in infants who have not had a previous infection, overwhelming RSV disease appears to be related to the lack of an adaptive cytotoxic T-cell response in the host; the result is dependence on the less effective innate immune response for the termination of viral replication. The fact that a more effective, adaptive cytotoxic T-cell response does not develop in such infants is supported by reports of a direct correlation between RSV load, as measured in nasopharyngeal aspirates obtained from children who have been hospitalized with bronchiolitis, and more severe disease, defined as a higher risk of apnea, a longer hospital stay, and a greater need for intensive care. However, not all reports are consistent with an association between a high viral load in respiratory secretions and greater severity of disease. A reasonable deduction is that direct cytotoxic injury induced by the virus and a robust host inflammatory response both contribute to the pathogenesis of RSV bronchiolitis, although the relative contribution of each remains uncertain.

Figure 1. Pathogenesis of Bronchiolitis Due to Respiratory Syncytial Virus (RSV).

Morning Report Questions

Q: What are some of the risk factors for the development of severe bronchiolitis?

A: Most infants who are hospitalized with RSV bronchiolitis were born at full term with no known risk factors. Chronologic age is the single most important predictor of the likelihood of severe bronchiolitis, given the observation that approximately two thirds of hospitalizations of infants with RSV infection occur in the first 5 months of life. Hospitalization rates that are attributable to RSV are highest between 30 and 90 days after birth, a period that corresponds to the declining concentration of transplacentally acquired maternal immunoglobulin. Because most maternal immunoglobulin transfer occurs in the third trimester, preterm infants may miss the period of greatest IgG transfer; this fact partly explains the higher risk of disease among preterm infants. Maternal RSV antibody concentrations vary seasonally, with significantly higher serum concentrations being observed later in the RSV season than earlier in the season. Lower serum concentrations of maternal RSV antibody (resulting from waning maternal immunity from infection during the previous season) may account for the more severe disease that is observed among infants born early in the RSV season, as compared with those who are born later.

Q: How is viral bronchiolitis managed, and is any type of prophylaxis available? 

A: No available treatment shortens the course of bronchiolitis or hastens the resolution of symptoms. Therapy is supportive, and the vast majority of children with bronchiolitis do well regardless of how it is managed. The intensity of therapy among hospitalized children has been shown to have little relationship to the severity of illness. The evidence-based guidelines of the American Academy of Pediatrics  emphasize that a diagnosis of bronchiolitis should be based on the history and physical examination and that radiographic and laboratory studies should not be obtained routinely. Short-acting β2-agonists, epinephrine, and systemic glucocorticoids are not recommended for the treatment of children with bronchiolitis. Clinicians may elect not to administer supplemental oxygen when oxyhemoglobin saturation exceeds 90%. Palivizumab, a humanized mouse IgG1 monoclonal antibody directed against a conserved epitope on the surface fusion protein of RSV, was licensed by the Food and Drug Administration in June 1998 for monthly prophylaxis for infants at high risk for RSV infection. Recommendations for more restrictive use of passive immunoprophylaxis have evolved since palivizumab was licensed as additional information has become available regarding the epidemiology of RSV and the limited benefit of prophylaxis. Several approaches to vaccine development are being investigated. Until safe and effective vaccines are available, reduction of the burden of disease due to bronchiolitis will focus on education about the importance of decreasing exposure to and transmission of respiratory viruses.

Table 2. American Academy of Pediatrics Guidance for Diagnosis and Management of Bronchiolitis.

Table 3. American Academy of Pediatrics Guidance for Palivizumab Immunoprophylaxis.

A Complementary Affair

Posted by Carla Rothaus • January 8th, 2016

1-5-2016 12-32-38 PMWhat is the most common type of cryoglobulinemia associated with Sjögren’s syndrome?

Sjögren’s syndrome, a systemic autoimmune disease that is characterized by diminished lacrimal-gland and salivary-gland function, is one of the most common connective-tissue diseases. Decreased glandular function leads to typical manifestations of dry eyes and dry mouth, or sicca complex. Although the disease typically follows an indolent course, this case shows that severe systemic complications of Sjögren’s syndrome can occur, including interstitial lung disease, interstitial nephritis, cutaneous vasculitis, and cryoglobulinemia. In this Clinical Problem-Solving article, a 57-year-old man with a history of Sjögren’s syndrome presented with several weeks of gradually worsening fatigue and exertional dyspnea. He reported no cough, fevers, chills, chest pain, palpitations, orthopnea, or paroxysmal nocturnal dyspnea.

Clinical Pearl

• How common are systemic symptoms in patients with Sjögren’s syndrome?

Whereas the primary manifestations of this autoimmune disease are diminished lacrimal-gland and salivary-gland function, extraglandular manifestations can occur. Systemic symptoms occur in 70 to 80% of patients, with articular, pulmonary, and peripheral neurologic involvement being the most common.

Clinical Pearl

• Which clinical features of Sjögren’s syndrome are associated with an increased risk of death?

A long-term concern in Sjögren’s syndrome is lymphoproliferative disease. Patients with extensive extraglandular manifestations of Sjögren’s syndrome are at particularly high risk for lymphoma and have an increased risk of death. Clinical features associated with an increased risk of lymphoproliferative disease include purpura, parotid enlargement, cryoglobulins, hypocomplementemia, and monoclonal bands. Glomerular involvement in primary Sjögren’s syndrome portends a poor prognosis, with an increased risk of death.

Morning Report Questions

Q: What is the most common type of cryoglobulinemia associated with Sjögren’s syndrome?

A: Cryoglobulinemia is a systemic inflammatory syndrome that is classified on the basis of the immunologic profile of the responsible cryoglobulin. Type I cryoglobulinemia, which is usually seen in lymphoproliferative diseases such as lymphoplasmacytic lymphoma (formerly called Waldenström’s macroglobulinemia), consists of a single monoclonal paraprotein and manifests as symptoms of vaso-occlusive disease. In contrast, mixed cryoglobulinemia refers to the autoantibody profile of a monoclonal IgM against polyclonal IgG (type II) or of polyclonal IgM against polyclonal IgG (type III). Distinguishing between the two conditions usually requires cryoprecipitate immunofixation, because routine serum protein electrophoresis is often not sufficiently sensitive to isolate a monoclonal, or M, spike in type II cryoglobulinemia. Type II is far more common in Sjögren’s syndrome than is type I or type III.

Q: Is cryoglobulinemia associated with Sjögren’s syndrome always symptomatic?

A: Neither the presence nor the quantity of cryoglobulins correlates with clinical disease expression. However, decreased levels of early complement proteins (C1q, C2, and C4) or a low level of CH50 indicates complement activation by immune complexes with associated clinical complications. In a large, prospective cohort study involving patients with Sjögren’s syndrome, 12% had detectable cryoglobulins at diagnosis and 17% were cryoglobulin-positive at some point, yet most had no associated clinical manifestations. Consequently, the cryoglobulinemia syndrome remains a clinical diagnosis; measurement of the cryocrit is, however, a useful way to follow response to therapy.

Treating Ebola with Convalescent Plasma

Posted by Bhavna Seth, M.D. • January 6th, 2016

photo credit: World Health Organization

photo credit: World Health Organization

On the eve of Christmas in 1891, Emil von Behring, the “Father of Serum Therapy,” injected Diphtheria therapeutic serum into an eight-year-old child suffering from severe diphtheria, and created history when the child was completely cured. He went on to win the Nobel Prize in 1901 for opening “a new road in the domain of medical science” and placing “in the hands of the physician a victorious weapon against illness and deaths.” The promise of serum therapy holds more importance now in the era of emerging infectious diseases. (1, 2)

In the midst of the largest Ebola outbreak to date, van Griensven et al. conducted a trial to evaluate the therapeutic potential of convalescent plasma for Ebola virus disease in Guinea. The NEJM has published a report of this open-label treatment experience, conducted in the volatile setting of an ongoing  outbreak situation, that attempts to assess the treatment efficacy and safety of convalescent plasma for acute Ebola infection. The study was conducted at Ebola treatment units in Conakry, Guinea, between February and August 2015. The control group was historically assembled from patients who had received treatment at the same facility in the previous five months.

The study primarily looked at the adjusted survival of patients, discharged as cured 3-16 days after diagnosis, between the two groups. After day 2 of diagnosis, per WHO Guidance (3), 400-500ml of convalescent plasma from 2 different donors, or 10ml/kg for small adults and children <45kg was given in two infusions. The estimated sample size of 130 patients for the intervention arm could not be assembled as the Data and Safety Monitoring Board advised early closure of the study owing to low caseloads.  The primary analysis included 84 patients in the intervention and 418 in the control groups. The mortality in the intervention arm was 31%, whilst that in the control arm was 38%. The absolute risk difference (-6.9%; 95% confidence interval (CI): -17.8% to 4.1%) was not statistically significant and did not achieve the targeted 20% reduction.

Considering the non-randomized nature of the study and the fact that a historical cohort was used as controls, there is a possibility that the results are affected by unadjusted confounders. The inability to achieve the targeted sample size was also a limitation.  In addition, the study was hampered by the absence of a clear understanding of the antibody titers in the convalescent plasma used or the optimal dosages and dosing frequency of convalescent plasma. NEJM Deputy Editor Dr. Lindsey R. Baden concurs, adding, “lack of real time controls is a tremendous limitation, and there was no way to ensure that this therapy included proper dosing of the antibody. But this is a critically important investigation to conduct under extreme circumstances.”

Emerging infectious diseases are a major threat to public health, mainly because these are novel diseases for which we have limited interventions available. In such a setting, devising a new intervention in time to control an outbreak situation is very difficult. Dr. Baden elaborates on this issue, stressing the importance of the study ‘’Convalescent plasma was part of the countermeasure plan in 1976 during the initial investigation which identified Ebola. Developing counter measures for emerging infectious diseases, especially those with explosive potential, is a high priority. Developing these measures in the midst of an epidemic is an extreme challenge”.

The current study goes a long way to establish the relative safety of convalescent plasma administration as a treatment modality and to assess the feasibility of obtaining and administering the convalescent plasma in the setting of an ongoing Ebola virus disease outbreak. Future studies need to look at dosing schedules, role of hyperimmune immunoglobulins, and changing patterns of antibody titers in the convalescence period to shed further light on these results.

bhavna_croppedBhavna Seth is a Resident in Internal Medicine at Boston University Medical Center.