Peanut Consumption in Infants

Posted by Carla Rothaus • February 27th, 2015

Children 4 to 11 months of age who were at high risk for development of peanut allergy were assigned to consumption or avoidance of peanuts until 60 months of age. Peanut allergy was more than five times as likely to develop in children assigned to peanut avoidance. (View a 1-minute Video Summary.  And, ask the authors and experts about the study in the NEJM Group Open Forum on

Several years ago, the Learning Early about Peanut Allergy (LEAP) researchers found that the risk of the development of peanut allergy was 10 times as high among Jewish children in the United Kingdom as it was in Israeli children of similar ancestry. This observation correlated with a striking difference in the time at which peanuts are introduced in the diet in these countries: in the United Kingdom infants typically do not consume peanut-based foods in the first year of life, whereas in Israel, peanut-based foods are usually introduced in the diet when infants are approximately 7 months of age. The LEAP trial was conceived to determine whether the early introduction of dietary peanut could serve as an effective primary and secondary strategy for the prevention of peanut allergy.

Clinical Pearls

- Is there evidence that eliminating allergenic foods from the diets of infants can prevent future allergy?

Clinical practice guidelines from the United Kingdom in 1998 and from the United States in 2000 recommended the exclusion of allergenic foods from the diets of infants at high risk for allergy and from the diets of their mothers during pregnancy and lactation. However, studies in which food allergens have been eliminated from the diet have consistently failed to show that elimination from the diet prevented the development of IgE-mediated food allergy.

- Does peanut consumption as compared with peanut avoidance decrease peanut allergy in at-risk infants with no preexisting peanut sensitivity?

The study by Du Toit et al. included infants aged 4 to 11 months who had severe eczema, egg allergy, or both. Among the 542 infants in the group with a negative result on an initial skin-prick test assessing preexisting peanut sensitivity, 530 (97.8%) could be evaluated for the primary outcome and were included in the intention-to-treat analysis. At 60 months of age, 13.7% of the avoidance group and 1.9% of the consumption group were allergic to peanuts; this absolute difference in risk of 11.8 percentage points (95% confidence interval [CI], 3.4 to 20.3; P<0.001) represents an 86.1% relative reduction in the prevalence of peanut allergy.

Morning Report Questions

Q: Does peanut consumption as compared with peanut avoidance decrease the development of peanut allergy in at-risk infants who have preexisting peanut sensitivity?

A: All 98 children in the group with positive results on the initial skin-prick test were evaluated and were included in the intention-to-treat analysis. At 60 months of age, 35.3% of the avoidance group and 10.6% of the consumption group were allergic to peanuts; the absolute difference in risk of 24.7 percentage points (95% CI, 4.9 to 43.3; P=0.004) represents a 70% relative reduction in the prevalence of peanut allergy.

Figure 2. Primary Outcome.

Q: How do levels of peanut-specific IgE, IgG, and IgG4 in infants who consume peanuts compare to those of infants who do not consume peanuts?

A: At 60 months, the number of participants with markedly elevated levels of peanut-specific IgE titers was higher in the peanut-avoidance group than in the consumption group. In contrast, the peanut-consumption group showed a significantly greater and earlier increase in levels of peanut-specific IgG and IgG4; this effect mirrors the immunologic changes seen in successful allergen immunotherapy. Furthermore, in the avoidance group, unless peanut-specific IgE levels were very high, elevated IgG4 levels were associated with the absence of an allergic reaction to peanuts. Both observations indicate that IgG4 is associated with a protective role against the development of allergy.

A Man with Oral Ulcers

Posted by Carla Rothaus • February 27th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 25-year-old man presented with oral ulcers and odynophagia. On examination, there were scattered pink papules and plaques on the trunk, thighs, and buttocks and multiple raised, erythematous nodules on both shins. A diagnostic procedure was performed.

Behcet’s disease affects young adults, usually starting during the third decade of life.

Clinical Pearls

- What is Behcet’s disease?

Behcet’s disease is a rare rheumatologic condition characterized by recurrent oral and genital ulcers, rash, inflammatory eye disease, and vasculitis. This disease occurs worldwide, but its incidence is highest in the Far East and Middle East regions and in countries around the Mediterranean basin.

- What are the characteristics of the oral and genital lesions that occur in patients with Behcet’s disease?

Mouth lesions that are indistinguishable from simple aphthous ulcers are seen in virtually all affected patients and may be located in the epithelial mucosa that covers the lips, cheeks, gums, tongue, palate, floor of the mouth, and pharynx, including the tonsils. However, as compared with common aphthous ulcers, oral ulcers related to Behcet’s disease generally occur in groups, are larger, and take a longer amount of time to heal, usually without scarring. Genital ulcers, which have a “punched-out” appearance, develop in approximately 80% of patients, typically involve the penile shaft and scrotum in men, and tend to heal within a month, leaving a scar; in some cases, genital ulcerations associated with Behcet’s disease can occur in the inguinal area and perineum.

Morning Report Questions

Q: What are additional clinical features of Behcet’s disease?

A: Additional cutaneous manifestations develop in the majority of patients with Behcet’s disease at some point during the course of the illness; these can include papulopustular, pseudofollicular, and acneiform eruptions and lesions resembling erythema nodosum. Arthralgias and nonerosive oligoarthritis are commonly described. In nearly half the cases of Behcet’s disease, a sterile pustule is formed within 48 hours after minor skin trauma (e.g., needle stick); this is especially common among patients from countries in the Far East or Middle East regions. This reaction, called the pathergy phenomenon, is not sensitive for but is highly specific for the diagnosis of Behcet’s disease. Inflammatory eye involvement may be seen in 25 to 75% of patients with Behcet’s disease and may be manifested as uveitis, retinal vasculitis, or optic neuritis. Less frequent manifestations include lesions involving the central nervous system, esophagogastrointestinal inflammation leading to mucosal erosions, cardiac involvement (e.g., pericarditis or myocarditis), epididymitis, and vasculitis with varying sizes of blood vessels, which may confer a predisposition to arterial and venous thrombosis.

Q: How is Behcet’s disease diagnosed and treated?

A: The diagnosis of Behcet’s disease is typically made on the basis of clinical evidence, but a skin or mucous-membrane biopsy may be performed to help confirm the diagnosis. Behcet’s disease has characteristics of both autoimmune and autoinflammatory diseases.

Treatment may target either the autoimmune or the autoinflammatory aspects of the disease, or it may target both. In addition, the choice of treatment is frequently determined on the basis of organ involvement. Mucocutaneous lesions are the most frequently occurring feature in patients with Behcet’s disease, although arthritis occurs in up to half the cases. Colchicine is often used to control these manifestations; clinical trials have shown its efficacy in treating both inflammatory arthritis and skin lesions. Isolated skin and genital lesions may be treated with topical glucocorticoids, and in cases of more severe skin involvement, azathioprine, thalidomide, and tumor necrosis factor inhibitors are alternative options, although toxic effects associated with thalidomide may preclude its use.

Systemic glucocorticoids, which are frequently used to treat Behcet’s disease, are probably more effective in controlling erythema nodosum than in managing oral and genital ulcers. Treatment of eye involvement in patients with Behcet’s disease is of paramount importance, because blindness or impaired vision may develop in up to 25% of affected patients.

Table 2. International Study Group Criteria for the Diagnosis of Behcet’s Disease.

New Conversations on the NEJM Group Open Forum

Posted by Jennifer Zeis • February 26th, 2015

NEJM Group Open Forum

Now on the NEJM Group Open Forum, NEJM authors and experts are discussing:

NEJM Group Open Forum (#NEJMForum) is a series of live discussions intended to generate active conversation around important — and sometimes controversial — ideas. NEJM Group and joined together to create the forum, and physicians and medical students are welcome to read the discussion boards or join in the conversation.

Medstro recently added one-click sign up with your Facebook, LinkedIn, or Twitter accounts to make it faster and easier to join.

What are you waiting for? Join the discussion now! The peanut allergy forum closes March 4, the precision medicine forum closes March 5, and the mitochondrial replacement forum opens March 3.

Outcomes of Pregnancy After Bariatric Surgery

Posted by Daniela Lamas • February 25th, 2015

Your patient has been trying to lose weight for years.

But no matter how many grapefruits she eats, whether she goes ‘gluten free’ or replaces her snacks with lean meats and long walks on the treadmill, the 35-year old’s weight has hit a plateau. And with the weight have come a series of troubling health effects, most recently high blood pressure and sleep apnea.

It’s time to consider bariatric surgery. She’s nervous but excited. You’ve referred a few patients to bariatric surgery before, so you’re prepared for most of her questions. But then she comes up with a question that has you stuck.

Your patient hopes to get pregnant in the future. Will her pregnancy face the same potential for poor outcomes – gestational diabetes, large birth and congenital malformations among them – as it would if she conceived now, prior to bariatric surgery? On the other hand, she wonders, does bariatric surgery bring with it a new host of pregnancy-related risk?

You aren’t sure. You know well that maternal obesity would place your patient and fetus at risk for gestational diabetes, complications with delivery, some congenital malformations and preterm birth. You know, too, that bariatric surgery can normalize glucose control in diabetics. But without a large-scale study investigating the effect of bariatric surgery on gestational diabetes on pregnancy outcomes, you aren’t sure how to respond.

A study published in this week’s NEJM might help answer your patient’s question.

In their paper, “Outcomes of Pregnancy in Women with Prior Bariatric Surgery,” Kari Johansson and colleagues set out to assess the risk of gestational diabetes, large-for-gestational-age (LGA) birth, small-for-gestational-age (SGA) birth, stillbirth, neonatal death and major congenital malformations in infants born to women who had undergone bariatric surgery.

To conduct this population wide study, the investigators tapped into the Swedish health system’s extensive nationwide registers and came up with 670 births to women who had undergone bariatric surgery and had a pre-surgery BMI recorded. The vast majority of these bariatric procedures were gastric bypass. The researchers then compared outcomes to another group of women who hadn’t undergone surgery and whose pre-pregnancy BMI was similar to the the pre-surgery BMI of the bariatric surgery group.

Their results? As expected, patients who had undergone bariatric surgery had lower rates of gestational diabetes (in just below two percent of the post-surgery group compare to nearly seven percent of the control group). As for the babies, post-surgery births were less likely to be large-for-maternal age – but more likely to be small-for-maternal age. While post-surgery pregnancies were shorter on average, there was no significant risk in the difference of preterm birth and no difference in the frequency of congenital malformations.

On a more troubling note, there was a suggestion of a higher risk of stillbirth and neonatal death in the infants delivered to post-surgery mothers (1.7 percent versus 0.7 percent), but this did not meet the cut-off for statistical significance.

The authors acknowledge some limitations to their study. It is an observational study and thus can’t make a determination as to cause and effect. Furthermore, as the Swedish population is mostly Caucasian, findings are not necessarily generalizable to other groups.

In an accompanying editorial, Aaron B. Caughey, who chairs the department of Obstetrics and Gynecology at Oregon Health and Science University, notes that with expanding rates of obesity in the US, obstetricians can expect to see an increasing number of women who have undergone bariatric surgery. While the current study does not lead to any direct change in management, he notes, “decisions regarding bariatric surgery in women of reproductive age should take into account the benefits and risks associated with this not inconsequential procedure in terms of both pregnancy and long-term health.”

Peanut Consumption in Infants at Risk for Peanut Allergy

Posted by Chana Sacks • February 23rd, 2015

In a famous “Peanuts” cartoon, a glum Charlie Brown sits alone on a bench, eating a sandwich; his thought bubble reads, “Nothing takes the taste out of peanut butter quite like unrequited love.”  Charles Schulz was perhaps better than any other at simply and brilliantly capturing the timeless angst that defines the human condition. And yet peanut butter – what in his 1964 cartoon aptly represents one of the joys of childhood itself – might today more likely be considered one of childhood’s real hazards, with dramatically rising rates of peanut allergy afflicting children around the world.

While the prevalence of peanut allergy is clearly increasing, a definitive reason for this rise and how to reverse it have remained mysteries.  In the effort to answer these questions, a group of investigators made an important observation: they found that Jewish children in the United Kingdom (UK) were 10 times as likely to develop a peanut allergy as compared with Israeli children of similar ancestry. Trying to understand why, they noted that in Israel, peanuts are usually introduced into the diet by 7 months of age; in the UK, peanuts are rarely introduced before age 1.  This led to the hypothesis that early exposure to peanuts might be protective against peanut allergy. These investigators designed and conducted a trial, sponsored by the United States National Institute of Allergy and Infectious Disease that seems to have proven them correct.

The Learning Early About Peanut Allergy (LEAP) study, now published in NEJM, was a randomized, open-label, single-center study designed to compare two strategies to prevent peanut allergy: consumption or avoidance of peanuts. The trial enrolled children 4-11 months of age who were thought to be at high risk for developing a peanut allergy based on a history of severe eczema or egg allergy.  Participants were given a skin prick test to evaluate for sensitivity to peanut.  Children with a negative skin prick result (meaning no measureable skin wheal) or moderately positive (1-4mm wheal) were included in the study; children with a highly positive result (wheal >4mm) were excluded.  Infants were then stratified based on their skin prick test results. 530 infants in the skin prick test negative group and 98 infants in the skin prick test positive group were randomly assigned to either consume 6g of peanut protein per week or to avoid peanuts.  The primary outcome was the proportion of participants with a peanut allergy at age 5, determined by response to an oral peanut protein challenge.

The results were impressive:  in the negative skin prick test group, the prevalence of peanut allergy at age 5 was 13.7% in the avoidance group versus 1.9% in the consumption group (P<0.001).  In the positive skin prick test group, 35.3% of those who avoided peanuts were allergic as compared with 10.6% of the consumption group (P=0.004). There were no significant differences in hospitalizations or other serious adverse events between groups.  The investigators did identify five categories of mild or moderate adverse events that were more common in the consumption group: upper respiratory tract infection, viral skin infection, gastroenteritis, urticaria, and conjunctivitis.

Dr. Jeffrey Drazen, Editor-in-Chief, describes these results as “important, new knowledge that provides practical answers about how to deal with peanut allergy specifically and also improves our understanding of the immunology of food allergy more generally.”

In an accompanying editorial, Drs. Rebecca Gruchalla and Hugh Sampson call the LEAP trial a “landmark study.” They write that some open questions remain –f or example, “If regular peanut consumption is discontinued for a prolonged period, will tolerance persist? Can the findings of the LEAP study be applied to other foods, such as milk, eggs, and tree nuts?”  However, even before we have those answers, they conclude “the LEAP study makes it clear that we can do something now to reverse the increasing prevalence of peanut allergy” – offering hope that peanut butter might one day be restored to its symbolic place, representing an uncomplicated joy of childhood.

A Boy with Coughing Spells

Posted by Carla Rothaus • February 20th, 2015

In the latest Case Record of the Massachusetts General Hospital, a 16-year-old boy presented with a 3-week history of cough and nasal congestion and a 3-day history of severe coughing spells, post-tussive emesis, and trouble breathing. A chest radiograph was normal. A diagnostic test was performed.

Since the mid-1980s, there has been a gradual upward trend in the incidence of pertussis, punctuated by spikes in outbreaks every 2 to 5 years — including in 2012, when more than 48,000 cases were reported in the United States, and in 2014, when approximately 10,000 were reported in California.

Clinical Pearls

- What conditions are included in the differential diagnosis for chronic cough?

Recurrent infection is the most frequent cause of prolonged (subacute or chronic) cough in children. Common causes of prolonged cough include asthma, gastroesophageal reflux disease, and the upper-airway cough syndrome. Other causes include passive or active smoking, cystic fibrosis, foreign-body aspiration, extrinsic airway compression, and interstitial lung disease. Pyogenic bacterial pneumonia or prolonged bacterial bronchitis can cause persistent cough. Tuberculosis can manifest as subacute or chronic cough.
Mycoplasma pneumoniae is a common cause of both upper and lower respiratory tract infections, especially in children and young adults. Onset of symptoms is often gradual and characterized by fever, headache, malaise, and cough that increases in severity over several days. Chlamydophila pneumoniae can cause similar upper and lower respiratory tract infections, including an atypical pneumonia syndrome. Several respiratory viral infections are associated with cough, which may be prolonged. Influenza can cause cough, with or without frank pneumonia. Adenovirus also causes acute respiratory disease, often with coryza and sore throat. The cough associated with rhinovirus often develops after the onset of nasal symptoms and persists after nasal symptoms have resolved. Respiratory syncytial virus is best known as a cause of bronchiolitis in infants but can also result in upper respiratory tract infection and cough in patients of all ages; in otherwise healthy children and young adults, symptoms are usually mild. Parainfluenza virus may cause an infection, usually an upper respiratory infection with a cough, in older children.

Table 1. Some Causes of Prolonged Cough in Children.

- What are the clinical features of , including its associated cough?

An unimmunized person with pertussis first presents with rhinorrhea, conjunctival irritation, and mild cough, with little or no fever. After 7 to 10 days, this catarrhal phase transitions to the paroxysmal phase, and the cough becomes more frequent and severe. Typical paroxysms consist of a series of several forceful coughs during a single expiration, followed by gasping inhalation; this can result in a whooping sound, especially in young children. Post-tussive vomiting is common among affected patients. Paroxysms may occur several times an hour and can be more prominent at night.
Patients are usually asymptomatic between paroxysms. After several weeks, the cough gradually diminishes. Infection in infants can manifest as apnea, with or without cough. Adolescents and adults with pertussis who have been previously immunized sometimes do not have the classic paroxysms; rather, the illness is characterized primarily by persistent cough and can be complicated by syncope, rib fracture, incontinence, pneumonia, seizures, or encephalopathy.

Morning Report Questions

Q: What duration of protective immunity is provided by the DTaP and Tdap vaccines?

A: It has become clear that the immunity evoked by the DTaP vaccine (an acellular pertussis vaccine), which has been in wide use since the late 1990s, is less durable than the immunity evoked by the diphtheria-tetanus-whole-cell pertussis (DTwP) vaccine. Studies have shown that the protective immunity evoked by DTaP wanes rapidly, with vaccine efficacy decreasing within 5 years after the final childhood dose is administered, at 4 to 6 years of age. Studies have also confirmed that adolescents who received only the DTaP vaccine have a substantially higher risk of contracting pertussis than do adolescents who had received any dose of the DTwP vaccine. The lowercase “d” and “p” in Tdap signify that the vaccine has a low dose of the diphtheria and pertussis components, as compared with the DTaP vaccine. Two of three studies that examined the efficacy of the Tdap vaccine showed significant efficacy in the first 2 years after vaccination.

Table 3. Efficacy Studies of the Tetanus Toxoid-Reduced Diphtheria Toxoid-Acellular Pertussis, Adsorbed (Tdap) Vaccine.

Q: Who should receive the Tdap vaccine?

A: Currently, the ACIP [Advisory Committee on Immunization Practices] recommends administering the Tdap vaccine only once and subsequently administering the tetanus-diphtheria (Td) vaccine every 10 years, as well as administering the Tdap vaccine to pregnant women. A single dose of Tdap is recommended for children 11 or 12 years of age and for adolescents or adults who have not previously received it. The Tdap vaccine may be administered regardless of the time since the last vaccine containing tetanus and diphtheria was administered. The ACIP also recommends the Tdap vaccine for persons 7 years of age or older who are not fully immunized with the DTaP vaccine.

Groin Hernias in Adults

Posted by Carla Rothaus • February 20th, 2015

Watchful waiting is safe for men with asymptomatic inguinal hernias, but data from randomized trials suggest that most men will ultimately undergo surgery, primarily because of pain. Watchful waiting is not recommended in women, given their higher prevalence of femoral hernias. Read the new Clinical Practice review on this topic.

The lifetime risk of development of a groin hernia has been estimated at 27% for men and 3% for women.

Clinical Pearls

- Describe the epidemiology of and risk factors for groin hernia.

Inguinal hernias are more common on the right side than on the left and are 10 times more common in men than in women. Among adults, the annual frequency of groin hernia repair was found to increase consistently with age, from 0.25% at 18 years of age to 4.2% at 75 to 80 years of age. Femoral hernias account for fewer than 5% of groin hernias; however, 35 to 40% of femoral hernias are not diagnosed until the patient presents with strangulation or bowel obstruction, and mortality is higher in association with emergency repair than with elective repair. Femoral hernias are more common in women than in men, but a woman with a groin mass is still 5 times more likely to have an inguinal hernia than a femoral hernia. A major risk factor for a groin hernia is a family history of groin hernias, which is associated with up to eight times the risk.

Figure 1. Types of Hernia and Hernia Anatomy from an Anterior Perspective.

- How are hernias diagnosed?

Inguinal hernias are diagnosed by means of a physical examination disclosing a visible bulge or an easily palpable mass on straining with an examining finger in the external ring. Differentiating an indirect from a direct inguinal hernia is unnecessary, because it does not affect treatment. It is not always possible to differentiate an inguinal hernia from a more worrisome femoral hernia during physical examination.
Imaging studies are required only in cases in which there are typical symptoms in the absence of physical findings, to rule out an occult hernia or other condition. Ultrasonography is relatively inexpensive and avoids the use of radiation, but its accuracy is operator-dependent. Computed tomography and magnetic resonance imaging (MRI) are alternatives; MRI provides the best anatomic detail and has the highest sensitivity and specificity.

Morning Report Questions

Q: How should an asymptomatic or minimally symptomatic groin hernia be managed?

A: Regardless of the type of hernia, symptomatic patients should be offered repair to improve quality of life. However, the results of two randomized trials comparing prompt repair with a strategy of watchful waiting for asymptomatic or minimally symptomatic inguinal hernias have argued against routine repair. One of these, a single-center randomized trial from the United Kingdom involving 160 patients, showed no significant difference between groups in pain scores and a minimal difference in scores on the 36-Item Short Form Health Survey at 1 year. In a larger multicenter trial from North
America, there was no significant difference at 2 years in pain or quality of life between the group that underwent surgery and the group that did not. In both studies, approximately one quarter of patients assigned to watchful waiting crossed over to surgery, primarily because of increasing pain; the delay did not affect the frequency of operative complications. Both studies have recently been updated with longer-term follow-up data. The estimated frequency of crossover to surgery from the watchful-waiting group was 72% by 7.5 years in the U.K. trial and 68% by 10 years in the North American trial; most crossovers to surgery were a result of increasing pain.
The logical conclusion is that watchful waiting is safe but only delays the inevitable surgery. Because the patients in both studies had presented to their physicians with concerns about their hernias, the results may not be generalizable to the larger group of patients with asymptomatic hernias and no concerns. Another important caveat is that these results apply only to inguinal hernias and not to femoral hernias, because of the higher risks of serious complications with the latter.

Q: How do laparoscopic herniorrhaphy and open surgical repair compare?

A: Laparoscopic herniorrhaphy results in less pain initially, an earlier return to normal activities, and easier repair of recurrent hernias that have previously undergone open repair, and it allows treatment of bilateral hernias through the same skin incisions. The risks of common surgical complications are similar for laparoscopic and open repair; complications include wound seroma or hematoma (approximately
7 to 8% risk), wound infection (approximately 1% risk), testicular complications (approximately 0.7% risk), and complications related to the mesh — for example, contraction, erosion, and infection.
However, laparoscopic repair is associated with a small risk life-threatening vascular or visceral injury (0.9 and 1.8 per 1000 procedures, respectively). Whereas laparoscopic repair requires general anesthesia, open repair can be performed under local anesthesia; the possibility of using local anesthesia is a particular advantage in older patients who require repair and have serious coexisting medical conditions. Laparoscopic herniorrhaphy is more expensive, but the costs of the procedure may be offset by an earlier return to daily function and work.

Figure 3. Laparoscopic Totally Extraperitoneal Herniorrhaphy.

Exercise-Induced Bronchoconstriction

Posted by Carla Rothaus • February 13th, 2015

Asthma or asthma-like conditions can limit the ability of athletes to perform. This article reviews the diagnosis and treatment of asthma and exercise-induced bronchoconstriction in athletes.

The term exercise-induced bronchoconstriction describes the transient narrowing of the airways after exercise, a phenomenon that occurs frequently among athletes who may not have a diagnosis of asthma or even have any respiratory symptoms.

Clinical Pearls

- Describe a key factor in the pathogenesis of exercise-induced bronchoconstriction.

The mechanism of exercise-induced bronchoconstriction has not been established with certainty; both airway cooling resulting from conditioning of inspired air and postexercise rewarming of airways have been proposed as mechanisms. However, the key stimulus is probably airway dehydration as a result of increased ventilation, resulting in augmented osmolarity of the airway-lining fluid. This is thought to trigger the release of mediators — such as histamine, cysteinyl leukotrienes, and prostaglandins — from airway inflammatory cells, which leads to airway smooth-muscle contraction and airway edema.

- How is asthma or exercise-induced bronchoconstriction in athletes diagnosed?

The demonstration of more than 10% diurnal variability in peak expiratory flows measured twice daily over a period of 2 weeks, or more than 12% (and >200 ml) variability in forced expiratory volume in 1 second (FEV1) over time or after 4 weeks of treatment, is consistent with a diagnosis of asthma or exercise-induced bronchoconstriction. The likelihood of airways to narrow can also be demonstrated, if airflow limitation is present, by a more than 12% (and >200 ml) change in the FEV1 after inhalation of an aerosolized beta2-agonist; if the baseline airway caliber is normal, this likelihood can be assessed as the presence of airway hyperresponsiveness documented with the use of bronchoprovocation testing. These tests include direct challenges (e.g., with inhaled methacholine), which act on airway smooth muscle to cause bronchoconstriction, and indirect challenges, such as eucapnic voluntary hyperpnea (particularly recommended for athletes), hyperosmolar tests with saline or mannitol, and laboratory or field exercise tests. However, athletes may have a positive response to only one of these types of tests, and airway responsiveness can normalize a few weeks after they stop intense training. Therefore, more than one type of test may be needed, and ideally the testing should be performed during a period of intense training.

Figure 1. Diagnosis of Asthma and Exercise-Induced in Athletes.

Morning Report Questions

Q: What general measures are recommended for the management of exercise-induced bronchoconstriction?

A: As for all patients with asthma, education about asthma self-management is essential; this should include advice about environmental measures, inhaler-use technique, and the use of an asthma action plan for the management of exacerbations, in addition to regular follow-up. Mechanical barriers such as face masks, although they are not always well tolerated, can help reduce the effects of cold air exposure in winter-sports athletes or the inhalation of particulate air pollutants. A pre-exercise warm-up
(i.e., low-intensity or variable-intensity precompetitive exercise) can result in a reduction in exercise-induced bronchoconstriction in more than half of persons. However, whenever possible, it is preferable for sensitized athletes not to exercise close to busy roads or during periods of high allergen exposure. Measures to reduce chloramine formation in chlorinated pools, improve ventilation of pool environments, and reduce exposure to other indoor and outdoor pollutants, including ozone, particulate matter, and nitrogen oxides, should also be promoted.

Q: What pharmacologic therapies are commonly used?

A: The most common management strategy for athletes with asthma or exercise-induced bronchoconstriction who are exercising daily is daily treatment with inhaled glucocorticoids, with short-acting inhaled beta2-agonists used occasionally before exercise. Inhaled glucocorticoids are the mainstay of asthma therapy in athletes, as they are in nonathletes; these agents are allowed by sports authorities. Apart from helping to control asthma and improve pulmonary function, an additional benefit of treatment with inhaled glucocorticoids is a progressive reduction, with regular use, in airway responses to various stimuli, including exercise. If low doses of inhaled glucocorticoids do not achieve asthma control, the addition of another controller drug should be considered, preferably a long-acting inhaled beta2-agonist. Leukotriene-receptor antagonists are also an option for maintenance treatment, and the combination of inhaled glucocorticoids and leukotriene-receptor antagonists may provide additional protection.

Table 1. Specific Issues in the Management of Asthma in Athletes.

Table 2. Treatment of Asthma and Exercise-Induced Bronchoconstriction in Athletes.

Table 3. Current Antidoping Status of Asthma Medications.

Smoking and Mortality

Posted by Carla Rothaus • February 13th, 2015

Using data from five U.S. cohort studies, the authors of a new report estimate that 17% of excess mortality among smokers is due to diseases not already established as caused by smoking; for example, renal failure, infections, and intestinal ischemia could potentially be linked to smoking.

Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases (12 types of cancer, 6 categories of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia including influenza) that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States.

Clinical Pearls

- Are current estimates of smoking-related mortality rates in the United States accurate?

The 2014 Surgeon General’s report estimates that cigarette smoking causes more than 480,000 deaths each year in the United States. This widely cited estimate of the mortality burden of smoking may be an underestimate, because it considers deaths only from the 21 diseases (mentioned above) that have been formally established as caused by smoking. Associations between smoking and the 30 most common causes of death in the United Kingdom in the Million Women Study suggest that the excess mortality observed among current smokers cannot be fully explained by these 21 diseases.

- Are there additional diseases that contribute to the excess mortality among current smokers in the United States?

In a prospective analysis, data were pooled from five contemporary U.S. cohort studies and included 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 to 2011.
During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking.
These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), and various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4).

Table 2. Relative Risks of Death from Specific Causes among Persons 55 Years of Age or Older, According to Sex and Smoking Status.

Morning Report Questions

Q: Is there an association between smoking and death from breast and prostate cancer?

A: In the analysis published in this week’s issue of the Journal, smoking remained significantly associated with death from breast cancer among women who were not current drinkers. However, associations between smoking and death from breast cancer may also be biased by differences in screening or treatment patterns among smokers, and information on these variables was not available in this study. Additional studies with detailed information on these factors may be useful in clarifying whether smoking is causally associated with death from breast cancer. Mortality from prostate cancer in this population was 43% higher among current smokers than among those who had never smoked, a finding that is consistent with most previous analyses of prostate-cancer mortality. The Surgeon General concluded that although there was insufficient evidence that smoking increases the incidence of prostate cancer, the available evidence suggested that current or recent smoking increases the risk of advanced-stage disease and of death from prostate cancer. Higher mortality from prostate cancer among smokers could be caused by delayed diagnosis owing to less intense medical surveillance or by a promoting effect of smoking on later stages of carcinogenesis and progression.

Table 3. Mortality and Excess Mortality, According to Sex and Smoking Status.

Q: To what extent does the 2014 Surgeon General’s report underestimate yearly deaths from smoking?

A: Results of this study suggest that the Surgeon General’s recent estimate of smoking-attributable mortality may have been an underestimate. The Surgeon General’s estimate, which took into account only the 21 diseases formally established as caused by smoking, was that approximately 437,000 deaths among adults are caused each year by active smoking (not including secondhand smoke).
However, the Surgeon General’s report presents an alternative estimate of 556,000 deaths among adults on the basis of the excess mortality from all causes. The difference between these two estimates is nearly 120,000 deaths. If, as suggested by the results in the cohort used in this study, at least half of this difference is due to associations of smoking with diseases that are causal but are not yet formally established as such, then at least 60,000 additional deaths each year among U.S. men and women may be caused by cigarette smoking.

Gastrointestinal Bleeding

Posted by Carla Rothaus • February 6th, 2015

In the latest Clinical Problem-Solving article, a 66-year-old man with ischemic cardiomyopathy presented to the hospital with a 2-day history of fatigue, dizziness on standing, and bright red blood from the rectum that transitioned to black, tarry stools. Angioectasias are increasingly recognized in patients with either pulsatile or nonpulsatile left ventricular assist devices (LVADs).

Clinical Pearls

What are angioectasias?

Angioectasias are thin-walled, dilated, ectatic blood vessels with or without an endothelial lining. Their pathogenesis is uncertain but may be associated with aging-related chronic obstruction of submucosal veins that extends to venules, capillaries, and arteries and ultimately results in loss of precapillary-sphincter competency and development of arteriovenous communications. Angioectasias occur most commonly in elderly patients, especially in those with renal failure or aortic stenosis. Multiple angioectasias may occur in patients with LVADs and other systemic processes and may involve any portion of the bowel, especially the small bowel.

- What is the connection between left ventricular assist devices and angioectasia formation and bleeding?

Angioectasias are increasingly recognized in patients with either pulsatile or nonpulsatile LVADs. Risk factors for angioectasia formation and bleeding are thought to be similar to those for aortic stenosis. In patients with either aortic stenosis or an LVAD, a narrow pulse pressure may result in hypoxia of intestinal tissue with subsequent vascular dilation and angioectasia formation. The mechanical pump in nonpulsatile LVADs creates high shear stress, causing consumption of high-molecular-weight von Willebrand factor multimers and acquired von Willebrand factor deficiency, thus conferring a predisposition to bleeding. High-molecular-weight von Willebrand factor levels have been reported to be reduced in patients with nonpulsatile LVADs and to normalize after removal of the device. According to one report, gastrointestinal bleeding is more common among patients with nonpulsatile LVADs than among patients with pulsatile LVADs (20% vs. 10%).

Morning Report Questions

Q: How are angioectasias treated?

A: Treatment of angioectasias is difficult, no matter what causes them, and randomized, controlled trials are lacking to guide therapy. Management involves supportive care, with iron supplementation, blood transfusion when indicated, and endoscopic therapy when feasible. Patients who require blood transfusions commonly undergo aggressive endoscopy in an attempt to identify and treat lesions. Although endoscopic therapy for angioectasias has been reported to reduce the rates of rebleeding, data are lacking with respect to the effects of this treatment in patients with LVADs. Endoscopic therapy includes argon plasma coagulation, placement of endoscopic hemoclips, contact thermal therapy (bipolar electrocautery or heater probe), or a combination of these techniques. In addition, an injection of normal saline or epinephrine may be used as an adjunct to one of these therapies. Patients with active clinical bleeding and hemodynamic instability should be treated with angiographic therapy, such as embolization or vasopressin infusion.

Q: Are there any effective medical therapies?

A: Medical therapies such as estrogen and octreotide have been ineffective in the treatment of bleeding angioectasias and thus are no longer recommended. In one randomized, controlled trial, thalidomide (which appears to have properties that are antiangiogenic, prothrombotic, or both) reduced bleeding from gastrointestinal angioectasias. However, the use of thalidomide is limited in patients with LVADs because it is associated with an increased risk of thrombosis.