Anti–Interleukin-5 Monoclonal Antibody to Treat Severe Eosinophilic Asthma

Posted by Daniela Lamas • September 24th, 2014

Most asthma patients who come to your pulmonary office get better. With a regimen of inhaled therapies and possibly a short course of oral corticosteroids, the wheeze and cough and shortness of breath remit. But the patient you are seeing in clinic today is still struggling.

She’s tried every inhaler at its maximum dose and still has been taking oral corticosteroids for more than six months now. Each year, she’s in the hospital at least three times with a severe exacerbation of her symptoms, and an elevated eosinophil count in her peripheral blood. Reaching the limits of your therapeutic armamentarium, you are considering referring her to bronchial thermoplasty but otherwise, you’re not sure what else to offer.

Now, two studies published in this week’s NEJM lend promising evidence to a new therapy that could benefit your patient – a monoclonal antibody, mepolizumab, that targets one aspect of the inflammatory cascade leading to asthma symptoms.

Mepolizumab works by binding to IL-5 – a cytokine that recruits eosinophils from the bone marrow. As blood and sputum eosinophilia correlate with worsened asthma control, it stands to reason that a drug that decreases eosinophilia might improve asthma control. But how to tell which patients with severe asthma might benefit? Initial studies failed to find a benefit across the entire spectrum of those with severe asthma, but smaller studies demonstrated better outcomes in patients with asthma characterized by elevated levels of eosinophils. The pair of studies in this week’s NEJM further characterizes how to administer this drug and to what group of patients.

In one of the studies, Hector Ortega and colleagues enrolled 576 patients with severe asthma. All had more than two exacerbations of their asthma in the prior year despite high dose inhaled corticosteroids, and an elevated blood eosinophil count (≥300cells/µL). Patients were randomly assigned to receive intravenous mepolizumab, subcutaneous mepolizumab or placebo every four weeks, for 32 weeks. They found that both routes of administration decreased frequency of exacerbations by about one-half and improved measures of quality of life and asthma control.

The companion study, by Elisabeth Bel and colleagues, looks specifically at a subset of patients with glucorticoid-dependent severe asthma and persistently elevated eosinophil levels. Patients received monthly subcutaneous mepolizumab or placebo for twenty weeks. Those who were randomly assigned to mepolizumab were able to reduce their glucorticoid dose by fifty percent and – despite the reduced steroid dose – had fewer exacerbations and reported improved asthma control. Both studies showed the drug to have similar adverse event rates to placebo.

In an editorial, Parameswaran Nair, a pulmonologist and asthma researcher, writes that these studies leave open some key questions, specifically whether tracking sputum eosinophil levels might improve drug dosing, and what the most effective route and frequency of administration might be. He also notes that even the placebo group in the Ortega trial saw a significant decrease in exacerbation rates (although the drop was smaller than in those taking the study drug). Perhaps, Nair writes, for some patients, improving adherence might negate the need for a costly therapy like mepolizumab.

Despite these concerns, he notes that anti-interleukin 5 therapy offers “an important advance in our ability to care for patients with severe eosinophilic asthma, particularly as a method of decreasing exacerbations in patients who are dependent on daily use of oral glucocorticoids.” He concludes, “it is reasonable to consider anti–interleukin-5 therapy for patients with severe asthma who are receiving high doses of systemic glucocorticoids and who continue to have an elevated eosinophil count in sputum or blood regardless of their atopic status.”

When it comes to your patient, then, first make sure she’s truly been adherent with her prescribed medications. If she has been, then she will need to wait for regulatory approval as mepolizumab has not been approved for use in asthma.



60 Year-Old Woman with Syncope

Posted by Sara Fazio • September 19th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 60-year-old woman was seen in the emergency department after a syncopal episode. Oxygen saturation was 71% while she was breathing ambient air. A focused cardiac ultrasound revealed right-sided heart strain and McConnell’s sign. Additional diagnostic procedures were performed.

A FOCUS examination, also referred to as clinician-performed ultrasonography or point-of-care ultrasonography, provides time-sensitive information that may narrow the differential diagnosis, inform resuscitation strategies, and guide treatment of patients with cardiovascular disease. The purpose of a FOCUS examination is to look for any evidence of pericardial effusion, assess global cardiac function and relative chamber size, and guide emergency procedures. A FOCUS examination is intended to serve as a complement to comprehensive echocardiography and is now considered an essential part of training in emergency medicine.

Clinical Pearls

What is “clot in transit”?

Clot in transit is a dangerous manifestation of pulmonary embolism that is seen in approximately 4% of cases, although this may be an underestimate. The mortality associated with pulmonary embolism with clot in transit is high (27 to 45%), with nearly all deaths occurring in the first 24 hours, so rapid and aggressive treatment is essential. With clot in transit, anticoagulation alone is unlikely to be sufficient because it is associated with a higher mortality (38%) than thrombolysis or surgery.

What is the role of systemic thrombolysis versus catheter-directed thrombolysis in massive pulmonary embolism?

In cases of massive, hemodynamically unstable pulmonary embolism and in the presence of clot in transit, systemic thrombolysis is associated with improved survival, as compared with anticoagulation alone. Thrombolytic therapy can be delivered locally through a catheter inserted into a pulmonary artery. The main advantage of a catheter-directed approach is that a low dose of the thrombolytic agent is typically used in someone with a higher risk of bleeding. However, in a patient with suspected clot in transit, passing a catheter through the right atrium is risky and could disrupt the clot.

Morning Report Questions

Q: What is the role of aspiration versus surgical thrombectomy in the treatment of pulmonary embolism?

A: Aspiration thrombectomy is a relatively new technique that allows clinicians to remove a large volume of thrombus from the right side of the heart or the proximal pulmonary artery. This procedure requires a venotomy and a perfusion team, but it is less invasive than an open surgical thrombectomy. Although there is a paucity of data describing its use in patients with a pulmonary embolism and clot in transit, the procedure is typically well tolerated. A major risk of this approach is that aspiration can fragment a fragile clot and lead to further embolization. In a patient with a patent foramen ovale, a fragmented clot could release emboli into the systemic circulation. Open surgical thrombectomy allows for rapid removal of clots from both the pulmonary arteries and the right side of the heart. The procedure requires a median sternotomy and cardiopulmonary bypass, but improvements in technique and patient selection have greatly increased survival over the past two decades.

Q: What is the duration of anticoagulation and evaluation recommended in a patient with an unprovoked pulmonary embolus?

A: Current guidelines suggest lifelong treatment in patients who have had unprovoked thrombosis. Routine screening according to the patient’s age, symptoms, and sex is usually advocated, but a more extensive evaluation is generally not warranted. For patients who have had an unprovoked event and who are reluctant to take anticoagulants on a lifelong basis, the risk of recurrence can be predicted by measuring the D-dimer level while the anticoagulant is withheld. Deep venous thrombosis and pulmonary embolism tend to recur in the same form as the initial clinical manifestation; which should also be considered before discontinuing anticoagulation.

Ultrasonography versus CT for Suspected Nephrolithiasis

Posted by Sara Fazio • September 19th, 2014

Patients with suspected nephrolithiasis were randomly assigned either to ultrasonography performed by an emergency physician or a radiologist or to CT for initial study. Ultrasonography was associated with lower cumulative radiation, with no significant difference in complications.

Pain from nephrolithiasis is a common reason for emergency department visits in the United States. Abdominal computed tomography (CT) has become the most common initial imaging test for suspected nephrolithiasis because of its high sensitivity for the diagnosis of urinary stone disease. However, CT entails exposure to ionizing radiation with attendant long-term cancer risk, is associated with a high rate of incidental findings that can lead to inappropriate follow-up referral and treatment, and contributes to growing annual care costs for acute nephrolithiasis, which are currently approximately $2 billion in the United States.

Clinical Pearls

What were the study results with respect to high-risk diagnoses with complications?

High-risk diagnoses with complications during the first 30 days after randomization were recorded in 11 patients (0.4%) — 6 patients (0.7%) assigned to point-of-care ultrasonography, 3 (0.3%) assigned to radiology ultrasonography, and 2 (0.2%) assigned to CT — with no significant difference according to study group (P=0.30).

Table 3. Primary and Secondary Study Outcomes According to Study Group. 

What were the results with respect to radiation exposure and serious adverse events between groups?

Over the course of the 6-month study period, the average cumulative radiation exposures were significantly lower in patients assigned to point-of-care ultrasonography and radiology ultrasonography than in those assigned to CT (10.1 mSv and 9.3 mSv, respectively, vs. 17.2 mSv; P<0.001). This difference is attributable to the imaging performed at the baseline emergency department visit. There were no significant differences among the study groups in the number of patients with serious adverse events: 113 of 908 patients (12.4%) assigned to point-of-care ultrasonography, 96 of 893 (10.8%) assigned to radiology ultrasonography, and 107 of 958 (11.2%) assigned to CT (P=0.50). A total of 466 serious adverse events occurred in these 316    patients; 426 (91.4%) were hospitalizations during the follow-up period, and 123 (26.4%) involved surgical treatment or complications of urinary stone disease.

Table 3. Primary and Secondary Study Outcomes According to Study Group.

Morning Report Questions

Q: Did the length of stay in the emergency department differ between groups?

A: The median length of stay in the emergency department was 6.3 hours in the point-of-care ultrasonography group, 7.0 hours in the radiology ultrasonography group, and 6.4 hours in the CT group (P<0.001 for the comparison of radiology ultrasonography with each of the other two groups). No significant differences were observed among the groups with respect to the proportion of patients who had a return visit to the emergency department within 7 or 30 days or who were admitted to the hospital within 7, 30, or 180 days or with respect to self-reported pain scores at any assessment.

Table 3. Primary and Secondary Study Outcomes According to Study Group. 

Q: In this study, after an analysis of accuracy of the first imaging test performed, what were the sensitivity and specificity of point-of-care ultrasound, radiology ultrasound and computed tomography in the diagnosis of suspected nephrolithiasis?

A: An analysis of diagnostic accuracy for nephrolithiasis that was performed on the basis of the result of the first imaging test patients underwent showed that ultrasonography had lower sensitivity and higher specificity than CT: the sensitivity was 54% (95% confidence interval [CI], 48 to 60) for point-of-care ultrasonography, 57% (95% CI, 51 to 64) for radiology ultrasonography, and 88% (95% CI, 84 to 92) for CT (P<0.001), and the specificity was 71% (95% CI, 67 to 75), 73% (95% CI, 69 to 77), and 58% (95% CI, 55 to 62), respectively (P<0.001). There was no significant differences in results between those with and those without complete follow-up.

Portrait of a Stone: CT versus Ultrasonography for Acute Nephrolithiasis

Posted by Rena Xu • September 17th, 2014

This summer, I started my residency in urology. My job for the first month was to see patients in the emergency department with urologic problems. Nephrolithiasis was one of the most frequently encountered diagnoses, and I soon learned the “drill” for working up kidney stones– check a white blood cell count, send off a urinalysis and urine culture, and, almost reflexively, order a CT scan.

Was the CT scan a necessary first imaging test?  Or would many of those patients have been just as well off with an ultrasound instead, sparing them radiation while still leading us to the same diagnosis and treatment plan?

This week’s NEJM reports findings from a multi-center comparative effectiveness trial that examined how initial imaging affects outcomes for patients with suspected nephrolithiasis. The study randomly assigned over twenty seven hundred patients who’d presented to the emergency department with symptoms suggestive of kidney stones to one of three initial imaging modalities– point-of-care ultrasonography, performed by a provider in the emergency department; ultrasonography in the radiology department, performed by a radiologist; or an abdominal CT scan.  Providers could order additional imaging subsequently, as they deemed appropriate.  The main outcomes were the rate of high-risk diagnoses with complications that could be related to missed or delayed diagnoses (appendicitis with rupture, diverticulitis with abscess, bowel ischemia, pyelonephritis with urosepsis, and so on); cumulative radiation exposure over six months; and total cost.

There was no significant difference in the rate of high-risk diagnoses with complications across the three study arms (0.7% for point-of-care ultrasonography; 0.3% for radiology ultrasonography; and 0.2% for CT).  There was also no difference across the study arms in the percentage of patients who experienced serious adverse events.  But patients who underwent ultrasonography as the initial imaging modality were exposed to a lower cumulative dose of radiation than patients who underwent an initial CT scan (10.1mSv and 9.3 mSv for point-of-care and radiology ultrasonography, respectively, versus 17.2 mSv for CT scan; P<0.001).

“It should be emphasized…that ultrasonography when used alone is not very sensitive for detecting stones,” Dr. Gary Curhan of Brigham and Women’s Hospital in Boston writes in an accompanying editorial.  He also points out that whether a patient had a known history of kidney stones may have influenced the interpretation of ultrasonographic findings.  “It is possible that the characteristic shadowing or hydronephrosis would have been more likely to be reported in a patient with a history of stone disease, particularly if a recent imaging study had identified a stone.  This latter possibility is supported by the study’s findings that among persons in the ultrasonography groups, those with a history of nephrolithiasis were less likely than those without such a history to undergo subsequent CT.”  If a documented history of nephrolithiasis biased imaging interpretation, then the effectiveness of ultrasonography at making a correct diagnosis while “saving” patients from unnecessary radiation may be more limited than these study findings otherwise imply.

Time is another consideration.  In this study, patients assigned to ultrasound by a radiologist ended up spending more time in the emergency department than patients in either of the other groups (5.1 hours for point-of-care ultrasonography; 6.4 hours for radiology ultrasonography; and 6.2 hours for CT scan; P<0.001).  It is possible that the use of ultrasonography could result in delays in patient care.  And while the point-of-care ultrasonography group spent less time in the emergency department, over 40% of those patients ended up getting a CT scan (versus 27% of patients who underwent radiology ultrasonography).  In terms of cost, the average emergency room stay cost slightly less– $25 — for patients assigned to ultrasonography as compared to patients assigned to CT scan (the complete findings of the cost analysis were not reported in the paper).

After a diagnosis of stone disease has been made, management decisions may rely on information that can be obtained from CT but not from ultrasonography.  If surgical management is being considered, a CT scan is valuable for localizing the stones and planning an operative approach.  In addition, a CT scan may be more likely to identify additional stones that are not yet symptomatic, prompting a more aggressive regimen to prevent further stone formation.

As Curhan states, “Although we want to limit radiation exposure from all sources, the decision to use ultrasonography needs to be balanced against the additional information obtained by CT, which may influence subsequent clinical decisions.”

In your practice, do you routinely order CT scans for patients with suspected stone disease?  For which patients do you first order an ultrasound?  How will the findings of this study affect your approach to the diagnostic workup and management of nephrolithiasis?

Pancreatic Adenocarcinoma

Posted by Sara Fazio • September 12th, 2014

Cancer of the pancreas is predominantly adenocarcinoma and involves activating KRAS mutations in the large majority of cases. Surgical resection can be effective in localized disease; combination chemotherapy offers some palliation in advanced disease. A new review article on this topic comes from Massachusetts General Hospital’s David Ryan, Theodore Hong, and Nabeel Bardeesy.

Pancreatic ductal adenocarcinoma is the most lethal common cancer because it is usually diagnosed at an advanced stage and is resistant to therapy.

Clinical Pearls

•Describe the epidemiology of pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is rarely diagnosed in persons younger than 40 years of age, and the median age at diagnosis is 71 years. Worldwide, the incidence of all types of pancreatic cancer (85% of which are adenocarcinomas) ranges from 1 to 10 cases per 100,000 people, is generally higher in developed countries and among men, and has remained stable for the past 30 years relative to the incidence of other common solid tumors. It is the eighth leading cause of death from cancer in men and the ninth leading cause of death from cancer in women throughout the world. In the United States this year, pancreatic cancer is expected to develop in 46,000 people, and 40,000 people are expected to die from it. Although it is estimated that 5 to 10% of pancreatic cancers have an inherited component, the genetic basis for familial aggregation has not been identified in most cases.

Table 1. Risk Factors and Inherited Syndromes Associated with Pancreatic Cancer.

What is the most common oncogenic mutation in pancreatic adenocarcinoma?

One of the defining features of pancreatic adenocarcinoma includes a very high rate of activating mutations in KRAS (>90%). As the most common oncogenic mutation in pancreatic adenocarcinoma, KRAS activation has been investigated in depth for its contributions to the tumorigenic growth of established cancers. Several studies have shown that the KRAS mutation is a marker of a poor prognosis in both patients with resectable tumors and those with unresectable tumors. Functional studies have shown that KRAS is critical for the sustained growth of advanced pancreatic adenocarcinoma.

Morning Report Questions

Q: What clinical features are associated with pancreatic cancer, and what initial diagnostic tests are most important?

A: Approximately 60 to 70% of pancreatic cancers are located in the head of the pancreas, and 20 to 25% are located in the body and tail of the pancreas. The presenting signs and symptoms are related to the location. Patients with pancreatic cancer most commonly present with abdominal pain, weight loss, asthenia, and anorexia. Jaundice is a common manifestation of tumors in the head of the pancreas. Diabetes is present in at least 50% of patients with pancreatic cancer. Once a pancreatic mass is detected, abdominal computed tomography with both arterial and venous phases is usually sufficient to determine the initial stage and treatment. Pancreatic cancer metastasizes primarily to the liver, abdomen, and lungs. A biopsy of the pancreatic mass is most often accomplished by means of endoscopic ultrasonography. Although the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have neither sensitivity nor specificity for use in screening to detect pancreatic cancer, if   elevated, they are useful in following patients with known disease.

Q: What is the prognosis of pancreatic cancer, and what treatment options are available for early stage disease?

A: More than 90% of patients who have received a diagnosis of pancreatic cancer die from the disease. Approximately 70% of these patients die from extensive metastatic disease; the other 30% have limited metastatic disease at the time of death, but many of them have bulky primary tumors. Surgical resection is the only potentially curative therapy for pancreatic cancer. A pancreaticoduodenectomy (the Whipple procedure) is required to remove tumors in the head and neck of the pancreas. Only 15 to 20% of patients are considered to be candidates for surgical resection, and many of these patients are found to have microscopically positive margins at the time of surgery. Adjuvant therapy includes systemic therapy to reduce the risk of distant metastases and chemoradiotherapy to reduce the risk of locoregional failure. A series of studies has established that 6 months of chemotherapy with either gemcitabine or fluorouracil, as compared with observation, improves overall survival. Although there is a clear consensus regarding the value of adjuvant chemotherapy, the role of adjuvant radiation therapy is controversial. Two European studies showed no benefit of adjuvant radiation therapy.

Figure 3. Anatomy and Surgical Resectability of Pancreatic Cancer. 

Table 2. Adjuvant Therapy for Pancreatic Cancer.

Rash, Headache, Fever, Nausea, and Photophobia

Posted by Sara Fazio • September 12th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 39-year-old man was admitted to the hospital, 10 days after receiving prednisone for severe contact dermatitis, because of headache, nausea, and photophobia. Examination of the cerebrospinal fluid revealed white cells and gram-positive cocci. Diagnostic tests were performed.  The most common cause of bacterial meningitis in the United States is Streptococcus pneumoniae, a gram-positive coccus that is responsible for 58% of all cases.

Clinical Pearls

What is the classic presentation of and CSF findings associated with a diagnosis of acute bacterial meningitis?

Abrupt onset of fever and neck stiffness are classic symptoms of acute bacterial meningitis that are found on initial physical examination in 95% and 88% of cases, respectively. CSF analysis typical for bacterial meningitis includes an elevated white-cell   count with neutrophil predominance, hypoglycorrhachia (a low CSF glucose level), and an elevated total protein level. A white-cell count of more than 2000 per cubic millimeter or the presence of more than 1180 neutrophils per cubic millimeter in the CSF is nearly 100% specific for the diagnosis of bacterial meningitis, as is the finding of bacteria on Gram’s staining of the CSF.

What are the symptoms of chronic strongyloidiasis?

The intestinal nematode Strongyloides stercoralis is endemic in tropical and subtropical areas, such as the Dominican Republic, and can survive for decades in a single host because it can complete its life cycle inside the human body without passing into the environment. Patients with chronic strongyloidiasis often have fluctuating eosinophilia, intermittent abdominal pain, and recurrent rashes, the two most common of which are urticaria around the waist and buttocks and larva currens, a rapidly migrating serpiginous dermatitis. These symptoms develop as filariform larvae, the infectious form of Strong. stercoralis, initiate the autoinfection cycle by penetrating the perianal skin or the intestinal wall.

Figure 1. Life Cycle of Strongyloides stercoralis.

Morning Report Questions

Q: What is the strongyloides hyperinfection syndrome?

A: The strongyloides hyperinfection syndrome can develop in patients with chronic strongyloidiasis when host immune function is impaired. The stongyloides autoinfection cycle accelerates, which leads to more egg-laying adult nematodes in the intestine and a subsequent vast increase in the number of migrating larvae. The administration of glucocorticoids and, increasingly, the use of tumor-necrosis-factor inhibitors are major risk factors for the strongyloides hyperinfection syndrome (also called severe complicated strongyloidiasis); even short courses of these medications can cause overwhelming infection and death. Eosinophilia is usually absent during hyperinfection. In the most fulminant form of the strongyloides hyperinfection syndrome, called disseminated strongyloidiasis, filariform larvae can migrate to the liver, brain, kidneys, meninges, and skin. Furthermore, migrating filariform larvae can carry enteric bacteria into the bloodstream and also cause breaks in the intestinal mucosa that may provide a portal of exit for intestinal bacteria. As a consequence, bacterial sepsis, pneumonia, and meningitis are common complications of the strongyloides hyperinfection syndrome. Bacterial meningitis that occurs concurrently with the strongyloides hyperinfection syndrome is often caused by enteric gram-negative organisms.

Figure 1. Life Cycle of Strongyloides stercoralis. 

Q: How is the strongyloides hyperinfection syndrome diagnosed?

A: The diagnosis of the strongyloides hyperinfection syndrome can be made by examining the stool for filariform or rhabditiform larvae. This approach is not sensitive for the diagnosis of chronic strongyloidiasis, but during hyperinfection, a large number of larvae are present in the intestine, which improves the diagnostic yield of a stool sample.

Take the Case Challenge: A Man with Diarrhea, Nausea, and Weight Loss

Posted by Karen Buckley • September 11th, 2014

A 29-year-old man was seen in the walk-in clinic because of diarrhea of 1 year’s duration and weight loss. Initial laboratory values included elevated hepatic aminotransferase levels and a ferritin level of 1716 ng per milliliter. A diagnostic procedure was performed. What is the diagnosis? What diagnostic tests are indicated?

Read the case description. Then vote and comment about what the diagnosis may be and what diagnostic tests will prove useful. Find the answers in the full text of the case to be published on September 25.  Follow the conversation on Facebook and Twitter with #NEJMCases.



Posted by Sara Fazio • September 5th, 2014

Initial management for internal hemorrhoids includes adequate fiber and water intake and avoidance of straining. Office procedures (e.g., rubber-band ligation) are helpful when medical therapy fails; excisional therapies such as hemorrhoidectomy are used for severe disease.  Read the new Clinical Practice review article on this topic.

Symptoms related to hemorrhoids are very common in Western and other industrialized societies. Although published estimates of prevalence vary widely, millions of people in the United States are affected yearly.

Clinical Pearls

How are hemorrhoids categorized?

Hemorrhoids are categorized according to their origin relative to the dentate line, which is typically located about 3 to 4 cm proximal to the anal verge. The line represents the site where the squamous epithelial cells derived from the ectoderm interface with the columnar mucosa cells of endodermal origin. Besides being the basis for categorizing hemorrhoidal complexes as internal (if proximal to the dentate line), external (if distal to the dentate line), or mixed (both proximal and distal), the different embryonic origins lead to distinctly different vascular drainages, epithelialization, and innervation. Tissues that are distal to the dentate line are innervated by somatic nerves and are more sensitive to pain and irritation than those that are located more proximally, which receive sympathetic or parasympathetic visceral innervation.

Figure 1. Hemorrhoidal Disease. 

What are the typical clinical manifestations of symptomatic hemorrhoids?

The clinical manifestations of symptomatic hemorrhoids vary with the extent of the disease process. Patients who present for diagnosis and treatment typically report hematochezia (approximately 60%), itching (approximately 55%), perianal discomfort (approximately 20%), soiling (approximately 10%), or some combination of these symptoms. The rectal bleeding typically occurs with or immediately after defecation. Blood may be noticed on toilet paper, in toilet water, or, occasionally, staining the underwear. Patients should be queried about their fiber and fluid intake, bowel patterns (including stool frequency), bathroom habits (e.g., reading while seated on the toilet), the need for digital manipulation of prolapsed tissue, and whether there is a history of soiling or incontinence. Other disease processes must be considered. Substantial pain is rare in patients with uncomplicated internal or external hemorrhoids. The presence of severe pain raises the possibility of other conditions, including  anal fissure, perirectal or perivaginal infection, abscess, and other inflammatory processes, although severe pain may occur with  complications of hemorrhoids (e.g., prolapse with incarceration and ischemia or thrombosis).

Morning Report Questions

Q: What imaging is necessary in a patient with hemorrhoids?

A: Flexible endoscopy is not as successful as anoscopy for examining the anorectum. The decision to perform a more extensive colorectal evaluation should be informed by the patient’s age, presenting signs and symptoms and their duration, and the nature of bleeding. Evaluation of the entire colon is indicated for patients with any of the following: anemia; bleeding that is not typical of hemorrhoids; a change in bowel patterns; a personal history of rectal or colon polyps; a family history of inflammatory bowel disease, colorectal cancer, or other hereditary colorectal diseases in a first-degree relative; or other suspected pathologic pelvic changes that could contribute to the patient’s symptoms. For symptomatic patients younger than 50 years of age who have no risk factors for colonic disease and no evidence of other anorectal abnormalities and in whom examination confirms the presence of uncomplicated disease, hemorrhoid treatment can be administered in lieu of endoscopy or imaging studies. Persistent bleeding or other symptoms after successful local treatment of hemorrhoids is an indication for further evaluation.

Q: How should patients with symptomatic hemorrhoids be treated?

A: All patients should be encouraged to ingest a sufficient amount of insoluble fiber (typically 25 to 35 g per day) and sufficient water to avoid constipation and straining and to limit the time spent on the toilet. A meta-analysis of controlled trials showed that fiber supplementation was associated with significant reductions in the risk of persistent symptoms and the risk of rectal bleeding, although the effects of fiber supplementation on mucosal prolapse, pain, and itching were not significant. Clinical experience indicates that use of topical glucocorticoids, vasoconstrictors (e.g., phenylephrine-based creams or suppositories), or analgesics may provide temporary relief of some symptoms. For patients who do not respond to conservative treatment, a meta-analysis of 18 randomized trials comparing various treatment methods for grade I to III hemorrhoids concluded that rubber-band ligation was more effective than sclerotherapy and that patients who underwent ligation were less likely to need subsequent therapy. Rubber-band ligation was less effective than hemorrhoidectomy but had fewer complications and caused less pain. It therefore is considered appropriate as first-line therapy.

Influenza Vaccination in Pregnant Women

Posted by Sara Fazio • September 5th, 2014

In two trials of a trivalent inactivated influenza vaccine in pregnant women in South Africa, HIV-infected and HIV-uninfected vaccine recipients had increased influenza antibody titers and decreased influenza attack rates.

Pregnant women are designated as a priority group for seasonal influenza vaccination by the World Health Organization (WHO) because of their heightened susceptibility to severe influenza from the second trimester to the early postpartum period.

Clinical Pearls

What were the results of this study of trivalent inactivated influenza vaccine in the HIV-uninfected cohort?

The attack rates for confirmed influenza among placebo recipients and IIV3 recipients were 3.6% and 1.8%, respectively, indicating a vaccine efficacy of 50.4% (95% confidence interval [CI], 14.5 to 71.2). The vaccine efficacy was similar when determined according to the vaccine strain (46.1%; 95% CI, 6.4 to 69.0). For the 2 years of the study, the predominant strain of influenza virus circulating among placebo recipients was A/H3N2 (57.9%), for which an exploratory analysis identified a vaccine efficacy of 57.5% (95% CI, 7.6 to 80.4). The attack rate was lower among infants whose mothers were HIV-infected and HIV-uninfected  recipients (1.9%) than among those whose mothers were placebo recipients (3.6%), indicating a vaccine efficacy of 48.8% (95% CI, 11.6 to 70.4).

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.

What were the results of this study in the HIV-infected cohort?

In the cohort of HIV-infected mothers, the attack rate was lower among IIV3 recipients than among placebo recipients (7.0% vs. 17.0%), indicating an adjusted vaccine efficacy of 57.7% (95% CI, 0.2 to 82.1). The attack rates were 5.0% and 6.8% among infants of IIV3 recipients and infants of placebo recipients, respectively (vaccine efficacy, 26.7%; P=0.60). In 6 of 11 infants of HIV-infected mothers with confirmed influenza (55%), including 2 infants whose mothers received IIV3, the mothers were infected with the same strain as their infants.

Table 4. Efficacy of IIV3 Vaccination in Mothers and Infants until 24 Weeks after Birth, Intention-to-Treat Population.

Figure 1. Kaplan-Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group.  

Morning Report Questions

Q: What were adverse effects associated with vaccination?

A: Injection-site reactions (mainly mild to moderate) were more frequent among IIV3 recipients than among placebo recipients in both cohorts, but there were no other significant differences in solicited reactions between the two study groups in either cohort. There were no significant between-group differences with regard to rates of miscarriage, stillbirth, or premature birth or birth weight in the HIV-uninfected cohort and in the HIV-infected cohort. Among the HIV-infected cohort, IIV3 did not affect the plasma HIV-1 viral load, minimizing concern about the possibility of an increased risk of vertical transmission of HIV in vaccinees.

Table 1. Baseline Characteristics of HIV-Uninfected Pregnant Women, Fetal Outcomes, and Newborn Characteristics. 

Q: How did the influenza attack rate among HIV-infected and HIV-uninfected recipients who received placebo differ in this study, and what are the implications?

A: The authors note that the attack rate among HIV-infected placebo recipients in this study (17.0%) was greater than that observed among HIV-uninfected placebo recipients (3.6%), a finding that highlights the greater susceptibility of HIV-infected persons to influenza, even when the HIV infection is managed with antiretroviral treatment.

PARADIGM-HF: The Experts’ Discussion

Posted by Karen Buckley • September 4th, 2014

The PARADIGM-HF trial, presented last weekend at the European Society of Cardiology (ESC) Annual Congress and published in NEJM, suggests that neprilysin inhibition may replace ACE inhibition for the treatment of heart failure.  NEJM and ESC brought together the study co-chairs, John McMurray and Milton Packer, and cardiologists Mariell Jessup, Keith Fox, and Michel Komajda to discuss these practice-changing results in PARADIGM-HF- The Experts’ Discussion. View the video now on

A new Perspective article includes an interactive timeline of select trials in heart-failure treatment since 1986. An accompanying editorial and concise video summary are also available on

If you’re looking for further discussion on this topic, CardioExchange has an interview with the investigators, Will There Be a PARADIGM Shift in Treatment of Heart Failure?, and a critical assessment,  Let’s Take a Close Look at PARADIGM-HF, from Vinay Prasad.  NEJM JournalWatch Cardiology editor Harlan Krumholz also provides summary and comment.