A Woman with Müllerian Carcinoma and Fever

Posted by • September 8th, 2016

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The spleen plays an important role in the clearance of encapsulated bacteria and of erythrocytes parasitized by protozoa, such as malaria and babesia. A 71-year-old woman with müllerian carcinoma was admitted to the hospital because of fever, fatigue, and myalgias 3.5 weeks after extensive cytoreductive surgery. Anorexia, abdominal pain, and bloating had developed 1 day earlier. Diagnostic studies were performed in a new Case Record.

Clinical Pearl

• What are some of the infectious agents that may be transmitted by blood transfusions?

Transmission of cytomegalovirus through blood transfusion is not uncommon. Dengue, chikungunya, and Zika virus infections may be transmitted through blood transfusion; they usually have incubation periods of 2 weeks or less, and are frequently associated with rash and arthralgia, although they rarely occur in the United States population. Malaria is rarely transmitted through blood transfusion in areas in which the disease is not endemic. The risk of transmission of pathogens for which the blood supply is routinely screened, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), is extremely low.

Clinical Pearl

• Is the blood supply routinely screened for babesiosis?

An infection for which the blood supply is not routinely screened but one that may be transmitted through transfusion is babesiosis, a tickborne zoonotic disease that is caused primarily by Babesia microti in the United States. Babesia is endemic in New England and regions of the upper Midwest, and transmission of babesiosis has been increasingly associated with blood transfusions in recent years. The incubation period for transfusion-related babesiosis ranges from 11 to 176 days (median, 37 days), and the diagnosis is often made unexpectedly, after a routine blood-smear examination.

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Morning Report Questions

Q: What are some of the clinical manifestations of B. microti infection?

A: The clinical manifestations of B. microti infection range from asymptomatic infection to severe disease resulting in hemolysis, shock, and death. The risk of severe infection is particularly high among patients who do not have a functional spleen or are immunocompromised. Symptoms such as fatigue, malaise, weakness, fever, nausea, anorexia, myalgias, abdominal pain, and diarrhea are frequently reported. Abnormal laboratory test results, such as thrombocytopenia, hemolytic anemia, and elevated aminotransferase and serum alkaline phosphatase levels, may occur, but none of these results are highly sensitive for the diagnosis of babesiosis.

Q: Can transfusion-transmitted babesiosis be eliminated by taking a thorough history from blood donors?

A: During 2010–2014, babesia species were responsible for 4 of the 15 deaths caused by transfusion-transmitted infections in the United States. Obtaining the donor history is largely ineffective in preventing transfusion-transmitted babesiosis, because 80% of infected persons are asymptomatic and may remain parasitemic for several months. In addition, babesia species survive in red cells that are stored in either liquid or frozen form. In regions in which babesia is endemic, approximately 1 to 2% of blood donors have laboratory evidence of current or past infection, with the prevalence reaching 10% in some hyperendemic areas. Currently, donors are deferred if they have a history of babesiosis or have been implicated in a case of transfusion-transmitted babesiosis. No laboratory tests are currently licensed for donor screening, although several are under development.

Origins of Chronic Obstructive Pulmonary Disease

Posted by • September 1st, 2016

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The conventional thinking about chronic obstructive pulmonary disease (COPD) is that exposures in adult life, such as smoking, lead to a low FEV1:FVC ratio, the physiological hallmark of COPD (a frequent cause of illness and death). Although smoking is still considered a major culprit, it is now known that genetic, environmental, and developmental factors that are associated with diverse biologic mechanisms and that exert their effects during the growing years can both diminish the maximally attained forced expiratory volume in 1 second (FEV1) and accelerate FEV1 decline in adult life, thus increasing the risk of COPD. In this new Review Article, the effect of early-life exposures on the lung that could lead to expiratory airflow limitation is reviewed.

Clinical Pearl

• What has been the prevailing theory regarding the development of COPD?

Until recently, the prevailing concept was that during development (i.e., from birth to approximately 25 years of age), all people — those destined to have no lung disease and those destined to have COPD — reached the same plateau for lung function as measured by the FEV1. It was thought that whether COPD developed was determined by the rate of subsequent decline in the FEV1 level.

Clinical Pearl

How are previous theories about the development of COPD being revised?

Emerging evidence has radically challenged the concept of a single natural history for COPD, indicating that the spectrum of patients presenting with chronic respiratory symptoms and irreversible airway obstruction (as assessed by an abnormally low FEV1) is much more heterogeneous than previously thought. Results from longitudinal cohort studies have shown that in a considerable proportion of patients with COPD the decline in the FEV1 was not steeper than that in healthy adults. It has also been shown that some people with COPD who do not show excessive lung-function decline reach a lower FEV1 level early in adult life than those with future rapid decline and normal populations. These findings thus implicate an entirely different pathway leading to the diagnosis of COPD from the rapid-decline form, one in which smoking can certainly play a role, especially in the clinical expression of the disease, but in which the central derangement is already present early in adult life. What emerges is a fundamentally new concept of COPD, in which the factors that determine the maximal (or “plateau”) FEV1 level attained during the third decade of life become major elements in the pathogenesis of the disease.

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Morning Report Questions

Q: What are some of the factors that may influence the maximal FEV1 level attained in early adulthood?

A: Approximately 10% of all births in the United States occur prematurely (i.e., before 37 weeks of gestation), and preterm birth has been shown to have profound effects on long-term lung function. Although the most severe consequences are observed in newborns with bronchopulmonary dysplasia, premature infants without the disorder also have FEV1 levels later in life that are 7.2% lower than those of children born at term. Several longitudinal studies have shown that children who have lower respiratory tract illnesses in early life are at increased risk for subsequent chronic respiratory symptoms and FEV1 deficits, which often persist into adult life. The largest deficits have been observed in adults who had radiologically ascertained pneumonia before 3 years of age, who had an FEV1:FVC ratio that was lower by approximately 0.04 than those with no early-life respiratory illnesses, whereas those with lower respiratory tract illnesses but no pneumonia had less severe impairment in the FEV1:FVC ratio. There is now convincing evidence that exposure to airborne contaminants is associated with reduced growth in lung function during adolescence and lower maximally attained FEV1 levels.

Q: What are some examples of childhood exposures that influence the effects of smoking in adult life? 

A: There is increasing evidence from longitudinal studies that childhood events and exposures can accelerate the rate of decline in the FEV1 level and induce early expression of chronic respiratory symptoms in both smokers and nonsmokers. Prenatal and postnatal parental smoking increases susceptibility to the ill effects of active smoking in adult life, with smokers who were exposed to parental smoking having greater deficits in FEV1 than those whose parents did not smoke. Smokers who had lower respiratory illnesses due to respiratory syncytial virus before 3 years of age are more likely to receive a diagnosis of asthma in the third decade of life than smokers without such an early-life history. Women who as young girls lived through the so-called Dutch famine, a circumscribed episode of severe human starvation that occurred between October 1944 and May 1945 in the Netherlands, were more likely to be hospitalized for COPD before 60 years of age than their age peers who were not exposed to famine. These effects were particularly noticeable among active smokers, suggesting that postnatal malnutrition may increase susceptibility to the deleterious effects of smoking.

Tip of the Tongue

Posted by • September 1st, 2016

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A clue to the diagnosis of leptomeningeal carcinomatosis is the presence of neurologic findings that localize to multiple anatomical locations, since access to the subarachnoid space allows the tumor to have effects at multiple neurologic levels. A 65-year-old woman with a history of HIV infection, hypertension, and hyperlipidemia had a 1-week history of cough with pink sputum and mild shortness of breath on exertion, but no fever, chills, night sweats, rhinorrhea, or nasal congestion. A new Clinical Problem-Solving article explains.

Clinical Pearl

• What is the incidence of leptomeningeal carcinomatosis among patients with solid cancers?

Leptomeningeal carcinomatosis occurs when solid-tumor cells gain access to the subarachnoid space. The overall incidence of leptomeningeal carcinomatosis is approximately 5% among patients with solid cancers, and this rate has increased over time, probably owing to better diagnostic methods as well as better therapies (which may treat systemic disease but not reach the protected subarachnoid space). The most common solid cancers with leptomeningeal metastases are breast cancer, lung cancer, gastrointestinal cancer, and melanoma.

Clinical Pearl

• What are some of the clinical manifestations associated with leptomeningeal carcinomatosis?

Signs and symptoms may originate in the cerebrum, cranial nerves, or spinal cord. Cerebral manifestations include headache, seizures, altered mental status, and ataxia. Nausea and vomiting may occur owing to increased intracranial pressure from disrupted CSF flow. Cranial neuropathies are caused by infiltration of nerves crossing the subarachnoid space. Involvement of the cranial nerves from II to XII has been described; the oculomotor, abducens, trochlear, facial, and vestibulocochlear nerves are most commonly affected. Manifestations of spinal involvement range from mild motor and sensory neuropathies (resulting in weakness, paresthesias, or pain) to the cauda equina syndrome.

Morning Report Questions

Q: What findings are expected on cerebrospinal fluid (CSF) analysis in a patient with leptomeningeal carcinomatosis?                                                                                     

A: Classic findings on CSF analysis in patients with leptomeningeal carcinomatosis include an elevated opening pressure, lymphocytic pleocytosis, an elevated protein level, and hypoglycorrhachia. Cytologic analysis of the initial CSF sample is negative in 30 to 50% of patients, and a second lumbar puncture should be performed if clinical suspicion is high; only 8% of patients require more than two assessments to yield positive cytologic results. To maximize sensitivity, at least 10 ml of CSF should be sent for cytologic analysis, and specimens should be examined within 48 hours after collection.

Q: What treatment options are available once leptomeningeal carcinomatosis is diagnosed?

A: The median survival when a solid cancer has spread to the leptomeninges is approximately 2 months; 90% of patients die within 1 year. Palliative radiation therapy is often administered and is directed to sites within the neuraxis that are thought to be causing symptoms. Chemotherapy is an additional option for patients with good performance status. Thiotepa, methotrexate, or cytarabine can be administered intrathecally or systemically, since they cross the blood–brain barrier. Randomized trials of intrathecal therapy have shown no overall survival benefit. In a randomized trial involving patients with breast cancer and leptomeningeal disease, intrathecal methotrexate in combination with standard chemoradiotherapy, as compared with standard chemoradiotherapy alone, did not increase survival and was associated with increased neurotoxicity.

Are Long-Acting Beta-Agonists Safe to Add to Treatment Regimens for Asthma in Children?

Posted by • August 31st, 2016

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Janine is a 9-year-old girl who you’ve been seeing in your clinic for years. She struggles with asthma despite treatment with low-dose inhaled glucocorticoids. You wonder if any other medications can be added to her treatment regimen, and peruse the literature on long-acting beta-agonists (LABAs). The literature is mixed – it seems clear that LABAs, when used alone, have been associated with increased risk of asthma-related deaths. However, more recent studies have reported that LABAs may be safer when combined with low-dose inhaled glucocorticoids. Indeed, in the recent AUSTRI study, there was no increased risk of serious asthma-related events in adults and adolescents with moderate asthma who received LABA with glucocorticoids, compared with those receiving glucocorticoids alone. However, this study did not include patients of Janine’s age, and thus, the safety of combining LABAs with glucocorticoids in children remains unclear.

In this week’s issue of NEJM, Stempel et al. address this issue in the VESTRI trial — a randomized, double-blind, international 26-week trial involving 6208 asthmatic children (aged 4-11 years). The children were randomized to receive either the glucocorticoid fluticasone propionate with the LABA salmeterol or fluticasone-alone. For the primary endpoint of asthma-related events, fluticasone-salmeterol combination therapy was noninferior to fluticasone-alone, with similar risk of asthma-related events in the two groups. Additionally, the fluticasone-salmeterol combination therapy group had a nonsignificant 14% reduction in severe asthma exacerbations compared to the fluticasone-alone group.

In an accompanying editorial, Bush and Frey applaud this trial for its large sample size and low number of adverse events. However, they caution against immediately starting patients like Janine on combination glucocorticoid-LABA therapy, especially as a first-line treatment. Most asthmatic children, they argue, can still be well controlled on inhaled glucocorticoid therapy, and checking with the family about action plans, adequacy of medication delivery technique, and other steps to control asthma should be taken before adding LABAs to the treatment plan.

Treatment of Patients with Cirrhosis

Posted by • August 25th, 2016

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In patients with compensated cirrhosis, the 10-year probabilities of ascites, hepatic encephalopathy, and gastrointestinal bleeding are 47%, 28%, and 25%, respectively. These are ominous landmarks; 15% of patients who receive a diagnosis of ascites die within 1 year, and 44% within 5 years. This guide to the practical treatment of patients with cirrhosis summarizes recent developments. It includes advice on medical management, invasive procedures, nutrition, prevention, and strategies to protect the cirrhotic liver from harm. A new Review Article explains in-depth.

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Clinical Pearl

• What are some of the medications that should be avoided, and some that may be used, in patients with cirrhosis?

Because of the risk of acute renal failure and gastrointestinal bleeding, nonsteroidal antiinflammatory drugs are contraindicated, except for low-dose aspirin in patients in whom the severity of cardiovascular disease exceeds the severity of cirrhosis. A large, placebo-controlled study involving patients with cirrhosis and ascites showed that although satavaptan alleviated hyponatremia, mortality was higher among patients with recurrent ascites who were receiving satavaptan than among those who were receiving placebo. Because of these findings as well as hepatotoxicity reported with respect to tolvaptan, the use of vaptans in patients with cirrhosis and ascites is not recommended. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) can be safely started and continued in patients with cirrhosis. Acetaminophen is effective and safe in patients with liver disease, provided that the patient does not drink alcohol.

Clinical Pearl

• When can paracentesis be safely performed in a patient with cirrhosis and coagulopathy?

Paracentesis is relatively safe, even in patients with marked coagulopathy, including an international normalized ratio as high as 8.7 and a platelet count as low as 19,000 per cubic millimeter. It is important not to delay paracentesis in patients with suspected spontaneous bacterial peritonitis. One study showed that diagnostic paracentesis that was performed within 12 hours after the time of first encounter with a physician was associated with increased short-term survival rates. Delayed paracentesis was associated with a risk of death that was 2.7 times as high as the risk associated with early paracentesis. Each hour of delay was associated with a 3.3% increase in in-hospital mortality.

Morning Report Questions

Q: What does the “window hypothesis” postulate about the use of beta-blockers in patients with cirrhosis?

A: Nonselective beta-blockers reduce portal pressures and are used in the primary and secondary prophylaxis of variceal hemorrhage. However, various studies caution the use of beta-blockers in situations such as decompensated cirrhosis with refractory ascites, spontaneous bacterial peritonitis, and severe alcoholic hepatitis. These studies led to the “window hypothesis,” which postulates that beta-blockers are associated with higher rates of survival only within a clinical window. In patients who have early cirrhosis without moderate-to-large varices, beta-blockers do not prevent the development of varices and also result in adverse effects. The clinical window opens when moderate-to-large esophageal varices develop, with or without variceal bleeding, and beta-blockers are indicated for primary and secondary prophylaxis of variceal bleeding. Increasingly, evidence suggests that the clinical window for beta-blockers closes and that they are no longer effective when refractory ascites, hypotension, the hepatorenal syndrome, spontaneous bacterial peritonitis, sepsis, or severe alcoholic hepatitis develops, owing to unfavorable hemodynamic effects in advanced cirrhosis.

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Q: What are some guidelines regarding the use of antihypertensives in patients with cirrhosis?

A: Patients with cirrhosis who have a history of hypertension gradually become normotensive and eventually hypotensive as cirrhosis progresses. Studies of blood pressure in patients with cirrhosis and ascites showed that a mean arterial pressure of 82 mm Hg or less was the single variable that was most strongly correlated with a reduced probability of survival. The probability of survival among patients with a mean arterial pressure of 82 mm Hg or less was 20% at 24 months and 0% at 48 months, as compared with 70% at 24 months and 50% at 48 months among patients with a mean arterial pressure of more than 82 mm Hg. In a similar study, hypotension with a cardiac index below 1.5 liters per minute per square meter of body-surface area predicted the development of the hepatorenal syndrome and decreased survival among patients with cirrhosis and ascites. Because of these hemodynamic changes, antihypertensive agents should be discontinued in patients who have decompensated cirrhosis with ascites or hypotension.

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A Woman with Back Pain

Posted by • August 25th, 2016

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A 28-year-old woman presented with intractable back pain with radiation to the leg. Examination of biopsy specimens revealed a giant-cell tumor of bone, which accounts for 5% of primary bone tumors and occurs most commonly around the knee. These tumors are usually highly vascular; in some instances it is possible to actually feel the tumor pulsate with each heartbeat. Management decisions were made in a new Case Record.

Clinical Pearl

• Is giant-cell tumor of bone a benign or malignant lesion?

Giant-cell tumor of bone is a benign but locally aggressive neoplasm of mesenchymal mononuclear cells that are thought to have an osteoblast-like phenotype. It was previously thought that the giant cells were composed of collections of mononuclear cells and that both components were neoplastic, but numerous lines of evidence now show that the mononuclear cells are the neoplastic cells and that they recruit large osteoclast-type giant cells that are reactive in nature.

Clinical Pearl

• What are the typical epidemiologic features of a patient with giant-cell tumor of bone?

The typical epidemiologic features of a patient with giant-cell tumor of bone include skeletal maturity, an age between 20 and 45 years, and female sex. Local recurrence is seen in approximately 25% of cases, whereas metastasis occurs in only 1 to 2% of cases and transformation to a high-grade sarcoma in less than 1% of cases. Although metastases usually involve the lung, they may in rare cases involve other distant sites. In contrast to frankly malignant tumors, pulmonary metastases often have an indolent behavior, and thus giant-cell tumor of bone has been considered to be among the rare benign metastasizing tumors.

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Morning Report Questions

Q: How is giant-cell tumor of bone treated? 

A: In the past, resection with wide surgical margins was the most common treatment for giant-cell tumor of bone, and recurrences were uncommon. However, reconstruction after such procedures was complex and associated with a high rate of complications. Because giant-cell tumor is typically benign, the current standard of care does not include a wide resection unless the tumor is located in an expendable bone (e.g., the clavicle, distal ulna, or proximal fibula) in which resection produces no clinically significant effect on function. Intralesional surgical procedures, which involve curettage of the tumor and débridement of the surface of the healthy bone with a burr, are the mainstay of therapy in most other cases. The local recurrence rates for giant-cell tumor of bone approach 20% among patients who have undergone intralesional surgical procedures; therefore, new local adjuvant and systemic therapies have been sought. Among patients who have undergone an intralesional procedure with cryosurgery, the local recurrence rates are less than 8%, because the freeze–thaw cycle kills cells farther from the burred surface, extending the depth of the effective curettage. However, pathologic fracture and vascular injury have been associated with this form of adjuvant therapy. Other adjuvant therapies, such as therapy with phenol, hydrogen peroxide, or an argon laser, have been used with varying degrees of success, but phenol and an argon laser are not used routinely when the tumor is close to nerves.

Q: Have any new therapies for giant-cell tumor of bone been approved in recent years? 

A: On June 13, 2013, denosumab was approved by the Food and Drug Administration to treat giant-cell tumor of bone. Denosumab is a fully human monoclonal antibody targeting RANKL (receptor activator of nuclear factor-κβ ligand). It was initially developed for the treatment of postmenopausal osteoporosis. RANKL is highly expressed on stromal cells in the tumor that, in turn, release cytokines that support osteoclasts, regulate osteoclastogenesis, and promote progression of giant-cell tumors of bone. A small pilot study involving 37 patients and a phase 2 study involving 282 patients showed that, in patients with either recurrent or unresectable giant-cell tumor of bone, denosumab elicited a tumor response (defined as a partial or complete response according to the RECIST [Response Evaluation Criteria in Solid Tumors] or EORTC [European Organisation for Research and Treatment of Cancer] criteria or the criteria of Choi et al.) in 136 of the 190 patients who could be radiographically evaluated and showed no disease progression in 179 of the 190 patients.

The 70-Gene Signature as an Aid to Treatment Decisions in Early Breast Cancer

Posted by • August 24th, 2016

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“Your cancer has been successfully removed with surgery, but there may be a role for chemotherapy to protect you in the future.” This message is expressed by oncologists in consulting rooms all over the world. In women with early-stage breast cancer, adjuvant chemotherapy may be offered as an insurance policy against cancer recurrence. Risk of recurrence can be estimated based on algorithms using patient and tumor characteristics, but following these algorithms can lead to overtreatment by exposing some patients to the toxicity of combination chemotherapy, without the benefit.

Genomic testing of tumors may provide greater accuracy in predicting risk of recurrence. However, genomic test results may conflict with existing conventional methods of risk stratification, and it is uncertain whether patients whose clinical and tumor characteristics suggest higher risk of recurrence but whose genomic tumor features suggest lower risk would benefit from adjuvant chemotherapy.

In a study published in this week’s NEJM, Cardoso and colleagues evaluated the role of a genomic testing tool in discordant cases. The study was part of the international multicentre, prospective, randomized-controlled MINDACT trial (Microarray in Node negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy). The MINDACT trial compared risk assessment based on the 70-gene-signature assay (MammaPrint®) to assessment with standard clinical-pathological criteria (modified version of Adjuvant!Online) to direct use of adjuvant chemotherapy in 6693 patients with early breast cancer (median age, 55 years); 79% of patients were node negative and 88% had estrogen-receptor/progesterone-receptor–positive breast cancer. Patients were divided into four groups based on clinical-pathological (C) and genomic (G) risk assessments: high C/ high G (n=1806), low C/low G (n=2745), high C/ low G (n=1550) and low C/high G (n=592).

Patients with high C/high G assessments were treated with chemotherapy and those with low C/ low G risk assessments did not receive chemotherapy. The study focussed on the discordant subset of 1550 patients with high C/low G risk. Patients from this group and those with low C/high G risk were randomized to either clinical or genetic risk assignments to determine if they should receive or forego adjuvant chemotherapy. The primary endpoint was to assess whether the distant metastasis-free 5-year survival exceeds 92% in the high C/low G risk group randomized to forgo chemotherapy. Investigators also compared distant metastasis-free 5-year survival rates in patients in the high C/low G risk group who did and did not receive chemotherapy.

In the high C/low G risk group randomized to omit chemotherapy, the primary endpoint was met as the distant metastasis-free 5-year survival was 94.7% (95% confidence interval (CI), 92.5–96.2%). There was a 1.5 percentage point difference in the distant metastasis-free 5-year survival favoring chemotherapy in the high C/low G risk group. However, this secondary analysis was underpowered and not statistically significant (adjusted hazard ratio 0.78, 95% CI: 0.50-1.21, P=0.267).

Of note, among patients with low clinical risk of recurrence, the genetic test provided no added benefit.  Patients with low C had similar outcomes whether they had high or low genetic risk.

In the accompanying editorial, Dr. Clifford A. Hudis and Dr. Maura Dickler consider the significance of a 1.5 percentage-point difference in distant metastasis-free 5-year survival in two women of different ages, priorities, and high clinical risk. They explain, “This difference does not precisely exclude a benefit that clinicians and patients might find meaningful.” The findings of this trial should be helpful in informing decisions about genetic testing of tumors and adjuvant chemotherapy. Despite these technological advances, patients will require careful discussion with their oncologist to determine their next steps.

A Man with Rectal Pain

Posted by • August 18th, 2016

rectal pain headerConditions that have a similar appearance to hemorrhoids include skin tags (which may be tender if they are associated with Crohn’s disease or chronic fissures), condylomata acuminata, condylomata lata, and anal tuberculosis. A 33-year-old man presented with painful bowel movements and rectal bleeding. Physical examination and sigmoidoscopy revealed sentinel skin tags, multiple fissures, and mucosal inflammation of the distal rectum. A diagnosis was made in a new Case Record article.

Clinical Pearl

• What clinical findings suggest that an anal fissure may be due to underlying systemic disease?

In describing anal fissures, the number and location matter. Most fissures are due to mechanical stress; 90% are located in the posterior midline, and 8% in the anterior midline. The presence of fissures in the lateral midline or of multiple fissures makes underlying systemic disease more likely.

Clinical Pearl

• What are the typical symptoms of proctitis?

Proctitis typically causes symptoms such as dyschezia, as well as urgency, tenesmus, and anal discharge. Proctitis is distinct from colitis, which is inflammation of the colon proximal to the rectum. Colitis is usually associated with symptoms such as diarrhea, abdominal pain, bloating, and weight loss. Some conditions cause either proctitis or colitis and others can cause both; the anatomical location of the inflamed region dictates the symptom profile.

Morning Report Questions

Q: What are some of the causes of proctitis that are associated with perianal findings?

A: Perianal abnormalities, including painful skin tags and fissures, are common among patients with Crohn’s disease. Two percent of patients with Crohn’s disease may present with isolated proctitis. Patients with lymphogranuloma venereum (caused by Chlamydia trachomatis serovar L1, L2, or L3) typically present with lymphadenitis. However, lymphogranuloma venereum causes an isolated proctitis without lymphadenitis in 83% of cases that are acquired by anogenital contact, and the secondary stage can mimic Crohn’s disease, with features including perianal fissures, fistulae, and abscesses. Lymphogranuloma venereum is an emerging cause of proctitis in the population of men who have sex with men (MSM) worldwide and is responsible for several outbreaks in Europe in the past 15 years. Although Neisseria gonorrhoeae and C. trachomatis (serovars D through K) are the two most common causes of proctitis among MSM (accounting for 30% and 19% of all infections, respectively), these infections typically do not cause chronic fissures or painful anal papules. Ulcerative colitis and lymphoid follicular proctitis typically do not cause perianal findings.

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Q: What are some of the reasons that a treatable cause of anal symptoms may be missed?

A: In MSM, symptoms attributable to anorectal infections are often mild or absent, whereas symptoms in the throat or urethra are more severe. Therefore, among MSM, even mild or ambiguous symptoms should prompt comprehensive testing, including urinary nucleic acid testing for gonorrhea and chlamydia and also rectal and pharyngeal culture and nucleic acid testing. Furthermore, MSM should be screened for sexually transmitted infections at regular intervals, even when they have no symptoms. The two most common reasons for missing a treatable cause of anal symptoms are that patients attribute their symptoms to hemorrhoids and that doctors believe them.

Genital Herpes

Posted by • August 18th, 2016

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Herpes simplex virus type 1 and type 2 cause genital herpes. Antiviral therapy is used for symptomatic outbreaks, and as daily suppressive therapy, it reduces recurrences of symptoms, asymptomatic viral shedding, and the risk of HSV-2 transmission. Only 10 to 25% of patients with serologically confirmed HSV-2 infection are aware that they have genital herpes. Persons with undiagnosed HSV-2 infection are the most important source of new transmissions. A new Clinical Practice article explains.

Clinical Pearl

• In what populations is HSV-1 a more common cause of initial episodes of genital herpes than HSV-2?

Among Americans who are 14 to 19 years of age, the seroprevalence of HSV-1 has decreased by 30% over the past 30 years; thus, an increasing proportion of adolescents lack protective HSV-1 antibodies when they become sexually active. This lack of HSV-1 antibodies has led to an increased frequency of HSV-1 genital herpes acquired from oral–genital sex practices. In some populations (especially young heterosexual women who are 18 to 22 years of age, non-Hispanic whites, and men who have sex with men), HSV-1 is a more common cause of initial episodes of genital herpes than HSV-2.

Clinical Pearl

• What are the clinical manifestations of genital herpes?

The clinical presentation of symptomatic initial genital herpes does not differ between HSV-1 and HSV-2 infection. After an incubation period of 4 to 7 days, multiple lesions appear on the genitals (or adjacent skin), usually bilaterally, and they progress through stages of erythema, papules, short-lived vesicles, painful ulcers, and crusts that resolve over a period of 2 to 3 weeks. Approximately half the patients with symptomatic genital lesions report headache, fever, malaise, dysuria, or tender inguinal lymphadenopathy. However, most patients with initial genital herpes do not have conspicuous lesions and systemic symptoms. In one study, 74% of initial genital herpes infections due to HSV-1 and 63% of initial genital herpes infections due to HSV-2 in women were asymptomatic. Symptomatic recurrences may be preceded by localized prodromal symptoms (e.g., itching or tingling) and are typically less severe than symptomatic initial disease. Lesions are usually unilateral and resolve within 5 to 10 days. Recurrent lesions can be atypical and appear as linear fissures or excoriations. On the basis of clinical examination, it is often impossible to determine definitively whether a first symptomatic episode of genital herpes is initial or recurrent disease, although the presence of a prodrome suggests a recurrence.

Morning Report Questions

Q: What antiviral therapies are used to treat genital herpes?

A: Acyclovir, valacyclovir, and famciclovir are effective therapies for genital herpes caused by HSV-1 or HSV-2 (although most published efficacy data relate to HSV-2). These antiviral medications have excellent safety profiles and rarely cause drug–drug interactions or allergic reactions. Since the efficacy is generally similar, selection of a specific drug is based on the convenience of administration, cost, and clinician preference. Intravenous acyclovir should be used when the manifestations of genital herpes are especially severe or are accompanied by complications, particularly in immunocompromised patients. Topical antiviral therapy for genital herpes is less effective than systemic therapy and is not recommended. Patients with symptomatic recurrences of genital herpes can receive episodic therapy (1 to 5 days of therapy for an acute recurrence) or suppressive therapy (long-term daily drug administration to reduce the frequency of symptomatic recurrences).

Q: What interventions may help reduce the risk of transmission of genital herpes to a susceptible partner?

A: Reactivation of latent HSV infection results in either symptomatic recurrence of genital herpes or asymptomatic viral shedding, which is defined as the presence of infectious HSV on mucosal or skin surfaces that is detectable by means of polymerase-chain-reaction (PCR) assay or culture, without clinical signs or symptoms. Transient episodes (often <24 hours) of asymptomatic shedding of infectious virus from multiple genital sites have been detected with the use of PCR in 80 to 90% of HSV-2–seropositive persons. Shedding occurs on 10 to 20% of days, but at unpredictable intervals. Suppressive therapy significantly reduces the frequency of asymptomatic shedding of HSV-2. In a study involving immunocompetent HSV-2–discordant heterosexual couples, the probability that a partner would acquire genital HSV-2 infection was significantly lower among those who received suppressive therapy with valacyclovir (at a dose of 500 mg once daily for 8 months) than among those who received placebo (14 of 743 susceptible partners with valacyclovir [1.9%] vs. 27 of 741 susceptible partners with placebo [3.6%]; hazard ratio, 0.25%; 95% CI, 0.08 to 0.75; P=0.008). The use of condoms, which reduces the risk of transmission of HSV from an infected partner to a susceptible partner by approximately 30%, should be routinely recommended. The efficacy of administration of antiviral therapy as prophylaxis for an uninfected partner or as postexposure prophylaxis against HSV has not been adequately studied.

Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes

Posted by • August 17th, 2016

closed loop insulin deliveryA 32-year-old woman with type 1 diabetes mellitus presents to your office. She is 8 weeks pregnant. Her blood sugar has been well controlled on a standard insulin pump, but she understands that blood sugar can be more difficult to control during pregnancy.  You have previously discussed the importance of tight glucose control in pregnancy to reduce the risk of complications such as neonatal death, preterm birth, and macrosomia. Your patient has heard about new advances in insulin delivery with closed-loop technology and wants to know if she is a candidate for this technology.

Closed-loop insulin systems use continuous glucose monitors (CGMs) to measure glucose in real time and a computer algorithm to adjust insulin-pump delivery, requiring less input from the patient than a standard insulin pump for daily management of insulin dosing. Studies of this technology in supervised outpatient settings and in the community have shown better glycemic control than with standard insulin pumps, but none of the studies included pregnant women.

A study published in this week’s NEJM addresses the effectiveness and safety of closed-loop insulin delivery in pregnancy. In a 4-week overnight, randomized, crossover study, followed by a 14-week feasibility study, 20 pregnant women (enrolled between 8 and 24 weeks gestation) with a diagnosis of type 1 diabetes and treated with insulin, were randomized to receive insulin treatment with either the closed-loop system (intervention) or a sensor-augmented pump (control), and then crossed over to the other system. After the crossover study and a 2-week washout, patients chose either the closed-loop system or sensor-augmented pump for use day and night through labor, delivery, and the postpartum period (feasibility phase).

The overnight closed-loop system delivered insulin via pump every 12 minutes based on a computer algorithm that calculates insulin doses using CGM. The sensor-augmented pump also uses CGM but requires patient involvement to calculate insulin dosing. Among the 16 patients who completed the crossover study, the primary outcome — the proportion of time with overnight glucose levels within target range (62–140 mg/dL) — was significantly greater during closed-loop treatment than during the control treatment (74.7% vs. 59.5%; P= 0.002). Closed-loop delivery was also associated with significantly lower mean glucose and rate of maternal hyperglycemia. The percentage of time spent hypoglycemic in both groups was low (<2.0%) and did not differ significantly.

During the 14-week feasibility phase, 14 participants chose to continue with the closed-loop device. During this phase, the women using the closed-loop technology had target glucose levels for a mean of 69% of the time; during the 24 hours before delivery, they had target levels for 87% of the time, and continued to have low rates of hypoglycemia.

The investigators conclude that overnight closed-loop therapy resulted in a significant increase in time spent within the glucose target range for pregnancy, without increasing the incidence of hypoglycemia. Despite daily and weekly changes in insulin pharmacokinetics during pregnancy, the system appeared to be safe through the antepartum, labor and delivery, and postpartum periods. Although small, this study provides important data to support the safety of the new closed-loop technology in pregnant women.