CORONADO, CALIF. – Patients with differentiated thyroid cancer who were younger than age 45 years were more likely to undergo total or near-total thyroidectomy and to receive radioactive iodine, compared with their older counterparts, a large registry analysis demonstrated.

In addition, younger patients were more likely to be Hispanic and female and to have papillary carcinoma, lead study author Dr. Thomas J. Semrad reported during the annual meeting of the American Thyroid Association.

Sharon Worcester/Frontline Medical News

“Not much is known about how treatment administration differs between younger and older patients with thyroid cancer,” Dr. Semrad of the division of hematology/oncology at the University of California, Davis, Comprehensive Cancer Center, Sacramento, said in an interview. “Some data suggest that perhaps patients younger than age 15 years may respond better to radioactive iodine and may present with more advanced disease. But not much is known about how they’re treated.”

To find out, Dr. Semrad and his associates used the California Cancer Registry to identify 23,629 patients who were diagnosed with differentiated thyroid cancer between 2004 and 2011. They divided the patients into two cohorts: younger (defined as those younger than 45 years) and older (those 45 years or older). Treatment variables of interest included total or near-total thyroidectomy, other types of thyroid surgery, and the administration of radioactive iodine (RAI). The researchers compared the descriptive statistics between the two groups and used univariate and multivariate logistic regression to identify predictors of the treatment administered.

Compared with older patients, younger patients were significantly more likely to be Hispanic (33% vs. 22%), to be female (83% vs. 75%), to have papillary carcinoma (93% vs. 91%), and to have lymph node involvement (32% vs. 20%, all P < .0001).

Overall, the majority of patients (86%) underwent total or near-total thyroidectomy, but the surgery was slightly and significantly more common in younger patients, compared with their older counterparts (88% vs. 85%, P < .0001). Younger patients also were significantly more likely to receive RAI (55% vs. 49%, P < .0001).

On multivariate analysis, statistically significant predictors of total thyroidectomy, compared with other thyroid surgery, included younger age (odds ratio, 1.193); higher socioeconomic status (OR, 1.263, for higher-middle SES and OR, 1.325, for highest SES); higher T stage (OR, 1.848, for T2; OR, 2.473, for T3; and OR, 2.908, for T4); and papillary histology (OR, 0.349).

At the same time, statistically significant predictors of RAI administration included younger age (OR, 1.116); higher SES (OR, 1.410, for higher-middle SES and OR, 1.307, for highest SES); more advanced T stage (OR, 2.194 for T2; OR, 2.084, for T3; and OR, 1.527, for T4); node positivity (OR, 0.481), and total thyroidectomy (OR, 3.76).

“As we expected, the younger population was more likely to be female, but we did find that the younger population was also more likely to be Hispanic,” Dr. Semrad said. “We don’t know if they were native Hispanics or if it has something to do with immigration rates.”

Dr. Semrad acknowledged certain limitations of the study, including the risk of misclassification bias in registry data, the lack of details about surgical procedures performed, and the fact that the radioiodine dose was not captured.

“We have data regarding the T stage, the nodal stage, and the number of lymph nodes examined, but we don’t have some of the finer histology data,” he said.

Even so, he characterized the findings as “provocative in suggesting that perhaps our treatment patterns in younger patients are different. With more aggressive surgery and more use of radioactive iodine, that can have potential implications in terms of long-term side effects and follow-up.”

The researchers said they plan to use linked administrative data to analyze initial and subsequent thyroid surgical procedures in this patient population.

The study was supported by a grant from the National Institutes of Health. Dr. Semrad reported having no relevant financial disclosures.

[email protected]


On Twitter @dougbrunk

CORONADO, CALIF. – Patients with differentiated thyroid cancer who were younger than age 45 years were more likely to undergo total or near-total thyroidectomy and to receive radioactive iodine, compared with their older counterparts, a large registry analysis demonstrated.

In addition, younger patients were more likely to be Hispanic and female and to have papillary carcinoma, lead study author Dr. Thomas J. Semrad reported during the annual meeting of the American Thyroid Association.

Sharon Worcester/Frontline Medical News

“Not much is known about how treatment administration differs between younger and older patients with thyroid cancer,” Dr. Semrad of the division of hematology/oncology at the University of California, Davis, Comprehensive Cancer Center, Sacramento, said in an interview. “Some data suggest that perhaps patients younger than age 15 years may respond better to radioactive iodine and may present with more advanced disease. But not much is known about how they’re treated.”

To find out, Dr. Semrad and his associates used the California Cancer Registry to identify 23,629 patients who were diagnosed with differentiated thyroid cancer between 2004 and 2011. They divided the patients into two cohorts: younger (defined as those younger than 45 years) and older (those 45 years or older). Treatment variables of interest included total or near-total thyroidectomy, other types of thyroid surgery, and the administration of radioactive iodine (RAI). The researchers compared the descriptive statistics between the two groups and used univariate and multivariate logistic regression to identify predictors of the treatment administered.

Compared with older patients, younger patients were significantly more likely to be Hispanic (33% vs. 22%), to be female (83% vs. 75%), to have papillary carcinoma (93% vs. 91%), and to have lymph node involvement (32% vs. 20%, all P < .0001).

Overall, the majority of patients (86%) underwent total or near-total thyroidectomy, but the surgery was slightly and significantly more common in younger patients, compared with their older counterparts (88% vs. 85%, P < .0001). Younger patients also were significantly more likely to receive RAI (55% vs. 49%, P < .0001).

On multivariate analysis, statistically significant predictors of total thyroidectomy, compared with other thyroid surgery, included younger age (odds ratio, 1.193); higher socioeconomic status (OR, 1.263, for higher-middle SES and OR, 1.325, for highest SES); higher T stage (OR, 1.848, for T2; OR, 2.473, for T3; and OR, 2.908, for T4); and papillary histology (OR, 0.349).

At the same time, statistically significant predictors of RAI administration included younger age (OR, 1.116); higher SES (OR, 1.410, for higher-middle SES and OR, 1.307, for highest SES); more advanced T stage (OR, 2.194 for T2; OR, 2.084, for T3; and OR, 1.527, for T4); node positivity (OR, 0.481), and total thyroidectomy (OR, 3.76).

“As we expected, the younger population was more likely to be female, but we did find that the younger population was also more likely to be Hispanic,” Dr. Semrad said. “We don’t know if they were native Hispanics or if it has something to do with immigration rates.”

Dr. Semrad acknowledged certain limitations of the study, including the risk of misclassification bias in registry data, the lack of details about surgical procedures performed, and the fact that the radioiodine dose was not captured.

“We have data regarding the T stage, the nodal stage, and the number of lymph nodes examined, but we don’t have some of the finer histology data,” he said.

Even so, he characterized the findings as “provocative in suggesting that perhaps our treatment patterns in younger patients are different. With more aggressive surgery and more use of radioactive iodine, that can have potential implications in terms of long-term side effects and follow-up.”

The researchers said they plan to use linked administrative data to analyze initial and subsequent thyroid surgical procedures in this patient population.

The study was supported by a grant from the National Institutes of Health. Dr. Semrad reported having no relevant financial disclosures.

[email protected]


On Twitter @dougbrunk

CORONADO, CALIF. – Patients with differentiated thyroid cancer who were younger than age 45 years were more likely to undergo total or near-total thyroidectomy and to receive radioactive iodine, compared with their older counterparts, a large registry analysis demonstrated.

In addition, younger patients were more likely to be Hispanic and female and to have papillary carcinoma, lead study author Dr. Thomas J. Semrad reported during the annual meeting of the American Thyroid Association.

Sharon Worcester/Frontline Medical News

“Not much is known about how treatment administration differs between younger and older patients with thyroid cancer,” Dr. Semrad of the division of hematology/oncology at the University of California, Davis, Comprehensive Cancer Center, Sacramento, said in an interview. “Some data suggest that perhaps patients younger than age 15 years may respond better to radioactive iodine and may present with more advanced disease. But not much is known about how they’re treated.”

To find out, Dr. Semrad and his associates used the California Cancer Registry to identify 23,629 patients who were diagnosed with differentiated thyroid cancer between 2004 and 2011. They divided the patients into two cohorts: younger (defined as those younger than 45 years) and older (those 45 years or older). Treatment variables of interest included total or near-total thyroidectomy, other types of thyroid surgery, and the administration of radioactive iodine (RAI). The researchers compared the descriptive statistics between the two groups and used univariate and multivariate logistic regression to identify predictors of the treatment administered.

Compared with older patients, younger patients were significantly more likely to be Hispanic (33% vs. 22%), to be female (83% vs. 75%), to have papillary carcinoma (93% vs. 91%), and to have lymph node involvement (32% vs. 20%, all P < .0001).

Overall, the majority of patients (86%) underwent total or near-total thyroidectomy, but the surgery was slightly and significantly more common in younger patients, compared with their older counterparts (88% vs. 85%, P < .0001). Younger patients also were significantly more likely to receive RAI (55% vs. 49%, P < .0001).

On multivariate analysis, statistically significant predictors of total thyroidectomy, compared with other thyroid surgery, included younger age (odds ratio, 1.193); higher socioeconomic status (OR, 1.263, for higher-middle SES and OR, 1.325, for highest SES); higher T stage (OR, 1.848, for T2; OR, 2.473, for T3; and OR, 2.908, for T4); and papillary histology (OR, 0.349).

At the same time, statistically significant predictors of RAI administration included younger age (OR, 1.116); higher SES (OR, 1.410, for higher-middle SES and OR, 1.307, for highest SES); more advanced T stage (OR, 2.194 for T2; OR, 2.084, for T3; and OR, 1.527, for T4); node positivity (OR, 0.481), and total thyroidectomy (OR, 3.76).

“As we expected, the younger population was more likely to be female, but we did find that the younger population was also more likely to be Hispanic,” Dr. Semrad said. “We don’t know if they were native Hispanics or if it has something to do with immigration rates.”

Dr. Semrad acknowledged certain limitations of the study, including the risk of misclassification bias in registry data, the lack of details about surgical procedures performed, and the fact that the radioiodine dose was not captured.

“We have data regarding the T stage, the nodal stage, and the number of lymph nodes examined, but we don’t have some of the finer histology data,” he said.

Even so, he characterized the findings as “provocative in suggesting that perhaps our treatment patterns in younger patients are different. With more aggressive surgery and more use of radioactive iodine, that can have potential implications in terms of long-term side effects and follow-up.”

The researchers said they plan to use linked administrative data to analyze initial and subsequent thyroid surgical procedures in this patient population.

The study was supported by a grant from the National Institutes of Health. Dr. Semrad reported having no relevant financial disclosures.

[email protected]


On Twitter @dougbrunk

A 28-year-old white woman, KR, presents to primary care with episodic diaphoresis and weakness that occur one to two hours after meals. There is no history of syncope or seizures. The hypoglycemic symptoms abate with intake of oral glucose and do not occur when the patient fasts.

KR underwent Roux-en-Y gastric bypass surgery 12 months ago. At the time, her body weight was 250 lbs and her height, 62 in (BMI, 46). She has lost 60 lbs since surgery (current BMI, 35). KR has no comorbid medical conditions. She denies use of insulin injection or oral hypoglycemic medication, as well as alcohol consumption. There is no history of diarrhea or abdominal pain. Her only medication is a daily multivitamin.

Physical exam reveals a blood pressure of 126/80 mm Hg; pulse, 82 beats/min; respiratory rate, 16 breaths/min; and O₂ saturation, 98%. Heart rate is regular with no murmur. Lungs are clear to auscultation. Abdominal and neurologic exams are unremarkable; musculoskeletal strength and orthostatic vital signs are normal.

The patient is instructed to test her blood sugar with a glucometer and return to the clinic in two weeks. Fingerstick monitoring reveals that her serum glucose level drops into the 40 to 50 mg/dL range approximately one to two hours after meals containing > 45 g of carbohydrate. Her fasting serum glucose readings are in the 80 to 95 mg/dL range.

The patient is presumptively diagnosed with dumping syndrome and receives nutritional counseling; she is instructed to reduce intake of simple carbohydrates and increase the protein content of meals. Despite these dietary modifications, the episodes of hypoglycemia persist.

The patient is then referred to endocrinology. Fasting labwork reveals a serum glucose level of 85 mg/dL; normal adrenocorticotropic hormone (ACTH) and cortisol levels; C-peptide level, 2.46 ng/mL (reference range, 0.80–4.00 ng/mL); and insulin level, 6.4 mIU/mL (reference range 2.6–24.9 mIU/mL). A 75-g two-hour oral glucose tolerance test (OGTT) reveals peak serum glucose of 180 mg/dL at 30 minutes followed by a nadir serum glucose of 48 mg/dL at 110 minutes, accompanied by hypoglycemic symptoms. The insulin and C-peptide levels are elevated during the entire two-hour test. The serum cortisol level is 22 mg/dL when the glucose level is 48 mg/dL. CT of the abdomen, previously ordered by the patient’s primary care provider, was unremarkable.

Since there is no laboratory evidence of fasting hypoglycemia and no pancreatic abnormalities are seen on imaging studies, the possibility of insulinoma is excluded from the differential diagnosis. Adrenal insufficiency is excluded based on the normal ACTH and cortisol levels. The possibility of noninsulinoma pancreatogenous hypoglycemia syndrome is considered.

The patient is prescribed verapamil ER 100 mg/d and notes significant reduction in the frequency of hypoglycemic episodes and symptoms. She is scheduled for follow-up in four weeks to assess for any changes in the frequency or severity of her hypoglycemic episodes.

BACKGROUND
Postprandial hypoglycemia is a rare but potentially serious complication of bariatric surgery procedures that divert nutrients into the small bowel.^1,2 The Bariatric Outcomes Longitudinal Database revealed a 0.1% incidence of hypoglycemia in patients who underwent Roux-en-Y gastric bypass surgery.³

The most common cause of hypoglycemia following gastric bypass surgery is dumping syndrome, which involves rapid emptying of gastric contents with reactive hypoglycemia due to increased postprandial insulin release. In dumping syndrome, hypoglycemic symptoms—flushing, diaphoresis, weakness, and dizziness—typically occur within two to three hours after meals; patients do not experience the more severe symptoms of neuroglycopenia (eg, cognitive impairment, seizures, and loss of consciousness).⁴ The symptoms of dumping syndrome typically improve with reduced intake of simple carbohydrates and increased protein consumption.¹

Other causes of postprandial hypoglycemia include insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Although both diagnoses are rare, they should be considered if no improvement in hypoglycemic symptoms occurs after dietary modification.¹

Insulinoma is the most common cause of persistent hyperinsulinemic hypoglycemia. It is defined by Whipple’s triad: symptomatic hypoglycemia during fasting, a serum glucose level > 50 mg/dL at the time of symptom onset, and relief of symptoms after administration of glucose.⁵

NIPHS is less common than insulinoma. It is characterized by postprandial hypoglycemia due to increased insulin secretion resulting from pancreatic b-cell hyperplasia. Hypoglycemia does not typically occur during a 72-hour fast. In addition, pancreatic imaging studies yield normal results in cases of NIPHS. The selective arterial calcium stimulation test is positive in NIPHS.⁵ NIPHS is definitively diagnosed by histopathologic examination of the pancreas, which reveals nesidioblastosis.⁶

Nesidioblastosis involves pathologic b-cell overgrowth in the pancreas that results in excess insulin secretion.⁴ Nesidioblastosis is characterized by pancreatic b-cell hypertrophy, islet hyperplasia, and increased b-cell mass.²

Nesidioblastosis is the leading cause of hyperinsulinemia in newborns and infants (annual incidence, 1 in 50,000 births) but is quite rare in adults, occurring in 0.5% to 7.0% of all those with hyperinsulinism.^7,8 Islet cell hypertrophy—characteristic of nesidioblastosis—is seen in both adults and children, whereas genetic mutations are present only in infants.⁷

Although rare in adults, nesidioblastosis is more common in the setting of gastric bypass than in the general population.⁷ As of 2011, there have been 40 cases of nesidioblastosis in adults who received gastric bypass.² With the rapid increase in the number of these surgeries performed each year, nesidioblastosis should be considered in the differential diagnosis for patients who experience hypoglycemia following the procedure.^2,7

Continue for hormonal mechanisms >>

HORMONAL MECHANISMS
There are multiple theories regarding the etiology of b-cell hyperplasia following bariatric surgery. The specific causes for NIPHS after gastric bypass remain under investigation.²

The most common theory is that b-cell hyperplasia may occur as a result of the surgical procedure itself and not due to obesity. The rapid delivery of food to the distal ileum after gastric bypass surgery may result in elevated production of incretin hormones (eg, GLP-1 and GIP), which increase b-cell proliferation, insulin secretion, and insulin sensitivity.⁷

Roux-en-Y gastric bypass also impairs ghrelin secretion. Ghrelin normally acts to suppress insulin secretion and directly opposes the action of insulin. Reduced levels of ghrelin may increase the likelihood of hypoglycemia. Other hormones that may contribute to the metabolic effects of bariatric surgery include peptide YY, oxyntomodulin, and others as yet unidentified.^5,6

CLINICAL MANIFESTATIONS
NIPHS is characterized by moderate to severe postprandial hypoglycemia. Symptoms include confusion, diaphoresis, tremulousness, anxiety, weakness, blurred vision, and disorientation, as well as more severe neuroglycopenic symptoms, such as cognitive impairment, seizures, and loss of consciousness.⁵

These symptoms do not typically manifest until several months after gastric bypass surgery. (By contrast, symptoms experienced with dumping syndrome typically manifest shortly after the procedure.) Of note, hypoglycemic symptoms of NIPHS do not typically improve after dietary modifications aimed at reducing carbohydrate intake.²

DIAGNOSIS
Diagnosis of NIPHS is based on hypoglycemic/neuroglycopenic signs and symptoms without fasting hypoglycemia; endogenous hyperinsulinemia in the presence of hypoglycemia; negative localization studies for insulinoma (using triple-phase spiral CT); and positive selective arterial calcium stimulation test.^4,6

If fasting hypoglycemia is reported or suspected, the patient should be evaluated for insulinoma using a 72-hour fast. During it, glucose, insulin, C-peptide, and pro-insulin levels should be tested every six hours; results will be normal in patients with NIPHS.⁵

The use of OGTT is controversial, as patients can experience variable degrees of postprandial hyperinsulinism and symptomatic hypoglycemia during the test. There are no guidelines on whether to perform OGTT in the work-up for NIPHS. In research protocols, it is common to perform a five-hour OGTT; subjects consume a mixed meal containing 50 g of carbohydrates, then their glucose, insulin, and C-peptide levels are tested every 30 to 60 minutes (or sooner if hypoglycemic symptoms occur).

Elevated insulin and C-peptide levels in the setting of hypogly­cemia are characteristic findings in patients with NIPHS.^5,9 In the setting of hypoglycemia, a cortisol level > 20 mg/dL is considered an appropriate adrenal response and excludes adrenal insufficiency. Triple-phase CT of the abdomen should be performed to rule out insulinoma if strongly suspected and if work-up for NIPHS is ­negative.⁵

The selective arterial calcium stimulation test is employed to confirm the diagnosis of NIPHS and to guide the extent of pancreatic resection, in an effort to minimize postoperative complications of insulin-dependent diabetes and exocrine insufficiency. In this procedure, the splenic, gastroduodenal, superior mesenteric, and hepatic arteries that supply the pancreas are selectively injected with calcium gluconate. After injection of calcium, the insulin level is measured within each artery.^4,5,7 The selective arterial calcium stimulation test can also be used to localize an insulinoma. NIPHS is distinguished from insulinoma by a diffuse increase in insulin secreted from multiple segments of the arteries that supply the pancreas, following calcium stimulation.^4,5,7

Continue for treatment >>

TREATMENT
There is no consensus on treatment of NIPHS in postbariatric surgery patients, and no “gold standard” exists. Pharmacologic treatment is recommended prior to surgical intervention in patients who present with symptomatic hypoglycemia without loss of consciousness or seizures.¹

Pharmacologic treatments include calcium channel blockers (eg, verapamil or nifedipine), the b-cell inhibitor diazoxide, the secretory inhibitor octreotide, and a-glucosidase inhibitors.¹ In one hospital group, patients were initially treated with verapamil ER 100 mg/d.⁵ If patients did not respond to this therapy or developed adverse effects, diazoxide was added (starting dose, 25 mg tid, titrated to 75 mg tid).⁵ If this combination did not produce results, octreotide (dose ranging from 25 mg/d to 50 mg tid, subcutaneously) was added. Acarbose can also be added, with the typical starting dose of 50 mg tid.¹

Distal or subtotal pancreatectomy to debulk the hypertrophic islets is the most common surgical method used in patients with severe hypoglycemia that is refractory to medical management.^2,5 The extent of pancreatic resection is guided by calcium angiography and typically ranges from 80% to 95%.⁷ Smaller pancreatic resection is associated with higher risk for persistent postoperative hypoglycemia.⁵ Complications associated with pancreatectomy include insulin-dependent diabetes and exocrine insufficiency.⁵

It is not uncommon for patients to experience recurrent symptoms after subtotal pancreatectomy, but the symptoms are typically easier to manage pharmacologically than they were pre-operatively. Occasionally, a second surgery with 95% to complete pancreatectomy is employed if recurrent hypoglycemia develops that is refractory to medical management.⁵

Reversal of Roux-en-Y bypass surgery has been described as an attempted treatment method in several case reports of patients with NIPHS. In at least one patient, hyperinsulinemic hypoglycemia persisted after Roux-en-Y gastric bypass reversal.² Adjustable gastric band placement was recently reported to reverse hypoglycemic symptoms and maintain weight loss, due to restricted gastric emptying.² Conversion of Roux-en-Y gastric banding to gastric sleeve may also be employed to restore normal gastrointestinal continuity and resolve hypoglycemia, though limited data is available regarding the efficacy of this procedure.²

Close monitoring is necessary in patients treated with pharmacologic therapy to ensure that symptoms are well controlled and that surgery is not necessary.¹

SUMMARY AND CONCLUSION
Symptomatic hypoglycemia is a potential complication associated with gastric bypass surgery and is most commonly caused by dumping syndrome. It is important to consider other causes of postprandial hypoglycemia, such as insulinoma and NIPHS, in patients who continue to experience hypoglycemia despite making dietary modifications.^1,4

NIPHS is a rare and poorly understood complication of gastric bypass surgery involving pathologic b-cell overgrowth, leading to hyperinsulinemia and potentially severe hypoglycemia.⁶ Some patients may present with complete relief of symptoms with pharmacologic treatment, while others will need surgical treatment with subtotal pancreatectomy.¹

The findings of increased levels of GLP-1 hormone in patients who have received gastric bypass surgery and the fact that only a very small subset of gastric bypass patients develop NIPHS with histologic features of nesidioblastosis are subjects for further research. Further understanding of the hormonal factors involved in the pathogenesis of NIPHS and adult-onset nesidioblastosis following gastric bypass surgery could lead to novel drug development to treat diabetes.⁶

REFERENCES
1. Moreira RO, Moreira RBM, Machado NAM, et al. Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose. Obes Surg. 2008;18:1618-1621.

2. Cui Y, Elahi D, Andersen D. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15:1879-1888.

3. Sarwar H, Chapman III WH, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg. 2014; 24(7):1120-1124.

4. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249-254.

5. Mathavan VK, Arregui M, Davis C, et al. Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia. Surg Endosc. 2010;24:2547-2555.

6. Cummings D. Gastric bypass and nesidioblastosis—too much of a good thing for islets? N Engl J Med. 2005;353(3):300-302.

7. Clancy TE, Moore FD, Zinner MJ. Post-gastric bypass hyperinsulinism with nesidioblastosis: subtotal or total pancreatectomy may be needed to prevent recurrent hypoglycemia. J Gastrointest Surg. 2006;10(8):1116-1119.

8. Kaczirek K, Niederle B. Nesidioblastosis: an old term and a new understanding. World J Surg. 2004;28:1227-1230.

9. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6): 2008-2017.

A 28-year-old white woman, KR, presents to primary care with episodic diaphoresis and weakness that occur one to two hours after meals. There is no history of syncope or seizures. The hypoglycemic symptoms abate with intake of oral glucose and do not occur when the patient fasts.

KR underwent Roux-en-Y gastric bypass surgery 12 months ago. At the time, her body weight was 250 lbs and her height, 62 in (BMI, 46). She has lost 60 lbs since surgery (current BMI, 35). KR has no comorbid medical conditions. She denies use of insulin injection or oral hypoglycemic medication, as well as alcohol consumption. There is no history of diarrhea or abdominal pain. Her only medication is a daily multivitamin.

Physical exam reveals a blood pressure of 126/80 mm Hg; pulse, 82 beats/min; respiratory rate, 16 breaths/min; and O₂ saturation, 98%. Heart rate is regular with no murmur. Lungs are clear to auscultation. Abdominal and neurologic exams are unremarkable; musculoskeletal strength and orthostatic vital signs are normal.

The patient is instructed to test her blood sugar with a glucometer and return to the clinic in two weeks. Fingerstick monitoring reveals that her serum glucose level drops into the 40 to 50 mg/dL range approximately one to two hours after meals containing > 45 g of carbohydrate. Her fasting serum glucose readings are in the 80 to 95 mg/dL range.

The patient is presumptively diagnosed with dumping syndrome and receives nutritional counseling; she is instructed to reduce intake of simple carbohydrates and increase the protein content of meals. Despite these dietary modifications, the episodes of hypoglycemia persist.

The patient is then referred to endocrinology. Fasting labwork reveals a serum glucose level of 85 mg/dL; normal adrenocorticotropic hormone (ACTH) and cortisol levels; C-peptide level, 2.46 ng/mL (reference range, 0.80–4.00 ng/mL); and insulin level, 6.4 mIU/mL (reference range 2.6–24.9 mIU/mL). A 75-g two-hour oral glucose tolerance test (OGTT) reveals peak serum glucose of 180 mg/dL at 30 minutes followed by a nadir serum glucose of 48 mg/dL at 110 minutes, accompanied by hypoglycemic symptoms. The insulin and C-peptide levels are elevated during the entire two-hour test. The serum cortisol level is 22 mg/dL when the glucose level is 48 mg/dL. CT of the abdomen, previously ordered by the patient’s primary care provider, was unremarkable.

Since there is no laboratory evidence of fasting hypoglycemia and no pancreatic abnormalities are seen on imaging studies, the possibility of insulinoma is excluded from the differential diagnosis. Adrenal insufficiency is excluded based on the normal ACTH and cortisol levels. The possibility of noninsulinoma pancreatogenous hypoglycemia syndrome is considered.

The patient is prescribed verapamil ER 100 mg/d and notes significant reduction in the frequency of hypoglycemic episodes and symptoms. She is scheduled for follow-up in four weeks to assess for any changes in the frequency or severity of her hypoglycemic episodes.

BACKGROUND
Postprandial hypoglycemia is a rare but potentially serious complication of bariatric surgery procedures that divert nutrients into the small bowel.^1,2 The Bariatric Outcomes Longitudinal Database revealed a 0.1% incidence of hypoglycemia in patients who underwent Roux-en-Y gastric bypass surgery.³

The most common cause of hypoglycemia following gastric bypass surgery is dumping syndrome, which involves rapid emptying of gastric contents with reactive hypoglycemia due to increased postprandial insulin release. In dumping syndrome, hypoglycemic symptoms—flushing, diaphoresis, weakness, and dizziness—typically occur within two to three hours after meals; patients do not experience the more severe symptoms of neuroglycopenia (eg, cognitive impairment, seizures, and loss of consciousness).⁴ The symptoms of dumping syndrome typically improve with reduced intake of simple carbohydrates and increased protein consumption.¹

Other causes of postprandial hypoglycemia include insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Although both diagnoses are rare, they should be considered if no improvement in hypoglycemic symptoms occurs after dietary modification.¹

Insulinoma is the most common cause of persistent hyperinsulinemic hypoglycemia. It is defined by Whipple’s triad: symptomatic hypoglycemia during fasting, a serum glucose level > 50 mg/dL at the time of symptom onset, and relief of symptoms after administration of glucose.⁵

NIPHS is less common than insulinoma. It is characterized by postprandial hypoglycemia due to increased insulin secretion resulting from pancreatic b-cell hyperplasia. Hypoglycemia does not typically occur during a 72-hour fast. In addition, pancreatic imaging studies yield normal results in cases of NIPHS. The selective arterial calcium stimulation test is positive in NIPHS.⁵ NIPHS is definitively diagnosed by histopathologic examination of the pancreas, which reveals nesidioblastosis.⁶

Nesidioblastosis involves pathologic b-cell overgrowth in the pancreas that results in excess insulin secretion.⁴ Nesidioblastosis is characterized by pancreatic b-cell hypertrophy, islet hyperplasia, and increased b-cell mass.²

Nesidioblastosis is the leading cause of hyperinsulinemia in newborns and infants (annual incidence, 1 in 50,000 births) but is quite rare in adults, occurring in 0.5% to 7.0% of all those with hyperinsulinism.^7,8 Islet cell hypertrophy—characteristic of nesidioblastosis—is seen in both adults and children, whereas genetic mutations are present only in infants.⁷

Although rare in adults, nesidioblastosis is more common in the setting of gastric bypass than in the general population.⁷ As of 2011, there have been 40 cases of nesidioblastosis in adults who received gastric bypass.² With the rapid increase in the number of these surgeries performed each year, nesidioblastosis should be considered in the differential diagnosis for patients who experience hypoglycemia following the procedure.^2,7

Continue for hormonal mechanisms >>

HORMONAL MECHANISMS
There are multiple theories regarding the etiology of b-cell hyperplasia following bariatric surgery. The specific causes for NIPHS after gastric bypass remain under investigation.²

The most common theory is that b-cell hyperplasia may occur as a result of the surgical procedure itself and not due to obesity. The rapid delivery of food to the distal ileum after gastric bypass surgery may result in elevated production of incretin hormones (eg, GLP-1 and GIP), which increase b-cell proliferation, insulin secretion, and insulin sensitivity.⁷

Roux-en-Y gastric bypass also impairs ghrelin secretion. Ghrelin normally acts to suppress insulin secretion and directly opposes the action of insulin. Reduced levels of ghrelin may increase the likelihood of hypoglycemia. Other hormones that may contribute to the metabolic effects of bariatric surgery include peptide YY, oxyntomodulin, and others as yet unidentified.^5,6

CLINICAL MANIFESTATIONS
NIPHS is characterized by moderate to severe postprandial hypoglycemia. Symptoms include confusion, diaphoresis, tremulousness, anxiety, weakness, blurred vision, and disorientation, as well as more severe neuroglycopenic symptoms, such as cognitive impairment, seizures, and loss of consciousness.⁵

These symptoms do not typically manifest until several months after gastric bypass surgery. (By contrast, symptoms experienced with dumping syndrome typically manifest shortly after the procedure.) Of note, hypoglycemic symptoms of NIPHS do not typically improve after dietary modifications aimed at reducing carbohydrate intake.²

DIAGNOSIS
Diagnosis of NIPHS is based on hypoglycemic/neuroglycopenic signs and symptoms without fasting hypoglycemia; endogenous hyperinsulinemia in the presence of hypoglycemia; negative localization studies for insulinoma (using triple-phase spiral CT); and positive selective arterial calcium stimulation test.^4,6

If fasting hypoglycemia is reported or suspected, the patient should be evaluated for insulinoma using a 72-hour fast. During it, glucose, insulin, C-peptide, and pro-insulin levels should be tested every six hours; results will be normal in patients with NIPHS.⁵

The use of OGTT is controversial, as patients can experience variable degrees of postprandial hyperinsulinism and symptomatic hypoglycemia during the test. There are no guidelines on whether to perform OGTT in the work-up for NIPHS. In research protocols, it is common to perform a five-hour OGTT; subjects consume a mixed meal containing 50 g of carbohydrates, then their glucose, insulin, and C-peptide levels are tested every 30 to 60 minutes (or sooner if hypoglycemic symptoms occur).

Elevated insulin and C-peptide levels in the setting of hypogly­cemia are characteristic findings in patients with NIPHS.^5,9 In the setting of hypoglycemia, a cortisol level > 20 mg/dL is considered an appropriate adrenal response and excludes adrenal insufficiency. Triple-phase CT of the abdomen should be performed to rule out insulinoma if strongly suspected and if work-up for NIPHS is ­negative.⁵

The selective arterial calcium stimulation test is employed to confirm the diagnosis of NIPHS and to guide the extent of pancreatic resection, in an effort to minimize postoperative complications of insulin-dependent diabetes and exocrine insufficiency. In this procedure, the splenic, gastroduodenal, superior mesenteric, and hepatic arteries that supply the pancreas are selectively injected with calcium gluconate. After injection of calcium, the insulin level is measured within each artery.^4,5,7 The selective arterial calcium stimulation test can also be used to localize an insulinoma. NIPHS is distinguished from insulinoma by a diffuse increase in insulin secreted from multiple segments of the arteries that supply the pancreas, following calcium stimulation.^4,5,7

Continue for treatment >>

TREATMENT
There is no consensus on treatment of NIPHS in postbariatric surgery patients, and no “gold standard” exists. Pharmacologic treatment is recommended prior to surgical intervention in patients who present with symptomatic hypoglycemia without loss of consciousness or seizures.¹

Pharmacologic treatments include calcium channel blockers (eg, verapamil or nifedipine), the b-cell inhibitor diazoxide, the secretory inhibitor octreotide, and a-glucosidase inhibitors.¹ In one hospital group, patients were initially treated with verapamil ER 100 mg/d.⁵ If patients did not respond to this therapy or developed adverse effects, diazoxide was added (starting dose, 25 mg tid, titrated to 75 mg tid).⁵ If this combination did not produce results, octreotide (dose ranging from 25 mg/d to 50 mg tid, subcutaneously) was added. Acarbose can also be added, with the typical starting dose of 50 mg tid.¹

Distal or subtotal pancreatectomy to debulk the hypertrophic islets is the most common surgical method used in patients with severe hypoglycemia that is refractory to medical management.^2,5 The extent of pancreatic resection is guided by calcium angiography and typically ranges from 80% to 95%.⁷ Smaller pancreatic resection is associated with higher risk for persistent postoperative hypoglycemia.⁵ Complications associated with pancreatectomy include insulin-dependent diabetes and exocrine insufficiency.⁵

It is not uncommon for patients to experience recurrent symptoms after subtotal pancreatectomy, but the symptoms are typically easier to manage pharmacologically than they were pre-operatively. Occasionally, a second surgery with 95% to complete pancreatectomy is employed if recurrent hypoglycemia develops that is refractory to medical management.⁵

Reversal of Roux-en-Y bypass surgery has been described as an attempted treatment method in several case reports of patients with NIPHS. In at least one patient, hyperinsulinemic hypoglycemia persisted after Roux-en-Y gastric bypass reversal.² Adjustable gastric band placement was recently reported to reverse hypoglycemic symptoms and maintain weight loss, due to restricted gastric emptying.² Conversion of Roux-en-Y gastric banding to gastric sleeve may also be employed to restore normal gastrointestinal continuity and resolve hypoglycemia, though limited data is available regarding the efficacy of this procedure.²

Close monitoring is necessary in patients treated with pharmacologic therapy to ensure that symptoms are well controlled and that surgery is not necessary.¹

SUMMARY AND CONCLUSION
Symptomatic hypoglycemia is a potential complication associated with gastric bypass surgery and is most commonly caused by dumping syndrome. It is important to consider other causes of postprandial hypoglycemia, such as insulinoma and NIPHS, in patients who continue to experience hypoglycemia despite making dietary modifications.^1,4

NIPHS is a rare and poorly understood complication of gastric bypass surgery involving pathologic b-cell overgrowth, leading to hyperinsulinemia and potentially severe hypoglycemia.⁶ Some patients may present with complete relief of symptoms with pharmacologic treatment, while others will need surgical treatment with subtotal pancreatectomy.¹

The findings of increased levels of GLP-1 hormone in patients who have received gastric bypass surgery and the fact that only a very small subset of gastric bypass patients develop NIPHS with histologic features of nesidioblastosis are subjects for further research. Further understanding of the hormonal factors involved in the pathogenesis of NIPHS and adult-onset nesidioblastosis following gastric bypass surgery could lead to novel drug development to treat diabetes.⁶

REFERENCES
1. Moreira RO, Moreira RBM, Machado NAM, et al. Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose. Obes Surg. 2008;18:1618-1621.

2. Cui Y, Elahi D, Andersen D. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15:1879-1888.

3. Sarwar H, Chapman III WH, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg. 2014; 24(7):1120-1124.

4. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249-254.

5. Mathavan VK, Arregui M, Davis C, et al. Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia. Surg Endosc. 2010;24:2547-2555.

6. Cummings D. Gastric bypass and nesidioblastosis—too much of a good thing for islets? N Engl J Med. 2005;353(3):300-302.

7. Clancy TE, Moore FD, Zinner MJ. Post-gastric bypass hyperinsulinism with nesidioblastosis: subtotal or total pancreatectomy may be needed to prevent recurrent hypoglycemia. J Gastrointest Surg. 2006;10(8):1116-1119.

8. Kaczirek K, Niederle B. Nesidioblastosis: an old term and a new understanding. World J Surg. 2004;28:1227-1230.

9. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6): 2008-2017.

A 28-year-old white woman, KR, presents to primary care with episodic diaphoresis and weakness that occur one to two hours after meals. There is no history of syncope or seizures. The hypoglycemic symptoms abate with intake of oral glucose and do not occur when the patient fasts.

KR underwent Roux-en-Y gastric bypass surgery 12 months ago. At the time, her body weight was 250 lbs and her height, 62 in (BMI, 46). She has lost 60 lbs since surgery (current BMI, 35). KR has no comorbid medical conditions. She denies use of insulin injection or oral hypoglycemic medication, as well as alcohol consumption. There is no history of diarrhea or abdominal pain. Her only medication is a daily multivitamin.

Physical exam reveals a blood pressure of 126/80 mm Hg; pulse, 82 beats/min; respiratory rate, 16 breaths/min; and O₂ saturation, 98%. Heart rate is regular with no murmur. Lungs are clear to auscultation. Abdominal and neurologic exams are unremarkable; musculoskeletal strength and orthostatic vital signs are normal.

The patient is instructed to test her blood sugar with a glucometer and return to the clinic in two weeks. Fingerstick monitoring reveals that her serum glucose level drops into the 40 to 50 mg/dL range approximately one to two hours after meals containing > 45 g of carbohydrate. Her fasting serum glucose readings are in the 80 to 95 mg/dL range.

The patient is presumptively diagnosed with dumping syndrome and receives nutritional counseling; she is instructed to reduce intake of simple carbohydrates and increase the protein content of meals. Despite these dietary modifications, the episodes of hypoglycemia persist.

The patient is then referred to endocrinology. Fasting labwork reveals a serum glucose level of 85 mg/dL; normal adrenocorticotropic hormone (ACTH) and cortisol levels; C-peptide level, 2.46 ng/mL (reference range, 0.80–4.00 ng/mL); and insulin level, 6.4 mIU/mL (reference range 2.6–24.9 mIU/mL). A 75-g two-hour oral glucose tolerance test (OGTT) reveals peak serum glucose of 180 mg/dL at 30 minutes followed by a nadir serum glucose of 48 mg/dL at 110 minutes, accompanied by hypoglycemic symptoms. The insulin and C-peptide levels are elevated during the entire two-hour test. The serum cortisol level is 22 mg/dL when the glucose level is 48 mg/dL. CT of the abdomen, previously ordered by the patient’s primary care provider, was unremarkable.

Since there is no laboratory evidence of fasting hypoglycemia and no pancreatic abnormalities are seen on imaging studies, the possibility of insulinoma is excluded from the differential diagnosis. Adrenal insufficiency is excluded based on the normal ACTH and cortisol levels. The possibility of noninsulinoma pancreatogenous hypoglycemia syndrome is considered.

The patient is prescribed verapamil ER 100 mg/d and notes significant reduction in the frequency of hypoglycemic episodes and symptoms. She is scheduled for follow-up in four weeks to assess for any changes in the frequency or severity of her hypoglycemic episodes.

BACKGROUND
Postprandial hypoglycemia is a rare but potentially serious complication of bariatric surgery procedures that divert nutrients into the small bowel.^1,2 The Bariatric Outcomes Longitudinal Database revealed a 0.1% incidence of hypoglycemia in patients who underwent Roux-en-Y gastric bypass surgery.³

The most common cause of hypoglycemia following gastric bypass surgery is dumping syndrome, which involves rapid emptying of gastric contents with reactive hypoglycemia due to increased postprandial insulin release. In dumping syndrome, hypoglycemic symptoms—flushing, diaphoresis, weakness, and dizziness—typically occur within two to three hours after meals; patients do not experience the more severe symptoms of neuroglycopenia (eg, cognitive impairment, seizures, and loss of consciousness).⁴ The symptoms of dumping syndrome typically improve with reduced intake of simple carbohydrates and increased protein consumption.¹

Other causes of postprandial hypoglycemia include insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Although both diagnoses are rare, they should be considered if no improvement in hypoglycemic symptoms occurs after dietary modification.¹

Insulinoma is the most common cause of persistent hyperinsulinemic hypoglycemia. It is defined by Whipple’s triad: symptomatic hypoglycemia during fasting, a serum glucose level > 50 mg/dL at the time of symptom onset, and relief of symptoms after administration of glucose.⁵

NIPHS is less common than insulinoma. It is characterized by postprandial hypoglycemia due to increased insulin secretion resulting from pancreatic b-cell hyperplasia. Hypoglycemia does not typically occur during a 72-hour fast. In addition, pancreatic imaging studies yield normal results in cases of NIPHS. The selective arterial calcium stimulation test is positive in NIPHS.⁵ NIPHS is definitively diagnosed by histopathologic examination of the pancreas, which reveals nesidioblastosis.⁶

Nesidioblastosis involves pathologic b-cell overgrowth in the pancreas that results in excess insulin secretion.⁴ Nesidioblastosis is characterized by pancreatic b-cell hypertrophy, islet hyperplasia, and increased b-cell mass.²

Nesidioblastosis is the leading cause of hyperinsulinemia in newborns and infants (annual incidence, 1 in 50,000 births) but is quite rare in adults, occurring in 0.5% to 7.0% of all those with hyperinsulinism.^7,8 Islet cell hypertrophy—characteristic of nesidioblastosis—is seen in both adults and children, whereas genetic mutations are present only in infants.⁷

Although rare in adults, nesidioblastosis is more common in the setting of gastric bypass than in the general population.⁷ As of 2011, there have been 40 cases of nesidioblastosis in adults who received gastric bypass.² With the rapid increase in the number of these surgeries performed each year, nesidioblastosis should be considered in the differential diagnosis for patients who experience hypoglycemia following the procedure.^2,7

Continue for hormonal mechanisms >>

HORMONAL MECHANISMS
There are multiple theories regarding the etiology of b-cell hyperplasia following bariatric surgery. The specific causes for NIPHS after gastric bypass remain under investigation.²

The most common theory is that b-cell hyperplasia may occur as a result of the surgical procedure itself and not due to obesity. The rapid delivery of food to the distal ileum after gastric bypass surgery may result in elevated production of incretin hormones (eg, GLP-1 and GIP), which increase b-cell proliferation, insulin secretion, and insulin sensitivity.⁷

Roux-en-Y gastric bypass also impairs ghrelin secretion. Ghrelin normally acts to suppress insulin secretion and directly opposes the action of insulin. Reduced levels of ghrelin may increase the likelihood of hypoglycemia. Other hormones that may contribute to the metabolic effects of bariatric surgery include peptide YY, oxyntomodulin, and others as yet unidentified.^5,6

CLINICAL MANIFESTATIONS
NIPHS is characterized by moderate to severe postprandial hypoglycemia. Symptoms include confusion, diaphoresis, tremulousness, anxiety, weakness, blurred vision, and disorientation, as well as more severe neuroglycopenic symptoms, such as cognitive impairment, seizures, and loss of consciousness.⁵

These symptoms do not typically manifest until several months after gastric bypass surgery. (By contrast, symptoms experienced with dumping syndrome typically manifest shortly after the procedure.) Of note, hypoglycemic symptoms of NIPHS do not typically improve after dietary modifications aimed at reducing carbohydrate intake.²

DIAGNOSIS
Diagnosis of NIPHS is based on hypoglycemic/neuroglycopenic signs and symptoms without fasting hypoglycemia; endogenous hyperinsulinemia in the presence of hypoglycemia; negative localization studies for insulinoma (using triple-phase spiral CT); and positive selective arterial calcium stimulation test.^4,6

If fasting hypoglycemia is reported or suspected, the patient should be evaluated for insulinoma using a 72-hour fast. During it, glucose, insulin, C-peptide, and pro-insulin levels should be tested every six hours; results will be normal in patients with NIPHS.⁵

The use of OGTT is controversial, as patients can experience variable degrees of postprandial hyperinsulinism and symptomatic hypoglycemia during the test. There are no guidelines on whether to perform OGTT in the work-up for NIPHS. In research protocols, it is common to perform a five-hour OGTT; subjects consume a mixed meal containing 50 g of carbohydrates, then their glucose, insulin, and C-peptide levels are tested every 30 to 60 minutes (or sooner if hypoglycemic symptoms occur).

Elevated insulin and C-peptide levels in the setting of hypogly­cemia are characteristic findings in patients with NIPHS.^5,9 In the setting of hypoglycemia, a cortisol level > 20 mg/dL is considered an appropriate adrenal response and excludes adrenal insufficiency. Triple-phase CT of the abdomen should be performed to rule out insulinoma if strongly suspected and if work-up for NIPHS is ­negative.⁵

The selective arterial calcium stimulation test is employed to confirm the diagnosis of NIPHS and to guide the extent of pancreatic resection, in an effort to minimize postoperative complications of insulin-dependent diabetes and exocrine insufficiency. In this procedure, the splenic, gastroduodenal, superior mesenteric, and hepatic arteries that supply the pancreas are selectively injected with calcium gluconate. After injection of calcium, the insulin level is measured within each artery.^4,5,7 The selective arterial calcium stimulation test can also be used to localize an insulinoma. NIPHS is distinguished from insulinoma by a diffuse increase in insulin secreted from multiple segments of the arteries that supply the pancreas, following calcium stimulation.^4,5,7

Continue for treatment >>

TREATMENT
There is no consensus on treatment of NIPHS in postbariatric surgery patients, and no “gold standard” exists. Pharmacologic treatment is recommended prior to surgical intervention in patients who present with symptomatic hypoglycemia without loss of consciousness or seizures.¹

Pharmacologic treatments include calcium channel blockers (eg, verapamil or nifedipine), the b-cell inhibitor diazoxide, the secretory inhibitor octreotide, and a-glucosidase inhibitors.¹ In one hospital group, patients were initially treated with verapamil ER 100 mg/d.⁵ If patients did not respond to this therapy or developed adverse effects, diazoxide was added (starting dose, 25 mg tid, titrated to 75 mg tid).⁵ If this combination did not produce results, octreotide (dose ranging from 25 mg/d to 50 mg tid, subcutaneously) was added. Acarbose can also be added, with the typical starting dose of 50 mg tid.¹

Distal or subtotal pancreatectomy to debulk the hypertrophic islets is the most common surgical method used in patients with severe hypoglycemia that is refractory to medical management.^2,5 The extent of pancreatic resection is guided by calcium angiography and typically ranges from 80% to 95%.⁷ Smaller pancreatic resection is associated with higher risk for persistent postoperative hypoglycemia.⁵ Complications associated with pancreatectomy include insulin-dependent diabetes and exocrine insufficiency.⁵

It is not uncommon for patients to experience recurrent symptoms after subtotal pancreatectomy, but the symptoms are typically easier to manage pharmacologically than they were pre-operatively. Occasionally, a second surgery with 95% to complete pancreatectomy is employed if recurrent hypoglycemia develops that is refractory to medical management.⁵

Reversal of Roux-en-Y bypass surgery has been described as an attempted treatment method in several case reports of patients with NIPHS. In at least one patient, hyperinsulinemic hypoglycemia persisted after Roux-en-Y gastric bypass reversal.² Adjustable gastric band placement was recently reported to reverse hypoglycemic symptoms and maintain weight loss, due to restricted gastric emptying.² Conversion of Roux-en-Y gastric banding to gastric sleeve may also be employed to restore normal gastrointestinal continuity and resolve hypoglycemia, though limited data is available regarding the efficacy of this procedure.²

Close monitoring is necessary in patients treated with pharmacologic therapy to ensure that symptoms are well controlled and that surgery is not necessary.¹

SUMMARY AND CONCLUSION
Symptomatic hypoglycemia is a potential complication associated with gastric bypass surgery and is most commonly caused by dumping syndrome. It is important to consider other causes of postprandial hypoglycemia, such as insulinoma and NIPHS, in patients who continue to experience hypoglycemia despite making dietary modifications.^1,4

NIPHS is a rare and poorly understood complication of gastric bypass surgery involving pathologic b-cell overgrowth, leading to hyperinsulinemia and potentially severe hypoglycemia.⁶ Some patients may present with complete relief of symptoms with pharmacologic treatment, while others will need surgical treatment with subtotal pancreatectomy.¹

The findings of increased levels of GLP-1 hormone in patients who have received gastric bypass surgery and the fact that only a very small subset of gastric bypass patients develop NIPHS with histologic features of nesidioblastosis are subjects for further research. Further understanding of the hormonal factors involved in the pathogenesis of NIPHS and adult-onset nesidioblastosis following gastric bypass surgery could lead to novel drug development to treat diabetes.⁶

REFERENCES
1. Moreira RO, Moreira RBM, Machado NAM, et al. Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose. Obes Surg. 2008;18:1618-1621.

2. Cui Y, Elahi D, Andersen D. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15:1879-1888.

3. Sarwar H, Chapman III WH, Pender JR, et al. Hypoglycemia after Roux-en-Y gastric bypass: the BOLD experience. Obes Surg. 2014; 24(7):1120-1124.

4. Service GJ, Thompson GB, Service FJ, et al. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249-254.

5. Mathavan VK, Arregui M, Davis C, et al. Management of postgastric bypass noninsulinoma pancreatogenous hypoglycemia. Surg Endosc. 2010;24:2547-2555.

6. Cummings D. Gastric bypass and nesidioblastosis—too much of a good thing for islets? N Engl J Med. 2005;353(3):300-302.

7. Clancy TE, Moore FD, Zinner MJ. Post-gastric bypass hyperinsulinism with nesidioblastosis: subtotal or total pancreatectomy may be needed to prevent recurrent hypoglycemia. J Gastrointest Surg. 2006;10(8):1116-1119.

8. Kaczirek K, Niederle B. Nesidioblastosis: an old term and a new understanding. World J Surg. 2004;28:1227-1230.

9. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6): 2008-2017.

ANSWER
The ECG shows normal sinus rhythm and left ventricular hypertrophy (LVH). LVH is indicated by high voltages in limb leads I and III (sum of R and S waves in leads I and III ≥ 25 mm) or in precordial leads V₁, V₅, and/or V₆ (sum of V₁ and either V₅ or V₆ ≥ 35 mm).

Subsequent work-up, including echocardiography and genetic testing, revealed a familial LVH.

ANSWER
The ECG shows normal sinus rhythm and left ventricular hypertrophy (LVH). LVH is indicated by high voltages in limb leads I and III (sum of R and S waves in leads I and III ≥ 25 mm) or in precordial leads V₁, V₅, and/or V₆ (sum of V₁ and either V₅ or V₆ ≥ 35 mm).

Subsequent work-up, including echocardiography and genetic testing, revealed a familial LVH.

ANSWER
The ECG shows normal sinus rhythm and left ventricular hypertrophy (LVH). LVH is indicated by high voltages in limb leads I and III (sum of R and S waves in leads I and III ≥ 25 mm) or in precordial leads V₁, V₅, and/or V₆ (sum of V₁ and either V₅ or V₆ ≥ 35 mm).

Subsequent work-up, including echocardiography and genetic testing, revealed a familial LVH.

ANSWER
The correct answer is poikiloderma of Civatte (choice “c”), details of which are discussed below.

Poikiloderma vasculare atrophicans (choice “a”) can be an early indication of T-cell lymphoma but would probably not be chronic or confined to sun-exposed skin.

Several forms of lupus (choice “b”) can present with poikilodermatous skin changes, but these would probably not be chronic.

Dermatoheliosis (choice “d”) is the term for the collective effects of overexposure to the sun, of which poikiloderma of Civatte is but one example.

DISCUSSION
The French dermatologist Achille Civatte (1877-1956) first described this particular pattern of sun damage in 1923—about the same time that sunbathing became fashionable among the well-off in the post-WWI era. He noted the distinct combination of telangiectasias, hyperpigmentation, and epidermal atrophy affecting the bilateral neck and lower face, combined with sharply defined sparing of the portion of the anterior neck shaded by the chin. Poikiloderma of Civatte (PC) is extremely common, especially in middle-aged women and, as one might expect, in those with a history of excessive sun exposure over a period of many years.

Though sun-caused, PC is a purely cosmetic issue and does not lead to skin cancer. While it typically causes no symptoms, it does become more obvious with time. The changes are so gradual that others typically notice them before the patient becomes aware.

Transposing these types of skin changes to other locations would make them considerably more worrisome, specifically in the context of possible incipient T-cell lymphoma—one of the very few types of skin cancer that can take years to evolve into frank cancer. But the atrophy, telangiectasias, and discoloration signaling early cutaneous T-cell lymphoma are usually seen in non–sun-exposed skin, particularly in the waistline and groin.

Poikiloderma vasculare atrophicans is only one of several manifestations termed premycotic. This refers to mycosis fungoides, one of the two most common forms of T-cell lymphoma. Serial biopsy, sometimes over the span of several years, is often used to track such changes.

Pulsed light devices and certain types of lasers have been used successfully to treat PC. Our patient, however, declined treatment, declaring her firm intention to maintain “a healthy tan” year-round.

ANSWER
The correct answer is poikiloderma of Civatte (choice “c”), details of which are discussed below.

Poikiloderma vasculare atrophicans (choice “a”) can be an early indication of T-cell lymphoma but would probably not be chronic or confined to sun-exposed skin.

Several forms of lupus (choice “b”) can present with poikilodermatous skin changes, but these would probably not be chronic.

Dermatoheliosis (choice “d”) is the term for the collective effects of overexposure to the sun, of which poikiloderma of Civatte is but one example.

DISCUSSION
The French dermatologist Achille Civatte (1877-1956) first described this particular pattern of sun damage in 1923—about the same time that sunbathing became fashionable among the well-off in the post-WWI era. He noted the distinct combination of telangiectasias, hyperpigmentation, and epidermal atrophy affecting the bilateral neck and lower face, combined with sharply defined sparing of the portion of the anterior neck shaded by the chin. Poikiloderma of Civatte (PC) is extremely common, especially in middle-aged women and, as one might expect, in those with a history of excessive sun exposure over a period of many years.

Though sun-caused, PC is a purely cosmetic issue and does not lead to skin cancer. While it typically causes no symptoms, it does become more obvious with time. The changes are so gradual that others typically notice them before the patient becomes aware.

Transposing these types of skin changes to other locations would make them considerably more worrisome, specifically in the context of possible incipient T-cell lymphoma—one of the very few types of skin cancer that can take years to evolve into frank cancer. But the atrophy, telangiectasias, and discoloration signaling early cutaneous T-cell lymphoma are usually seen in non–sun-exposed skin, particularly in the waistline and groin.

Poikiloderma vasculare atrophicans is only one of several manifestations termed premycotic. This refers to mycosis fungoides, one of the two most common forms of T-cell lymphoma. Serial biopsy, sometimes over the span of several years, is often used to track such changes.

Pulsed light devices and certain types of lasers have been used successfully to treat PC. Our patient, however, declined treatment, declaring her firm intention to maintain “a healthy tan” year-round.

ANSWER
The correct answer is poikiloderma of Civatte (choice “c”), details of which are discussed below.

Poikiloderma vasculare atrophicans (choice “a”) can be an early indication of T-cell lymphoma but would probably not be chronic or confined to sun-exposed skin.

Several forms of lupus (choice “b”) can present with poikilodermatous skin changes, but these would probably not be chronic.

Dermatoheliosis (choice “d”) is the term for the collective effects of overexposure to the sun, of which poikiloderma of Civatte is but one example.

DISCUSSION
The French dermatologist Achille Civatte (1877-1956) first described this particular pattern of sun damage in 1923—about the same time that sunbathing became fashionable among the well-off in the post-WWI era. He noted the distinct combination of telangiectasias, hyperpigmentation, and epidermal atrophy affecting the bilateral neck and lower face, combined with sharply defined sparing of the portion of the anterior neck shaded by the chin. Poikiloderma of Civatte (PC) is extremely common, especially in middle-aged women and, as one might expect, in those with a history of excessive sun exposure over a period of many years.

Though sun-caused, PC is a purely cosmetic issue and does not lead to skin cancer. While it typically causes no symptoms, it does become more obvious with time. The changes are so gradual that others typically notice them before the patient becomes aware.

Transposing these types of skin changes to other locations would make them considerably more worrisome, specifically in the context of possible incipient T-cell lymphoma—one of the very few types of skin cancer that can take years to evolve into frank cancer. But the atrophy, telangiectasias, and discoloration signaling early cutaneous T-cell lymphoma are usually seen in non–sun-exposed skin, particularly in the waistline and groin.

Poikiloderma vasculare atrophicans is only one of several manifestations termed premycotic. This refers to mycosis fungoides, one of the two most common forms of T-cell lymphoma. Serial biopsy, sometimes over the span of several years, is often used to track such changes.

Pulsed light devices and certain types of lasers have been used successfully to treat PC. Our patient, however, declined treatment, declaring her firm intention to maintain “a healthy tan” year-round.

The number of prescriptions for antibiotic prophylaxis before invasive dental procedures has dropped sharply in England since 2008, while the incidence of infective endocarditis has risen significantly in the same time period, researchers found.

A study led by Dr. Martin Thornhill of the University of Sheffield (England) School of Clinical Dentistry, and published online Nov. 18 in the Lancet (doi: 10.1016/S0140-6736(14)62007-9) showed that after the National Institute for Health and Care Excellence issued guidelines against antibiotic prophylaxis, even for patients at high risk of endocarditis, prescriptions fell precipitously from a mean 10,900 per month in 2004-2008 in England to a mean 2,236 a month between April 2008 and April 2013, with only 1,235 issued in the last month of the study period. The NICE guidance, which went further than other published recommendations that have aimed to limit, but not eliminate, the use of antibiotic prophylaxis as a form of endocarditis prevention, cited the absence of a robust evidence base supporting its effectiveness, and also the risk of adverse drug reactions.

Dr. Thornhill and his colleagues reviewed both national prescription records and hospital discharge records for patients with a primary diagnosis of infective endocarditis. Prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell significantly after introduction of the NICE guidance.

The incidence of infective endocarditis, in contrast, rose by 0.11 cases per 10 million people per month following the 2008 guidance (95% confidence interval, 0.05-0.16; P < .0001). By March 2013, the researchers found that there were 34.9 more cases per month than would have been expected had the previous trend continued (95% CI, 7.9-61.9). Moreover, the increase was significant for patients determined to be at low or moderate risk as well as for those deemed high risk. The researchers did not find a statistically significant increase in endocarditis-related mortality corresponding to the drop in prescriptions.

Dr. Thornhill and his colleagues cautioned that their results did not establish a causal association between the drop in prescriptions and the rise in cases, and that further investigations were now warranted.

The study was funded by Heart Research UK, Simplyhealth, and the U.S. National Institutes of Health. Two of its authors were involved in guidelines on infective endocarditis issued by the American Heart Association in 2007. One author helped produce European Society of Cardiology endocarditis guidelines in 2009, and also acted as a consultant to NICE during the drafting of the 2008 guidelines on antibiotic prophylaxis in endocarditis.

The number of prescriptions for antibiotic prophylaxis before invasive dental procedures has dropped sharply in England since 2008, while the incidence of infective endocarditis has risen significantly in the same time period, researchers found.

A study led by Dr. Martin Thornhill of the University of Sheffield (England) School of Clinical Dentistry, and published online Nov. 18 in the Lancet (doi: 10.1016/S0140-6736(14)62007-9) showed that after the National Institute for Health and Care Excellence issued guidelines against antibiotic prophylaxis, even for patients at high risk of endocarditis, prescriptions fell precipitously from a mean 10,900 per month in 2004-2008 in England to a mean 2,236 a month between April 2008 and April 2013, with only 1,235 issued in the last month of the study period. The NICE guidance, which went further than other published recommendations that have aimed to limit, but not eliminate, the use of antibiotic prophylaxis as a form of endocarditis prevention, cited the absence of a robust evidence base supporting its effectiveness, and also the risk of adverse drug reactions.

Dr. Thornhill and his colleagues reviewed both national prescription records and hospital discharge records for patients with a primary diagnosis of infective endocarditis. Prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell significantly after introduction of the NICE guidance.

The incidence of infective endocarditis, in contrast, rose by 0.11 cases per 10 million people per month following the 2008 guidance (95% confidence interval, 0.05-0.16; P < .0001). By March 2013, the researchers found that there were 34.9 more cases per month than would have been expected had the previous trend continued (95% CI, 7.9-61.9). Moreover, the increase was significant for patients determined to be at low or moderate risk as well as for those deemed high risk. The researchers did not find a statistically significant increase in endocarditis-related mortality corresponding to the drop in prescriptions.

Dr. Thornhill and his colleagues cautioned that their results did not establish a causal association between the drop in prescriptions and the rise in cases, and that further investigations were now warranted.

The study was funded by Heart Research UK, Simplyhealth, and the U.S. National Institutes of Health. Two of its authors were involved in guidelines on infective endocarditis issued by the American Heart Association in 2007. One author helped produce European Society of Cardiology endocarditis guidelines in 2009, and also acted as a consultant to NICE during the drafting of the 2008 guidelines on antibiotic prophylaxis in endocarditis.

The number of prescriptions for antibiotic prophylaxis before invasive dental procedures has dropped sharply in England since 2008, while the incidence of infective endocarditis has risen significantly in the same time period, researchers found.

A study led by Dr. Martin Thornhill of the University of Sheffield (England) School of Clinical Dentistry, and published online Nov. 18 in the Lancet (doi: 10.1016/S0140-6736(14)62007-9) showed that after the National Institute for Health and Care Excellence issued guidelines against antibiotic prophylaxis, even for patients at high risk of endocarditis, prescriptions fell precipitously from a mean 10,900 per month in 2004-2008 in England to a mean 2,236 a month between April 2008 and April 2013, with only 1,235 issued in the last month of the study period. The NICE guidance, which went further than other published recommendations that have aimed to limit, but not eliminate, the use of antibiotic prophylaxis as a form of endocarditis prevention, cited the absence of a robust evidence base supporting its effectiveness, and also the risk of adverse drug reactions.

Dr. Thornhill and his colleagues reviewed both national prescription records and hospital discharge records for patients with a primary diagnosis of infective endocarditis. Prescriptions of antibiotic prophylaxis for the prevention of infective endocarditis fell significantly after introduction of the NICE guidance.

The incidence of infective endocarditis, in contrast, rose by 0.11 cases per 10 million people per month following the 2008 guidance (95% confidence interval, 0.05-0.16; P < .0001). By March 2013, the researchers found that there were 34.9 more cases per month than would have been expected had the previous trend continued (95% CI, 7.9-61.9). Moreover, the increase was significant for patients determined to be at low or moderate risk as well as for those deemed high risk. The researchers did not find a statistically significant increase in endocarditis-related mortality corresponding to the drop in prescriptions.

Dr. Thornhill and his colleagues cautioned that their results did not establish a causal association between the drop in prescriptions and the rise in cases, and that further investigations were now warranted.

The study was funded by Heart Research UK, Simplyhealth, and the U.S. National Institutes of Health. Two of its authors were involved in guidelines on infective endocarditis issued by the American Heart Association in 2007. One author helped produce European Society of Cardiology endocarditis guidelines in 2009, and also acted as a consultant to NICE during the drafting of the 2008 guidelines on antibiotic prophylaxis in endocarditis.

Bronchiolitis is the most common cause of hospitalization among infants during the first 12 months of life. Approximately 100,000 bronchiolitis admissions occur annually in children in the United States, at an estimated cost of $1.73 billion. The American Academy of Pediatrics recently published new guidelines for the diagnosis, management, and prevention of bronchiolitis in children younger than 2 years.

Diagnosis

Diagnosis is based on patient history and physical examination. The course and severity of bronchiolitis vary, ranging from mild disease with simple runny nose and cough, to transient apneic events, and on to progressive respiratory distress secondary to airway obstruction. Management of bronchiolitis must be determined in the context of increased risk factors for severe disease, including age less than 12 weeks, history of prematurity, underlying cardiopulmonary disease, and immunodeficiency. Current evidence does not support routine labs or diagnostic imaging as helping with risk assessment. Abnormalities on chest x-ray, which are common in children with bronchiolitis, do reliably predict severity of disease, so chest x-rays are only indicated when another etiology of respiratory distress such as pneumothorax or pneumonia is a concern. Routine virologic testing is not recommended, as it does not appear to aid in guiding the treatment of the child with bronchiolitis.

Management

Randomized trials have not shown any benefit from alpha- or beta-adrenergic agonist administration. Bronchodilators can lessen symptoms scores, but their use does not speed disease resolution or decrease the length of stay or need for hospitalization. A Cochrane analysis concluded that there was no benefit to giving bronchodilators to infants with bronchiolitis. Adverse effects included tachycardia, tremors, and cost, all of which outweigh potential benefits. While previous versions of the AAP guidelines recommended bronchodilators as an option, the 2014 guidelines state, “Clinicians should not administer albuterol (or salbutamol) to infants and children with a diagnosis of bronchiolitis (Evidence Quality: B; Recommendation Strength: Strong).” It is noted that there may be some children who have reversible airway obstruction, but it is impossible to tell ahead of time who they are; and due to the variability of the disease, it is even hard to tell in whom the medication is effective. It is acknowledged that children with severe disease were usually excluded from the studies of bronchodilators. Epinephrine should also not be used except potentially as a rescue agent in severe disease.

Nebulized hypertonic saline appears to increase mucociliary clearance. Nebulized 3% saline is safe and effective in improving symptoms of mild to moderate bronchiolitis when measured after 24 hours of use, and it possibly decreases the length of hospital stay in studies where the length of stay exceeded 3 days. The guidelines conclude that hypertonic saline may be helpful to infants who are hospitalized with bronchiolitis, but probably is of very little benefit when administered in an emergency department setting.

Although there is strong evidence of benefit of systemic corticosteroids in asthma and croup, there is no evidence that systemic corticosteroids provide benefit in bronchiolitis. In addition, there is some evidence that corticosteroids may prolong viral shedding. For these reasons, the 2014 guidelines state, “Clinicians should not administer systemic corticosteroids to infants with a diagnosis of bronchiolitis in any setting (Evidence Quality: A; Recommendation Strength: Strong Recommendation).”

Physicians may choose not to give supplemental oxygen if oxyhemoglobin saturation is more than 90%, and also not to use continuous pulse oximetry given that it is prone to errors of measurement. Chest physiotherapy is not recommended. Antibiotics use is not recommended unless there is a concomitant bacterial infection or strong suspicion of one.

Prevention

The guidelines advise that palivizumab (Synagis) should not be given to otherwise healthy infants with a gestational age of 29 weeks or greater. Palivizumab should be given in the first year of life to infants with hemodynamically significant heart disease or chronic lung disease of prematurity (defined as infants of less than 32 weeks’ gestation who required more than 21% oxygen for at least the first 28 days of life). Infants who qualify for palivizumab at the start of respiratory syncytial virus season should receive a maximum of five monthly doses (15 mg/kg per dose) of palivizumab or until the end of RSV season, whichever comes first. Because of the low risk of RSV hospitalization in the second year of life, palivizumab prophylaxis is not recommended for children in the second year of life, unless the child meets the criteria for chronic lung disease and continues to require supplemental oxygen or is on chronic corticosteroids or diuretic therapy within 6 months of the onset of the second RSV season.

Reference

Ralston S.L. "Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis." Pediatrics 2014;134:e1474-502).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Rastogi is a third-year resident in the family medicine residency program at Abington Memorial Hospital.

Bronchiolitis is the most common cause of hospitalization among infants during the first 12 months of life. Approximately 100,000 bronchiolitis admissions occur annually in children in the United States, at an estimated cost of $1.73 billion. The American Academy of Pediatrics recently published new guidelines for the diagnosis, management, and prevention of bronchiolitis in children younger than 2 years.

Diagnosis

Diagnosis is based on patient history and physical examination. The course and severity of bronchiolitis vary, ranging from mild disease with simple runny nose and cough, to transient apneic events, and on to progressive respiratory distress secondary to airway obstruction. Management of bronchiolitis must be determined in the context of increased risk factors for severe disease, including age less than 12 weeks, history of prematurity, underlying cardiopulmonary disease, and immunodeficiency. Current evidence does not support routine labs or diagnostic imaging as helping with risk assessment. Abnormalities on chest x-ray, which are common in children with bronchiolitis, do reliably predict severity of disease, so chest x-rays are only indicated when another etiology of respiratory distress such as pneumothorax or pneumonia is a concern. Routine virologic testing is not recommended, as it does not appear to aid in guiding the treatment of the child with bronchiolitis.

Management

Randomized trials have not shown any benefit from alpha- or beta-adrenergic agonist administration. Bronchodilators can lessen symptoms scores, but their use does not speed disease resolution or decrease the length of stay or need for hospitalization. A Cochrane analysis concluded that there was no benefit to giving bronchodilators to infants with bronchiolitis. Adverse effects included tachycardia, tremors, and cost, all of which outweigh potential benefits. While previous versions of the AAP guidelines recommended bronchodilators as an option, the 2014 guidelines state, “Clinicians should not administer albuterol (or salbutamol) to infants and children with a diagnosis of bronchiolitis (Evidence Quality: B; Recommendation Strength: Strong).” It is noted that there may be some children who have reversible airway obstruction, but it is impossible to tell ahead of time who they are; and due to the variability of the disease, it is even hard to tell in whom the medication is effective. It is acknowledged that children with severe disease were usually excluded from the studies of bronchodilators. Epinephrine should also not be used except potentially as a rescue agent in severe disease.

Nebulized hypertonic saline appears to increase mucociliary clearance. Nebulized 3% saline is safe and effective in improving symptoms of mild to moderate bronchiolitis when measured after 24 hours of use, and it possibly decreases the length of hospital stay in studies where the length of stay exceeded 3 days. The guidelines conclude that hypertonic saline may be helpful to infants who are hospitalized with bronchiolitis, but probably is of very little benefit when administered in an emergency department setting.

Although there is strong evidence of benefit of systemic corticosteroids in asthma and croup, there is no evidence that systemic corticosteroids provide benefit in bronchiolitis. In addition, there is some evidence that corticosteroids may prolong viral shedding. For these reasons, the 2014 guidelines state, “Clinicians should not administer systemic corticosteroids to infants with a diagnosis of bronchiolitis in any setting (Evidence Quality: A; Recommendation Strength: Strong Recommendation).”

Physicians may choose not to give supplemental oxygen if oxyhemoglobin saturation is more than 90%, and also not to use continuous pulse oximetry given that it is prone to errors of measurement. Chest physiotherapy is not recommended. Antibiotics use is not recommended unless there is a concomitant bacterial infection or strong suspicion of one.

Prevention

The guidelines advise that palivizumab (Synagis) should not be given to otherwise healthy infants with a gestational age of 29 weeks or greater. Palivizumab should be given in the first year of life to infants with hemodynamically significant heart disease or chronic lung disease of prematurity (defined as infants of less than 32 weeks’ gestation who required more than 21% oxygen for at least the first 28 days of life). Infants who qualify for palivizumab at the start of respiratory syncytial virus season should receive a maximum of five monthly doses (15 mg/kg per dose) of palivizumab or until the end of RSV season, whichever comes first. Because of the low risk of RSV hospitalization in the second year of life, palivizumab prophylaxis is not recommended for children in the second year of life, unless the child meets the criteria for chronic lung disease and continues to require supplemental oxygen or is on chronic corticosteroids or diuretic therapy within 6 months of the onset of the second RSV season.

Reference

Ralston S.L. "Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis." Pediatrics 2014;134:e1474-502).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Rastogi is a third-year resident in the family medicine residency program at Abington Memorial Hospital.

Bronchiolitis is the most common cause of hospitalization among infants during the first 12 months of life. Approximately 100,000 bronchiolitis admissions occur annually in children in the United States, at an estimated cost of $1.73 billion. The American Academy of Pediatrics recently published new guidelines for the diagnosis, management, and prevention of bronchiolitis in children younger than 2 years.

Diagnosis

Diagnosis is based on patient history and physical examination. The course and severity of bronchiolitis vary, ranging from mild disease with simple runny nose and cough, to transient apneic events, and on to progressive respiratory distress secondary to airway obstruction. Management of bronchiolitis must be determined in the context of increased risk factors for severe disease, including age less than 12 weeks, history of prematurity, underlying cardiopulmonary disease, and immunodeficiency. Current evidence does not support routine labs or diagnostic imaging as helping with risk assessment. Abnormalities on chest x-ray, which are common in children with bronchiolitis, do reliably predict severity of disease, so chest x-rays are only indicated when another etiology of respiratory distress such as pneumothorax or pneumonia is a concern. Routine virologic testing is not recommended, as it does not appear to aid in guiding the treatment of the child with bronchiolitis.

Management

Randomized trials have not shown any benefit from alpha- or beta-adrenergic agonist administration. Bronchodilators can lessen symptoms scores, but their use does not speed disease resolution or decrease the length of stay or need for hospitalization. A Cochrane analysis concluded that there was no benefit to giving bronchodilators to infants with bronchiolitis. Adverse effects included tachycardia, tremors, and cost, all of which outweigh potential benefits. While previous versions of the AAP guidelines recommended bronchodilators as an option, the 2014 guidelines state, “Clinicians should not administer albuterol (or salbutamol) to infants and children with a diagnosis of bronchiolitis (Evidence Quality: B; Recommendation Strength: Strong).” It is noted that there may be some children who have reversible airway obstruction, but it is impossible to tell ahead of time who they are; and due to the variability of the disease, it is even hard to tell in whom the medication is effective. It is acknowledged that children with severe disease were usually excluded from the studies of bronchodilators. Epinephrine should also not be used except potentially as a rescue agent in severe disease.

Nebulized hypertonic saline appears to increase mucociliary clearance. Nebulized 3% saline is safe and effective in improving symptoms of mild to moderate bronchiolitis when measured after 24 hours of use, and it possibly decreases the length of hospital stay in studies where the length of stay exceeded 3 days. The guidelines conclude that hypertonic saline may be helpful to infants who are hospitalized with bronchiolitis, but probably is of very little benefit when administered in an emergency department setting.

Although there is strong evidence of benefit of systemic corticosteroids in asthma and croup, there is no evidence that systemic corticosteroids provide benefit in bronchiolitis. In addition, there is some evidence that corticosteroids may prolong viral shedding. For these reasons, the 2014 guidelines state, “Clinicians should not administer systemic corticosteroids to infants with a diagnosis of bronchiolitis in any setting (Evidence Quality: A; Recommendation Strength: Strong Recommendation).”

Physicians may choose not to give supplemental oxygen if oxyhemoglobin saturation is more than 90%, and also not to use continuous pulse oximetry given that it is prone to errors of measurement. Chest physiotherapy is not recommended. Antibiotics use is not recommended unless there is a concomitant bacterial infection or strong suspicion of one.

Prevention

The guidelines advise that palivizumab (Synagis) should not be given to otherwise healthy infants with a gestational age of 29 weeks or greater. Palivizumab should be given in the first year of life to infants with hemodynamically significant heart disease or chronic lung disease of prematurity (defined as infants of less than 32 weeks’ gestation who required more than 21% oxygen for at least the first 28 days of life). Infants who qualify for palivizumab at the start of respiratory syncytial virus season should receive a maximum of five monthly doses (15 mg/kg per dose) of palivizumab or until the end of RSV season, whichever comes first. Because of the low risk of RSV hospitalization in the second year of life, palivizumab prophylaxis is not recommended for children in the second year of life, unless the child meets the criteria for chronic lung disease and continues to require supplemental oxygen or is on chronic corticosteroids or diuretic therapy within 6 months of the onset of the second RSV season.

Reference

Ralston S.L. "Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis." Pediatrics 2014;134:e1474-502).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Rastogi is a third-year resident in the family medicine residency program at Abington Memorial Hospital.

ANSWER
The radiograph shows two areas of concern: Within the apex of the right lung, there is a vague haziness that, in the setting of trauma, is suggestive of a contusion or even aspiration pneumonia. Another possibility is some sort of neoplasm. In addition, the patient has what appears to be a rounded density within the left lung, also suspicious for neoplasm. Additional work-up with contrast-enhanced CT is warranted.

Through further questioning, the patient denies any current symptoms or previous/recent diagnosis of cancer. CT of the chest confirmed the presence of masses in the right upper and left lower lobes. Subsequent biopsy was consistent with a moderate to poorly differentiated squamous cell carcinoma.

ANSWER
The radiograph shows two areas of concern: Within the apex of the right lung, there is a vague haziness that, in the setting of trauma, is suggestive of a contusion or even aspiration pneumonia. Another possibility is some sort of neoplasm. In addition, the patient has what appears to be a rounded density within the left lung, also suspicious for neoplasm. Additional work-up with contrast-enhanced CT is warranted.

Through further questioning, the patient denies any current symptoms or previous/recent diagnosis of cancer. CT of the chest confirmed the presence of masses in the right upper and left lower lobes. Subsequent biopsy was consistent with a moderate to poorly differentiated squamous cell carcinoma.

ANSWER
The radiograph shows two areas of concern: Within the apex of the right lung, there is a vague haziness that, in the setting of trauma, is suggestive of a contusion or even aspiration pneumonia. Another possibility is some sort of neoplasm. In addition, the patient has what appears to be a rounded density within the left lung, also suspicious for neoplasm. Additional work-up with contrast-enhanced CT is warranted.

Through further questioning, the patient denies any current symptoms or previous/recent diagnosis of cancer. CT of the chest confirmed the presence of masses in the right upper and left lower lobes. Subsequent biopsy was consistent with a moderate to poorly differentiated squamous cell carcinoma.

Editor in Chief Robert L. Barbieri, MD, provides an overview of three articles appearing in OBG Management’s November 2014 issue. Listen to his take on why these articles are of particular importance to women’s health professionals.

Access all of the articles in the November 2014 issue here.

Editor in Chief Robert L. Barbieri, MD, provides an overview of three articles appearing in OBG Management’s November 2014 issue. Listen to his take on why these articles are of particular importance to women’s health professionals.

Access all of the articles in the November 2014 issue here.

Editor in Chief Robert L. Barbieri, MD, provides an overview of three articles appearing in OBG Management’s November 2014 issue. Listen to his take on why these articles are of particular importance to women’s health professionals.

Access all of the articles in the November 2014 issue here.

CHICAGO – Once-daily, low-dose aspirin failed to reduce the combined outcome of cardiovascular death, nonfatal stroke, and nonfatal MI in elderly Japanese patients with atherosclerotic risk factors in the JPPP study.

The cumulative rate of the composite primary outcome was 2.77% with 100 mg/day of aspirin and 2.96% with no aspirin (HR, 0.94; P = .54), Dr. Kazuyuki Shimada reported at the American Heart Association scientific sessions.

However, patients randomized to aspirin did have reductions of 47% and 43% in the individual endpoints of nonfatal MI and transient ischemic attack, respectively.

These benefits had to be weighed against an 85% increase in serious extracranial hemorrhage in those on aspirin, according to results of the Japanese Primary Prevention Project (JPPP), simultaneously published online in JAMA (doi:10.1001/jama.2014.15690).

How generalizable are these results, and is this the end of the road for aspirin in primary prevention? We asked several experts, including invited discussant Dr. Dorairaj Prabhakaran of the Public Health Foundation of India, Dr. Karol Watson of the UCLA Center for Cholesterol and Lipid Management, and Dr. Donald Lloyd-Jonesof Northwestern University in Chicago.

The study was sponsored by the Japanese Ministry of Health, Labor, and Welfare, and the Waksman Foundation of Japan. Bayer Yakuhin provided the aspirin. Dr. Shimada reported honorarium from MSD, Shionogi, Takeda, Daiichi-Sankyo, and Dainippon-Sumitomo, and serving as a consultant/advisory board member for Omron.

Dr. Prabhakaran and Dr. Jones reported no conflicting interests. Dr. Watson reported participating in the clinical trials adjudication committee for Merck.

[email protected]

CHICAGO – Once-daily, low-dose aspirin failed to reduce the combined outcome of cardiovascular death, nonfatal stroke, and nonfatal MI in elderly Japanese patients with atherosclerotic risk factors in the JPPP study.

The cumulative rate of the composite primary outcome was 2.77% with 100 mg/day of aspirin and 2.96% with no aspirin (HR, 0.94; P = .54), Dr. Kazuyuki Shimada reported at the American Heart Association scientific sessions.

However, patients randomized to aspirin did have reductions of 47% and 43% in the individual endpoints of nonfatal MI and transient ischemic attack, respectively.

These benefits had to be weighed against an 85% increase in serious extracranial hemorrhage in those on aspirin, according to results of the Japanese Primary Prevention Project (JPPP), simultaneously published online in JAMA (doi:10.1001/jama.2014.15690).

How generalizable are these results, and is this the end of the road for aspirin in primary prevention? We asked several experts, including invited discussant Dr. Dorairaj Prabhakaran of the Public Health Foundation of India, Dr. Karol Watson of the UCLA Center for Cholesterol and Lipid Management, and Dr. Donald Lloyd-Jonesof Northwestern University in Chicago.

The study was sponsored by the Japanese Ministry of Health, Labor, and Welfare, and the Waksman Foundation of Japan. Bayer Yakuhin provided the aspirin. Dr. Shimada reported honorarium from MSD, Shionogi, Takeda, Daiichi-Sankyo, and Dainippon-Sumitomo, and serving as a consultant/advisory board member for Omron.

Dr. Prabhakaran and Dr. Jones reported no conflicting interests. Dr. Watson reported participating in the clinical trials adjudication committee for Merck.

[email protected]

CHICAGO – Once-daily, low-dose aspirin failed to reduce the combined outcome of cardiovascular death, nonfatal stroke, and nonfatal MI in elderly Japanese patients with atherosclerotic risk factors in the JPPP study.

The cumulative rate of the composite primary outcome was 2.77% with 100 mg/day of aspirin and 2.96% with no aspirin (HR, 0.94; P = .54), Dr. Kazuyuki Shimada reported at the American Heart Association scientific sessions.

However, patients randomized to aspirin did have reductions of 47% and 43% in the individual endpoints of nonfatal MI and transient ischemic attack, respectively.

These benefits had to be weighed against an 85% increase in serious extracranial hemorrhage in those on aspirin, according to results of the Japanese Primary Prevention Project (JPPP), simultaneously published online in JAMA (doi:10.1001/jama.2014.15690).

How generalizable are these results, and is this the end of the road for aspirin in primary prevention? We asked several experts, including invited discussant Dr. Dorairaj Prabhakaran of the Public Health Foundation of India, Dr. Karol Watson of the UCLA Center for Cholesterol and Lipid Management, and Dr. Donald Lloyd-Jonesof Northwestern University in Chicago.

The study was sponsored by the Japanese Ministry of Health, Labor, and Welfare, and the Waksman Foundation of Japan. Bayer Yakuhin provided the aspirin. Dr. Shimada reported honorarium from MSD, Shionogi, Takeda, Daiichi-Sankyo, and Dainippon-Sumitomo, and serving as a consultant/advisory board member for Omron.

Dr. Prabhakaran and Dr. Jones reported no conflicting interests. Dr. Watson reported participating in the clinical trials adjudication committee for Merck.

[email protected]

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A 3-month course of levofloxacin after kidney transplant didn’t prevent BK virus from colonizing the urine, setting the stage for viremia in these immunosuppressed patients.

However, the antibiotic was associated with a significant 75% increase in the risk of developing a quinolone-resistant infection, compared with placebo, Dr. Greg A. Knoll and his colleagues reported in the Nov. 15 issue of JAMA (2014 [doi:10.1001/jama.2014.14721]).In a randomized trial of 154 kidney transplant patients, BK virus developed in 29% of those taking levofloxacin and in 33% of those taking placebo, a nonsignificant difference, coauthor Greg Knoll said at a late-breaking poster session during Kidney Week 2014, where the study was simultaneously presented.Levofloxacin, a quinolone antibiotic, has been shown to have some antiviral properties, especially against polyomaviruses – including BK virus, said Dr. Knoll of the University of Ottawa and the Ottawa Hospital.

Almost everyone harbors latent BK virus, Dr. Knoll said in an interview. It sometimes causes mild cold symptoms when first contracted, but often there’s no indication of illness at all. “If you’re otherwise healthy, it goes dormant and stays that way,” he noted.

But it can cause serious problems in immunocompromised patients, especially those with a kidney transplant. “BK virus tends to live in the bladder and urinary tract,” Dr. Knoll said, “So, when it reactivates, that’s the site where it does its damage.”

The virus will first appear in the urine, and then follow a logical progression through the ureters and into the kidney. If it remains unchecked, it causes very severe kidney inflammation. That inflammation “looks a lot like rejection,” Dr. Knoll said. “In fact, for years, we were very confused about this and ended up giving patients with BK viremia more immunosuppressants – when we actually should have been giving them less.”

It’s been tough to find the right balance of treatment to combat BK infections and immunosuppressants to maintain the allograft, he said.

Some retrospective studies suggested that quinolone antibiotics – including levofloxacin – could help fight cytomegalovirus infections and viral pneumonia, and decrease inflammatory markers in the urine of kidney transplant patients. “This was the little bit of evidence we needed to launch this study,” Dr. Knoll said.

The study investigators examined the time to first occurrence of BK viruria within the first year of transplant. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival.

Patients’ mean age was 48 years. They had undergone kidney transplant for a variety of reasons, including glomerulonephritis, polycystic kidney disease, diabetes, and hypertension. Comorbidities were common and included diabetes, history of cancer, cardiovascular disease, and hepatitis C and B infections. Most had received a living donor transplant (60%); the rest had kidneys from deceased donors.

Treatment began soon after transplantation. Patients were randomized to a target dose of 500 mg/day levofloxacin for 3 months. The mean length of follow-up was 46 weeks.

The primary outcome of BK viruria occurred in 46 patients – 29% of those in the levofloxacin group and 33.3% of those in the placebo group. That translated to a nonsignificant increased viruria risk of about 4%.

The time to viruria was not significantly different between the groups, with nearly 25% of each group developing it by 25 weeks. Nor was there a between-group difference in the occurrence of sustained viruria.

The secondary endpoint of BK viremia occurred in 7.9% of the levofloxacin group and 11.5% of the placebo group, also a nonsignificant finding. Infections were similar in both group, occurring in 59% of those taking levofloxacin and 45% of those taking placebo. The types of infections were similar: urinary tract/pyelonephritis (37% active vs. 38% placebo); cytomegalovirus (35% vs. 33%); pneumonia (3.5% vs. 1.7%); cellulitis (2.7% vs. 0.8%); and line infections and bacteremias, which were less than 1% in each group. No patient developed a Clostridium difficile infection.

However, patients taking levofloxacin developed significantly more quinolone-resistant infections (46.7% vs. 32.6%). Among isolates that are usually sensitive to quinolones, those patients taking the study drug were 75% more likely than were placebo patients to have a resistant strain (58.3% vs. 33.3%).

Because quinolones are an important part of infection prophylaxis in kidney transplant patients, “This would have significant implications for the management of common infections after transplantation,” Dr. Knoll said. “Our results don’t support the use of levofloxacin for preventing infections in patients with kidney transplants.”

The researchers were disappointed in the outcomes, “but there were people doing this already, and now we have the evidence to tell them to stop,” Dr. Knoll explained. “Of course, we are back to square one, with no proven treatment.”

He added that the quinolones remain critical antibiotics for kidney transplant patients – and that the study in no way suggests that should change.

“We were using these daily for 3 months, and that’s where we got into the resistance trouble,” he said. “That’s not anything like a 7- to 10-day course for a urinary tract infection.”

Dr. Knoll reported receiving investigator-initiated research grants from Astellas Canada and Pfizer Canada. The other coauthors had a number of financial relationships with pharmaceutical companies.

[email protected]

On Twitter @alz_gal