The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 45-year-old woman presented to the emergency department with 2 days of generalized, progressive weakness. Her ability to walk and perform daily chores was increasingly limited. On the morning of her presentation, she was unable to stand up without falling.

A complaint of weakness must be classified as either functional weakness related to a systemic process or true neurologic weakness from dysfunction of the central nervous system (eg, brain, spinal cord) or peripheral nervous system (eg, anterior horn cell, nerve, neuromuscular junction, or muscle). More information on her clinical course and a detailed neurologic exam will help clarify this key branch point.

She was 2 weeks status-post laparoscopic Roux-en-Y gastric bypass and gastric band removal performed in Europe.  Immediately following surgery, she experienced abdominal discomfort and nausea with occasional nonbloody, nonbilious emesis, attributed to expected postoperative anatomical changes. She developed a postoperative pneumonia treated with amoxicillin-clavulanate.  She tolerated her flight back to the United States, but her abdominal discomfort persisted and she had minimal oral intake due to her nausea.

Functional weakness may stem from hypovolemia from insufficient oral intake, anemia related to the recent surgery, electrolyte abnormalities, chronic nutritional issues associated with obesity and weight-reduction surgery, and pneumonia. Prolonged air travel, obesity, and recent surgery place her at risk for venous thromboembolism, which may manifest as reduced exercise tolerance. Nausea, vomiting, and abdominal pain persisting for 2 weeks after a Roux-en-Y gastric bypass surgery raises several concerns, including gastric remnant distension (although hiccups are often prominent); stomal stenosis, which typically presents several weeks after surgery; marginal ulceration; or infection at the surgical site or from an anastomotic leak. She may also have a surgery- or medication-related myopathy.

The patient had a history of obesity, hypertension, hyperlipidemia, migraine headaches, and nonalcoholic steatohepatitis. Four years previously, she had undergone gastric banding complicated by band migration and ulceration at the banding site. Her medications were amlodipine, losartan, ranitidine, acetaminophen, and nadroparin for venous thromboembolism prophylaxis during her flight. She denied alcohol, tobacco, or illicit drug use. On further questioning, she reported diaphoresis, mild dyspnea, loose stools, and a sensation of numbness and “heaviness” in her arms. Her abdominal pain was limited to the surgical incision and was controlled with acetaminophen. She denied fevers, cough, chest pain, diplopia, or dysphagia.

Heaviness in both arms could result from an acutely presenting myopathic or neuropathic process, while the coexistence of numbness suggests a sensorimotor polyneuropathy. Obesity and gastric bypass surgery increase her nutritional risk, and thiamine deficiency may present as an acute axonal polyneuropathy (ie, beriberi). Unlike vitamin B12 deficiency, which may take years to develop, thiamine deficiency can present within 4 weeks of gastric bypass surgery. Her dyspnea may be a manifestation of diaphragmatic weakness, although her ostensibly treated pneumonia or as of yet unproven postoperative anemia may be contributing. Chemoprophylaxis mitigates her risk of venous thromboembolism, which is, nonetheless, unlikely to account for the gastrointestinal symptoms and upper extremity weakness. If she is continuing to take amlodipine and losartan but has become volume-depleted, hypotension may be contributing to the generalized weakness.

Physical examination revealed an obese, pale and diaphoretic woman. Her temperature was 36.9°C, heart rate 77 beats per minute, blood pressure 158/90 mm Hg, respiratory rate 28 breaths per minute, and O₂ saturation 99% on ambient air. She had no cervical lymphadenopathy and a normal thyroid exam. There were no murmurs on cardiac examination, and jugular venous pressure was estimated at 10 cm of water. Her lung sounds were clear. Her abdomen was soft, nondistended, with localized tenderness and fluctuance around the midline surgical incision with a small amount of purulent drainage. She was alert and oriented to name, date, place, and situation. Cranial nerves II through XII were grossly intact. Strength was 4/5 in bilateral biceps, triceps and distal hand and finger extensors, 3/5 in bilateral deltoids. Strength in hip flexors was 4/5 and it was 5/5 in distal lower extremities. Sensation was intact to pinprick in upper and lower extremities. Biceps reflexes were absent; patellar and ankle reflexes were 1+ and symmetric. The remainder of the physical exam was unremarkable.

The patient has symmetric proximal muscle weakness with upper extremity predominance and preserved strength in her distal lower extremities. A myopathy could explain this pattern of weakness, further substantiated by absent reflexes and reportedly intact sensation. Subacute causes of myopathy include hypokalemia, hyperkalemia, toxic myopathies from medications, or infection-induced rhabdomyolysis. However, she does not report muscle pain, and the loss of reflexes is faster than would be expected with a myopathy. A more thorough sensory examination would inform the assessment of potential neuropathic processes. Guillain-Barré syndrome (GBS) is possible; it most commonly presents as an ascending, distally predominant acute inflammatory demyelinating polyneuropathy (AIDP), although her upper extremity weakness predominates and there are no clear sensory changes. It remains to be determined how her wound infection might relate to her overall presentation.

Her white blood cell count was 12,600/μL (reference range: 3,400-10,000/μL), hemoglobin was 10.2 g/dL, and platelet count was 698,000/μL. Mean corpuscular volume was 86 fL. Serum chemistries were: sodium 138 mEq/L, potassium 3.8 mEq/L, chloride 106 mmol/L, bicarbonate 15 mmol/L, blood urea nitrogen 5 mg/dL, creatinine 0.65 mg/dL, glucose 125 mg/dL, calcium 8.3 mg/dL, magnesium 1.9 mg/dL, phosphorous 2.4 mg/dL, and lactate 1.8 mmol/L (normal: < 2.0 mmol/L). Creatinine kinase (CK), liver function tests, and coagulation panel were normal. Total protein was 6.4 g/dL, and albumin was 2.7 g/dL. Venous blood gas was: pH 7.39 and PCO₂ 25 mmHg. Urinalysis revealed ketones. Blood and wound cultures were sent for evaluation. A chest x-ray was unremarkable. An electrocardiogram showed normal sinus rhythm. Computed tomography (CT) of the abdomen and pelvis revealed a multiloculated rim-enhancing fluid collection in the anterior abdominal wall (Figure 1).

She does not have any notable electrolyte derangements that would account for her weakness, and the normal creatinine kinase lowers the probability of a myopathy and excludes rhabdomyolysis. Progression of weakness from proximal to distal muscles in a symmetric fashion is consistent with botulism, and she has an intra-abdominal wound infection that could be harboring Clostridium botulinum. Nonetheless, the normal cranial nerve exam and the rarity of botulism occurring with surgical wounds argue against this diagnosis. She should receive intravenous (IV) thiamine for the possibility of beriberi. A lumbar puncture should be performed to assess for albuminocytologic dissociation, which can be seen in patients with GBS.

The patient received high-dose IV thiamine, IV vancomycin, IV piperacillin-tazobactam, and acetaminophen. Over the subsequent 4 hours, her anion gap acidosis worsened. She declined arterial puncture. Repeat venous blood gas was: pH 7.22, PCO2 28 mmHg, and bicarbonate 11 mmol/L. Lactate and glucose were normal. Serum osmolarity was 292 mmol/kg (reference range: 283-301 mmol/kg). She was started on an IV sodium bicarbonate infusion without improvement in her acidemia.

An acute anion gap metabolic acidosis suggests a limited differential diagnosis that includes lactic acidosis, D-lactic acidosis, severe starvation ketoacidosis, acute renal failure, salicylate, or other drug or poison ingestion. Starvation ketoacidosis may be contributing, but a bicarbonate value this low would be unusual. There is no history of alcohol use or other ingestions, and the normal serum osmolality and low osmolal gap (less than 10 mOsm/kg) argue against a poisoning with ethanol, ethylene glycol, or methanol. The initial combined anion gap metabolic acidosis and respiratory alkalosis is consistent with salicylate toxicity, but she does not report aspirin ingestion. Acetaminophen use in the setting of malnutrition or starvation physiology raises the possibility of 5-oxoproline accumulation.

Routine serum lactate does not detect D-lactate, which is produced by colonic bacteria and has been reported in short bowel syndrome and following intestinal bypass surgery. This may occur weeks to months after intestinal procedures, following ingestion of a heavy carbohydrate load, and almost invariably presents with altered mental status and increased anion gap metabolic acidosis, although generalized weakness has been reported.

A surgical consultant drained her wound infection. Fluid Gram stain was negative. D-lactate, salicylate and acetaminophen levels were undetectable. Thiamine pyrophosphate level was 229 nmol/L (reference range: 78-185 nmol/L). Acetaminophen was discontinued and N-acetylcysteine infusion was started for possible 5-oxoprolinemia. Her anion gap acidosis rapidly improved. Twelve hours after admission, she reported sudden onset of blurry vision. Her vital signs were: temperature 37^oC, heart rate 110 beats per minute, respiratory rate 40 breaths per minute, blood pressure 168/90, and oxygen saturation 100% on ambient air. Telemetry showed ventricular bigeminy. On examination, she was unable to abduct her right eye; muscle strength was 1/5 in all extremities; biceps, ankle, and patellar reflexes were absent.  

Her neurological deficits have progressed over hours to near complete paralysis, asymmetric cranial nerve paresis, and areflexia. Although botulism can cause blurred vision and absent deep tendon reflexes, patients almost always have symmetrical bulbar findings followed by descending paralysis. Should the “numbness” in her arms reported earlier represent undetected sensory deficits, this, too would be inconsistent with botulism.

A diagnosis of GBS ties together several aspects of her presentation and clinical course. Several variants show different patterns of weakness and may involve cranial nerves. Her tachypnea and dyspnea are concerning signs of potential impending respiratory failure. The ventricular bigeminy and mild hypertension could represent autonomic dysfunction that is seen in many cases of GBS.

She was intubated for airway protection. Computed tomography angiography and magnetic resonance imaging of her brain were normal. Cerebral spinal fluid analysis obtained through lumbar puncture showed the following: white blood cell count 3/μL, red blood cell count 11/μL, protein 63 mg/dL (reference range: 15-60mg/dL), and glucose 128 mg/dL (reference range: 40-80mg/dL).

The lumbar puncture is consistent with GBS given the slightly elevated protein and cell count well below 50/μL. Given the severity of her symptoms, treatment with IV immunoglobulin or plasmapheresis should be initiated. Nerve conduction studies (NCS) and electromyography (EMG) are indicated for diagnostic confirmation.

EMG and NCS revealed a severe sensorimotor polyneuropathy with demyelinating features including a conduction block at a noncompressible site, consistent with AIDP. Left sural nerve biopsy confirmed acute demyelinating and mild axonal neuropathy (Figure 2). On hospital day 2, treatment with IV immunoglobulins (IVIG) was initiated; however, she developed anaphylaxis following her second administration and subsequently received plasmapheresis. A tracheostomy was performed for respiratory muscle weakness, and she was discharged to a nursing facility. C. botulinum cultures from the wound eventually returned negative. Following her hospitalization, a serum 5-oxoproline level sent 10 hours after admission returned as elevated, confirming the additional diagnosis of 5-oxoprolinemia. On follow-up, she can sit up and feed herself without assistance, and her gait continues to improve with physical therapy.

This patient presented with rapidly progressive weakness that developed in the 2 weeks following bariatric surgery. In the postsurgical setting, patient complaints of weakness are commonly encountered and can pose a diagnostic challenge. Asthenia (ie, general loss of strength or energy) is frequently reported in the immediate postoperative period, and may result from the stress of surgery, pain, deconditioning, or infection. This must be distinguished from true neurologic weakness, which results from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, or muscle. The initial history can help elucidate the inciting events such as preceding surgery, infections or ingestions, and can also categorize the pattern of weakness. The neurologic examination can localize the pathology within the neuraxis. EMG and NCS can distinguish neuropathy from radiculopathy, and categorize the process as axonal, demyelinating, or mixed. In this case, the oculomotor weakness, sensory abnormalities and areflexia signaled a severe sensorimotor polyneuropathy, and EMG/NCS confirmed a demyelinating process consistent with GBS.

Guillain-Barré syndrome is an acute, immune-mediated polyneuropathy. Patients with GBS often present with a preceding respiratory or diarrheal illness; however, the stress of a recent surgery can serve as an inciting event. The syndrome, acute postgastric reduction surgery (APGARS) neuropathy, was introduced in the literature in 2002, describing 3 patients who presented with progressive vomiting, weakness, and hyporeflexia following bariatric surgery.¹ The term has been used to describe bariatric surgery patients who developed postoperative quadriparesis, cranial nerve deficits, and respiratory compromise.² Given the clinical heterogeneity in the literature with relation to APGARS, it is probable that the cases described could result from multiple etiologies. While GBS is purely immune-mediated and can be precipitated by the stress of surgery itself, postbariatric surgery patients are susceptible to many nutritional deficiencies that can lead to similar presentations.³ For example, thiamine (vitamin B1) and cobalamin (vitamin B12) deficiencies cause distinct postbariatric surgery neuropathies.⁴ Thiamine deficiency may manifest weeks to months after surgery and can rapidly progress, whereas cobalamin deficiency generally develops over 3 to 5 years. Both of these syndromes demonstrate an axonal pattern of nerve injury on EMG/NCS, in contrast to the demyelinating pattern typically seen in GBS. In addition, bariatric surgery patients are at higher risk for copper deficiency, which usually presents as a myeloneuropathy with subacute gait decline and upper motor neuron signs including spasticity.

Although GBS classically presents with symmetric ascending weakness and sensory abnormalities, it may manifest in myriad ways. Factors influencing the presentation include the types of nerve fibers involved (motor, sensory, cranial or autonomic), the predominant mode of injury (axonal vs demyelinating), and the presence or absence of alteration in consciousness.⁵ The most common form of GBS is AIDP. The classic presentation involves paresthesias in the fingertips and toes followed by lower extremity weakness that ascends over hours to days to involve the arms and potentially the muscles of respiration. A minority of patients with GBS first experience weakness in the upper extremities or facial muscles, and oculomotor involvement is rare.⁵ Pain is common and often severe.⁶ Dysautonomia affects most patients with GBS and may manifest as labile blood pressure or arrhythmias.⁵ Several variant GBS presentation patterns have been described, including acute motor axonal neuropathy, a pure motor form of GBS; ophthalmoplegia, ataxia, and areflexia in Miller Fisher syndrome; and alteration in consciousness, hyperreflexia, ataxia, and ophthalmoparesis in Bickerstaff’s brain stem encephalitis.⁵

Patients with GBS can progress rapidly to respiratory failure. Serial neurologic exams may signal the diagnosis and inform triage to the appropriate level of care. Measurement of bedside pulmonary function, including mean inspiratory force and functional vital capacity, help to determine if there is weakness of diaphragmatic muscles. Patients with signs or symptoms of diaphragmatic weakness require monitoring in an intensive care unit and potentially early intubation. Treatment with IVIG or plasmapheresis has been found to hasten recovery from GBS, including earlier improvement in muscle strength and a reduced need for mechanical ventilation.⁷ Treatment selection is based on available resources as both modalities are felt to be equivalent.The majority of patients with GBS make a full recovery over a period of weeks to months, although many have persistent motor weakness. Despite immunotherapy, up to 20% of patients remain severely disabled and approximately 5% die.⁸ Advanced age, rapid progression of weakness over a period of less than 72 hours, need for mechanical ventilation, and absent compound muscle action potentials on NCS are all associated with prolonged and incomplete recovery.⁹

This patient developed respiratory failure within 12 hours of hospitalization, prior to being diagnosed with GBS. Even in that short time, the treating clinicians encountered a series of clinical diversions. The initial proximal pattern of muscle weakness suggested a possible myopathic process; the wound infection introduced the possibility of botulism; obesity and recent bariatric surgery triggered concern for thiamine deficiency; and the anion gap acidosis from 5-oxoprolinemia created yet another clinical detour. While the path from presentation to diagnosis is seldom a straight line, when faced with rapidly progressive weakness, it is paramount to forge ahead with an efficient diagnostic evaluation and timely therapeutic intervention.

• A complaint of general weakness requires distinction between asthenia (ie, general loss of strength or energy) and true neuromuscular weakness from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, and/or muscle.
• Guillain-Barré syndrome may present in a variety of atypical fashions not limited to ascending, distally predominant weakness.
• Acute postgastric reduction surgery neuropathy should be considered in patients presenting with weakness, vomiting, or hyporeflexia after bariatric surgery.
• Acute inflammatory demyelinating polyneuropathy may rapidly progress to respiratory failure, and warrants serial neurologic examinations, monitoring of pulmonary function, and an expedited diagnostic evaluation.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 45-year-old woman presented to the emergency department with 2 days of generalized, progressive weakness. Her ability to walk and perform daily chores was increasingly limited. On the morning of her presentation, she was unable to stand up without falling.

A complaint of weakness must be classified as either functional weakness related to a systemic process or true neurologic weakness from dysfunction of the central nervous system (eg, brain, spinal cord) or peripheral nervous system (eg, anterior horn cell, nerve, neuromuscular junction, or muscle). More information on her clinical course and a detailed neurologic exam will help clarify this key branch point.

She was 2 weeks status-post laparoscopic Roux-en-Y gastric bypass and gastric band removal performed in Europe.  Immediately following surgery, she experienced abdominal discomfort and nausea with occasional nonbloody, nonbilious emesis, attributed to expected postoperative anatomical changes. She developed a postoperative pneumonia treated with amoxicillin-clavulanate.  She tolerated her flight back to the United States, but her abdominal discomfort persisted and she had minimal oral intake due to her nausea.

Functional weakness may stem from hypovolemia from insufficient oral intake, anemia related to the recent surgery, electrolyte abnormalities, chronic nutritional issues associated with obesity and weight-reduction surgery, and pneumonia. Prolonged air travel, obesity, and recent surgery place her at risk for venous thromboembolism, which may manifest as reduced exercise tolerance. Nausea, vomiting, and abdominal pain persisting for 2 weeks after a Roux-en-Y gastric bypass surgery raises several concerns, including gastric remnant distension (although hiccups are often prominent); stomal stenosis, which typically presents several weeks after surgery; marginal ulceration; or infection at the surgical site or from an anastomotic leak. She may also have a surgery- or medication-related myopathy.

The patient had a history of obesity, hypertension, hyperlipidemia, migraine headaches, and nonalcoholic steatohepatitis. Four years previously, she had undergone gastric banding complicated by band migration and ulceration at the banding site. Her medications were amlodipine, losartan, ranitidine, acetaminophen, and nadroparin for venous thromboembolism prophylaxis during her flight. She denied alcohol, tobacco, or illicit drug use. On further questioning, she reported diaphoresis, mild dyspnea, loose stools, and a sensation of numbness and “heaviness” in her arms. Her abdominal pain was limited to the surgical incision and was controlled with acetaminophen. She denied fevers, cough, chest pain, diplopia, or dysphagia.

Heaviness in both arms could result from an acutely presenting myopathic or neuropathic process, while the coexistence of numbness suggests a sensorimotor polyneuropathy. Obesity and gastric bypass surgery increase her nutritional risk, and thiamine deficiency may present as an acute axonal polyneuropathy (ie, beriberi). Unlike vitamin B12 deficiency, which may take years to develop, thiamine deficiency can present within 4 weeks of gastric bypass surgery. Her dyspnea may be a manifestation of diaphragmatic weakness, although her ostensibly treated pneumonia or as of yet unproven postoperative anemia may be contributing. Chemoprophylaxis mitigates her risk of venous thromboembolism, which is, nonetheless, unlikely to account for the gastrointestinal symptoms and upper extremity weakness. If she is continuing to take amlodipine and losartan but has become volume-depleted, hypotension may be contributing to the generalized weakness.

Physical examination revealed an obese, pale and diaphoretic woman. Her temperature was 36.9°C, heart rate 77 beats per minute, blood pressure 158/90 mm Hg, respiratory rate 28 breaths per minute, and O₂ saturation 99% on ambient air. She had no cervical lymphadenopathy and a normal thyroid exam. There were no murmurs on cardiac examination, and jugular venous pressure was estimated at 10 cm of water. Her lung sounds were clear. Her abdomen was soft, nondistended, with localized tenderness and fluctuance around the midline surgical incision with a small amount of purulent drainage. She was alert and oriented to name, date, place, and situation. Cranial nerves II through XII were grossly intact. Strength was 4/5 in bilateral biceps, triceps and distal hand and finger extensors, 3/5 in bilateral deltoids. Strength in hip flexors was 4/5 and it was 5/5 in distal lower extremities. Sensation was intact to pinprick in upper and lower extremities. Biceps reflexes were absent; patellar and ankle reflexes were 1+ and symmetric. The remainder of the physical exam was unremarkable.

The patient has symmetric proximal muscle weakness with upper extremity predominance and preserved strength in her distal lower extremities. A myopathy could explain this pattern of weakness, further substantiated by absent reflexes and reportedly intact sensation. Subacute causes of myopathy include hypokalemia, hyperkalemia, toxic myopathies from medications, or infection-induced rhabdomyolysis. However, she does not report muscle pain, and the loss of reflexes is faster than would be expected with a myopathy. A more thorough sensory examination would inform the assessment of potential neuropathic processes. Guillain-Barré syndrome (GBS) is possible; it most commonly presents as an ascending, distally predominant acute inflammatory demyelinating polyneuropathy (AIDP), although her upper extremity weakness predominates and there are no clear sensory changes. It remains to be determined how her wound infection might relate to her overall presentation.

Her white blood cell count was 12,600/μL (reference range: 3,400-10,000/μL), hemoglobin was 10.2 g/dL, and platelet count was 698,000/μL. Mean corpuscular volume was 86 fL. Serum chemistries were: sodium 138 mEq/L, potassium 3.8 mEq/L, chloride 106 mmol/L, bicarbonate 15 mmol/L, blood urea nitrogen 5 mg/dL, creatinine 0.65 mg/dL, glucose 125 mg/dL, calcium 8.3 mg/dL, magnesium 1.9 mg/dL, phosphorous 2.4 mg/dL, and lactate 1.8 mmol/L (normal: < 2.0 mmol/L). Creatinine kinase (CK), liver function tests, and coagulation panel were normal. Total protein was 6.4 g/dL, and albumin was 2.7 g/dL. Venous blood gas was: pH 7.39 and PCO₂ 25 mmHg. Urinalysis revealed ketones. Blood and wound cultures were sent for evaluation. A chest x-ray was unremarkable. An electrocardiogram showed normal sinus rhythm. Computed tomography (CT) of the abdomen and pelvis revealed a multiloculated rim-enhancing fluid collection in the anterior abdominal wall (Figure 1).

She does not have any notable electrolyte derangements that would account for her weakness, and the normal creatinine kinase lowers the probability of a myopathy and excludes rhabdomyolysis. Progression of weakness from proximal to distal muscles in a symmetric fashion is consistent with botulism, and she has an intra-abdominal wound infection that could be harboring Clostridium botulinum. Nonetheless, the normal cranial nerve exam and the rarity of botulism occurring with surgical wounds argue against this diagnosis. She should receive intravenous (IV) thiamine for the possibility of beriberi. A lumbar puncture should be performed to assess for albuminocytologic dissociation, which can be seen in patients with GBS.

The patient received high-dose IV thiamine, IV vancomycin, IV piperacillin-tazobactam, and acetaminophen. Over the subsequent 4 hours, her anion gap acidosis worsened. She declined arterial puncture. Repeat venous blood gas was: pH 7.22, PCO2 28 mmHg, and bicarbonate 11 mmol/L. Lactate and glucose were normal. Serum osmolarity was 292 mmol/kg (reference range: 283-301 mmol/kg). She was started on an IV sodium bicarbonate infusion without improvement in her acidemia.

An acute anion gap metabolic acidosis suggests a limited differential diagnosis that includes lactic acidosis, D-lactic acidosis, severe starvation ketoacidosis, acute renal failure, salicylate, or other drug or poison ingestion. Starvation ketoacidosis may be contributing, but a bicarbonate value this low would be unusual. There is no history of alcohol use or other ingestions, and the normal serum osmolality and low osmolal gap (less than 10 mOsm/kg) argue against a poisoning with ethanol, ethylene glycol, or methanol. The initial combined anion gap metabolic acidosis and respiratory alkalosis is consistent with salicylate toxicity, but she does not report aspirin ingestion. Acetaminophen use in the setting of malnutrition or starvation physiology raises the possibility of 5-oxoproline accumulation.

Routine serum lactate does not detect D-lactate, which is produced by colonic bacteria and has been reported in short bowel syndrome and following intestinal bypass surgery. This may occur weeks to months after intestinal procedures, following ingestion of a heavy carbohydrate load, and almost invariably presents with altered mental status and increased anion gap metabolic acidosis, although generalized weakness has been reported.

A surgical consultant drained her wound infection. Fluid Gram stain was negative. D-lactate, salicylate and acetaminophen levels were undetectable. Thiamine pyrophosphate level was 229 nmol/L (reference range: 78-185 nmol/L). Acetaminophen was discontinued and N-acetylcysteine infusion was started for possible 5-oxoprolinemia. Her anion gap acidosis rapidly improved. Twelve hours after admission, she reported sudden onset of blurry vision. Her vital signs were: temperature 37^oC, heart rate 110 beats per minute, respiratory rate 40 breaths per minute, blood pressure 168/90, and oxygen saturation 100% on ambient air. Telemetry showed ventricular bigeminy. On examination, she was unable to abduct her right eye; muscle strength was 1/5 in all extremities; biceps, ankle, and patellar reflexes were absent.  

Her neurological deficits have progressed over hours to near complete paralysis, asymmetric cranial nerve paresis, and areflexia. Although botulism can cause blurred vision and absent deep tendon reflexes, patients almost always have symmetrical bulbar findings followed by descending paralysis. Should the “numbness” in her arms reported earlier represent undetected sensory deficits, this, too would be inconsistent with botulism.

A diagnosis of GBS ties together several aspects of her presentation and clinical course. Several variants show different patterns of weakness and may involve cranial nerves. Her tachypnea and dyspnea are concerning signs of potential impending respiratory failure. The ventricular bigeminy and mild hypertension could represent autonomic dysfunction that is seen in many cases of GBS.

She was intubated for airway protection. Computed tomography angiography and magnetic resonance imaging of her brain were normal. Cerebral spinal fluid analysis obtained through lumbar puncture showed the following: white blood cell count 3/μL, red blood cell count 11/μL, protein 63 mg/dL (reference range: 15-60mg/dL), and glucose 128 mg/dL (reference range: 40-80mg/dL).

The lumbar puncture is consistent with GBS given the slightly elevated protein and cell count well below 50/μL. Given the severity of her symptoms, treatment with IV immunoglobulin or plasmapheresis should be initiated. Nerve conduction studies (NCS) and electromyography (EMG) are indicated for diagnostic confirmation.

EMG and NCS revealed a severe sensorimotor polyneuropathy with demyelinating features including a conduction block at a noncompressible site, consistent with AIDP. Left sural nerve biopsy confirmed acute demyelinating and mild axonal neuropathy (Figure 2). On hospital day 2, treatment with IV immunoglobulins (IVIG) was initiated; however, she developed anaphylaxis following her second administration and subsequently received plasmapheresis. A tracheostomy was performed for respiratory muscle weakness, and she was discharged to a nursing facility. C. botulinum cultures from the wound eventually returned negative. Following her hospitalization, a serum 5-oxoproline level sent 10 hours after admission returned as elevated, confirming the additional diagnosis of 5-oxoprolinemia. On follow-up, she can sit up and feed herself without assistance, and her gait continues to improve with physical therapy.

This patient presented with rapidly progressive weakness that developed in the 2 weeks following bariatric surgery. In the postsurgical setting, patient complaints of weakness are commonly encountered and can pose a diagnostic challenge. Asthenia (ie, general loss of strength or energy) is frequently reported in the immediate postoperative period, and may result from the stress of surgery, pain, deconditioning, or infection. This must be distinguished from true neurologic weakness, which results from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, or muscle. The initial history can help elucidate the inciting events such as preceding surgery, infections or ingestions, and can also categorize the pattern of weakness. The neurologic examination can localize the pathology within the neuraxis. EMG and NCS can distinguish neuropathy from radiculopathy, and categorize the process as axonal, demyelinating, or mixed. In this case, the oculomotor weakness, sensory abnormalities and areflexia signaled a severe sensorimotor polyneuropathy, and EMG/NCS confirmed a demyelinating process consistent with GBS.

Guillain-Barré syndrome is an acute, immune-mediated polyneuropathy. Patients with GBS often present with a preceding respiratory or diarrheal illness; however, the stress of a recent surgery can serve as an inciting event. The syndrome, acute postgastric reduction surgery (APGARS) neuropathy, was introduced in the literature in 2002, describing 3 patients who presented with progressive vomiting, weakness, and hyporeflexia following bariatric surgery.¹ The term has been used to describe bariatric surgery patients who developed postoperative quadriparesis, cranial nerve deficits, and respiratory compromise.² Given the clinical heterogeneity in the literature with relation to APGARS, it is probable that the cases described could result from multiple etiologies. While GBS is purely immune-mediated and can be precipitated by the stress of surgery itself, postbariatric surgery patients are susceptible to many nutritional deficiencies that can lead to similar presentations.³ For example, thiamine (vitamin B1) and cobalamin (vitamin B12) deficiencies cause distinct postbariatric surgery neuropathies.⁴ Thiamine deficiency may manifest weeks to months after surgery and can rapidly progress, whereas cobalamin deficiency generally develops over 3 to 5 years. Both of these syndromes demonstrate an axonal pattern of nerve injury on EMG/NCS, in contrast to the demyelinating pattern typically seen in GBS. In addition, bariatric surgery patients are at higher risk for copper deficiency, which usually presents as a myeloneuropathy with subacute gait decline and upper motor neuron signs including spasticity.

Although GBS classically presents with symmetric ascending weakness and sensory abnormalities, it may manifest in myriad ways. Factors influencing the presentation include the types of nerve fibers involved (motor, sensory, cranial or autonomic), the predominant mode of injury (axonal vs demyelinating), and the presence or absence of alteration in consciousness.⁵ The most common form of GBS is AIDP. The classic presentation involves paresthesias in the fingertips and toes followed by lower extremity weakness that ascends over hours to days to involve the arms and potentially the muscles of respiration. A minority of patients with GBS first experience weakness in the upper extremities or facial muscles, and oculomotor involvement is rare.⁵ Pain is common and often severe.⁶ Dysautonomia affects most patients with GBS and may manifest as labile blood pressure or arrhythmias.⁵ Several variant GBS presentation patterns have been described, including acute motor axonal neuropathy, a pure motor form of GBS; ophthalmoplegia, ataxia, and areflexia in Miller Fisher syndrome; and alteration in consciousness, hyperreflexia, ataxia, and ophthalmoparesis in Bickerstaff’s brain stem encephalitis.⁵

Patients with GBS can progress rapidly to respiratory failure. Serial neurologic exams may signal the diagnosis and inform triage to the appropriate level of care. Measurement of bedside pulmonary function, including mean inspiratory force and functional vital capacity, help to determine if there is weakness of diaphragmatic muscles. Patients with signs or symptoms of diaphragmatic weakness require monitoring in an intensive care unit and potentially early intubation. Treatment with IVIG or plasmapheresis has been found to hasten recovery from GBS, including earlier improvement in muscle strength and a reduced need for mechanical ventilation.⁷ Treatment selection is based on available resources as both modalities are felt to be equivalent.The majority of patients with GBS make a full recovery over a period of weeks to months, although many have persistent motor weakness. Despite immunotherapy, up to 20% of patients remain severely disabled and approximately 5% die.⁸ Advanced age, rapid progression of weakness over a period of less than 72 hours, need for mechanical ventilation, and absent compound muscle action potentials on NCS are all associated with prolonged and incomplete recovery.⁹

This patient developed respiratory failure within 12 hours of hospitalization, prior to being diagnosed with GBS. Even in that short time, the treating clinicians encountered a series of clinical diversions. The initial proximal pattern of muscle weakness suggested a possible myopathic process; the wound infection introduced the possibility of botulism; obesity and recent bariatric surgery triggered concern for thiamine deficiency; and the anion gap acidosis from 5-oxoprolinemia created yet another clinical detour. While the path from presentation to diagnosis is seldom a straight line, when faced with rapidly progressive weakness, it is paramount to forge ahead with an efficient diagnostic evaluation and timely therapeutic intervention.

• A complaint of general weakness requires distinction between asthenia (ie, general loss of strength or energy) and true neuromuscular weakness from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, and/or muscle.
• Guillain-Barré syndrome may present in a variety of atypical fashions not limited to ascending, distally predominant weakness.
• Acute postgastric reduction surgery neuropathy should be considered in patients presenting with weakness, vomiting, or hyporeflexia after bariatric surgery.
• Acute inflammatory demyelinating polyneuropathy may rapidly progress to respiratory failure, and warrants serial neurologic examinations, monitoring of pulmonary function, and an expedited diagnostic evaluation.

Disclosure

Nothing to report.

The approach to clinical conundrums by an expert clinician is revealed through the presentation of an actual patient’s case in an approach typical of a morning report. Similarly to patient care, sequential pieces of information are provided to the clinician, who is unfamiliar with the case. The focus is on the thought processes of both the clinical team caring for the patient and the discussant. The bolded text represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

A 45-year-old woman presented to the emergency department with 2 days of generalized, progressive weakness. Her ability to walk and perform daily chores was increasingly limited. On the morning of her presentation, she was unable to stand up without falling.

A complaint of weakness must be classified as either functional weakness related to a systemic process or true neurologic weakness from dysfunction of the central nervous system (eg, brain, spinal cord) or peripheral nervous system (eg, anterior horn cell, nerve, neuromuscular junction, or muscle). More information on her clinical course and a detailed neurologic exam will help clarify this key branch point.

She was 2 weeks status-post laparoscopic Roux-en-Y gastric bypass and gastric band removal performed in Europe.  Immediately following surgery, she experienced abdominal discomfort and nausea with occasional nonbloody, nonbilious emesis, attributed to expected postoperative anatomical changes. She developed a postoperative pneumonia treated with amoxicillin-clavulanate.  She tolerated her flight back to the United States, but her abdominal discomfort persisted and she had minimal oral intake due to her nausea.

Functional weakness may stem from hypovolemia from insufficient oral intake, anemia related to the recent surgery, electrolyte abnormalities, chronic nutritional issues associated with obesity and weight-reduction surgery, and pneumonia. Prolonged air travel, obesity, and recent surgery place her at risk for venous thromboembolism, which may manifest as reduced exercise tolerance. Nausea, vomiting, and abdominal pain persisting for 2 weeks after a Roux-en-Y gastric bypass surgery raises several concerns, including gastric remnant distension (although hiccups are often prominent); stomal stenosis, which typically presents several weeks after surgery; marginal ulceration; or infection at the surgical site or from an anastomotic leak. She may also have a surgery- or medication-related myopathy.

The patient had a history of obesity, hypertension, hyperlipidemia, migraine headaches, and nonalcoholic steatohepatitis. Four years previously, she had undergone gastric banding complicated by band migration and ulceration at the banding site. Her medications were amlodipine, losartan, ranitidine, acetaminophen, and nadroparin for venous thromboembolism prophylaxis during her flight. She denied alcohol, tobacco, or illicit drug use. On further questioning, she reported diaphoresis, mild dyspnea, loose stools, and a sensation of numbness and “heaviness” in her arms. Her abdominal pain was limited to the surgical incision and was controlled with acetaminophen. She denied fevers, cough, chest pain, diplopia, or dysphagia.

Heaviness in both arms could result from an acutely presenting myopathic or neuropathic process, while the coexistence of numbness suggests a sensorimotor polyneuropathy. Obesity and gastric bypass surgery increase her nutritional risk, and thiamine deficiency may present as an acute axonal polyneuropathy (ie, beriberi). Unlike vitamin B12 deficiency, which may take years to develop, thiamine deficiency can present within 4 weeks of gastric bypass surgery. Her dyspnea may be a manifestation of diaphragmatic weakness, although her ostensibly treated pneumonia or as of yet unproven postoperative anemia may be contributing. Chemoprophylaxis mitigates her risk of venous thromboembolism, which is, nonetheless, unlikely to account for the gastrointestinal symptoms and upper extremity weakness. If she is continuing to take amlodipine and losartan but has become volume-depleted, hypotension may be contributing to the generalized weakness.

Physical examination revealed an obese, pale and diaphoretic woman. Her temperature was 36.9°C, heart rate 77 beats per minute, blood pressure 158/90 mm Hg, respiratory rate 28 breaths per minute, and O₂ saturation 99% on ambient air. She had no cervical lymphadenopathy and a normal thyroid exam. There were no murmurs on cardiac examination, and jugular venous pressure was estimated at 10 cm of water. Her lung sounds were clear. Her abdomen was soft, nondistended, with localized tenderness and fluctuance around the midline surgical incision with a small amount of purulent drainage. She was alert and oriented to name, date, place, and situation. Cranial nerves II through XII were grossly intact. Strength was 4/5 in bilateral biceps, triceps and distal hand and finger extensors, 3/5 in bilateral deltoids. Strength in hip flexors was 4/5 and it was 5/5 in distal lower extremities. Sensation was intact to pinprick in upper and lower extremities. Biceps reflexes were absent; patellar and ankle reflexes were 1+ and symmetric. The remainder of the physical exam was unremarkable.

The patient has symmetric proximal muscle weakness with upper extremity predominance and preserved strength in her distal lower extremities. A myopathy could explain this pattern of weakness, further substantiated by absent reflexes and reportedly intact sensation. Subacute causes of myopathy include hypokalemia, hyperkalemia, toxic myopathies from medications, or infection-induced rhabdomyolysis. However, she does not report muscle pain, and the loss of reflexes is faster than would be expected with a myopathy. A more thorough sensory examination would inform the assessment of potential neuropathic processes. Guillain-Barré syndrome (GBS) is possible; it most commonly presents as an ascending, distally predominant acute inflammatory demyelinating polyneuropathy (AIDP), although her upper extremity weakness predominates and there are no clear sensory changes. It remains to be determined how her wound infection might relate to her overall presentation.

Her white blood cell count was 12,600/μL (reference range: 3,400-10,000/μL), hemoglobin was 10.2 g/dL, and platelet count was 698,000/μL. Mean corpuscular volume was 86 fL. Serum chemistries were: sodium 138 mEq/L, potassium 3.8 mEq/L, chloride 106 mmol/L, bicarbonate 15 mmol/L, blood urea nitrogen 5 mg/dL, creatinine 0.65 mg/dL, glucose 125 mg/dL, calcium 8.3 mg/dL, magnesium 1.9 mg/dL, phosphorous 2.4 mg/dL, and lactate 1.8 mmol/L (normal: < 2.0 mmol/L). Creatinine kinase (CK), liver function tests, and coagulation panel were normal. Total protein was 6.4 g/dL, and albumin was 2.7 g/dL. Venous blood gas was: pH 7.39 and PCO₂ 25 mmHg. Urinalysis revealed ketones. Blood and wound cultures were sent for evaluation. A chest x-ray was unremarkable. An electrocardiogram showed normal sinus rhythm. Computed tomography (CT) of the abdomen and pelvis revealed a multiloculated rim-enhancing fluid collection in the anterior abdominal wall (Figure 1).

She does not have any notable electrolyte derangements that would account for her weakness, and the normal creatinine kinase lowers the probability of a myopathy and excludes rhabdomyolysis. Progression of weakness from proximal to distal muscles in a symmetric fashion is consistent with botulism, and she has an intra-abdominal wound infection that could be harboring Clostridium botulinum. Nonetheless, the normal cranial nerve exam and the rarity of botulism occurring with surgical wounds argue against this diagnosis. She should receive intravenous (IV) thiamine for the possibility of beriberi. A lumbar puncture should be performed to assess for albuminocytologic dissociation, which can be seen in patients with GBS.

The patient received high-dose IV thiamine, IV vancomycin, IV piperacillin-tazobactam, and acetaminophen. Over the subsequent 4 hours, her anion gap acidosis worsened. She declined arterial puncture. Repeat venous blood gas was: pH 7.22, PCO2 28 mmHg, and bicarbonate 11 mmol/L. Lactate and glucose were normal. Serum osmolarity was 292 mmol/kg (reference range: 283-301 mmol/kg). She was started on an IV sodium bicarbonate infusion without improvement in her acidemia.

An acute anion gap metabolic acidosis suggests a limited differential diagnosis that includes lactic acidosis, D-lactic acidosis, severe starvation ketoacidosis, acute renal failure, salicylate, or other drug or poison ingestion. Starvation ketoacidosis may be contributing, but a bicarbonate value this low would be unusual. There is no history of alcohol use or other ingestions, and the normal serum osmolality and low osmolal gap (less than 10 mOsm/kg) argue against a poisoning with ethanol, ethylene glycol, or methanol. The initial combined anion gap metabolic acidosis and respiratory alkalosis is consistent with salicylate toxicity, but she does not report aspirin ingestion. Acetaminophen use in the setting of malnutrition or starvation physiology raises the possibility of 5-oxoproline accumulation.

Routine serum lactate does not detect D-lactate, which is produced by colonic bacteria and has been reported in short bowel syndrome and following intestinal bypass surgery. This may occur weeks to months after intestinal procedures, following ingestion of a heavy carbohydrate load, and almost invariably presents with altered mental status and increased anion gap metabolic acidosis, although generalized weakness has been reported.

A surgical consultant drained her wound infection. Fluid Gram stain was negative. D-lactate, salicylate and acetaminophen levels were undetectable. Thiamine pyrophosphate level was 229 nmol/L (reference range: 78-185 nmol/L). Acetaminophen was discontinued and N-acetylcysteine infusion was started for possible 5-oxoprolinemia. Her anion gap acidosis rapidly improved. Twelve hours after admission, she reported sudden onset of blurry vision. Her vital signs were: temperature 37^oC, heart rate 110 beats per minute, respiratory rate 40 breaths per minute, blood pressure 168/90, and oxygen saturation 100% on ambient air. Telemetry showed ventricular bigeminy. On examination, she was unable to abduct her right eye; muscle strength was 1/5 in all extremities; biceps, ankle, and patellar reflexes were absent.  

Her neurological deficits have progressed over hours to near complete paralysis, asymmetric cranial nerve paresis, and areflexia. Although botulism can cause blurred vision and absent deep tendon reflexes, patients almost always have symmetrical bulbar findings followed by descending paralysis. Should the “numbness” in her arms reported earlier represent undetected sensory deficits, this, too would be inconsistent with botulism.

A diagnosis of GBS ties together several aspects of her presentation and clinical course. Several variants show different patterns of weakness and may involve cranial nerves. Her tachypnea and dyspnea are concerning signs of potential impending respiratory failure. The ventricular bigeminy and mild hypertension could represent autonomic dysfunction that is seen in many cases of GBS.

She was intubated for airway protection. Computed tomography angiography and magnetic resonance imaging of her brain were normal. Cerebral spinal fluid analysis obtained through lumbar puncture showed the following: white blood cell count 3/μL, red blood cell count 11/μL, protein 63 mg/dL (reference range: 15-60mg/dL), and glucose 128 mg/dL (reference range: 40-80mg/dL).

The lumbar puncture is consistent with GBS given the slightly elevated protein and cell count well below 50/μL. Given the severity of her symptoms, treatment with IV immunoglobulin or plasmapheresis should be initiated. Nerve conduction studies (NCS) and electromyography (EMG) are indicated for diagnostic confirmation.

EMG and NCS revealed a severe sensorimotor polyneuropathy with demyelinating features including a conduction block at a noncompressible site, consistent with AIDP. Left sural nerve biopsy confirmed acute demyelinating and mild axonal neuropathy (Figure 2). On hospital day 2, treatment with IV immunoglobulins (IVIG) was initiated; however, she developed anaphylaxis following her second administration and subsequently received plasmapheresis. A tracheostomy was performed for respiratory muscle weakness, and she was discharged to a nursing facility. C. botulinum cultures from the wound eventually returned negative. Following her hospitalization, a serum 5-oxoproline level sent 10 hours after admission returned as elevated, confirming the additional diagnosis of 5-oxoprolinemia. On follow-up, she can sit up and feed herself without assistance, and her gait continues to improve with physical therapy.

This patient presented with rapidly progressive weakness that developed in the 2 weeks following bariatric surgery. In the postsurgical setting, patient complaints of weakness are commonly encountered and can pose a diagnostic challenge. Asthenia (ie, general loss of strength or energy) is frequently reported in the immediate postoperative period, and may result from the stress of surgery, pain, deconditioning, or infection. This must be distinguished from true neurologic weakness, which results from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, or muscle. The initial history can help elucidate the inciting events such as preceding surgery, infections or ingestions, and can also categorize the pattern of weakness. The neurologic examination can localize the pathology within the neuraxis. EMG and NCS can distinguish neuropathy from radiculopathy, and categorize the process as axonal, demyelinating, or mixed. In this case, the oculomotor weakness, sensory abnormalities and areflexia signaled a severe sensorimotor polyneuropathy, and EMG/NCS confirmed a demyelinating process consistent with GBS.

Guillain-Barré syndrome is an acute, immune-mediated polyneuropathy. Patients with GBS often present with a preceding respiratory or diarrheal illness; however, the stress of a recent surgery can serve as an inciting event. The syndrome, acute postgastric reduction surgery (APGARS) neuropathy, was introduced in the literature in 2002, describing 3 patients who presented with progressive vomiting, weakness, and hyporeflexia following bariatric surgery.¹ The term has been used to describe bariatric surgery patients who developed postoperative quadriparesis, cranial nerve deficits, and respiratory compromise.² Given the clinical heterogeneity in the literature with relation to APGARS, it is probable that the cases described could result from multiple etiologies. While GBS is purely immune-mediated and can be precipitated by the stress of surgery itself, postbariatric surgery patients are susceptible to many nutritional deficiencies that can lead to similar presentations.³ For example, thiamine (vitamin B1) and cobalamin (vitamin B12) deficiencies cause distinct postbariatric surgery neuropathies.⁴ Thiamine deficiency may manifest weeks to months after surgery and can rapidly progress, whereas cobalamin deficiency generally develops over 3 to 5 years. Both of these syndromes demonstrate an axonal pattern of nerve injury on EMG/NCS, in contrast to the demyelinating pattern typically seen in GBS. In addition, bariatric surgery patients are at higher risk for copper deficiency, which usually presents as a myeloneuropathy with subacute gait decline and upper motor neuron signs including spasticity.

Although GBS classically presents with symmetric ascending weakness and sensory abnormalities, it may manifest in myriad ways. Factors influencing the presentation include the types of nerve fibers involved (motor, sensory, cranial or autonomic), the predominant mode of injury (axonal vs demyelinating), and the presence or absence of alteration in consciousness.⁵ The most common form of GBS is AIDP. The classic presentation involves paresthesias in the fingertips and toes followed by lower extremity weakness that ascends over hours to days to involve the arms and potentially the muscles of respiration. A minority of patients with GBS first experience weakness in the upper extremities or facial muscles, and oculomotor involvement is rare.⁵ Pain is common and often severe.⁶ Dysautonomia affects most patients with GBS and may manifest as labile blood pressure or arrhythmias.⁵ Several variant GBS presentation patterns have been described, including acute motor axonal neuropathy, a pure motor form of GBS; ophthalmoplegia, ataxia, and areflexia in Miller Fisher syndrome; and alteration in consciousness, hyperreflexia, ataxia, and ophthalmoparesis in Bickerstaff’s brain stem encephalitis.⁵

Patients with GBS can progress rapidly to respiratory failure. Serial neurologic exams may signal the diagnosis and inform triage to the appropriate level of care. Measurement of bedside pulmonary function, including mean inspiratory force and functional vital capacity, help to determine if there is weakness of diaphragmatic muscles. Patients with signs or symptoms of diaphragmatic weakness require monitoring in an intensive care unit and potentially early intubation. Treatment with IVIG or plasmapheresis has been found to hasten recovery from GBS, including earlier improvement in muscle strength and a reduced need for mechanical ventilation.⁷ Treatment selection is based on available resources as both modalities are felt to be equivalent.The majority of patients with GBS make a full recovery over a period of weeks to months, although many have persistent motor weakness. Despite immunotherapy, up to 20% of patients remain severely disabled and approximately 5% die.⁸ Advanced age, rapid progression of weakness over a period of less than 72 hours, need for mechanical ventilation, and absent compound muscle action potentials on NCS are all associated with prolonged and incomplete recovery.⁹

This patient developed respiratory failure within 12 hours of hospitalization, prior to being diagnosed with GBS. Even in that short time, the treating clinicians encountered a series of clinical diversions. The initial proximal pattern of muscle weakness suggested a possible myopathic process; the wound infection introduced the possibility of botulism; obesity and recent bariatric surgery triggered concern for thiamine deficiency; and the anion gap acidosis from 5-oxoprolinemia created yet another clinical detour. While the path from presentation to diagnosis is seldom a straight line, when faced with rapidly progressive weakness, it is paramount to forge ahead with an efficient diagnostic evaluation and timely therapeutic intervention.

• A complaint of general weakness requires distinction between asthenia (ie, general loss of strength or energy) and true neuromuscular weakness from dysfunction of the brain, spinal cord, nerve, neuromuscular junction, and/or muscle.
• Guillain-Barré syndrome may present in a variety of atypical fashions not limited to ascending, distally predominant weakness.
• Acute postgastric reduction surgery neuropathy should be considered in patients presenting with weakness, vomiting, or hyporeflexia after bariatric surgery.
• Acute inflammatory demyelinating polyneuropathy may rapidly progress to respiratory failure, and warrants serial neurologic examinations, monitoring of pulmonary function, and an expedited diagnostic evaluation.

Disclosure

Nothing to report.

The US healthcare system is highly fragmented, with patients typically receiving treatment from multiple providers during an episode of care and from many more providers over their lifetime.^1,2 As patients move between care delivery settings, whether and how their information follows them is determined by a haphazard and error-prone patchwork of telephone, fax, and electronic communication channels.³ The existence of more robust electronic communication channels is often dictated by factors such as which providers share the same electronic health record (EHR) vendor rather than which providers share the highest volume of patients. As a result, providers often make clinical decisions with incomplete information, increasing the chances of misdiagnosis, unsafe or suboptimal treatment, and duplicative utilization.

Providers across the continuum of care encounter challenges to optimal clinical decision-making as a result of incomplete information. These are particularly problematic among clinicians in hospitals and emergency departments (EDs). Clinical decision-making in EDs often involves urgent and critical conditions in which decisions are made under pressure. Time constraints limit provider ability to find key clinical information to accurately diagnose and safely treat patients.^4-6 Even for planned inpatient care, providers are often unfamiliar with patients, and they make safer decisions when they have full access to information from outside providers.^7,8

Transitions of care between hospitals and primary care settings are also fraught with gaps in information sharing. Clinical decisions made in primary care can set patients on treatment trajectories that are greatly affected by the quality of information available to the care team at the time of initial diagnosis as well as in their subsequent treatment. Primary care physicians are not universally notified when their patients are hospitalized and may not have access to detailed information about the hospitalization, which can impair their ability to provide high quality care.^9-11

Widespread and effective electronic health information exchange (HIE) holds the potential to address these challenges.³ With robust, interconnected electronic systems, key pieces of a patient’s health record can be electronically accessed and reconciled during planned and unplanned care transitions. The concept of HIE is simple—make all relevant patient data available to the clinical care team at the point of care, regardless of where that information was generated. The estimated value of nationwide interoperable EHR adoption suggests large savings from the more efficient, less duplicative, and higher quality care that likely results.^12,13

There has been substantial funding and activity at federal, state, and local levels to promote the development of HIE in the US. The 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act has the specific goal of accelerating adoption and use of certified EHR technology coupled with the ability to exchange clinical information to support patient care.¹⁴ The HITECH programs supported specific types of HIE that were believed to be particularly critical to improving patient care and included them in the federally-defined criteria for Meaningful Use (MU) of EHRs (ie, providers receive financial incentives for achieving specific objectives). The MU criteria evolve, moving from data capture in stage 1 to improved patient outcomes in stage 3.¹⁵ The HIE criteria focus on sending and receiving summary-of-care records during care transitions.

Despite the clear benefits of HIE and substantial support stated in policy initiatives, the spread of national HIE has been slow. Today, HIE in the US is highly heterogeneous: as a result of multiple federal-, state-, community-, enterprise- and EHR vendor-level efforts, only some provider organizations are able to engage in HIE with the other provider organizations with which they routinely share patients. In this review, we offer a framework and a corresponding set of definitions to understand the current state of HIE in the US. We describe key challenges to HIE progress and offer insights into the likely path to ensure that clinicians have routine, electronic access to patient information.

While the concept of HIE is simple—electronic access to clinical information across healthcare settings—the operationalization of HIE occurs in many different ways.¹⁶ While the terms “health information exchange” and “interoperability” are often used interchangeably, they can have different meanings. In this section, we describe 4 important dimensions that serve as a framework for understanding any given effort to enable HIE (Table).

(1) What Is Exchanged? Types of Information

The term “health information exchange” is ambiguous with respect to the type(s) of information that are accessible. Health information exchange may refer to the process of 2 providers electronically sharing a wide range of data, from a single type of information (eg, lab test results), summary of care records, to complete patient records.¹⁷ Part of this ambiguity may stem from uncertainty about the scope of information that should be shared, and how this varies based on the type of clinical encounter. For example, critical types of information in the ED setting may differ from those relevant to a primary care team after a referral. While the ability to access only particular types of information will not address all information gaps, providing access to complete patient records may result in information overload that inhibits the ability to find the subset of information relevant in a given clinical encounter.

(2) Who is Exchanging? Relationship Between Provider Organizations

The types of information accessed electronically are effectively agnostic to the relationship between the provider organizations that are sharing information. Traditionally, HIE has been considered as information that is electronically shared among 2 or more unaffiliated organizations. However, there is increasing recognition that some providers may not have electronic access to all information about their patients that exists within their organization, often after a merger or acquisition between 2 providers with different EHR systems.^18,19 In these cases, a primary care team in a large integrated delivery system may have as many information gaps as a primary care team in a small, independent practice. Fulfilling clinical information needs may require both intra- and interorganizational HIE, which complicates the design of HIE processes and how the care team approaches incorporating information from both types of organizations into their decision-making. It is also important to recognize that some provider organizations, particularly small, rural practices, may not have the information technology and connectivity infrastructure required to engage in HIE.

(3) How Is Information Exchanged? Types of Electronic Access: Push vs Pull Exchange

To minimize information gaps, electronic access to information from external settings needs to offer both “push” and “pull” options. Push exchange, which can direct information electronically to a targeted recipient, works in scenarios in which there is a known information gap and known information source. The classic use for push exchange is care coordination, such as primary care physician-specialist referrals or hospital-primary care physician transitions postdischarge. Pull exchange accommodates scenarios in which there is a known information gap but the source(s) of information are unknown; it requires that clinical care teams search for and locate the clinical information that exists about the patient in external settings. Here, the classic use is emergency care in which the care team may encounter a new patient and want to retrieve records.

Widespread use of provider portals that offer view-only access into EHRs and other clinical data repositories maintained by external organizations complicate the picture. Portals are commonly used by hospitals to enable community providers to view information from a hospitalization.²¹ While this does not fall under the commonly held notion of HIE because no exchange occurs, portals support a pull approach to accessing information electronically among care settings that treat the same patients but use different EHRs.

Regardless of whether information is pushed or pulled, this may happen with varying degrees of human effort. This distinction gives rise to the difference between HIE and interoperability. Health information exchange reflects the ability of EHRs to exchange information, while interoperability additionally requires that EHRs be able to use exchanged information. From an operational perspective, the key distinction between HIE and interoperability is the extent of human involvement. Health information exchange requires that a human read and decide how to enter information from external settings (eg, a chart in PDF format sent between 2 EHRs), while interoperability enables the EHR that receives the information to understand the content and automatically triage or reconcile information, such as a medication list, without any human action.²¹ Health information exchange, therefore, relies on the diligence of the receiving clinician, while interoperability does not.

(4) What Governance Entity Defines the “Rules” of Exchange?

When more than 1 provider organization shares patient-identified data, a governance entity must specify the framework that governs the exchange. While the specifics of HIE governance vary, there are 3 predominant types of HIE networks, based on the type of organization that governs exchange: enterprise HIE networks, EHR vendor HIE networks or community HIE networks.

Enterprise HIE networks exist when 1 or more provider organizations electronically share clinical information to support patient care with some restriction, beyond geography, that dictates which organizations are involved. Typically, restrictions are driven by strategic, proprietary interests.^22,23 Although broad-based information access across settings would be in the best interest of the patient, provider organizations are sensitive to the competitive implications of sharing data and may pursue such sharing in a strategic way.²⁴ A common scenario is when hospitals choose to strategically affiliate with select ambulatory providers and exclusively exchange information with them. This should facilitate better care coordination for patients shared by the hospital and those providers but can also benefit the hospital by increasing the referrals from those providers. While there is little direct evidence quantifying the extent to which this type of strategic sharing takes place, there have been anecdotal reports as well as indirect findings that for-profit hospitals in competitive markets are less likely to share patient data.^19,25

EHR vendor HIE networks exist when exchange occurs within a community of provider organizations that use an EHR from the same vendor. A subset of EHR vendors have made this capability available; EPIC’s CareEverywhere solution²⁷ is the best-known example. Providers with an EPIC EHR are able to query for and retrieve summary of care records and other documents from any provider organization with EPIC that has activated this functionality. There are also multivendor efforts, such as CommonWell²⁷ and the Sequoia Project’s Carequality collaborative,²⁸ which are initiatives that seek to provide a common interoperability framework across a diverse set of stakeholders, including provider organizations with different EHR systems, in a similar fashion to HIE modules like CareEverywhere. To date, growth in these cross-vendor collaborations has been slow, and they have limited participation. While HIE networks that involve EHR vendors are likely to grow, it is difficult to predict how quickly because they are still in an early phase of development, and face nontechnical barriers such as patient consent policies that vary between providers and across states.

Community HIE networks—also referred to as health information organizations (HIOs) or regional health information organizations (RHIOs)—exist when provider organizations in a community, frequently state-level organizations that were funded through HITECH grants,¹⁴ set up the technical infrastructure and governance approach to engage in HIE to improve patient care. In contrast to enterprise or vendor HIE networks that have pursued HIE in ways that appear strategically beneficial, the only restriction on participation in community and state HIE networks is usually geography because they view information exchange as a public good. Seventy­one percent of hospital service areas (HSAs) are covered by at least 1 of the 106 operational HIOs, with 309,793 clinicians (licensed prescribers) participating in those exchange networks. Even with early infusions of public and other grant-funding, community HIE networks have experienced significant challenges to sustained operation, and many have ceased operating.²⁹

Thus, for any given provider organization, available HIE networks are primarily shaped by 3 factors:

1. Geographic location, which determines the available community and state HIE networks (as well as other basic information technology and connectivity infrastructure); providers located outside the service areas covered by an operational HIE have little incentive to participate because they do not connect them to providers with whom they share patients. Providers in rural areas may simply not have the needed infrastructure to pursue HIE.

2. Type of organization to which they belong, which determines the available enterprise HIE networks; providers who are not members of large health systems may be excluded from participation in these types of networks.

3. EHR vendor, which determines whether they have access to an EHR vendor HIE network.

Despite agreement about the substantial potential of HIE to reduce costs and increase the quality of care delivered across a broad range of providers, HIE progress has been slow. While HITECH has successfully increased EHR adoption in hospitals and ambulatory practices,³⁰ HIE has lagged. This is largely because many complex, intertwined barriers must be addressed for HIE to be widespread.

Lack of a Defined Goal

The cost and complexity associated with the exchange of a single type of data (eg, medications) is substantially less than the cost and complexity of sharing complete patient records. There has been little industry consensus on the target goal—do we need to enable sharing of complete patient records across all providers, or will summary of care records suffice? If the latter, as is the focus of the current MU criteria, what types of information should be included in a summary of care record, and should content and/or structure vary depending on the type of care transition? While the MU criteria require the exchange of a summary of care record with defined data fields, it remains unclear whether this is the end state or whether we should continue to push towards broad-based sharing of all patient data as structured elements. Without a clear picture of the ideal end state, there has been significant heterogeneity in the development of HIE capabilities across providers and vendors, and difficulty coordinating efforts to continue to advance towards a nationwide approach. Addressing this issue also requires progress to define HIE usability, that is, how information from external organizations should be presented and integrated into clinical workflow and clinical decisions. Currently, where HIE is occurring and clinicians are receiving summary of care records, they find them long, cluttered, and difficult to locate key information.

Numerous, Complex Barriers Spanning Multiple Stakeholders

In the context of any individual HIE effort, even after the goal is defined, there are a myriad of challenges. In a recent survey of HIO efforts, many identified the following barriers as substantially impeding their development: establishing a sustainable business model, lack of funding, integration of HIE into provider workflow, limitations of current data standards, and working with governmental policy and mandates.³⁰ What is notable about this list is that the barriers span an array of areas, including financial incentives and identifying a sustainable business model, technical barriers such as working within the limitations of data standards, and regulatory issues such as state laws that govern the requirements for patient consent to exchange personal health information. Overcoming any of these issues is challenging, but trying to tackle all of them simultaneously clearly reveals why progress has been slow. Further, resolving many of the issues involve different groups of stakeholders. For example, implementing appropriate patient consent procedures can require engaging with and harmonizing the regulations of multiple states, as well as the Health Insurance Portability and Accountability Act (HIPAA) and regulations specific to substance abuse data.

Weak or Misaligned Incentives

Among the top barriers to HIE efforts are those related to funding and lack of a sustainable business model. This reflects the fact that economic incentives in the current market have not promoted provider engagement in HIE. Traditional fee-for-service payment structures do not reward providers for avoiding duplicative care.³¹ Further, hospitals perceive patient data as a “key strategic asset, tying physicians and patients to their organization,”²⁴ and are reluctant to share data with competitors. Compounding the problem is that EHR vendors have a business interest in using HIE as a lever to increase revenue. In the short-term, they can charge high fees for interfaces and other HIE-related functionality. In the long-run, vendors may try to influence provider choice of system by making it difficult to engage in cross-vendor exchange.³² Information blocking—when providers or vendors knowingly interfere with HIE³³—reflects not only weak incentives, but perverse incentives. While not all providers and vendors experience perverse incentives, the combination of weak and perverse incentives suggests the need to strengthen incentives, so that both types of stakeholders are motivated to tackle the barriers to HIE development. Key to strengthening incentives are payers, who are thought to be the largest beneficiaries of HIE. Payers have been reluctant to make significant investments in HIE without a more active voice in its implementation,³⁴ but a shift to value-based payment may increase their engagement.

Despite the continued challenges to nationwide HIE, several policy and technology developments show promise. Stage 3 meaningful use criteria continue to build on previous stages in increasing HIE requirements, raising the threshold for electronic exchange and EHR integration of summary of care documentation in patient transitions. The recently released Medicare Access and CHIP Reauthorization Act (MACRA) Merit-based Incentive Payment System (MIPS) proposed rule replaces stage 3 meaningful use for Medicare-eligible providers with advancing care information (ACI), which accounts for 25% of a provider’s overall incentive reimbursement and includes multiple HIE criteria for providers to report as part of the base and performance score, and follows a very similar framework to stage 3 MU with its criteria regarding HIE.³⁵ While the Centers for Medicare and Medicaid Services (CMS) has not publicly declared that stage 3 MU will be replaced by ACI for hospitals and Medicaid providers, it is likely it will align those programs with the newly announced Medicare incentives.

MACRA also included changes to the Office of the National Coordinator (ONC) EHR certification program in an attempt to further encourage HIE. Vendors and providers must attest that they do not engage in information blocking and will cooperate with the Office’s surveillance programs to that effect. They also must attest that, to the greatest degree possible, their EHR systems allow for bi-directional interoperability with other providers, including those with different EHR vendors, and timely access for patients to view, download, and transmit their health data. In addition, there are emerging federal efforts to pursue a more standardized approach to patient matching and harmonize consent policies across states. These types of new policy initiatives indicate a continued interest in prioritizing HIE and interoperability.²¹

New technologies may also help spur HIE progress. The newest policy initiatives from CMS, including stage 3 MU and MACRA, have looked to incentivize the creation of application program interfaces (APIs), a set of publicly available tools from EHR vendors to allow developers to build applications that can directly interface with, and retrieve data from, their EHRs. While most patient access to electronic health data to date has been accomplished via patient portals, open APIs would enable developers to build an array of programs for consumers to view, download, and transmit their health data.

Even more promising is the development of the newest Health Level 7 data transmission standard, Fast Healthcare Interoperability Resources (FHIR), which promises to dramatically simplify the technical aspects of interoperability. FHIR utilizes a human-readable, easy to implement modular “resources” standard that may alleviate many technical challenges that come with implementation of an HIE system, enabling cheaper and simpler interoperability.³⁶ A consortium of EHR vendors are working together to test these standards.²⁸ The new FHIR standards also work in conjunction with APIs to allow easier development of consumer-facing applications³⁷ that may empower patients to take ownership of their health data.

While HIE holds great promise to reduce the cost and improve the quality of care, progress towards a nationally interoperable health system has been slow. Simply defining HIE and what types of HIE are needed in different clinical scenarios has proven challenging. The additional challenges to implementing HIE in complex technology, legal/regulatory, governance, and incentive environment are not without solutions. Continued policy interventions, private sector collaborations, and new technologies may hold the keys to realizing the vast potential of electronic HIE.

Disclosure

Nothing to report.

The US healthcare system is highly fragmented, with patients typically receiving treatment from multiple providers during an episode of care and from many more providers over their lifetime.^1,2 As patients move between care delivery settings, whether and how their information follows them is determined by a haphazard and error-prone patchwork of telephone, fax, and electronic communication channels.³ The existence of more robust electronic communication channels is often dictated by factors such as which providers share the same electronic health record (EHR) vendor rather than which providers share the highest volume of patients. As a result, providers often make clinical decisions with incomplete information, increasing the chances of misdiagnosis, unsafe or suboptimal treatment, and duplicative utilization.

Providers across the continuum of care encounter challenges to optimal clinical decision-making as a result of incomplete information. These are particularly problematic among clinicians in hospitals and emergency departments (EDs). Clinical decision-making in EDs often involves urgent and critical conditions in which decisions are made under pressure. Time constraints limit provider ability to find key clinical information to accurately diagnose and safely treat patients.^4-6 Even for planned inpatient care, providers are often unfamiliar with patients, and they make safer decisions when they have full access to information from outside providers.^7,8

Transitions of care between hospitals and primary care settings are also fraught with gaps in information sharing. Clinical decisions made in primary care can set patients on treatment trajectories that are greatly affected by the quality of information available to the care team at the time of initial diagnosis as well as in their subsequent treatment. Primary care physicians are not universally notified when their patients are hospitalized and may not have access to detailed information about the hospitalization, which can impair their ability to provide high quality care.^9-11

Widespread and effective electronic health information exchange (HIE) holds the potential to address these challenges.³ With robust, interconnected electronic systems, key pieces of a patient’s health record can be electronically accessed and reconciled during planned and unplanned care transitions. The concept of HIE is simple—make all relevant patient data available to the clinical care team at the point of care, regardless of where that information was generated. The estimated value of nationwide interoperable EHR adoption suggests large savings from the more efficient, less duplicative, and higher quality care that likely results.^12,13

There has been substantial funding and activity at federal, state, and local levels to promote the development of HIE in the US. The 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act has the specific goal of accelerating adoption and use of certified EHR technology coupled with the ability to exchange clinical information to support patient care.¹⁴ The HITECH programs supported specific types of HIE that were believed to be particularly critical to improving patient care and included them in the federally-defined criteria for Meaningful Use (MU) of EHRs (ie, providers receive financial incentives for achieving specific objectives). The MU criteria evolve, moving from data capture in stage 1 to improved patient outcomes in stage 3.¹⁵ The HIE criteria focus on sending and receiving summary-of-care records during care transitions.

Despite the clear benefits of HIE and substantial support stated in policy initiatives, the spread of national HIE has been slow. Today, HIE in the US is highly heterogeneous: as a result of multiple federal-, state-, community-, enterprise- and EHR vendor-level efforts, only some provider organizations are able to engage in HIE with the other provider organizations with which they routinely share patients. In this review, we offer a framework and a corresponding set of definitions to understand the current state of HIE in the US. We describe key challenges to HIE progress and offer insights into the likely path to ensure that clinicians have routine, electronic access to patient information.

While the concept of HIE is simple—electronic access to clinical information across healthcare settings—the operationalization of HIE occurs in many different ways.¹⁶ While the terms “health information exchange” and “interoperability” are often used interchangeably, they can have different meanings. In this section, we describe 4 important dimensions that serve as a framework for understanding any given effort to enable HIE (Table).

(1) What Is Exchanged? Types of Information

The term “health information exchange” is ambiguous with respect to the type(s) of information that are accessible. Health information exchange may refer to the process of 2 providers electronically sharing a wide range of data, from a single type of information (eg, lab test results), summary of care records, to complete patient records.¹⁷ Part of this ambiguity may stem from uncertainty about the scope of information that should be shared, and how this varies based on the type of clinical encounter. For example, critical types of information in the ED setting may differ from those relevant to a primary care team after a referral. While the ability to access only particular types of information will not address all information gaps, providing access to complete patient records may result in information overload that inhibits the ability to find the subset of information relevant in a given clinical encounter.

(2) Who is Exchanging? Relationship Between Provider Organizations

The types of information accessed electronically are effectively agnostic to the relationship between the provider organizations that are sharing information. Traditionally, HIE has been considered as information that is electronically shared among 2 or more unaffiliated organizations. However, there is increasing recognition that some providers may not have electronic access to all information about their patients that exists within their organization, often after a merger or acquisition between 2 providers with different EHR systems.^18,19 In these cases, a primary care team in a large integrated delivery system may have as many information gaps as a primary care team in a small, independent practice. Fulfilling clinical information needs may require both intra- and interorganizational HIE, which complicates the design of HIE processes and how the care team approaches incorporating information from both types of organizations into their decision-making. It is also important to recognize that some provider organizations, particularly small, rural practices, may not have the information technology and connectivity infrastructure required to engage in HIE.

(3) How Is Information Exchanged? Types of Electronic Access: Push vs Pull Exchange

To minimize information gaps, electronic access to information from external settings needs to offer both “push” and “pull” options. Push exchange, which can direct information electronically to a targeted recipient, works in scenarios in which there is a known information gap and known information source. The classic use for push exchange is care coordination, such as primary care physician-specialist referrals or hospital-primary care physician transitions postdischarge. Pull exchange accommodates scenarios in which there is a known information gap but the source(s) of information are unknown; it requires that clinical care teams search for and locate the clinical information that exists about the patient in external settings. Here, the classic use is emergency care in which the care team may encounter a new patient and want to retrieve records.

Widespread use of provider portals that offer view-only access into EHRs and other clinical data repositories maintained by external organizations complicate the picture. Portals are commonly used by hospitals to enable community providers to view information from a hospitalization.²¹ While this does not fall under the commonly held notion of HIE because no exchange occurs, portals support a pull approach to accessing information electronically among care settings that treat the same patients but use different EHRs.

Regardless of whether information is pushed or pulled, this may happen with varying degrees of human effort. This distinction gives rise to the difference between HIE and interoperability. Health information exchange reflects the ability of EHRs to exchange information, while interoperability additionally requires that EHRs be able to use exchanged information. From an operational perspective, the key distinction between HIE and interoperability is the extent of human involvement. Health information exchange requires that a human read and decide how to enter information from external settings (eg, a chart in PDF format sent between 2 EHRs), while interoperability enables the EHR that receives the information to understand the content and automatically triage or reconcile information, such as a medication list, without any human action.²¹ Health information exchange, therefore, relies on the diligence of the receiving clinician, while interoperability does not.

(4) What Governance Entity Defines the “Rules” of Exchange?

When more than 1 provider organization shares patient-identified data, a governance entity must specify the framework that governs the exchange. While the specifics of HIE governance vary, there are 3 predominant types of HIE networks, based on the type of organization that governs exchange: enterprise HIE networks, EHR vendor HIE networks or community HIE networks.

Enterprise HIE networks exist when 1 or more provider organizations electronically share clinical information to support patient care with some restriction, beyond geography, that dictates which organizations are involved. Typically, restrictions are driven by strategic, proprietary interests.^22,23 Although broad-based information access across settings would be in the best interest of the patient, provider organizations are sensitive to the competitive implications of sharing data and may pursue such sharing in a strategic way.²⁴ A common scenario is when hospitals choose to strategically affiliate with select ambulatory providers and exclusively exchange information with them. This should facilitate better care coordination for patients shared by the hospital and those providers but can also benefit the hospital by increasing the referrals from those providers. While there is little direct evidence quantifying the extent to which this type of strategic sharing takes place, there have been anecdotal reports as well as indirect findings that for-profit hospitals in competitive markets are less likely to share patient data.^19,25

EHR vendor HIE networks exist when exchange occurs within a community of provider organizations that use an EHR from the same vendor. A subset of EHR vendors have made this capability available; EPIC’s CareEverywhere solution²⁷ is the best-known example. Providers with an EPIC EHR are able to query for and retrieve summary of care records and other documents from any provider organization with EPIC that has activated this functionality. There are also multivendor efforts, such as CommonWell²⁷ and the Sequoia Project’s Carequality collaborative,²⁸ which are initiatives that seek to provide a common interoperability framework across a diverse set of stakeholders, including provider organizations with different EHR systems, in a similar fashion to HIE modules like CareEverywhere. To date, growth in these cross-vendor collaborations has been slow, and they have limited participation. While HIE networks that involve EHR vendors are likely to grow, it is difficult to predict how quickly because they are still in an early phase of development, and face nontechnical barriers such as patient consent policies that vary between providers and across states.

Community HIE networks—also referred to as health information organizations (HIOs) or regional health information organizations (RHIOs)—exist when provider organizations in a community, frequently state-level organizations that were funded through HITECH grants,¹⁴ set up the technical infrastructure and governance approach to engage in HIE to improve patient care. In contrast to enterprise or vendor HIE networks that have pursued HIE in ways that appear strategically beneficial, the only restriction on participation in community and state HIE networks is usually geography because they view information exchange as a public good. Seventy­one percent of hospital service areas (HSAs) are covered by at least 1 of the 106 operational HIOs, with 309,793 clinicians (licensed prescribers) participating in those exchange networks. Even with early infusions of public and other grant-funding, community HIE networks have experienced significant challenges to sustained operation, and many have ceased operating.²⁹

Thus, for any given provider organization, available HIE networks are primarily shaped by 3 factors:

1. Geographic location, which determines the available community and state HIE networks (as well as other basic information technology and connectivity infrastructure); providers located outside the service areas covered by an operational HIE have little incentive to participate because they do not connect them to providers with whom they share patients. Providers in rural areas may simply not have the needed infrastructure to pursue HIE.

2. Type of organization to which they belong, which determines the available enterprise HIE networks; providers who are not members of large health systems may be excluded from participation in these types of networks.

3. EHR vendor, which determines whether they have access to an EHR vendor HIE network.

Despite agreement about the substantial potential of HIE to reduce costs and increase the quality of care delivered across a broad range of providers, HIE progress has been slow. While HITECH has successfully increased EHR adoption in hospitals and ambulatory practices,³⁰ HIE has lagged. This is largely because many complex, intertwined barriers must be addressed for HIE to be widespread.

Lack of a Defined Goal

The cost and complexity associated with the exchange of a single type of data (eg, medications) is substantially less than the cost and complexity of sharing complete patient records. There has been little industry consensus on the target goal—do we need to enable sharing of complete patient records across all providers, or will summary of care records suffice? If the latter, as is the focus of the current MU criteria, what types of information should be included in a summary of care record, and should content and/or structure vary depending on the type of care transition? While the MU criteria require the exchange of a summary of care record with defined data fields, it remains unclear whether this is the end state or whether we should continue to push towards broad-based sharing of all patient data as structured elements. Without a clear picture of the ideal end state, there has been significant heterogeneity in the development of HIE capabilities across providers and vendors, and difficulty coordinating efforts to continue to advance towards a nationwide approach. Addressing this issue also requires progress to define HIE usability, that is, how information from external organizations should be presented and integrated into clinical workflow and clinical decisions. Currently, where HIE is occurring and clinicians are receiving summary of care records, they find them long, cluttered, and difficult to locate key information.

Numerous, Complex Barriers Spanning Multiple Stakeholders

In the context of any individual HIE effort, even after the goal is defined, there are a myriad of challenges. In a recent survey of HIO efforts, many identified the following barriers as substantially impeding their development: establishing a sustainable business model, lack of funding, integration of HIE into provider workflow, limitations of current data standards, and working with governmental policy and mandates.³⁰ What is notable about this list is that the barriers span an array of areas, including financial incentives and identifying a sustainable business model, technical barriers such as working within the limitations of data standards, and regulatory issues such as state laws that govern the requirements for patient consent to exchange personal health information. Overcoming any of these issues is challenging, but trying to tackle all of them simultaneously clearly reveals why progress has been slow. Further, resolving many of the issues involve different groups of stakeholders. For example, implementing appropriate patient consent procedures can require engaging with and harmonizing the regulations of multiple states, as well as the Health Insurance Portability and Accountability Act (HIPAA) and regulations specific to substance abuse data.

Weak or Misaligned Incentives

Among the top barriers to HIE efforts are those related to funding and lack of a sustainable business model. This reflects the fact that economic incentives in the current market have not promoted provider engagement in HIE. Traditional fee-for-service payment structures do not reward providers for avoiding duplicative care.³¹ Further, hospitals perceive patient data as a “key strategic asset, tying physicians and patients to their organization,”²⁴ and are reluctant to share data with competitors. Compounding the problem is that EHR vendors have a business interest in using HIE as a lever to increase revenue. In the short-term, they can charge high fees for interfaces and other HIE-related functionality. In the long-run, vendors may try to influence provider choice of system by making it difficult to engage in cross-vendor exchange.³² Information blocking—when providers or vendors knowingly interfere with HIE³³—reflects not only weak incentives, but perverse incentives. While not all providers and vendors experience perverse incentives, the combination of weak and perverse incentives suggests the need to strengthen incentives, so that both types of stakeholders are motivated to tackle the barriers to HIE development. Key to strengthening incentives are payers, who are thought to be the largest beneficiaries of HIE. Payers have been reluctant to make significant investments in HIE without a more active voice in its implementation,³⁴ but a shift to value-based payment may increase their engagement.

Despite the continued challenges to nationwide HIE, several policy and technology developments show promise. Stage 3 meaningful use criteria continue to build on previous stages in increasing HIE requirements, raising the threshold for electronic exchange and EHR integration of summary of care documentation in patient transitions. The recently released Medicare Access and CHIP Reauthorization Act (MACRA) Merit-based Incentive Payment System (MIPS) proposed rule replaces stage 3 meaningful use for Medicare-eligible providers with advancing care information (ACI), which accounts for 25% of a provider’s overall incentive reimbursement and includes multiple HIE criteria for providers to report as part of the base and performance score, and follows a very similar framework to stage 3 MU with its criteria regarding HIE.³⁵ While the Centers for Medicare and Medicaid Services (CMS) has not publicly declared that stage 3 MU will be replaced by ACI for hospitals and Medicaid providers, it is likely it will align those programs with the newly announced Medicare incentives.

MACRA also included changes to the Office of the National Coordinator (ONC) EHR certification program in an attempt to further encourage HIE. Vendors and providers must attest that they do not engage in information blocking and will cooperate with the Office’s surveillance programs to that effect. They also must attest that, to the greatest degree possible, their EHR systems allow for bi-directional interoperability with other providers, including those with different EHR vendors, and timely access for patients to view, download, and transmit their health data. In addition, there are emerging federal efforts to pursue a more standardized approach to patient matching and harmonize consent policies across states. These types of new policy initiatives indicate a continued interest in prioritizing HIE and interoperability.²¹

New technologies may also help spur HIE progress. The newest policy initiatives from CMS, including stage 3 MU and MACRA, have looked to incentivize the creation of application program interfaces (APIs), a set of publicly available tools from EHR vendors to allow developers to build applications that can directly interface with, and retrieve data from, their EHRs. While most patient access to electronic health data to date has been accomplished via patient portals, open APIs would enable developers to build an array of programs for consumers to view, download, and transmit their health data.

Even more promising is the development of the newest Health Level 7 data transmission standard, Fast Healthcare Interoperability Resources (FHIR), which promises to dramatically simplify the technical aspects of interoperability. FHIR utilizes a human-readable, easy to implement modular “resources” standard that may alleviate many technical challenges that come with implementation of an HIE system, enabling cheaper and simpler interoperability.³⁶ A consortium of EHR vendors are working together to test these standards.²⁸ The new FHIR standards also work in conjunction with APIs to allow easier development of consumer-facing applications³⁷ that may empower patients to take ownership of their health data.

While HIE holds great promise to reduce the cost and improve the quality of care, progress towards a nationally interoperable health system has been slow. Simply defining HIE and what types of HIE are needed in different clinical scenarios has proven challenging. The additional challenges to implementing HIE in complex technology, legal/regulatory, governance, and incentive environment are not without solutions. Continued policy interventions, private sector collaborations, and new technologies may hold the keys to realizing the vast potential of electronic HIE.

Disclosure

Nothing to report.

The US healthcare system is highly fragmented, with patients typically receiving treatment from multiple providers during an episode of care and from many more providers over their lifetime.^1,2 As patients move between care delivery settings, whether and how their information follows them is determined by a haphazard and error-prone patchwork of telephone, fax, and electronic communication channels.³ The existence of more robust electronic communication channels is often dictated by factors such as which providers share the same electronic health record (EHR) vendor rather than which providers share the highest volume of patients. As a result, providers often make clinical decisions with incomplete information, increasing the chances of misdiagnosis, unsafe or suboptimal treatment, and duplicative utilization.

Providers across the continuum of care encounter challenges to optimal clinical decision-making as a result of incomplete information. These are particularly problematic among clinicians in hospitals and emergency departments (EDs). Clinical decision-making in EDs often involves urgent and critical conditions in which decisions are made under pressure. Time constraints limit provider ability to find key clinical information to accurately diagnose and safely treat patients.^4-6 Even for planned inpatient care, providers are often unfamiliar with patients, and they make safer decisions when they have full access to information from outside providers.^7,8

Transitions of care between hospitals and primary care settings are also fraught with gaps in information sharing. Clinical decisions made in primary care can set patients on treatment trajectories that are greatly affected by the quality of information available to the care team at the time of initial diagnosis as well as in their subsequent treatment. Primary care physicians are not universally notified when their patients are hospitalized and may not have access to detailed information about the hospitalization, which can impair their ability to provide high quality care.^9-11

Widespread and effective electronic health information exchange (HIE) holds the potential to address these challenges.³ With robust, interconnected electronic systems, key pieces of a patient’s health record can be electronically accessed and reconciled during planned and unplanned care transitions. The concept of HIE is simple—make all relevant patient data available to the clinical care team at the point of care, regardless of where that information was generated. The estimated value of nationwide interoperable EHR adoption suggests large savings from the more efficient, less duplicative, and higher quality care that likely results.^12,13

There has been substantial funding and activity at federal, state, and local levels to promote the development of HIE in the US. The 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act has the specific goal of accelerating adoption and use of certified EHR technology coupled with the ability to exchange clinical information to support patient care.¹⁴ The HITECH programs supported specific types of HIE that were believed to be particularly critical to improving patient care and included them in the federally-defined criteria for Meaningful Use (MU) of EHRs (ie, providers receive financial incentives for achieving specific objectives). The MU criteria evolve, moving from data capture in stage 1 to improved patient outcomes in stage 3.¹⁵ The HIE criteria focus on sending and receiving summary-of-care records during care transitions.

Despite the clear benefits of HIE and substantial support stated in policy initiatives, the spread of national HIE has been slow. Today, HIE in the US is highly heterogeneous: as a result of multiple federal-, state-, community-, enterprise- and EHR vendor-level efforts, only some provider organizations are able to engage in HIE with the other provider organizations with which they routinely share patients. In this review, we offer a framework and a corresponding set of definitions to understand the current state of HIE in the US. We describe key challenges to HIE progress and offer insights into the likely path to ensure that clinicians have routine, electronic access to patient information.

While the concept of HIE is simple—electronic access to clinical information across healthcare settings—the operationalization of HIE occurs in many different ways.¹⁶ While the terms “health information exchange” and “interoperability” are often used interchangeably, they can have different meanings. In this section, we describe 4 important dimensions that serve as a framework for understanding any given effort to enable HIE (Table).

(1) What Is Exchanged? Types of Information

The term “health information exchange” is ambiguous with respect to the type(s) of information that are accessible. Health information exchange may refer to the process of 2 providers electronically sharing a wide range of data, from a single type of information (eg, lab test results), summary of care records, to complete patient records.¹⁷ Part of this ambiguity may stem from uncertainty about the scope of information that should be shared, and how this varies based on the type of clinical encounter. For example, critical types of information in the ED setting may differ from those relevant to a primary care team after a referral. While the ability to access only particular types of information will not address all information gaps, providing access to complete patient records may result in information overload that inhibits the ability to find the subset of information relevant in a given clinical encounter.

(2) Who is Exchanging? Relationship Between Provider Organizations

The types of information accessed electronically are effectively agnostic to the relationship between the provider organizations that are sharing information. Traditionally, HIE has been considered as information that is electronically shared among 2 or more unaffiliated organizations. However, there is increasing recognition that some providers may not have electronic access to all information about their patients that exists within their organization, often after a merger or acquisition between 2 providers with different EHR systems.^18,19 In these cases, a primary care team in a large integrated delivery system may have as many information gaps as a primary care team in a small, independent practice. Fulfilling clinical information needs may require both intra- and interorganizational HIE, which complicates the design of HIE processes and how the care team approaches incorporating information from both types of organizations into their decision-making. It is also important to recognize that some provider organizations, particularly small, rural practices, may not have the information technology and connectivity infrastructure required to engage in HIE.

(3) How Is Information Exchanged? Types of Electronic Access: Push vs Pull Exchange

To minimize information gaps, electronic access to information from external settings needs to offer both “push” and “pull” options. Push exchange, which can direct information electronically to a targeted recipient, works in scenarios in which there is a known information gap and known information source. The classic use for push exchange is care coordination, such as primary care physician-specialist referrals or hospital-primary care physician transitions postdischarge. Pull exchange accommodates scenarios in which there is a known information gap but the source(s) of information are unknown; it requires that clinical care teams search for and locate the clinical information that exists about the patient in external settings. Here, the classic use is emergency care in which the care team may encounter a new patient and want to retrieve records.

Widespread use of provider portals that offer view-only access into EHRs and other clinical data repositories maintained by external organizations complicate the picture. Portals are commonly used by hospitals to enable community providers to view information from a hospitalization.²¹ While this does not fall under the commonly held notion of HIE because no exchange occurs, portals support a pull approach to accessing information electronically among care settings that treat the same patients but use different EHRs.

Regardless of whether information is pushed or pulled, this may happen with varying degrees of human effort. This distinction gives rise to the difference between HIE and interoperability. Health information exchange reflects the ability of EHRs to exchange information, while interoperability additionally requires that EHRs be able to use exchanged information. From an operational perspective, the key distinction between HIE and interoperability is the extent of human involvement. Health information exchange requires that a human read and decide how to enter information from external settings (eg, a chart in PDF format sent between 2 EHRs), while interoperability enables the EHR that receives the information to understand the content and automatically triage or reconcile information, such as a medication list, without any human action.²¹ Health information exchange, therefore, relies on the diligence of the receiving clinician, while interoperability does not.

(4) What Governance Entity Defines the “Rules” of Exchange?

When more than 1 provider organization shares patient-identified data, a governance entity must specify the framework that governs the exchange. While the specifics of HIE governance vary, there are 3 predominant types of HIE networks, based on the type of organization that governs exchange: enterprise HIE networks, EHR vendor HIE networks or community HIE networks.

Enterprise HIE networks exist when 1 or more provider organizations electronically share clinical information to support patient care with some restriction, beyond geography, that dictates which organizations are involved. Typically, restrictions are driven by strategic, proprietary interests.^22,23 Although broad-based information access across settings would be in the best interest of the patient, provider organizations are sensitive to the competitive implications of sharing data and may pursue such sharing in a strategic way.²⁴ A common scenario is when hospitals choose to strategically affiliate with select ambulatory providers and exclusively exchange information with them. This should facilitate better care coordination for patients shared by the hospital and those providers but can also benefit the hospital by increasing the referrals from those providers. While there is little direct evidence quantifying the extent to which this type of strategic sharing takes place, there have been anecdotal reports as well as indirect findings that for-profit hospitals in competitive markets are less likely to share patient data.^19,25

EHR vendor HIE networks exist when exchange occurs within a community of provider organizations that use an EHR from the same vendor. A subset of EHR vendors have made this capability available; EPIC’s CareEverywhere solution²⁷ is the best-known example. Providers with an EPIC EHR are able to query for and retrieve summary of care records and other documents from any provider organization with EPIC that has activated this functionality. There are also multivendor efforts, such as CommonWell²⁷ and the Sequoia Project’s Carequality collaborative,²⁸ which are initiatives that seek to provide a common interoperability framework across a diverse set of stakeholders, including provider organizations with different EHR systems, in a similar fashion to HIE modules like CareEverywhere. To date, growth in these cross-vendor collaborations has been slow, and they have limited participation. While HIE networks that involve EHR vendors are likely to grow, it is difficult to predict how quickly because they are still in an early phase of development, and face nontechnical barriers such as patient consent policies that vary between providers and across states.

Community HIE networks—also referred to as health information organizations (HIOs) or regional health information organizations (RHIOs)—exist when provider organizations in a community, frequently state-level organizations that were funded through HITECH grants,¹⁴ set up the technical infrastructure and governance approach to engage in HIE to improve patient care. In contrast to enterprise or vendor HIE networks that have pursued HIE in ways that appear strategically beneficial, the only restriction on participation in community and state HIE networks is usually geography because they view information exchange as a public good. Seventy­one percent of hospital service areas (HSAs) are covered by at least 1 of the 106 operational HIOs, with 309,793 clinicians (licensed prescribers) participating in those exchange networks. Even with early infusions of public and other grant-funding, community HIE networks have experienced significant challenges to sustained operation, and many have ceased operating.²⁹

Thus, for any given provider organization, available HIE networks are primarily shaped by 3 factors:

1. Geographic location, which determines the available community and state HIE networks (as well as other basic information technology and connectivity infrastructure); providers located outside the service areas covered by an operational HIE have little incentive to participate because they do not connect them to providers with whom they share patients. Providers in rural areas may simply not have the needed infrastructure to pursue HIE.

2. Type of organization to which they belong, which determines the available enterprise HIE networks; providers who are not members of large health systems may be excluded from participation in these types of networks.

3. EHR vendor, which determines whether they have access to an EHR vendor HIE network.

Despite agreement about the substantial potential of HIE to reduce costs and increase the quality of care delivered across a broad range of providers, HIE progress has been slow. While HITECH has successfully increased EHR adoption in hospitals and ambulatory practices,³⁰ HIE has lagged. This is largely because many complex, intertwined barriers must be addressed for HIE to be widespread.

Lack of a Defined Goal

The cost and complexity associated with the exchange of a single type of data (eg, medications) is substantially less than the cost and complexity of sharing complete patient records. There has been little industry consensus on the target goal—do we need to enable sharing of complete patient records across all providers, or will summary of care records suffice? If the latter, as is the focus of the current MU criteria, what types of information should be included in a summary of care record, and should content and/or structure vary depending on the type of care transition? While the MU criteria require the exchange of a summary of care record with defined data fields, it remains unclear whether this is the end state or whether we should continue to push towards broad-based sharing of all patient data as structured elements. Without a clear picture of the ideal end state, there has been significant heterogeneity in the development of HIE capabilities across providers and vendors, and difficulty coordinating efforts to continue to advance towards a nationwide approach. Addressing this issue also requires progress to define HIE usability, that is, how information from external organizations should be presented and integrated into clinical workflow and clinical decisions. Currently, where HIE is occurring and clinicians are receiving summary of care records, they find them long, cluttered, and difficult to locate key information.

Numerous, Complex Barriers Spanning Multiple Stakeholders

In the context of any individual HIE effort, even after the goal is defined, there are a myriad of challenges. In a recent survey of HIO efforts, many identified the following barriers as substantially impeding their development: establishing a sustainable business model, lack of funding, integration of HIE into provider workflow, limitations of current data standards, and working with governmental policy and mandates.³⁰ What is notable about this list is that the barriers span an array of areas, including financial incentives and identifying a sustainable business model, technical barriers such as working within the limitations of data standards, and regulatory issues such as state laws that govern the requirements for patient consent to exchange personal health information. Overcoming any of these issues is challenging, but trying to tackle all of them simultaneously clearly reveals why progress has been slow. Further, resolving many of the issues involve different groups of stakeholders. For example, implementing appropriate patient consent procedures can require engaging with and harmonizing the regulations of multiple states, as well as the Health Insurance Portability and Accountability Act (HIPAA) and regulations specific to substance abuse data.

Weak or Misaligned Incentives

Among the top barriers to HIE efforts are those related to funding and lack of a sustainable business model. This reflects the fact that economic incentives in the current market have not promoted provider engagement in HIE. Traditional fee-for-service payment structures do not reward providers for avoiding duplicative care.³¹ Further, hospitals perceive patient data as a “key strategic asset, tying physicians and patients to their organization,”²⁴ and are reluctant to share data with competitors. Compounding the problem is that EHR vendors have a business interest in using HIE as a lever to increase revenue. In the short-term, they can charge high fees for interfaces and other HIE-related functionality. In the long-run, vendors may try to influence provider choice of system by making it difficult to engage in cross-vendor exchange.³² Information blocking—when providers or vendors knowingly interfere with HIE³³—reflects not only weak incentives, but perverse incentives. While not all providers and vendors experience perverse incentives, the combination of weak and perverse incentives suggests the need to strengthen incentives, so that both types of stakeholders are motivated to tackle the barriers to HIE development. Key to strengthening incentives are payers, who are thought to be the largest beneficiaries of HIE. Payers have been reluctant to make significant investments in HIE without a more active voice in its implementation,³⁴ but a shift to value-based payment may increase their engagement.

Despite the continued challenges to nationwide HIE, several policy and technology developments show promise. Stage 3 meaningful use criteria continue to build on previous stages in increasing HIE requirements, raising the threshold for electronic exchange and EHR integration of summary of care documentation in patient transitions. The recently released Medicare Access and CHIP Reauthorization Act (MACRA) Merit-based Incentive Payment System (MIPS) proposed rule replaces stage 3 meaningful use for Medicare-eligible providers with advancing care information (ACI), which accounts for 25% of a provider’s overall incentive reimbursement and includes multiple HIE criteria for providers to report as part of the base and performance score, and follows a very similar framework to stage 3 MU with its criteria regarding HIE.³⁵ While the Centers for Medicare and Medicaid Services (CMS) has not publicly declared that stage 3 MU will be replaced by ACI for hospitals and Medicaid providers, it is likely it will align those programs with the newly announced Medicare incentives.

MACRA also included changes to the Office of the National Coordinator (ONC) EHR certification program in an attempt to further encourage HIE. Vendors and providers must attest that they do not engage in information blocking and will cooperate with the Office’s surveillance programs to that effect. They also must attest that, to the greatest degree possible, their EHR systems allow for bi-directional interoperability with other providers, including those with different EHR vendors, and timely access for patients to view, download, and transmit their health data. In addition, there are emerging federal efforts to pursue a more standardized approach to patient matching and harmonize consent policies across states. These types of new policy initiatives indicate a continued interest in prioritizing HIE and interoperability.²¹

New technologies may also help spur HIE progress. The newest policy initiatives from CMS, including stage 3 MU and MACRA, have looked to incentivize the creation of application program interfaces (APIs), a set of publicly available tools from EHR vendors to allow developers to build applications that can directly interface with, and retrieve data from, their EHRs. While most patient access to electronic health data to date has been accomplished via patient portals, open APIs would enable developers to build an array of programs for consumers to view, download, and transmit their health data.

Even more promising is the development of the newest Health Level 7 data transmission standard, Fast Healthcare Interoperability Resources (FHIR), which promises to dramatically simplify the technical aspects of interoperability. FHIR utilizes a human-readable, easy to implement modular “resources” standard that may alleviate many technical challenges that come with implementation of an HIE system, enabling cheaper and simpler interoperability.³⁶ A consortium of EHR vendors are working together to test these standards.²⁸ The new FHIR standards also work in conjunction with APIs to allow easier development of consumer-facing applications³⁷ that may empower patients to take ownership of their health data.

While HIE holds great promise to reduce the cost and improve the quality of care, progress towards a nationally interoperable health system has been slow. Simply defining HIE and what types of HIE are needed in different clinical scenarios has proven challenging. The additional challenges to implementing HIE in complex technology, legal/regulatory, governance, and incentive environment are not without solutions. Continued policy interventions, private sector collaborations, and new technologies may hold the keys to realizing the vast potential of electronic HIE.

Disclosure

Nothing to report.

On July 30, 1965, Lyndon B. Johnson signed H.R. 6675 into law, establishing Medicare and Medicaid as Title XVIII and Title XIX of the Social Security Act.¹ Shortly after, Medicare’s “extended care benefit” began, offering Medicare beneficiaries skilled nursing facility (SNF) care after a qualifying stay of 3 or more consecutive inpatient midnights.² Fifty years later, the word “inpatient” remains embedded in statute, limiting SNF coverage for Medicare beneficiaries hospitalized as outpatients under observation for part or all of a 3-midnight stay.³

At the individual Medicare beneficiary level, the financial impact of this policy is clear. The Office of Inspector General (OIG) reported a $10,503 beneficiary out-of-pocket cost per uncovered SNF stay following an observation hospitalization in 2012.⁴ But the actual number of Medicare beneficiaries impacted by this coverage gap is unknown. Using 2009 claims data, Feng et al.⁵ estimated that 0.75% of previously community dwelling Medicare beneficiaries are discharged to a SNF following an observation hospitalization, and the OIG reported 617,702 beneficiary hospital stays of 3 or more midnights not meeting the 3-midnight inpatient requirement in 2012, with 4% of these beneficiaries discharging to SNFs.⁴ Yet these studies based on Medicare claims data only capture actual SNF utilization, failing to answer the critical question: How many Medicare beneficiaries need, but forgo, SNF care following a non-qualifying observation hospital stay? In this issue of the Journal of Hospital Medicine, Goldstein et al.⁶ provide insight to that question. Using chart review of physical therapy and case management recommendations for post-acute SNF care, Goldstein et al.⁶ compare actual discharge rate to SNF or acute inpatient rehabilitation following an observation stay when such disposition is recommended. In their two-hospital system, fewer than 20% of previously community-dwelling hospitalist patients followed recommendation for post-acute facility stay after observation hospitalization, and more than 40% cited financial concerns as the reason for declining. Patients recommended for SNF also were more likely to be rehospitalized in the subsequent 30 days after discharge, confirming this as a vulnerable patient population. Given Medicare’s original intent to improve health care access for seniors, the case for change seems clear, and the repercussions of not addressing the plight of patients hospitalized under observation is having negative financial and overall detrimental health impacts.

But there are other compelling reasons why this 50-year-old law needs to be improved. Hospital care today is vastly different than when Medicare became law. Average hospital length of stay for patients 65 years and older was 14.2 days in 1965⁷ compared to 5.2 days today,⁸ clearly a shift in what 3 days of hospital care means. Most importantly, observation stays have become a major part of hospital care. Between 2006 and 2014, per-beneficiary outpatient visits (which include all observation stays) increased 44.2% nationally, while inpatient discharges decreased 19.9%.⁹ In 2012, the Centers for Medicare & Medicaid Services (CMS) received 1.7 million outpatient observation claims and an additional 700,000 inpatient claims that started with observation days.¹⁰ CMS also expected the 2-midnight rule to reduce outpatient observation stays,⁴ but a recent OIG report¹¹ found that outpatient stays increased 8.1% in the first year (FY 2014) under the new rule, and there were still 748,337 long observation stays (those lasting 2 midnights or longer) in 2014, only a small (2.8%) decrease from the prior year. These factors limit Medicare beneficiary post–acute SNF eligibility in ways that could not have been anticipated when the extended care benefit was created to help seniors access needed health care.

Policymakers must consider cost when considering statutory change. Waiver programs in the 1980s suspending the 3-midnight requirement raised concerns over potential increase in both SNF utilization and associated costs.¹² However, more recent data suggest that altering the 3-midnight requirement may not increase post-acute SNF utilization. From 2006 to 2010, Medicare Advantage programs that waived the 3-midnight requirement saw a decrease in hospital length of stay without increased SNF utilization or SNF length of stay, indicating that access to the right level of care at the right time could be cost-saving.¹³ Recent data from the Bundled Payments for Care Improvement (BPCI) program found savings were largely related to decreased SNF utilization when payments were episode-based,¹⁴ a trend that may continue as Medicare moves away from fee-for-service towards bundled payments for more conditions. And although neither example directly tests changing the 3-midnight requirement to include observation midnights, both studies suggest that innovative health care delivery and modification of SNF access did not result in increased SNF utilization or greater post-acute costs. In fact, as Goldstein et al.⁶ showed, patients recommended for post-acute SNF following observation stay were more likely to be rehospitalized within 30 days, an additional cost that could potentially be avoided if these patients had SNF access. We believe that these correlations strongly support rescinding the 3-midnight requirement, or at least amending it to allow nights spend under observation to count as “inpatient” for the purposes of SNF benefit coverage.

That being said, what can be done? In 2015, the Medicare Payment Advisory Commission (MedPAC) recommended changing the 3-night requirement to require just one of 3 midnights to be inpatient to make a qualifying stay.¹⁰ Although an improvement over current law, this proposal would not help the majority of beneficiaries who are exclusively hospitalized under observation status. The “Improving Access to Medicare Coverage Act of 2015”, to be reintroduced in Congress in the coming weeks, would count any midnight spent in the hospital towards the 3-midnight stay requirement, and has bipartisan, bicameral support and cosponsorship.¹⁵ In 2015, through unanimous bipartisan, bicameral support, Congress passed the NOTICE Act (PL 114-42), which requires hospitals to inform Medicare beneficiaries hospitalized under observation.¹⁶ We believe that the data are clear to both sides of the aisle that Congress should now work together using scientifically-supported research to improve the exact observation policies they felt patients should be informed of. Passing the Improving Access to Medicare Coverage Act is the logical next step in this arena.

Medicare was intended to give seniors access to the healthcare they need. Growth in hospital-based observation care begs for modernization of the statutory 3-inpatient midnight rule. Counting all midnights towards the 3-midnight requirement, whether those midnights are outpatient observation or inpatient, is the right first step.

Disclosures

Representative Courtney is the bill sponsor of the Improving Access to Medicare Coverage Act. The authors report no other conflicts.

On July 30, 1965, Lyndon B. Johnson signed H.R. 6675 into law, establishing Medicare and Medicaid as Title XVIII and Title XIX of the Social Security Act.¹ Shortly after, Medicare’s “extended care benefit” began, offering Medicare beneficiaries skilled nursing facility (SNF) care after a qualifying stay of 3 or more consecutive inpatient midnights.² Fifty years later, the word “inpatient” remains embedded in statute, limiting SNF coverage for Medicare beneficiaries hospitalized as outpatients under observation for part or all of a 3-midnight stay.³

At the individual Medicare beneficiary level, the financial impact of this policy is clear. The Office of Inspector General (OIG) reported a $10,503 beneficiary out-of-pocket cost per uncovered SNF stay following an observation hospitalization in 2012.⁴ But the actual number of Medicare beneficiaries impacted by this coverage gap is unknown. Using 2009 claims data, Feng et al.⁵ estimated that 0.75% of previously community dwelling Medicare beneficiaries are discharged to a SNF following an observation hospitalization, and the OIG reported 617,702 beneficiary hospital stays of 3 or more midnights not meeting the 3-midnight inpatient requirement in 2012, with 4% of these beneficiaries discharging to SNFs.⁴ Yet these studies based on Medicare claims data only capture actual SNF utilization, failing to answer the critical question: How many Medicare beneficiaries need, but forgo, SNF care following a non-qualifying observation hospital stay? In this issue of the Journal of Hospital Medicine, Goldstein et al.⁶ provide insight to that question. Using chart review of physical therapy and case management recommendations for post-acute SNF care, Goldstein et al.⁶ compare actual discharge rate to SNF or acute inpatient rehabilitation following an observation stay when such disposition is recommended. In their two-hospital system, fewer than 20% of previously community-dwelling hospitalist patients followed recommendation for post-acute facility stay after observation hospitalization, and more than 40% cited financial concerns as the reason for declining. Patients recommended for SNF also were more likely to be rehospitalized in the subsequent 30 days after discharge, confirming this as a vulnerable patient population. Given Medicare’s original intent to improve health care access for seniors, the case for change seems clear, and the repercussions of not addressing the plight of patients hospitalized under observation is having negative financial and overall detrimental health impacts.

But there are other compelling reasons why this 50-year-old law needs to be improved. Hospital care today is vastly different than when Medicare became law. Average hospital length of stay for patients 65 years and older was 14.2 days in 1965⁷ compared to 5.2 days today,⁸ clearly a shift in what 3 days of hospital care means. Most importantly, observation stays have become a major part of hospital care. Between 2006 and 2014, per-beneficiary outpatient visits (which include all observation stays) increased 44.2% nationally, while inpatient discharges decreased 19.9%.⁹ In 2012, the Centers for Medicare & Medicaid Services (CMS) received 1.7 million outpatient observation claims and an additional 700,000 inpatient claims that started with observation days.¹⁰ CMS also expected the 2-midnight rule to reduce outpatient observation stays,⁴ but a recent OIG report¹¹ found that outpatient stays increased 8.1% in the first year (FY 2014) under the new rule, and there were still 748,337 long observation stays (those lasting 2 midnights or longer) in 2014, only a small (2.8%) decrease from the prior year. These factors limit Medicare beneficiary post–acute SNF eligibility in ways that could not have been anticipated when the extended care benefit was created to help seniors access needed health care.

Policymakers must consider cost when considering statutory change. Waiver programs in the 1980s suspending the 3-midnight requirement raised concerns over potential increase in both SNF utilization and associated costs.¹² However, more recent data suggest that altering the 3-midnight requirement may not increase post-acute SNF utilization. From 2006 to 2010, Medicare Advantage programs that waived the 3-midnight requirement saw a decrease in hospital length of stay without increased SNF utilization or SNF length of stay, indicating that access to the right level of care at the right time could be cost-saving.¹³ Recent data from the Bundled Payments for Care Improvement (BPCI) program found savings were largely related to decreased SNF utilization when payments were episode-based,¹⁴ a trend that may continue as Medicare moves away from fee-for-service towards bundled payments for more conditions. And although neither example directly tests changing the 3-midnight requirement to include observation midnights, both studies suggest that innovative health care delivery and modification of SNF access did not result in increased SNF utilization or greater post-acute costs. In fact, as Goldstein et al.⁶ showed, patients recommended for post-acute SNF following observation stay were more likely to be rehospitalized within 30 days, an additional cost that could potentially be avoided if these patients had SNF access. We believe that these correlations strongly support rescinding the 3-midnight requirement, or at least amending it to allow nights spend under observation to count as “inpatient” for the purposes of SNF benefit coverage.

That being said, what can be done? In 2015, the Medicare Payment Advisory Commission (MedPAC) recommended changing the 3-night requirement to require just one of 3 midnights to be inpatient to make a qualifying stay.¹⁰ Although an improvement over current law, this proposal would not help the majority of beneficiaries who are exclusively hospitalized under observation status. The “Improving Access to Medicare Coverage Act of 2015”, to be reintroduced in Congress in the coming weeks, would count any midnight spent in the hospital towards the 3-midnight stay requirement, and has bipartisan, bicameral support and cosponsorship.¹⁵ In 2015, through unanimous bipartisan, bicameral support, Congress passed the NOTICE Act (PL 114-42), which requires hospitals to inform Medicare beneficiaries hospitalized under observation.¹⁶ We believe that the data are clear to both sides of the aisle that Congress should now work together using scientifically-supported research to improve the exact observation policies they felt patients should be informed of. Passing the Improving Access to Medicare Coverage Act is the logical next step in this arena.

Medicare was intended to give seniors access to the healthcare they need. Growth in hospital-based observation care begs for modernization of the statutory 3-inpatient midnight rule. Counting all midnights towards the 3-midnight requirement, whether those midnights are outpatient observation or inpatient, is the right first step.

Disclosures

Representative Courtney is the bill sponsor of the Improving Access to Medicare Coverage Act. The authors report no other conflicts.

On July 30, 1965, Lyndon B. Johnson signed H.R. 6675 into law, establishing Medicare and Medicaid as Title XVIII and Title XIX of the Social Security Act.¹ Shortly after, Medicare’s “extended care benefit” began, offering Medicare beneficiaries skilled nursing facility (SNF) care after a qualifying stay of 3 or more consecutive inpatient midnights.² Fifty years later, the word “inpatient” remains embedded in statute, limiting SNF coverage for Medicare beneficiaries hospitalized as outpatients under observation for part or all of a 3-midnight stay.³

At the individual Medicare beneficiary level, the financial impact of this policy is clear. The Office of Inspector General (OIG) reported a $10,503 beneficiary out-of-pocket cost per uncovered SNF stay following an observation hospitalization in 2012.⁴ But the actual number of Medicare beneficiaries impacted by this coverage gap is unknown. Using 2009 claims data, Feng et al.⁵ estimated that 0.75% of previously community dwelling Medicare beneficiaries are discharged to a SNF following an observation hospitalization, and the OIG reported 617,702 beneficiary hospital stays of 3 or more midnights not meeting the 3-midnight inpatient requirement in 2012, with 4% of these beneficiaries discharging to SNFs.⁴ Yet these studies based on Medicare claims data only capture actual SNF utilization, failing to answer the critical question: How many Medicare beneficiaries need, but forgo, SNF care following a non-qualifying observation hospital stay? In this issue of the Journal of Hospital Medicine, Goldstein et al.⁶ provide insight to that question. Using chart review of physical therapy and case management recommendations for post-acute SNF care, Goldstein et al.⁶ compare actual discharge rate to SNF or acute inpatient rehabilitation following an observation stay when such disposition is recommended. In their two-hospital system, fewer than 20% of previously community-dwelling hospitalist patients followed recommendation for post-acute facility stay after observation hospitalization, and more than 40% cited financial concerns as the reason for declining. Patients recommended for SNF also were more likely to be rehospitalized in the subsequent 30 days after discharge, confirming this as a vulnerable patient population. Given Medicare’s original intent to improve health care access for seniors, the case for change seems clear, and the repercussions of not addressing the plight of patients hospitalized under observation is having negative financial and overall detrimental health impacts.

But there are other compelling reasons why this 50-year-old law needs to be improved. Hospital care today is vastly different than when Medicare became law. Average hospital length of stay for patients 65 years and older was 14.2 days in 1965⁷ compared to 5.2 days today,⁸ clearly a shift in what 3 days of hospital care means. Most importantly, observation stays have become a major part of hospital care. Between 2006 and 2014, per-beneficiary outpatient visits (which include all observation stays) increased 44.2% nationally, while inpatient discharges decreased 19.9%.⁹ In 2012, the Centers for Medicare & Medicaid Services (CMS) received 1.7 million outpatient observation claims and an additional 700,000 inpatient claims that started with observation days.¹⁰ CMS also expected the 2-midnight rule to reduce outpatient observation stays,⁴ but a recent OIG report¹¹ found that outpatient stays increased 8.1% in the first year (FY 2014) under the new rule, and there were still 748,337 long observation stays (those lasting 2 midnights or longer) in 2014, only a small (2.8%) decrease from the prior year. These factors limit Medicare beneficiary post–acute SNF eligibility in ways that could not have been anticipated when the extended care benefit was created to help seniors access needed health care.

Policymakers must consider cost when considering statutory change. Waiver programs in the 1980s suspending the 3-midnight requirement raised concerns over potential increase in both SNF utilization and associated costs.¹² However, more recent data suggest that altering the 3-midnight requirement may not increase post-acute SNF utilization. From 2006 to 2010, Medicare Advantage programs that waived the 3-midnight requirement saw a decrease in hospital length of stay without increased SNF utilization or SNF length of stay, indicating that access to the right level of care at the right time could be cost-saving.¹³ Recent data from the Bundled Payments for Care Improvement (BPCI) program found savings were largely related to decreased SNF utilization when payments were episode-based,¹⁴ a trend that may continue as Medicare moves away from fee-for-service towards bundled payments for more conditions. And although neither example directly tests changing the 3-midnight requirement to include observation midnights, both studies suggest that innovative health care delivery and modification of SNF access did not result in increased SNF utilization or greater post-acute costs. In fact, as Goldstein et al.⁶ showed, patients recommended for post-acute SNF following observation stay were more likely to be rehospitalized within 30 days, an additional cost that could potentially be avoided if these patients had SNF access. We believe that these correlations strongly support rescinding the 3-midnight requirement, or at least amending it to allow nights spend under observation to count as “inpatient” for the purposes of SNF benefit coverage.

That being said, what can be done? In 2015, the Medicare Payment Advisory Commission (MedPAC) recommended changing the 3-night requirement to require just one of 3 midnights to be inpatient to make a qualifying stay.¹⁰ Although an improvement over current law, this proposal would not help the majority of beneficiaries who are exclusively hospitalized under observation status. The “Improving Access to Medicare Coverage Act of 2015”, to be reintroduced in Congress in the coming weeks, would count any midnight spent in the hospital towards the 3-midnight stay requirement, and has bipartisan, bicameral support and cosponsorship.¹⁵ In 2015, through unanimous bipartisan, bicameral support, Congress passed the NOTICE Act (PL 114-42), which requires hospitals to inform Medicare beneficiaries hospitalized under observation.¹⁶ We believe that the data are clear to both sides of the aisle that Congress should now work together using scientifically-supported research to improve the exact observation policies they felt patients should be informed of. Passing the Improving Access to Medicare Coverage Act is the logical next step in this arena.

Medicare was intended to give seniors access to the healthcare they need. Growth in hospital-based observation care begs for modernization of the statutory 3-inpatient midnight rule. Counting all midnights towards the 3-midnight requirement, whether those midnights are outpatient observation or inpatient, is the right first step.

Disclosures

Representative Courtney is the bill sponsor of the Improving Access to Medicare Coverage Act. The authors report no other conflicts.

In the article by Riddle et al,¹ the authors state that in the example of Cluster A type personality disorder, the elderly male patient’s paranoid disorder should be ignored, rather than confronting the paranoia. We do not need to confront the paranoia, but we need to treat the paranoid disorder. The symptom of paranoia extends beyond the single diagnostic category of delusional disorder and has been noted in many elderly patients with other underlying disorders.² This patient needs early psychiatric consultation and therapy.

They also give recommendations regarding Ms. B for her ever-increasing need of opiates. I find it too naïve for me to offer this patient “…choices, such as walking with her around the unit or listen to the music.” This patient needs pain physician consultations and aggressive interventional pain control.³

In the article by Riddle et al,¹ the authors state that in the example of Cluster A type personality disorder, the elderly male patient’s paranoid disorder should be ignored, rather than confronting the paranoia. We do not need to confront the paranoia, but we need to treat the paranoid disorder. The symptom of paranoia extends beyond the single diagnostic category of delusional disorder and has been noted in many elderly patients with other underlying disorders.² This patient needs early psychiatric consultation and therapy.

They also give recommendations regarding Ms. B for her ever-increasing need of opiates. I find it too naïve for me to offer this patient “…choices, such as walking with her around the unit or listen to the music.” This patient needs pain physician consultations and aggressive interventional pain control.³

In the article by Riddle et al,¹ the authors state that in the example of Cluster A type personality disorder, the elderly male patient’s paranoid disorder should be ignored, rather than confronting the paranoia. We do not need to confront the paranoia, but we need to treat the paranoid disorder. The symptom of paranoia extends beyond the single diagnostic category of delusional disorder and has been noted in many elderly patients with other underlying disorders.² This patient needs early psychiatric consultation and therapy.

They also give recommendations regarding Ms. B for her ever-increasing need of opiates. I find it too naïve for me to offer this patient “…choices, such as walking with her around the unit or listen to the music.” This patient needs pain physician consultations and aggressive interventional pain control.³

Thank you for the opportunity to reply to Dr. Hunasikatti’s comments regarding our article.¹ He brings up some excellent points and we appreciate the opportunity to clarify.

With regards to our example of Cluster A personality, the elderly individual with paranoia, we agree that the differential must include delirium and dementia and an appropriate work-up completed.  The intent of the vignette was to illustrate a functional but eccentric individual with paranoid beliefs.  The paranoia associated with paranoid personality disorder is classically not responsive to medications—nor are patients typically amenable to such treatment—and behavioral interventions remain paramount, minimizing the negative impact of paranoia on the individual’s care.^2,3

Regarding Ms. B, the vignette stated that the pain service was consulted, as Dr. Hunasikatti suggested it should be, but despite aggressive pain control, requests for opiates continued.  We agree that appropriate pain management is critical in management of all patients, and pain can exacerbate behavioral issues when insufficiently treated.  However, individuals who look to external sources of comfort may continue to request pain medications beyond what is clinically prudent and can benefit from learning additional skills to self-soothe and manage the psychological aspects of pain.^4,5

Thank you for the opportunity to reply to Dr. Hunasikatti’s comments regarding our article.¹ He brings up some excellent points and we appreciate the opportunity to clarify.

With regards to our example of Cluster A personality, the elderly individual with paranoia, we agree that the differential must include delirium and dementia and an appropriate work-up completed.  The intent of the vignette was to illustrate a functional but eccentric individual with paranoid beliefs.  The paranoia associated with paranoid personality disorder is classically not responsive to medications—nor are patients typically amenable to such treatment—and behavioral interventions remain paramount, minimizing the negative impact of paranoia on the individual’s care.^2,3

Regarding Ms. B, the vignette stated that the pain service was consulted, as Dr. Hunasikatti suggested it should be, but despite aggressive pain control, requests for opiates continued.  We agree that appropriate pain management is critical in management of all patients, and pain can exacerbate behavioral issues when insufficiently treated.  However, individuals who look to external sources of comfort may continue to request pain medications beyond what is clinically prudent and can benefit from learning additional skills to self-soothe and manage the psychological aspects of pain.^4,5

Thank you for the opportunity to reply to Dr. Hunasikatti’s comments regarding our article.¹ He brings up some excellent points and we appreciate the opportunity to clarify.

With regards to our example of Cluster A personality, the elderly individual with paranoia, we agree that the differential must include delirium and dementia and an appropriate work-up completed.  The intent of the vignette was to illustrate a functional but eccentric individual with paranoid beliefs.  The paranoia associated with paranoid personality disorder is classically not responsive to medications—nor are patients typically amenable to such treatment—and behavioral interventions remain paramount, minimizing the negative impact of paranoia on the individual’s care.^2,3

Regarding Ms. B, the vignette stated that the pain service was consulted, as Dr. Hunasikatti suggested it should be, but despite aggressive pain control, requests for opiates continued.  We agree that appropriate pain management is critical in management of all patients, and pain can exacerbate behavioral issues when insufficiently treated.  However, individuals who look to external sources of comfort may continue to request pain medications beyond what is clinically prudent and can benefit from learning additional skills to self-soothe and manage the psychological aspects of pain.^4,5

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo courtesy of Celgene

The US Food and Drug Administration (FDA) has approved a new indication for lenalidomide (Revlimid).

The drug is now approved for use as maintenance therapy after autologous hematopoietic stem cell transplant (auto-HSCT) in patients with multiple myeloma (MM).

The expanded indication makes lenalidomide the first treatment to receive FDA approval for maintenance following auto-HSCT.

The drug was previously FDA-approved for use in combination with dexamethasone to treat patients with MM.

Lenalidomide is also FDA-approved to treat patients with transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes associated with deletion 5q, with or without additional cytogenetic abnormalities.

And lenalidomide is FDA-approved to treat patients with mantle cell lymphoma who have relapsed or progressed after 2 prior therapies, one of which included bortezomib.

Lenalidomide is a product of Celgene.

Studies: Lenalidomide maintenance

The latest approval for lenalidomide was based on results of 2 cooperative group-led studies, CALGB 10010410 and IFM 2005-0211.

Results from both studies were published in NEJM in May 2012 (CALGB 100104, IFM 2005-02). The updated data reported here are included in the prescribing information for lenalidomide.

CALGB 100104 was a phase 3, double-blind study of 460 patients with newly diagnosed MM undergoing auto-HSCT. The patients received continuous daily treatment with lenalidomide or placebo until relapse.

IFM 2005-02 was a phase 3, double-blind study of 614 patients newly diagnosed with MM. The patients were randomized to receive a 2-month consolidation regimen after auto-HSCT, which consisted of lenalidomide monotherapy followed by continuous daily treatment with lenalidomide or placebo until relapse.

Survival

In both studies, the primary efficacy endpoint was progression-free survival (PFS). The PFS data for both studies were updated to reflect results as of March 2015.

In the CALGB study, the median PFS was 5.7 years in the lenalidomide arm and 1.9 years in the placebo arm (hazard ratio [HR]=0.38 [95% CI: 0.28-0.50]).

In the IFM study, the median PFS was 3.9 years in the lenalidomide arm and 2 years in the placebo arm (HR=0.53 [95% CI: 0.44-0.64]).

These studies were not powered for an overall survival (OS) endpoint. However, OS was recorded, and the OS data for both studies were updated to reflect results as of February 2016.

The median OS in the CALGB study was 9.3 years in the lenalidomide arm and 7 years in the placebo arm (HR=0.59 [95% CI: 0.44-0.78]).

In the IFM study, the median OS was 8.8 years in the lenalidomide arm and 7.3 years in the placebo arm (HR=0.90 [95% CI: 0.72-1.13]).

Adverse events

The most frequently reported adverse events in ≥20% of patients in the lenalidomide arm across both  studies (CALGB and IFM, respectively) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%).

The most frequently reported grade 3/4 events (more than 20% in the lenalidomide arm) were neutropenia, thrombocytopenia, and leukopenia.

Hematologic second primary malignancies (SPM) occurred in 7.5% of patients receiving lenalidomide maintenance and 3.3% of controls.

The incidence of hematologic plus solid tumor SPM (excluding squamous cell carcinoma and basal cell carcinoma) was 14.9% in the lenalidomide group and 8.8% in the control group, with a median follow-up of 91.5 months.

Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving lenalidomide maintenance and 2.6% of controls.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Photo by Bill Branson

ORLANDO, FL—Results of a phase 3 trial suggest an inactivated varicella zoster virus (VZV) vaccine known as V212 can reduce the risk of herpes zoster (HZ) in patients who have undergone autologous hematopoietic stem cell transplant (HSCT).

V212 reduced the hazard rate of HZ by an estimated 64% compared to placebo.

The vaccine also reduced the incidence of moderate-to-severe HZ pain and other HZ-related complications, such as hospitalization.

The overall incidence of adverse events (AEs) and the incidence of serious AEs were similar among vaccinated patients and those who received placebo.

Drew J. Winston, MD, of the University of California Los Angeles Medical Center, presented these results as one of the “Best Abstracts” at the 2017 BMT Tandem Meetings (abstract 6). The trial was sponsored by Merck, the company developing V212.

Treatment

This randomized, double-blind trial enrolled 1230 patients age 18 and older who were undergoing HSCT for any indication and had a history of varicella infection and/or were seropositive for VZV antibody.

The patients were randomized to receive:

• A 4-dose regimen of V212 (n=560) from a consistency lot (a lot having a targeted potency as required by regulators in order to demonstrate that the vaccine can be manufactured consistently)
• A 4-dose regimen of V212 (n=106) from a high-antigen lot (a lot having a higher antigen potency added to assess the safety profile of V212)
• Placebo (n=564).

Randomization was stratified by age (< 50 years vs ≥ 50 years) and by intended duration of post-transplant antiviral prophylaxis (≤3 months vs >3 to 6 months).

Dose 1 of V212 or placebo was given within approximately 30 days before HSCT, and doses 2, 3, and 4 were given approximately 30, 60, and 90 days after HSCT.

Patient characteristics

The median patient age was 57 (range, 19-76) for the consistency lot group, 56 (range, 21-75) for the high-antigen lot group, and 56 (range, 19-79) for the placebo group.

Underlying diseases were non-Hodgkin lymphoma (42%, 40%, and 44%, respectively), Hodgkin lymphoma (10%, 9%, and 9%, respectively), multiple myeloma (44%, 47% and 41%, respectively), acute leukemia (2%, 1%, and 2%, respectively), and “other” diseases (2%, 3% and 4%, respectively).

Roughly 30% of patients in each group received anti-viral agents for 3 months or less after HSCT. Twenty percent to 25% received antiviral therapy for more than 3 months to 6 months.

Thirty-seven percent to 40% received antiviral agents for more than 6 months. And 7% to 12% of patients did not receive any antiviral therapy.

HZ incidence

The average follow-up time for HZ surveillance was approximately 2.3 years (median: 2.6 years) post-vaccination.

Confirmed HZ occurred in 42 of the 538 patients who received V212 from a consistency lot and 113 of the 535 patients who received placebo. (Patients receiving V212 from a high-antigen lot were only included in the safety analysis.)

The estimated efficacy of V212 was 63.8% after adjustment for patient age and the duration of antiviral prophylaxis. Vaccine efficacy against HZ was defined as the relative reduction of hazard rate of HZ in vaccine recipients compared with placebo recipients.

The vaccine met the pre-specified criterion for success, as the lower bound of the 95% confidence interval (CI) was greater than 25%. The 95% CI was 48.4% to 74.6% (P<0.0001).

“The study demonstrates that the inactivated varicella vaccine is very effective for preventing herpes zoster after autologous stem cell transplantation,” Dr Winston said.

Pain, PHN, and other complications

V212 also reduced the incidence of moderate-to-severe HZ pain—according to the Zoster Brief Pain Inventory (ZBPI) score—by an estimated 69.5% (95% CI, 0.490-0.818).

Nineteen patients in the V212 consistency lot group had moderate-to-severe pain, as did 61 placebo-treated patients.

V212 conferred an estimated 83.7% (95% CI, 0.446-0.952) reduction in the incidence of post-herpetic neuralgia (PHN). Three patients in the V212 consistency lot group and 18 patients in the placebo group had PHN.

PHN was defined as pain in the area of the HZ rash with a “worst pain in the last 24 hours” score of 3 or greater (on a 0-10 scale) on the ZBPI that persists or appears 90 days or beyond after HZ rash onset following HSCT.

Patients who received V212 also saw an estimated 73.5% (95% CI, 0.498-0.860) reduction in “other” HZ complications. Twelve patients in the V212 consistency group and 44 in the placebo group had such complications.

“Other” complications included hospitalization or prolongation of hospitalization due to HZ, disseminated HZ (including disseminated HZ rash or VZV viremia), visceral HZ, ophthalmic HZ, neurological impairment due to HZ, and the administration of intravenous acyclovir therapy for the treatment of HZ post-HSCT.

Safety

All patients who received at least 1 dose of the vaccine or placebo and had follow-up data were included in the safety analysis. Patients were followed for AEs up to 28 days after the fourth vaccination dose.

AEs occurred in 97% of patients who received the vaccine (consistency and high-antigen groups assessed together) and 96.9% of placebo-treated patients. Vaccine-related AEs occurred in 32.6% and 12.6%, respectively.

“Of course, in this population of autologous stem cell transplant patients, adverse events of any type were very common in almost all patients,” Dr Winston said. “However, vaccine-related adverse events were greater in the vaccine recipients compared to the placebo patients, but this was primarily due to an increased incidence of injection-site adverse events in the vaccine recipients.”

Injection-site reactions occurred in 191 vaccinated patients and 36 placebo-treated patients.

The most common systemic AEs—in vaccinated and placebo-treated patients, respectively—were diarrhea (60.1% and 61.9%), nausea (56.5% and 57.8%), pyrexia (49.8% and 46.9%), mucosal inflammation (39.7% and 41.7%), thrombocytopenia (36.4% and 38.4%), febrile neutropenia (33.9% and 28.3%), vomiting (32.6% and 36.6%), anemia (26.6% and 24.4%), neutropenia (25.1% and 23.5%), decreased appetite (23.1% and 23.8%), fatigue (21.8% and 20.7%), hypokalemia (21.3% and 19.9%), and constipation (16.1% and 18.4%).

The incidence of serious AEs was 32.9% in vaccinated patients and 32.7% in the placebo group. The incidence of serious vaccine-related AEs was 0.8% and 0.9%, respectively.

The most common serious AEs—in vaccinated and placebo-treated patients, respectively—were infection (12.3% and 11.9%), relapsed malignancy (7.8% for both), febrile neutropenia (5.3% and 4.9%), pyrexia (3.2% and 4.0%), gastrointestinal disorders (3.2% and 3.6%), respiratory failure (2.7% and 2.2%), cardiac disorders (1.7% and 1.6%), and mucositis (1.2% and 0.9%).

Death occurred in 6.2% of vaccinated patients and 6.3% of placebo-treated patients. Three percent and 3.1%, respectively, discontinued the study due to AEs.

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays. 

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays. 

Kristyna Wentz-Graff

A newly discovered issue with the Ba/F3 transformation assay could “jeopardize attempts to characterize the signaling mechanisms and drug sensitivities of leukemic oncogenes,” researchers reported in Oncotarget.

The researchers said the assay “remains an invaluable tool” for validating activating mutations in primary leukemias.

However, the assay is prone to a previously unreported flaw, where Ba/F3 cells can acquire additional mutations.

This issue was discovered by Kevin Watanabe-Smith, PhD, of Oregon Health & Science University in Portland.

He identified the problem while studying a growth-activating mutation in a patient with T-cell leukemia. (The results of that research were published in Leukemia in April 2016).

“When I was sequencing the patient’s DNA to make sure the original, known mutation is there, I was finding additional, unexpected mutations in the gene that I didn’t put there,” Dr Watanabe-Smith said. “And I was getting different mutations every time.”

“After we saw this in several cases, we knew it was worth further study,” added Cristina Tognon, PhD, of Oregon Health & Science University.

So the researchers decided to study Ba/F3 cell lines with and without 4 mutations (found in 3 cytokine receptors) that have “known transformative capacity,” including:

• CSF2RB R461C, a germline mutation found in a patient with T-cell acute lymphoblastic leukemia (ALL)
• CSF3R T618I, a mutation found in chronic neutrophilic leukemia (CNL) and atypical chronic myelogenous leukemia (aCML)
• CSF3R W791X, also found in CNL and aCML
• IL7R 243InsPPCL, which was found in a patient with B-cell ALL.

The researchers said they observed acquired mutations in 1 of 3 CSF2RB wild-type cell lines that transformed and all 4 CSF3R wild-type cell lines, which all transformed.

Furthermore, most CSF2RB R461C lines (4/5) and CSF3R W791X lines (3/4) had additional acquired mutations. However, the CSF3R T618I lines and the IL7R 243InsPPCL lines did not contain acquired mutations.

The researchers said acquired mutations were observed only in weakly transforming oncogenes, which were defined as mutations with a weaker ability to transform cells (less than 1 in every 200 cells) or a slower time to outgrowth (5 days or longer to reach a 5-fold increase over the initial cell number).

The team also said their findings indicate that the majority of the acquired mutations likely exist before IL-3 withdrawal but only expand to levels detectable by Sanger sequencing in the absence of IL-3.

“The potential impact [of these acquired mutations] is that a non-functional mutation could appear functional, and a researcher could publish results that would not be reproducible,” Dr Watanabe-Smith said.

To overcome this problem, Dr Watanabe-Smith and his colleagues recommended taking an additional step when using the Ba/F3 assay—sequencing outgrown cell lines. They also said additional research is needed to devise methods that reduce the incidence of acquired mutations in such assays. 

Image from CDC/Mae Melvin

An investigational malaria vaccine can protect healthy adults from infection with a malaria strain different from that contained in the vaccine, according to a phase 1 study published in PNAS.

The vaccine, known as the PfSPZ Vaccine, contains weakened Plasmodium falciparum sporozoites that are able to generate a protective immune response against live malaria infection.

Prior research showed that the PfSPZ Vaccine can provide long-term protection against a single malaria strain matched to the vaccine.

The new study has shown that the PfSPZ Vaccine can protect against a different strain of P falciparum as well.

“An effective malaria vaccine will need to protect people living in endemic areas against multiple strains of the mosquito-borne disease,” said Anthony S. Fauci, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

“These new findings showing cross-protection with the PfSPZ Vaccine suggest that it may be able to accomplish this goal.”

The PfSPZ Vaccine was developed by Sanaria Inc. The company designed, manufactured, and provided PfSPZ Vaccine and the heterologous challenge mosquitoes for this trial. The NIAID supported the development of the vaccine through several grants.

Study details

The study enrolled 31 healthy, malaria-naive adults ages 19 to 45.

Fifteen subjects were scheduled to receive 3 doses of the PfSPZ Vaccine—9.0 × 10⁵ PfSPZ administered intravenously 3 times at 8-week intervals. The remaining subjects served as controls.

Nineteen weeks after receiving the final dose of the test vaccine, vaccinated subjects and controls were exposed to bites from mosquitoes infected with the same strain of P falciparum parasites (NF54) that were used to manufacture PfSPZ Vaccine.

Nine of the 14 subjects (64%) who received PfSPZ Vaccine demonstrated no evidence of malaria parasites. All 6 of the non-vaccinated subjects who were challenged at the same time had malaria parasites in their blood.

Of the 9 subjects who showed no evidence of malaria, 6 subjects were again exposed to mosquito bites, this time from mosquitoes infected with a different strain of P falciparum (Pf7G8), 33 weeks after the final immunization.

In this group, 5 of the 6 subjects (83%) were protected against malaria infection. None of the 6 control subjects who were challenged were protected.

“Achieving durable protection against a malaria strain different from the vaccine strain, over 8 months after vaccination, is an indication of this vaccine’s potential,” said Robert A. Seder, MD, of NIAID.

“If we can build on these findings with the PfSPZ Vaccine and induce higher efficacy, we may be on our way to a vaccine that could effectively protect people against a variety of malaria parasites where the disease is prevalent.”

The researchers found the PfSPZ Vaccine activated T cells and induced antibody responses in all vaccine recipients. Vaccine-specific T-cell responses were comparable when measured against both malaria challenge strains, providing some insight into how the vaccine was mediating protection.

Ongoing research should determine whether protective efficacy can be improved by changes to the PfSPZ Vaccine dose and number of immunizations.

A phase 2 trial testing 3 different dosages in a 3-dose vaccine regimen is now underway in 5-to 12-month-old infants in Western Kenya to assess safety and efficacy of the vaccine against natural infection.

Image from CDC/Mae Melvin

An investigational malaria vaccine can protect healthy adults from infection with a malaria strain different from that contained in the vaccine, according to a phase 1 study published in PNAS.

The vaccine, known as the PfSPZ Vaccine, contains weakened Plasmodium falciparum sporozoites that are able to generate a protective immune response against live malaria infection.

Prior research showed that the PfSPZ Vaccine can provide long-term protection against a single malaria strain matched to the vaccine.

The new study has shown that the PfSPZ Vaccine can protect against a different strain of P falciparum as well.

“An effective malaria vaccine will need to protect people living in endemic areas against multiple strains of the mosquito-borne disease,” said Anthony S. Fauci, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

“These new findings showing cross-protection with the PfSPZ Vaccine suggest that it may be able to accomplish this goal.”

The PfSPZ Vaccine was developed by Sanaria Inc. The company designed, manufactured, and provided PfSPZ Vaccine and the heterologous challenge mosquitoes for this trial. The NIAID supported the development of the vaccine through several grants.

Study details

The study enrolled 31 healthy, malaria-naive adults ages 19 to 45.

Fifteen subjects were scheduled to receive 3 doses of the PfSPZ Vaccine—9.0 × 10⁵ PfSPZ administered intravenously 3 times at 8-week intervals. The remaining subjects served as controls.

Nineteen weeks after receiving the final dose of the test vaccine, vaccinated subjects and controls were exposed to bites from mosquitoes infected with the same strain of P falciparum parasites (NF54) that were used to manufacture PfSPZ Vaccine.

Nine of the 14 subjects (64%) who received PfSPZ Vaccine demonstrated no evidence of malaria parasites. All 6 of the non-vaccinated subjects who were challenged at the same time had malaria parasites in their blood.

Of the 9 subjects who showed no evidence of malaria, 6 subjects were again exposed to mosquito bites, this time from mosquitoes infected with a different strain of P falciparum (Pf7G8), 33 weeks after the final immunization.

In this group, 5 of the 6 subjects (83%) were protected against malaria infection. None of the 6 control subjects who were challenged were protected.

“Achieving durable protection against a malaria strain different from the vaccine strain, over 8 months after vaccination, is an indication of this vaccine’s potential,” said Robert A. Seder, MD, of NIAID.

“If we can build on these findings with the PfSPZ Vaccine and induce higher efficacy, we may be on our way to a vaccine that could effectively protect people against a variety of malaria parasites where the disease is prevalent.”

The researchers found the PfSPZ Vaccine activated T cells and induced antibody responses in all vaccine recipients. Vaccine-specific T-cell responses were comparable when measured against both malaria challenge strains, providing some insight into how the vaccine was mediating protection.

Ongoing research should determine whether protective efficacy can be improved by changes to the PfSPZ Vaccine dose and number of immunizations.

A phase 2 trial testing 3 different dosages in a 3-dose vaccine regimen is now underway in 5-to 12-month-old infants in Western Kenya to assess safety and efficacy of the vaccine against natural infection.

Image from CDC/Mae Melvin

An investigational malaria vaccine can protect healthy adults from infection with a malaria strain different from that contained in the vaccine, according to a phase 1 study published in PNAS.

The vaccine, known as the PfSPZ Vaccine, contains weakened Plasmodium falciparum sporozoites that are able to generate a protective immune response against live malaria infection.

Prior research showed that the PfSPZ Vaccine can provide long-term protection against a single malaria strain matched to the vaccine.

The new study has shown that the PfSPZ Vaccine can protect against a different strain of P falciparum as well.

“An effective malaria vaccine will need to protect people living in endemic areas against multiple strains of the mosquito-borne disease,” said Anthony S. Fauci, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

“These new findings showing cross-protection with the PfSPZ Vaccine suggest that it may be able to accomplish this goal.”

The PfSPZ Vaccine was developed by Sanaria Inc. The company designed, manufactured, and provided PfSPZ Vaccine and the heterologous challenge mosquitoes for this trial. The NIAID supported the development of the vaccine through several grants.

Study details

The study enrolled 31 healthy, malaria-naive adults ages 19 to 45.

Fifteen subjects were scheduled to receive 3 doses of the PfSPZ Vaccine—9.0 × 10⁵ PfSPZ administered intravenously 3 times at 8-week intervals. The remaining subjects served as controls.

Nineteen weeks after receiving the final dose of the test vaccine, vaccinated subjects and controls were exposed to bites from mosquitoes infected with the same strain of P falciparum parasites (NF54) that were used to manufacture PfSPZ Vaccine.

Nine of the 14 subjects (64%) who received PfSPZ Vaccine demonstrated no evidence of malaria parasites. All 6 of the non-vaccinated subjects who were challenged at the same time had malaria parasites in their blood.

Of the 9 subjects who showed no evidence of malaria, 6 subjects were again exposed to mosquito bites, this time from mosquitoes infected with a different strain of P falciparum (Pf7G8), 33 weeks after the final immunization.

In this group, 5 of the 6 subjects (83%) were protected against malaria infection. None of the 6 control subjects who were challenged were protected.

“Achieving durable protection against a malaria strain different from the vaccine strain, over 8 months after vaccination, is an indication of this vaccine’s potential,” said Robert A. Seder, MD, of NIAID.

“If we can build on these findings with the PfSPZ Vaccine and induce higher efficacy, we may be on our way to a vaccine that could effectively protect people against a variety of malaria parasites where the disease is prevalent.”

The researchers found the PfSPZ Vaccine activated T cells and induced antibody responses in all vaccine recipients. Vaccine-specific T-cell responses were comparable when measured against both malaria challenge strains, providing some insight into how the vaccine was mediating protection.

Ongoing research should determine whether protective efficacy can be improved by changes to the PfSPZ Vaccine dose and number of immunizations.

A phase 2 trial testing 3 different dosages in a 3-dose vaccine regimen is now underway in 5-to 12-month-old infants in Western Kenya to assess safety and efficacy of the vaccine against natural infection.

Features of the plenary session (P151) at this year’s American Academy of Dermatology annual meeting include the Clarence S. Livingood, MD Memorial Award and Lectureship, on “Telemedicine and the Future of Medicine,” presented by Carrie L. Kovarik, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia.

Dr. Kovarik’s presentation will be followed by the AAD president’s address, by outgoing president Abel Torres, MD, JD, professor and chairman of the department of dermatology at Case Western Reserve University MetroHealth Systems, Cleveland; and professor and chairman of the department of dermatology at Loma Linda University Medical Center, Loma Linda, California.

Christine Léauté-Labrèze, MD, of the Hôpital Pellegrin–Enfants, Centre Hospitalier Universitaire, Bordeaux, France, will then present the Eugene J. Van Scott Award for Innovative Therapy of the Skin and Phillip Frost Leadership Lecture: “Propranolol in Infantile Hemangiomas: A Successful Drug Repurposing.” Dr. Léauté-Labrèze was the lead author of the multicenter, randomized controlled study that evaluated the efficacy and safety of oral propranolol for treating infantile hemangiomas (N Engl J Med. 2015;372:735-46).

Incoming AAD president Henry W. Lim, MD, will follow, with the president-elect’s address. Dr. Lim is the chairman of the department of dermatology and Clarence S. Livingood Chair in Dermatology at Henry Ford Health System in Detroit.

Boris C. Bastian, MD, professor of dermatology and pathology, University of California, San Francisco, will give the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, on “How Moles Become Cancer.” Dr. Bastian is also the director of the Clinical Cancer Genomics Laboratory at UCSF.

This year, the Marion B. Sulzberger, MD, Memorial Award and Lectureship – titled “Getting to the Heart (and other Comorbidities) of Psoriasis” – will be given by Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania.

Finally, this year’s guest speaker is the Center for Disease Control and Prevention’s Jordan W. Tappero, MD, whose lecture is titled: “The West African Ebola Epidemic and the Global Health Security Agenda.” Dr. Tappero is director of the Division of Global Health Protection, in the CDC’s Center for Global Health.



The plenary session is scheduled for Sunday March 5, 8 AM to 11:30 AM, in the Chapin Theater at the Orange County Convention Center, Orlando.

[email protected]
 

Features of the plenary session (P151) at this year’s American Academy of Dermatology annual meeting include the Clarence S. Livingood, MD Memorial Award and Lectureship, on “Telemedicine and the Future of Medicine,” presented by Carrie L. Kovarik, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia.

Dr. Kovarik’s presentation will be followed by the AAD president’s address, by outgoing president Abel Torres, MD, JD, professor and chairman of the department of dermatology at Case Western Reserve University MetroHealth Systems, Cleveland; and professor and chairman of the department of dermatology at Loma Linda University Medical Center, Loma Linda, California.

Christine Léauté-Labrèze, MD, of the Hôpital Pellegrin–Enfants, Centre Hospitalier Universitaire, Bordeaux, France, will then present the Eugene J. Van Scott Award for Innovative Therapy of the Skin and Phillip Frost Leadership Lecture: “Propranolol in Infantile Hemangiomas: A Successful Drug Repurposing.” Dr. Léauté-Labrèze was the lead author of the multicenter, randomized controlled study that evaluated the efficacy and safety of oral propranolol for treating infantile hemangiomas (N Engl J Med. 2015;372:735-46).

Incoming AAD president Henry W. Lim, MD, will follow, with the president-elect’s address. Dr. Lim is the chairman of the department of dermatology and Clarence S. Livingood Chair in Dermatology at Henry Ford Health System in Detroit.

Boris C. Bastian, MD, professor of dermatology and pathology, University of California, San Francisco, will give the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, on “How Moles Become Cancer.” Dr. Bastian is also the director of the Clinical Cancer Genomics Laboratory at UCSF.

This year, the Marion B. Sulzberger, MD, Memorial Award and Lectureship – titled “Getting to the Heart (and other Comorbidities) of Psoriasis” – will be given by Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania.

Finally, this year’s guest speaker is the Center for Disease Control and Prevention’s Jordan W. Tappero, MD, whose lecture is titled: “The West African Ebola Epidemic and the Global Health Security Agenda.” Dr. Tappero is director of the Division of Global Health Protection, in the CDC’s Center for Global Health.



The plenary session is scheduled for Sunday March 5, 8 AM to 11:30 AM, in the Chapin Theater at the Orange County Convention Center, Orlando.

[email protected]
 

Features of the plenary session (P151) at this year’s American Academy of Dermatology annual meeting include the Clarence S. Livingood, MD Memorial Award and Lectureship, on “Telemedicine and the Future of Medicine,” presented by Carrie L. Kovarik, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia.

Dr. Kovarik’s presentation will be followed by the AAD president’s address, by outgoing president Abel Torres, MD, JD, professor and chairman of the department of dermatology at Case Western Reserve University MetroHealth Systems, Cleveland; and professor and chairman of the department of dermatology at Loma Linda University Medical Center, Loma Linda, California.

Christine Léauté-Labrèze, MD, of the Hôpital Pellegrin–Enfants, Centre Hospitalier Universitaire, Bordeaux, France, will then present the Eugene J. Van Scott Award for Innovative Therapy of the Skin and Phillip Frost Leadership Lecture: “Propranolol in Infantile Hemangiomas: A Successful Drug Repurposing.” Dr. Léauté-Labrèze was the lead author of the multicenter, randomized controlled study that evaluated the efficacy and safety of oral propranolol for treating infantile hemangiomas (N Engl J Med. 2015;372:735-46).

Incoming AAD president Henry W. Lim, MD, will follow, with the president-elect’s address. Dr. Lim is the chairman of the department of dermatology and Clarence S. Livingood Chair in Dermatology at Henry Ford Health System in Detroit.

Boris C. Bastian, MD, professor of dermatology and pathology, University of California, San Francisco, will give the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, on “How Moles Become Cancer.” Dr. Bastian is also the director of the Clinical Cancer Genomics Laboratory at UCSF.

This year, the Marion B. Sulzberger, MD, Memorial Award and Lectureship – titled “Getting to the Heart (and other Comorbidities) of Psoriasis” – will be given by Joel M. Gelfand, MD, professor of dermatology, University of Pennsylvania.

Finally, this year’s guest speaker is the Center for Disease Control and Prevention’s Jordan W. Tappero, MD, whose lecture is titled: “The West African Ebola Epidemic and the Global Health Security Agenda.” Dr. Tappero is director of the Division of Global Health Protection, in the CDC’s Center for Global Health.



The plenary session is scheduled for Sunday March 5, 8 AM to 11:30 AM, in the Chapin Theater at the Orange County Convention Center, Orlando.

[email protected]