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A shocking diagnosis
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 75-year-old man was brought by ambulance to the emergency department (ED) after the acute onset of palpitations, lightheadedness, and confusion. His medical history, provided by his wife, included osteoarthritis and remote cholecystectomy. He was not a smoker but drank 2 to 4 cans of beer daily. His medications were aspirin 162 mg daily and naproxen as needed. There was no history of bruising, diarrhea, melena, or bleeding.
Palpitations may represent an arrhythmia arising from an ischemic or alcoholic cardiomyopathy. Mental status changes usually have metabolic, infectious, structural (eg, hemorrhage, tumor), or toxic causes. Lightheadedness and confusion could occur with arrhythmia-associated cerebral hypoperfusion or a seizure. Daily alcohol use could cause confusion through acute intoxication, thiamine or B12 deficiency, repeated head trauma, or liver failure.
The patient’s systolic blood pressure (BP) was 60 mm Hg, heart rate (HR) was 120 beats per minute (bpm), and oral temperature was 98.4°F. Rousing him was difficult. There were no localizing neurologic abnormalities, and the rest of the physical examination findings were normal. Point-of-care blood glucose level was 155 mg/dL. Blood cultures were obtained and broad-spectrum antibiotics initiated. After fluid resuscitation, BP improved to 116/87 mm Hg, HR fell to 105 bpm, and the patient became alert and oriented. He denied chest pain, fever, or diaphoresis.
The patient’s improvement with intravenous (IV) fluids makes cardiogenic shock unlikely but does not exclude an underlying compensated cardiomyopathy that may be predisposing to arrhythmia. Hypotension, tachycardia, and somnolence may represent sepsis, but the near normalization of vital signs and mental status shortly after administration of IV fluids, the normal temperature, and the absence of localizing signs of infection favor withholding additional antibiotics. Other causes of hypotension are hypovolemia, medication effects, adrenal insufficiency, anaphylaxis, and autonomic insufficiency. There was no reported nausea, vomiting, diarrhea, bleeding, polyuria, or impaired oral intake to support hypovolemia, though the response to IV fluids suggests hypovolemia may still be playing a role.
White blood cell (WBC) count was 15,450/µL with a normal differential; hemoglobin level was 15.8 g/dL; and platelet count was 176,000/µL. Electrolytes, liver function tests, cardiac enzymes, and urinalysis were normal. Electrocardiogram showed sinus tachycardia with premature atrial complexes and no ST-segment abnormalities. Radiograph of the chest and computed tomography scan of the head were normal. Echocardiogram showed moderate left ventricular hypertrophy with a normal ejection fraction and no valvular abnormalities. Exercise nuclear cardiac stress test was negative for ischemia. Blood cultures were sterile. The patient quickly became asymptomatic and remained so during his 3-day hospitalization. There were no arrhythmias on telemetry. The patient was discharged with follow-up scheduled with his primary care physician.
The nonlocalizing history and physical examination findings, normal chest radiograph and urinalysis, absence of fevers, negative blood cultures, and quick recovery make infection unlikely, despite the moderate leukocytosis. Conditions that present with acute and transient hypotension and altered mental status include arrhythmias, seizures, and reactions to drugs or toxins. Given the cardiac test results, a chronic cardiomyopathy seems unlikely, but arrhythmia is still possible. Continuous outpatient monitoring is required to assess the palpitations and the frequency of the premature atrial complexes.
Two days after discharge, the patient suddenly became diaphoretic and lost consciousness while walking to the bathroom. He was taken to the ED, where his BP was 90/60 mm Hg and HR was 108 bpm. Family members reported that he had appeared flushed during the syncopal episode, showed no seizure activity, and been unconscious for 15 to 20 minutes. The patient denied chest pain, dyspnea, fever, bowel or bladder incontinence, focal weakness, slurred speech, visual changes, nausea or vomiting either before or after the episode. Physical examination revealed a tongue laceration and facial erythema; all other findings were normal. In the ED, there was an asymptomatic 7-beat run of nonsustained ventricular tachycardia, and the hypotension resolved after fluid resuscitation. The patient now reported 2 similar syncopal episodes in the past. The first occurred in a restaurant 6 years earlier, and the second occurred 3 years later, at which time he was hospitalized and no etiology was found.
The loss of consciousness is attributable to cerebral hypoperfusion. Hypotension has 3 principal categories: hypovolemic, cardiogenic, and distributive. With syncopal episodes recurring over several years, hypovolemia seems unlikely. Given the palpitations and ventricular tachycardia, it is reasonable to suspect a cardiogenic cause. Although his heart appears to be structurally normal on echocardiogram, genetic, electrophysiologic, or magnetic resonance imaging (MRI) testing will occasionally reveal an unsuspected substrate for arrhythmia.
The recurring yet self-limited nature, diaphoresis, flushing, and facial erythema suggest a non-sepsis distributive cause of hypotension. It is possible the patient is recurrently exposed to a toxin (eg, alcohol) that causes both flushing and dehydration. Flushing disorders include carcinoid syndrome, pheochromocytoma, drug reaction with eosinophilia and systemic symptoms (DRESS), and mastocytosis. Carcinoid syndrome is characterized by bronchospasm and diarrhea and, in some cases, right-sided valvulopathy, all of which are absent in this patient. Pheochromocytoma is associated with orthostasis, but patients typically are hypertensive at baseline. DRESS, which may arise from nonsteroidal anti-inflammatory drug (NSAID) or aspirin use, can cause facial erythema and swelling but is also characterized by liver, renal, and hematologic abnormalities, none of which was demonstrated. Furthermore, DRESS typically does not cause hypotension. Mastocytosis can manifest as isolated or recurrent anaphylaxis.
It is important to investigate antecedents of these syncopal episodes. If the earlier episodes were food-related—one occurred at a restaurant—then deglutition syncope (syncope precipitated by swallowing) should be considered. If an NSAID or aspirin was ingested before each episode, then medication hypersensitivity or mast cell degranulation (which can be triggered by these medications) should be further examined. Loss of consciousness lasting 20 minutes without causing any neurologic sequelae is unusual for most causes of recurrent syncope. This feature raises the possibility that a toxin or mediator might still be present in the patient’s system.
Serial cardiac enzymes and electrocardiogram were normal. A tilt-table study was negative. The cortisol response to ACTH (cosyntropin) stimulation was normal. The level of serum tryptase, drawn 2 days after syncope, was 18.4 ng/dL (normal, <11.5 ng/dL). Computed tomography scan of chest and abdomen was negative for pulmonary embolism but showed a 1.4×1.3-cm hypervascular lesion in the tail of pancreas. The following neuroendocrine tests were within normal limits: serum and urine catecholamines; urine 5-hydroxyindoleacetic acid (5-HIAA); and serum chromogranin A, insulin, serotonin, vasoactive intestinal polypeptide (VIP), and somatostatin (Table 1). The patient remained asymptomatic during his hospital stay and was discharged home with appointments for cardiology follow-up and endoscopic ultrasound-guided biopsy of the pancreatic mass.
Pheochromocytoma is unlikely with normal serum and urine catecholamine levels and normal adrenal images. The differential diagnosis for a pancreatic mass includes pancreatic carcinoma, lymphoma, cystic neoplasm, and neuroendocrine tumor. All markers of neuroendocrine excess are normal, though elevations can be episodic. The normal 5-HIAA level makes carcinoid syndrome unlikely. VIPomas are associated with flushing, but the absence of profound and protracted diarrhea makes a VIPoma unlikely.
As hypoglycemia from a pancreatic insulinoma is plausible as a cause of episodic loss of consciousness lasting 15 minutes or more, it is important to inquire if giving food or drink helped resolve previous episodes. The normal insulin level reported here is of limited value, because it is the combination of insulin and C-peptide levels at time of hypoglycemia that is diagnostic. The normal glucose level recorded during one of the earlier episodes and the hypotension argue against hypoglycemia.
The elevated tryptase level is an indicator of mast cell degranulation. Tryptase levels are transiently elevated during the initial 2 to 4 hours after an anaphylactic episode and then normalize. An elevated level many hours or days later is considered a sign of mast cell excess. Although there is no evidence of the multi-organ disease (eg, cytopenia, bone disease, hepatosplenomegaly) seen in patients with a high systemic burden of mast cells, mast cell disorders exist on a spectrum. There may be a focal excess of mast cells confined to one organ or an isolated mass.
The same day as discharge, the patient’s wife drove them to the grocery store. He remained in the car while she shopped. When she returned, she found him confused and minimally responsive with subsequent brief loss of consciousness. He was taken to an ED, where he was flushed and hypotensive (systolic BP, 60 mm Hg) and tachycardic. Other examination findings were normal. After fluid resuscitation he became alert and oriented. WBC count was 20,850/μL with 89% neutrophils, hemoglobin level was 14.6 g/dL, and platelet count was 168,000/μL. Serum lactate level was 3.7 mmol/L (normal, <2.3 mmol/L). Chest radiograph was normal. He was treated with broad-spectrum antibiotic therapy and admitted to the hospital. Blood and urine cultures were sterile. Fine-needle aspiration of the pancreatic mass demonstrated nonspecific inflammation. Four days after admission (3 days after pancreatic mass biopsy) the patient developed palpitations, felt unwell, and had marked flushing of the face and trunk, with concomitant BP of 90/50 mm Hg and HR of 140 bpm.
The salient features of this case are recurrent hypotension, tachycardia, and flushing. Autonomic insufficiency, to which elderly patients are prone, causes hemodynamic perturbations but rarely flushing. The patient does not have diabetes mellitus, Parkinson disease, or another condition that puts him at risk for dysautonomia. Pancreatic neuroendocrine tumors secrete mediators that lead to vasodilation and hypotension but are unlikely given the clinical and biochemical data.
The patient’s symptoms are consistent with anaphylaxis, though prototypical immunoglobulin E (IgE)–mediated anaphylaxis is usually accompanied by urticaria, angioedema, and wheezing, which have been absent during his presentations. There are no clear food, pharmacologic, or environmental precipitants.
Recurrent anaphylaxis can be a manifestation of mast cell excess (eg, cutaneous or systemic mastocytosis). A markedly elevated tryptase level during an anaphylactic episode is consistent with mastocytosis or IgE-mediated anaphylaxis. An elevated baseline tryptase level days after an anaphylactic episode signals increased mast cell burden. There may be a reservoir of mast cells in the bone marrow. Alternatively, the hypervascular pancreatic mass may be a mastocytoma or a mast cell sarcoma (missed because of inadequate sampling or staining).
The lactic acidosis likely reflects global tissue hypoperfusion from vasodilatory hypotension. The leukocytosis may reflect WBC mobilization secondary to endogenous corticosteroids and catecholamines in response to hypotension or may be a direct response to the release of mast cell–derived mediators of inflammation.
The patient was treated with diphenhydramine and ranitidine. Serum tryptase level was 46.8 ng/mL (normal, <11.5 ng/mL), and 24-hour urine histamine level was 95 µ g/dL (normal, <60 µ g/dL). Bone marrow biopsy results showed multifocal dense infiltrative aggregates of mast cells (>15 cells/aggregate), which were confirmed by CD117 (Kit) and tryptase positivity (Figure). Mutation analysis for Kit Asp816Val, which is present in 80% to 90% of patients with mastocytosis, was positive. He fulfilled the 2008 World Health Organization criteria for systemic mastocytosis (Table 2). Prednisone, histamine inhibitors, and montelukast were prescribed. Six months later, magnetic resonance imaging of the abdomen showed no change in the pancreatic mass, which was now characterized as a possible splenule. The patient had no additional episodes of flushing or syncope over 2 years.
DISCUSSION
Cardiovascular collapse (hypotension, tachycardia, syncope) in an elderly patient prompts clinicians to focus on life-threatening conditions, such as acute coronary syndrome, pulmonary embolus, arrhythmia, and sepsis. Each of these diagnoses was considered early in the course of this patient’s presentations, but each was deemed unlikely as it became apparent that the episodes were self-limited and recurrent over years. Incorporating flushing into the diagnostic problem representation allowed the clinicians to focus on a subset of causes of hypotension.
Flushing disorders may be classified by whether they are mediated by the autonomic nervous system (wet flushes, because they are usually accompanied by diaphoresis) or by exogenous or endogenous vasoactive substances (dry flushes).1 Autonomic nervous system flushing is triggered by emotions, fever, exercise, perimenopause (hot flashes), and neurologic conditions (eg, Parkinson disease, spinal cord injury, multiple sclerosis). Vasoactive flushing precipitants include drugs (eg, niacin); alcohol (secondary to cutaneous vasodilation, or acetaldehyde particularly in people with insufficient acetaldehyde dehydrogenase activity)2; foods that contain capsaicin, tyramine, sulfites, or histamine (eg, eating improperly handled fish can cause scombroid poisoning); and anaphylaxis. Rare causes of vasoactive flushing include carcinoid syndrome, pheochromocytoma, medullary thyroid carcinoma, VIPoma, and mastocytosis.2
Mastocytosis is a rare clonal disorder characterized by the accumulation of abnormal mast cells in the skin (cutaneous mastocytosis), in multiple organs (systemic mastocytosis), or in a solid tumor (mastocytoma). Urticaria pigmentosa is the most common form of cutaneous mastocytosis; it is seen more often in children than in adults and typically is associated with a maculopapular rash and dermatographism. Systemic mastocytosis is the most common form of the disorder in adults.3 Symptoms are related to mast cell infiltration or mast cell mediator–related effects, which range from itching, flushing, and diarrhea to hypotension and anaphylaxis. Other manifestations are fatigue, urticaria pigmentosa, osteoporosis, hepatosplenomegaly, bone pain, cytopenias, and lymphadenopathy.4
Systemic mastocytosis can occur at any age and should be considered in patients with recurrent unexplained flushing, syncope, or hypotension. Eighty percent to 90% of patients with systemic mastocytosis have a mutation in Kit,5 a transmembrane tyrosine kinase that is the receptor for stem cell factor. The Asp816Val mutation leads to increased proliferation and reduced apoptosis of mast cells.3,6,7 Proposed diagnostic algorithms8-11 involve measurement of serum tryptase levels and examination of bone marrow. Bone marrow biopsy and testing for the Asp816Val
The primary goals of treatment are managing mast cell–mediated symptoms and, in advanced cases, achieving cytoreduction. Alcohol can trigger mast cell degranulation in indolent systemic mastocytosis and should be avoided. Mast cell–mediated symptoms are managed with histamine blockers, leukotriene antagonists, and mast cell stabilizers.12 Targeted therapy with tyrosine kinase inhibitors (eg, imatinib) in patients with transmembrane Kit mutation (eg, Phe522Cys, Lys509Ile) associated with systemic mastocytosis has had promising results.13,14 However, this patient’s Asp816Val mutation is in the Kit catalytic domain, not the transmembrane region, and therefore would not be expected to respond to imatinib. A recent open-label trial of the multikinase inhibitor midostaurin demonstrated resolution of organ damage, reduced bone marrow burden, and lowered serum tryptase levels in patients with advanced systemic mastocytosis.15 Interferon, cladribine, and high-dose corticosteroids are prescribed in patients for whom other therapies have been ineffective.8
The differential diagnosis is broad for both hypotension and for flushing, but the differential diagnosis for recurrent hypotension and flushing is limited. Recognizing that flushing was an essential feature of this patient’s hypotensive condition, and not an epiphenomenon of syncope, allowed the clinicians to focus on the overlap and make a shocking diagnosis.
Acknowledgment
The authors thank David Bosler, MD (Cleveland Clinic) for interpreting the pathology image.
Disclosure
Nothing to report.
1. Wilkin JK. The red face: flushing disorders. Clin Dermatol. 1993;11(2):211-223. PubMed
2. Izikson L, English JC 3rd, Zirwas MJ. The flushing patient: differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006;55(2):193-208. PubMed
3. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37(6):435-453. PubMed
4. Hermans MA, Rietveld MJ, van Laar JA, et al. Systemic mastocytosis: a cohort study on clinical characteristics of 136 patients in a large tertiary centre. Eur J Intern Med. 2016;30:25-30. PubMed
5. Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MB, Broesby-Olsen S; Mastocytosis Centre, Odense University Hospital (MastOUH). Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014;89(5):493-498. PubMed
6. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol. 2013;90(2):89-98. PubMed
7. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366-2372. PubMed
8. Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015;90(3):250-262. PubMed
9. Valent P, Aberer E, Beham-Schmid C, et al. Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian Competence Network (AUCNM). Am J Blood Res. 2013;3(2):174-180. PubMed
10. Valent P, Escribano L, Broesby-Olsen S, et al; European Competence Network on Mastocytosis. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014;69(10):1267-1274. PubMed
11. Akin C, Soto D, Brittain E, et al. Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels. Clin Immunol. 2007;123(3):268-271. PubMed
12. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373(19):1885-1886. PubMed
13. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004;103(8):3222-3225. PubMed
14. Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT identified in familial mastocytosis—in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006;30(4):373-378. PubMed
15. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541. PubMed
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 75-year-old man was brought by ambulance to the emergency department (ED) after the acute onset of palpitations, lightheadedness, and confusion. His medical history, provided by his wife, included osteoarthritis and remote cholecystectomy. He was not a smoker but drank 2 to 4 cans of beer daily. His medications were aspirin 162 mg daily and naproxen as needed. There was no history of bruising, diarrhea, melena, or bleeding.
Palpitations may represent an arrhythmia arising from an ischemic or alcoholic cardiomyopathy. Mental status changes usually have metabolic, infectious, structural (eg, hemorrhage, tumor), or toxic causes. Lightheadedness and confusion could occur with arrhythmia-associated cerebral hypoperfusion or a seizure. Daily alcohol use could cause confusion through acute intoxication, thiamine or B12 deficiency, repeated head trauma, or liver failure.
The patient’s systolic blood pressure (BP) was 60 mm Hg, heart rate (HR) was 120 beats per minute (bpm), and oral temperature was 98.4°F. Rousing him was difficult. There were no localizing neurologic abnormalities, and the rest of the physical examination findings were normal. Point-of-care blood glucose level was 155 mg/dL. Blood cultures were obtained and broad-spectrum antibiotics initiated. After fluid resuscitation, BP improved to 116/87 mm Hg, HR fell to 105 bpm, and the patient became alert and oriented. He denied chest pain, fever, or diaphoresis.
The patient’s improvement with intravenous (IV) fluids makes cardiogenic shock unlikely but does not exclude an underlying compensated cardiomyopathy that may be predisposing to arrhythmia. Hypotension, tachycardia, and somnolence may represent sepsis, but the near normalization of vital signs and mental status shortly after administration of IV fluids, the normal temperature, and the absence of localizing signs of infection favor withholding additional antibiotics. Other causes of hypotension are hypovolemia, medication effects, adrenal insufficiency, anaphylaxis, and autonomic insufficiency. There was no reported nausea, vomiting, diarrhea, bleeding, polyuria, or impaired oral intake to support hypovolemia, though the response to IV fluids suggests hypovolemia may still be playing a role.
White blood cell (WBC) count was 15,450/µL with a normal differential; hemoglobin level was 15.8 g/dL; and platelet count was 176,000/µL. Electrolytes, liver function tests, cardiac enzymes, and urinalysis were normal. Electrocardiogram showed sinus tachycardia with premature atrial complexes and no ST-segment abnormalities. Radiograph of the chest and computed tomography scan of the head were normal. Echocardiogram showed moderate left ventricular hypertrophy with a normal ejection fraction and no valvular abnormalities. Exercise nuclear cardiac stress test was negative for ischemia. Blood cultures were sterile. The patient quickly became asymptomatic and remained so during his 3-day hospitalization. There were no arrhythmias on telemetry. The patient was discharged with follow-up scheduled with his primary care physician.
The nonlocalizing history and physical examination findings, normal chest radiograph and urinalysis, absence of fevers, negative blood cultures, and quick recovery make infection unlikely, despite the moderate leukocytosis. Conditions that present with acute and transient hypotension and altered mental status include arrhythmias, seizures, and reactions to drugs or toxins. Given the cardiac test results, a chronic cardiomyopathy seems unlikely, but arrhythmia is still possible. Continuous outpatient monitoring is required to assess the palpitations and the frequency of the premature atrial complexes.
Two days after discharge, the patient suddenly became diaphoretic and lost consciousness while walking to the bathroom. He was taken to the ED, where his BP was 90/60 mm Hg and HR was 108 bpm. Family members reported that he had appeared flushed during the syncopal episode, showed no seizure activity, and been unconscious for 15 to 20 minutes. The patient denied chest pain, dyspnea, fever, bowel or bladder incontinence, focal weakness, slurred speech, visual changes, nausea or vomiting either before or after the episode. Physical examination revealed a tongue laceration and facial erythema; all other findings were normal. In the ED, there was an asymptomatic 7-beat run of nonsustained ventricular tachycardia, and the hypotension resolved after fluid resuscitation. The patient now reported 2 similar syncopal episodes in the past. The first occurred in a restaurant 6 years earlier, and the second occurred 3 years later, at which time he was hospitalized and no etiology was found.
The loss of consciousness is attributable to cerebral hypoperfusion. Hypotension has 3 principal categories: hypovolemic, cardiogenic, and distributive. With syncopal episodes recurring over several years, hypovolemia seems unlikely. Given the palpitations and ventricular tachycardia, it is reasonable to suspect a cardiogenic cause. Although his heart appears to be structurally normal on echocardiogram, genetic, electrophysiologic, or magnetic resonance imaging (MRI) testing will occasionally reveal an unsuspected substrate for arrhythmia.
The recurring yet self-limited nature, diaphoresis, flushing, and facial erythema suggest a non-sepsis distributive cause of hypotension. It is possible the patient is recurrently exposed to a toxin (eg, alcohol) that causes both flushing and dehydration. Flushing disorders include carcinoid syndrome, pheochromocytoma, drug reaction with eosinophilia and systemic symptoms (DRESS), and mastocytosis. Carcinoid syndrome is characterized by bronchospasm and diarrhea and, in some cases, right-sided valvulopathy, all of which are absent in this patient. Pheochromocytoma is associated with orthostasis, but patients typically are hypertensive at baseline. DRESS, which may arise from nonsteroidal anti-inflammatory drug (NSAID) or aspirin use, can cause facial erythema and swelling but is also characterized by liver, renal, and hematologic abnormalities, none of which was demonstrated. Furthermore, DRESS typically does not cause hypotension. Mastocytosis can manifest as isolated or recurrent anaphylaxis.
It is important to investigate antecedents of these syncopal episodes. If the earlier episodes were food-related—one occurred at a restaurant—then deglutition syncope (syncope precipitated by swallowing) should be considered. If an NSAID or aspirin was ingested before each episode, then medication hypersensitivity or mast cell degranulation (which can be triggered by these medications) should be further examined. Loss of consciousness lasting 20 minutes without causing any neurologic sequelae is unusual for most causes of recurrent syncope. This feature raises the possibility that a toxin or mediator might still be present in the patient’s system.
Serial cardiac enzymes and electrocardiogram were normal. A tilt-table study was negative. The cortisol response to ACTH (cosyntropin) stimulation was normal. The level of serum tryptase, drawn 2 days after syncope, was 18.4 ng/dL (normal, <11.5 ng/dL). Computed tomography scan of chest and abdomen was negative for pulmonary embolism but showed a 1.4×1.3-cm hypervascular lesion in the tail of pancreas. The following neuroendocrine tests were within normal limits: serum and urine catecholamines; urine 5-hydroxyindoleacetic acid (5-HIAA); and serum chromogranin A, insulin, serotonin, vasoactive intestinal polypeptide (VIP), and somatostatin (Table 1). The patient remained asymptomatic during his hospital stay and was discharged home with appointments for cardiology follow-up and endoscopic ultrasound-guided biopsy of the pancreatic mass.
Pheochromocytoma is unlikely with normal serum and urine catecholamine levels and normal adrenal images. The differential diagnosis for a pancreatic mass includes pancreatic carcinoma, lymphoma, cystic neoplasm, and neuroendocrine tumor. All markers of neuroendocrine excess are normal, though elevations can be episodic. The normal 5-HIAA level makes carcinoid syndrome unlikely. VIPomas are associated with flushing, but the absence of profound and protracted diarrhea makes a VIPoma unlikely.
As hypoglycemia from a pancreatic insulinoma is plausible as a cause of episodic loss of consciousness lasting 15 minutes or more, it is important to inquire if giving food or drink helped resolve previous episodes. The normal insulin level reported here is of limited value, because it is the combination of insulin and C-peptide levels at time of hypoglycemia that is diagnostic. The normal glucose level recorded during one of the earlier episodes and the hypotension argue against hypoglycemia.
The elevated tryptase level is an indicator of mast cell degranulation. Tryptase levels are transiently elevated during the initial 2 to 4 hours after an anaphylactic episode and then normalize. An elevated level many hours or days later is considered a sign of mast cell excess. Although there is no evidence of the multi-organ disease (eg, cytopenia, bone disease, hepatosplenomegaly) seen in patients with a high systemic burden of mast cells, mast cell disorders exist on a spectrum. There may be a focal excess of mast cells confined to one organ or an isolated mass.
The same day as discharge, the patient’s wife drove them to the grocery store. He remained in the car while she shopped. When she returned, she found him confused and minimally responsive with subsequent brief loss of consciousness. He was taken to an ED, where he was flushed and hypotensive (systolic BP, 60 mm Hg) and tachycardic. Other examination findings were normal. After fluid resuscitation he became alert and oriented. WBC count was 20,850/μL with 89% neutrophils, hemoglobin level was 14.6 g/dL, and platelet count was 168,000/μL. Serum lactate level was 3.7 mmol/L (normal, <2.3 mmol/L). Chest radiograph was normal. He was treated with broad-spectrum antibiotic therapy and admitted to the hospital. Blood and urine cultures were sterile. Fine-needle aspiration of the pancreatic mass demonstrated nonspecific inflammation. Four days after admission (3 days after pancreatic mass biopsy) the patient developed palpitations, felt unwell, and had marked flushing of the face and trunk, with concomitant BP of 90/50 mm Hg and HR of 140 bpm.
The salient features of this case are recurrent hypotension, tachycardia, and flushing. Autonomic insufficiency, to which elderly patients are prone, causes hemodynamic perturbations but rarely flushing. The patient does not have diabetes mellitus, Parkinson disease, or another condition that puts him at risk for dysautonomia. Pancreatic neuroendocrine tumors secrete mediators that lead to vasodilation and hypotension but are unlikely given the clinical and biochemical data.
The patient’s symptoms are consistent with anaphylaxis, though prototypical immunoglobulin E (IgE)–mediated anaphylaxis is usually accompanied by urticaria, angioedema, and wheezing, which have been absent during his presentations. There are no clear food, pharmacologic, or environmental precipitants.
Recurrent anaphylaxis can be a manifestation of mast cell excess (eg, cutaneous or systemic mastocytosis). A markedly elevated tryptase level during an anaphylactic episode is consistent with mastocytosis or IgE-mediated anaphylaxis. An elevated baseline tryptase level days after an anaphylactic episode signals increased mast cell burden. There may be a reservoir of mast cells in the bone marrow. Alternatively, the hypervascular pancreatic mass may be a mastocytoma or a mast cell sarcoma (missed because of inadequate sampling or staining).
The lactic acidosis likely reflects global tissue hypoperfusion from vasodilatory hypotension. The leukocytosis may reflect WBC mobilization secondary to endogenous corticosteroids and catecholamines in response to hypotension or may be a direct response to the release of mast cell–derived mediators of inflammation.
The patient was treated with diphenhydramine and ranitidine. Serum tryptase level was 46.8 ng/mL (normal, <11.5 ng/mL), and 24-hour urine histamine level was 95 µ g/dL (normal, <60 µ g/dL). Bone marrow biopsy results showed multifocal dense infiltrative aggregates of mast cells (>15 cells/aggregate), which were confirmed by CD117 (Kit) and tryptase positivity (Figure). Mutation analysis for Kit Asp816Val, which is present in 80% to 90% of patients with mastocytosis, was positive. He fulfilled the 2008 World Health Organization criteria for systemic mastocytosis (Table 2). Prednisone, histamine inhibitors, and montelukast were prescribed. Six months later, magnetic resonance imaging of the abdomen showed no change in the pancreatic mass, which was now characterized as a possible splenule. The patient had no additional episodes of flushing or syncope over 2 years.
DISCUSSION
Cardiovascular collapse (hypotension, tachycardia, syncope) in an elderly patient prompts clinicians to focus on life-threatening conditions, such as acute coronary syndrome, pulmonary embolus, arrhythmia, and sepsis. Each of these diagnoses was considered early in the course of this patient’s presentations, but each was deemed unlikely as it became apparent that the episodes were self-limited and recurrent over years. Incorporating flushing into the diagnostic problem representation allowed the clinicians to focus on a subset of causes of hypotension.
Flushing disorders may be classified by whether they are mediated by the autonomic nervous system (wet flushes, because they are usually accompanied by diaphoresis) or by exogenous or endogenous vasoactive substances (dry flushes).1 Autonomic nervous system flushing is triggered by emotions, fever, exercise, perimenopause (hot flashes), and neurologic conditions (eg, Parkinson disease, spinal cord injury, multiple sclerosis). Vasoactive flushing precipitants include drugs (eg, niacin); alcohol (secondary to cutaneous vasodilation, or acetaldehyde particularly in people with insufficient acetaldehyde dehydrogenase activity)2; foods that contain capsaicin, tyramine, sulfites, or histamine (eg, eating improperly handled fish can cause scombroid poisoning); and anaphylaxis. Rare causes of vasoactive flushing include carcinoid syndrome, pheochromocytoma, medullary thyroid carcinoma, VIPoma, and mastocytosis.2
Mastocytosis is a rare clonal disorder characterized by the accumulation of abnormal mast cells in the skin (cutaneous mastocytosis), in multiple organs (systemic mastocytosis), or in a solid tumor (mastocytoma). Urticaria pigmentosa is the most common form of cutaneous mastocytosis; it is seen more often in children than in adults and typically is associated with a maculopapular rash and dermatographism. Systemic mastocytosis is the most common form of the disorder in adults.3 Symptoms are related to mast cell infiltration or mast cell mediator–related effects, which range from itching, flushing, and diarrhea to hypotension and anaphylaxis. Other manifestations are fatigue, urticaria pigmentosa, osteoporosis, hepatosplenomegaly, bone pain, cytopenias, and lymphadenopathy.4
Systemic mastocytosis can occur at any age and should be considered in patients with recurrent unexplained flushing, syncope, or hypotension. Eighty percent to 90% of patients with systemic mastocytosis have a mutation in Kit,5 a transmembrane tyrosine kinase that is the receptor for stem cell factor. The Asp816Val mutation leads to increased proliferation and reduced apoptosis of mast cells.3,6,7 Proposed diagnostic algorithms8-11 involve measurement of serum tryptase levels and examination of bone marrow. Bone marrow biopsy and testing for the Asp816Val
The primary goals of treatment are managing mast cell–mediated symptoms and, in advanced cases, achieving cytoreduction. Alcohol can trigger mast cell degranulation in indolent systemic mastocytosis and should be avoided. Mast cell–mediated symptoms are managed with histamine blockers, leukotriene antagonists, and mast cell stabilizers.12 Targeted therapy with tyrosine kinase inhibitors (eg, imatinib) in patients with transmembrane Kit mutation (eg, Phe522Cys, Lys509Ile) associated with systemic mastocytosis has had promising results.13,14 However, this patient’s Asp816Val mutation is in the Kit catalytic domain, not the transmembrane region, and therefore would not be expected to respond to imatinib. A recent open-label trial of the multikinase inhibitor midostaurin demonstrated resolution of organ damage, reduced bone marrow burden, and lowered serum tryptase levels in patients with advanced systemic mastocytosis.15 Interferon, cladribine, and high-dose corticosteroids are prescribed in patients for whom other therapies have been ineffective.8
The differential diagnosis is broad for both hypotension and for flushing, but the differential diagnosis for recurrent hypotension and flushing is limited. Recognizing that flushing was an essential feature of this patient’s hypotensive condition, and not an epiphenomenon of syncope, allowed the clinicians to focus on the overlap and make a shocking diagnosis.
Acknowledgment
The authors thank David Bosler, MD (Cleveland Clinic) for interpreting the pathology image.
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 75-year-old man was brought by ambulance to the emergency department (ED) after the acute onset of palpitations, lightheadedness, and confusion. His medical history, provided by his wife, included osteoarthritis and remote cholecystectomy. He was not a smoker but drank 2 to 4 cans of beer daily. His medications were aspirin 162 mg daily and naproxen as needed. There was no history of bruising, diarrhea, melena, or bleeding.
Palpitations may represent an arrhythmia arising from an ischemic or alcoholic cardiomyopathy. Mental status changes usually have metabolic, infectious, structural (eg, hemorrhage, tumor), or toxic causes. Lightheadedness and confusion could occur with arrhythmia-associated cerebral hypoperfusion or a seizure. Daily alcohol use could cause confusion through acute intoxication, thiamine or B12 deficiency, repeated head trauma, or liver failure.
The patient’s systolic blood pressure (BP) was 60 mm Hg, heart rate (HR) was 120 beats per minute (bpm), and oral temperature was 98.4°F. Rousing him was difficult. There were no localizing neurologic abnormalities, and the rest of the physical examination findings were normal. Point-of-care blood glucose level was 155 mg/dL. Blood cultures were obtained and broad-spectrum antibiotics initiated. After fluid resuscitation, BP improved to 116/87 mm Hg, HR fell to 105 bpm, and the patient became alert and oriented. He denied chest pain, fever, or diaphoresis.
The patient’s improvement with intravenous (IV) fluids makes cardiogenic shock unlikely but does not exclude an underlying compensated cardiomyopathy that may be predisposing to arrhythmia. Hypotension, tachycardia, and somnolence may represent sepsis, but the near normalization of vital signs and mental status shortly after administration of IV fluids, the normal temperature, and the absence of localizing signs of infection favor withholding additional antibiotics. Other causes of hypotension are hypovolemia, medication effects, adrenal insufficiency, anaphylaxis, and autonomic insufficiency. There was no reported nausea, vomiting, diarrhea, bleeding, polyuria, or impaired oral intake to support hypovolemia, though the response to IV fluids suggests hypovolemia may still be playing a role.
White blood cell (WBC) count was 15,450/µL with a normal differential; hemoglobin level was 15.8 g/dL; and platelet count was 176,000/µL. Electrolytes, liver function tests, cardiac enzymes, and urinalysis were normal. Electrocardiogram showed sinus tachycardia with premature atrial complexes and no ST-segment abnormalities. Radiograph of the chest and computed tomography scan of the head were normal. Echocardiogram showed moderate left ventricular hypertrophy with a normal ejection fraction and no valvular abnormalities. Exercise nuclear cardiac stress test was negative for ischemia. Blood cultures were sterile. The patient quickly became asymptomatic and remained so during his 3-day hospitalization. There were no arrhythmias on telemetry. The patient was discharged with follow-up scheduled with his primary care physician.
The nonlocalizing history and physical examination findings, normal chest radiograph and urinalysis, absence of fevers, negative blood cultures, and quick recovery make infection unlikely, despite the moderate leukocytosis. Conditions that present with acute and transient hypotension and altered mental status include arrhythmias, seizures, and reactions to drugs or toxins. Given the cardiac test results, a chronic cardiomyopathy seems unlikely, but arrhythmia is still possible. Continuous outpatient monitoring is required to assess the palpitations and the frequency of the premature atrial complexes.
Two days after discharge, the patient suddenly became diaphoretic and lost consciousness while walking to the bathroom. He was taken to the ED, where his BP was 90/60 mm Hg and HR was 108 bpm. Family members reported that he had appeared flushed during the syncopal episode, showed no seizure activity, and been unconscious for 15 to 20 minutes. The patient denied chest pain, dyspnea, fever, bowel or bladder incontinence, focal weakness, slurred speech, visual changes, nausea or vomiting either before or after the episode. Physical examination revealed a tongue laceration and facial erythema; all other findings were normal. In the ED, there was an asymptomatic 7-beat run of nonsustained ventricular tachycardia, and the hypotension resolved after fluid resuscitation. The patient now reported 2 similar syncopal episodes in the past. The first occurred in a restaurant 6 years earlier, and the second occurred 3 years later, at which time he was hospitalized and no etiology was found.
The loss of consciousness is attributable to cerebral hypoperfusion. Hypotension has 3 principal categories: hypovolemic, cardiogenic, and distributive. With syncopal episodes recurring over several years, hypovolemia seems unlikely. Given the palpitations and ventricular tachycardia, it is reasonable to suspect a cardiogenic cause. Although his heart appears to be structurally normal on echocardiogram, genetic, electrophysiologic, or magnetic resonance imaging (MRI) testing will occasionally reveal an unsuspected substrate for arrhythmia.
The recurring yet self-limited nature, diaphoresis, flushing, and facial erythema suggest a non-sepsis distributive cause of hypotension. It is possible the patient is recurrently exposed to a toxin (eg, alcohol) that causes both flushing and dehydration. Flushing disorders include carcinoid syndrome, pheochromocytoma, drug reaction with eosinophilia and systemic symptoms (DRESS), and mastocytosis. Carcinoid syndrome is characterized by bronchospasm and diarrhea and, in some cases, right-sided valvulopathy, all of which are absent in this patient. Pheochromocytoma is associated with orthostasis, but patients typically are hypertensive at baseline. DRESS, which may arise from nonsteroidal anti-inflammatory drug (NSAID) or aspirin use, can cause facial erythema and swelling but is also characterized by liver, renal, and hematologic abnormalities, none of which was demonstrated. Furthermore, DRESS typically does not cause hypotension. Mastocytosis can manifest as isolated or recurrent anaphylaxis.
It is important to investigate antecedents of these syncopal episodes. If the earlier episodes were food-related—one occurred at a restaurant—then deglutition syncope (syncope precipitated by swallowing) should be considered. If an NSAID or aspirin was ingested before each episode, then medication hypersensitivity or mast cell degranulation (which can be triggered by these medications) should be further examined. Loss of consciousness lasting 20 minutes without causing any neurologic sequelae is unusual for most causes of recurrent syncope. This feature raises the possibility that a toxin or mediator might still be present in the patient’s system.
Serial cardiac enzymes and electrocardiogram were normal. A tilt-table study was negative. The cortisol response to ACTH (cosyntropin) stimulation was normal. The level of serum tryptase, drawn 2 days after syncope, was 18.4 ng/dL (normal, <11.5 ng/dL). Computed tomography scan of chest and abdomen was negative for pulmonary embolism but showed a 1.4×1.3-cm hypervascular lesion in the tail of pancreas. The following neuroendocrine tests were within normal limits: serum and urine catecholamines; urine 5-hydroxyindoleacetic acid (5-HIAA); and serum chromogranin A, insulin, serotonin, vasoactive intestinal polypeptide (VIP), and somatostatin (Table 1). The patient remained asymptomatic during his hospital stay and was discharged home with appointments for cardiology follow-up and endoscopic ultrasound-guided biopsy of the pancreatic mass.
Pheochromocytoma is unlikely with normal serum and urine catecholamine levels and normal adrenal images. The differential diagnosis for a pancreatic mass includes pancreatic carcinoma, lymphoma, cystic neoplasm, and neuroendocrine tumor. All markers of neuroendocrine excess are normal, though elevations can be episodic. The normal 5-HIAA level makes carcinoid syndrome unlikely. VIPomas are associated with flushing, but the absence of profound and protracted diarrhea makes a VIPoma unlikely.
As hypoglycemia from a pancreatic insulinoma is plausible as a cause of episodic loss of consciousness lasting 15 minutes or more, it is important to inquire if giving food or drink helped resolve previous episodes. The normal insulin level reported here is of limited value, because it is the combination of insulin and C-peptide levels at time of hypoglycemia that is diagnostic. The normal glucose level recorded during one of the earlier episodes and the hypotension argue against hypoglycemia.
The elevated tryptase level is an indicator of mast cell degranulation. Tryptase levels are transiently elevated during the initial 2 to 4 hours after an anaphylactic episode and then normalize. An elevated level many hours or days later is considered a sign of mast cell excess. Although there is no evidence of the multi-organ disease (eg, cytopenia, bone disease, hepatosplenomegaly) seen in patients with a high systemic burden of mast cells, mast cell disorders exist on a spectrum. There may be a focal excess of mast cells confined to one organ or an isolated mass.
The same day as discharge, the patient’s wife drove them to the grocery store. He remained in the car while she shopped. When she returned, she found him confused and minimally responsive with subsequent brief loss of consciousness. He was taken to an ED, where he was flushed and hypotensive (systolic BP, 60 mm Hg) and tachycardic. Other examination findings were normal. After fluid resuscitation he became alert and oriented. WBC count was 20,850/μL with 89% neutrophils, hemoglobin level was 14.6 g/dL, and platelet count was 168,000/μL. Serum lactate level was 3.7 mmol/L (normal, <2.3 mmol/L). Chest radiograph was normal. He was treated with broad-spectrum antibiotic therapy and admitted to the hospital. Blood and urine cultures were sterile. Fine-needle aspiration of the pancreatic mass demonstrated nonspecific inflammation. Four days after admission (3 days after pancreatic mass biopsy) the patient developed palpitations, felt unwell, and had marked flushing of the face and trunk, with concomitant BP of 90/50 mm Hg and HR of 140 bpm.
The salient features of this case are recurrent hypotension, tachycardia, and flushing. Autonomic insufficiency, to which elderly patients are prone, causes hemodynamic perturbations but rarely flushing. The patient does not have diabetes mellitus, Parkinson disease, or another condition that puts him at risk for dysautonomia. Pancreatic neuroendocrine tumors secrete mediators that lead to vasodilation and hypotension but are unlikely given the clinical and biochemical data.
The patient’s symptoms are consistent with anaphylaxis, though prototypical immunoglobulin E (IgE)–mediated anaphylaxis is usually accompanied by urticaria, angioedema, and wheezing, which have been absent during his presentations. There are no clear food, pharmacologic, or environmental precipitants.
Recurrent anaphylaxis can be a manifestation of mast cell excess (eg, cutaneous or systemic mastocytosis). A markedly elevated tryptase level during an anaphylactic episode is consistent with mastocytosis or IgE-mediated anaphylaxis. An elevated baseline tryptase level days after an anaphylactic episode signals increased mast cell burden. There may be a reservoir of mast cells in the bone marrow. Alternatively, the hypervascular pancreatic mass may be a mastocytoma or a mast cell sarcoma (missed because of inadequate sampling or staining).
The lactic acidosis likely reflects global tissue hypoperfusion from vasodilatory hypotension. The leukocytosis may reflect WBC mobilization secondary to endogenous corticosteroids and catecholamines in response to hypotension or may be a direct response to the release of mast cell–derived mediators of inflammation.
The patient was treated with diphenhydramine and ranitidine. Serum tryptase level was 46.8 ng/mL (normal, <11.5 ng/mL), and 24-hour urine histamine level was 95 µ g/dL (normal, <60 µ g/dL). Bone marrow biopsy results showed multifocal dense infiltrative aggregates of mast cells (>15 cells/aggregate), which were confirmed by CD117 (Kit) and tryptase positivity (Figure). Mutation analysis for Kit Asp816Val, which is present in 80% to 90% of patients with mastocytosis, was positive. He fulfilled the 2008 World Health Organization criteria for systemic mastocytosis (Table 2). Prednisone, histamine inhibitors, and montelukast were prescribed. Six months later, magnetic resonance imaging of the abdomen showed no change in the pancreatic mass, which was now characterized as a possible splenule. The patient had no additional episodes of flushing or syncope over 2 years.
DISCUSSION
Cardiovascular collapse (hypotension, tachycardia, syncope) in an elderly patient prompts clinicians to focus on life-threatening conditions, such as acute coronary syndrome, pulmonary embolus, arrhythmia, and sepsis. Each of these diagnoses was considered early in the course of this patient’s presentations, but each was deemed unlikely as it became apparent that the episodes were self-limited and recurrent over years. Incorporating flushing into the diagnostic problem representation allowed the clinicians to focus on a subset of causes of hypotension.
Flushing disorders may be classified by whether they are mediated by the autonomic nervous system (wet flushes, because they are usually accompanied by diaphoresis) or by exogenous or endogenous vasoactive substances (dry flushes).1 Autonomic nervous system flushing is triggered by emotions, fever, exercise, perimenopause (hot flashes), and neurologic conditions (eg, Parkinson disease, spinal cord injury, multiple sclerosis). Vasoactive flushing precipitants include drugs (eg, niacin); alcohol (secondary to cutaneous vasodilation, or acetaldehyde particularly in people with insufficient acetaldehyde dehydrogenase activity)2; foods that contain capsaicin, tyramine, sulfites, or histamine (eg, eating improperly handled fish can cause scombroid poisoning); and anaphylaxis. Rare causes of vasoactive flushing include carcinoid syndrome, pheochromocytoma, medullary thyroid carcinoma, VIPoma, and mastocytosis.2
Mastocytosis is a rare clonal disorder characterized by the accumulation of abnormal mast cells in the skin (cutaneous mastocytosis), in multiple organs (systemic mastocytosis), or in a solid tumor (mastocytoma). Urticaria pigmentosa is the most common form of cutaneous mastocytosis; it is seen more often in children than in adults and typically is associated with a maculopapular rash and dermatographism. Systemic mastocytosis is the most common form of the disorder in adults.3 Symptoms are related to mast cell infiltration or mast cell mediator–related effects, which range from itching, flushing, and diarrhea to hypotension and anaphylaxis. Other manifestations are fatigue, urticaria pigmentosa, osteoporosis, hepatosplenomegaly, bone pain, cytopenias, and lymphadenopathy.4
Systemic mastocytosis can occur at any age and should be considered in patients with recurrent unexplained flushing, syncope, or hypotension. Eighty percent to 90% of patients with systemic mastocytosis have a mutation in Kit,5 a transmembrane tyrosine kinase that is the receptor for stem cell factor. The Asp816Val mutation leads to increased proliferation and reduced apoptosis of mast cells.3,6,7 Proposed diagnostic algorithms8-11 involve measurement of serum tryptase levels and examination of bone marrow. Bone marrow biopsy and testing for the Asp816Val
The primary goals of treatment are managing mast cell–mediated symptoms and, in advanced cases, achieving cytoreduction. Alcohol can trigger mast cell degranulation in indolent systemic mastocytosis and should be avoided. Mast cell–mediated symptoms are managed with histamine blockers, leukotriene antagonists, and mast cell stabilizers.12 Targeted therapy with tyrosine kinase inhibitors (eg, imatinib) in patients with transmembrane Kit mutation (eg, Phe522Cys, Lys509Ile) associated with systemic mastocytosis has had promising results.13,14 However, this patient’s Asp816Val mutation is in the Kit catalytic domain, not the transmembrane region, and therefore would not be expected to respond to imatinib. A recent open-label trial of the multikinase inhibitor midostaurin demonstrated resolution of organ damage, reduced bone marrow burden, and lowered serum tryptase levels in patients with advanced systemic mastocytosis.15 Interferon, cladribine, and high-dose corticosteroids are prescribed in patients for whom other therapies have been ineffective.8
The differential diagnosis is broad for both hypotension and for flushing, but the differential diagnosis for recurrent hypotension and flushing is limited. Recognizing that flushing was an essential feature of this patient’s hypotensive condition, and not an epiphenomenon of syncope, allowed the clinicians to focus on the overlap and make a shocking diagnosis.
Acknowledgment
The authors thank David Bosler, MD (Cleveland Clinic) for interpreting the pathology image.
Disclosure
Nothing to report.
1. Wilkin JK. The red face: flushing disorders. Clin Dermatol. 1993;11(2):211-223. PubMed
2. Izikson L, English JC 3rd, Zirwas MJ. The flushing patient: differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006;55(2):193-208. PubMed
3. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37(6):435-453. PubMed
4. Hermans MA, Rietveld MJ, van Laar JA, et al. Systemic mastocytosis: a cohort study on clinical characteristics of 136 patients in a large tertiary centre. Eur J Intern Med. 2016;30:25-30. PubMed
5. Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MB, Broesby-Olsen S; Mastocytosis Centre, Odense University Hospital (MastOUH). Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014;89(5):493-498. PubMed
6. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol. 2013;90(2):89-98. PubMed
7. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366-2372. PubMed
8. Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015;90(3):250-262. PubMed
9. Valent P, Aberer E, Beham-Schmid C, et al. Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian Competence Network (AUCNM). Am J Blood Res. 2013;3(2):174-180. PubMed
10. Valent P, Escribano L, Broesby-Olsen S, et al; European Competence Network on Mastocytosis. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014;69(10):1267-1274. PubMed
11. Akin C, Soto D, Brittain E, et al. Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels. Clin Immunol. 2007;123(3):268-271. PubMed
12. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373(19):1885-1886. PubMed
13. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004;103(8):3222-3225. PubMed
14. Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT identified in familial mastocytosis—in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006;30(4):373-378. PubMed
15. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541. PubMed
1. Wilkin JK. The red face: flushing disorders. Clin Dermatol. 1993;11(2):211-223. PubMed
2. Izikson L, English JC 3rd, Zirwas MJ. The flushing patient: differential diagnosis, workup, and treatment. J Am Acad Dermatol. 2006;55(2):193-208. PubMed
3. Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37(6):435-453. PubMed
4. Hermans MA, Rietveld MJ, van Laar JA, et al. Systemic mastocytosis: a cohort study on clinical characteristics of 136 patients in a large tertiary centre. Eur J Intern Med. 2016;30:25-30. PubMed
5. Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MB, Broesby-Olsen S; Mastocytosis Centre, Odense University Hospital (MastOUH). Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014;89(5):493-498. PubMed
6. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol. 2013;90(2):89-98. PubMed
7. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366-2372. PubMed
8. Pardanani A. Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management. Am J Hematol. 2015;90(3):250-262. PubMed
9. Valent P, Aberer E, Beham-Schmid C, et al. Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian Competence Network (AUCNM). Am J Blood Res. 2013;3(2):174-180. PubMed
10. Valent P, Escribano L, Broesby-Olsen S, et al; European Competence Network on Mastocytosis. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014;69(10):1267-1274. PubMed
11. Akin C, Soto D, Brittain E, et al. Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels. Clin Immunol. 2007;123(3):268-271. PubMed
12. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373(19):1885-1886. PubMed
13. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004;103(8):3222-3225. PubMed
14. Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT identified in familial mastocytosis—in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006;30(4):373-378. PubMed
15. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541. PubMed
© 2017 Society of Hospital Medicine
SCHOLAR Project
The structure and function of academic hospital medicine programs (AHPs) has evolved significantly with the growth of hospital medicine.[1, 2, 3, 4] Many AHPs formed in response to regulatory and financial changes, which drove demand for increased trainee oversight, improved clinical efficiency, and growth in nonteaching services staffed by hospitalists. Differences in local organizational contexts and needs have contributed to great variability in AHP program design and operations. As AHPs have become more established, the need to engage academic hospitalists in scholarship and activities that support professional development and promotion has been recognized. Defining sustainable and successful positions for academic hospitalists is a priority called for by leaders in the field.[5, 6]
In this rapidly evolving context, AHPs have employed a variety of approaches to organizing clinical and academic faculty roles, without guiding evidence or consensus‐based performance benchmarks. A number of AHPs have achieved success along traditional academic metrics of research, scholarship, and education. Currently, it is not known whether specific approaches to AHP organization, structure, or definition of faculty roles are associated with achievement of more traditional markers of academic success.
The Academic Committee of the Society of Hospital Medicine (SHM), and the Academic Hospitalist Task Force of the Society of General Internal Medicine (SGIM) had separately initiated projects to explore characteristics associated with success in AHPs. In 2012, these organizations combined efforts to jointly develop and implement the SCHOLAR (SuCcessful HOspitaLists in Academics and Research) project. The goals were to identify successful AHPs using objective criteria, and to then study those groups in greater detail to generate insights that would be broadly relevant to the field. Efforts to clarify the factors within AHPs linked to success by traditional academic metrics will benefit hospitalists, their leaders, and key stakeholders striving to achieve optimal balance between clinical and academic roles. We describe the initial work of the SCHOLAR project, our definitions of academic success in AHPs, and the characteristics of a cohort of exemplary AHPs who achieved the highest levels on these metrics.
METHODS
Defining Success
The 11 members of the SCHOLAR project held a variety of clinical and academic roles within a geographically diverse group of AHPs. We sought to create a functional definition of success applicable to AHPs. As no gold standard currently exists, we used a consensus process among task force members to arrive at a definition that was quantifiable, feasible, and meaningful. The first step was brainstorming on conference calls held 1 to 2 times monthly over 4 months. Potential defining characteristics that emerged from these discussions related to research, teaching, and administrative activities. When potential characteristics were proposed, we considered how to operationalize each one. Each characteristic was discussed until there was consensus from the entire group. Those around education and administration were the most complex, as many roles are locally driven and defined, and challenging to quantify. For this reason, we focused on promotion as a more global approach to assessing academic hospitalist success in these areas. Although criteria for academic advancement also vary across institutions, we felt that promotion generally reflected having met some threshold of academic success. We also wanted to recognize that scholarship occurs outside the context of funded research. Ultimately, 3 key domains emerged: research grant funding, faculty promotion, and scholarship.
After these 3 domains were identified, the group sought to define quantitative metrics to assess performance. These discussions occurred on subsequent calls over a 4‐month period. Between calls, group members gathered additional information to facilitate assessment of the feasibility of proposed metrics, reporting on progress via email. Again, group consensus was sought for each metric considered. Data on grant funding and successful promotions were available from a previous survey conducted through the SHM in 2011. Leaders from 170 AHPs were contacted, with 50 providing complete responses to the 21‐item questionnaire (see Supporting Information, Appendix 1, in the online version of this article). Results of the survey, heretofore referred to as the Leaders of Academic Hospitalist Programs survey (LAHP‐50), have been described elsewhere.[7] For the purposes of this study, we used the self‐reported data about grant funding and promotions contained in the survey to reflect the current state of the field. Although the survey response rate was approximately 30%, the survey was not anonymous, and many reputationally prominent academic hospitalist programs were represented. For these reasons, the group members felt that the survey results were relevant for the purposes of assessing academic success.
In the LAHP‐50, funding was defined as principal investigator or coinvestigator roles on federally and nonfederally funded research, clinical trials, internal grants, and any other extramurally funded projects. Mean and median funding for the overall sample was calculated. Through a separate question, each program's total faculty full‐time equivalent (FTE) count was reported, allowing us to adjust for group size by assessing both total funding per group and funding/FTE for each responding AHP.
Promotions were defined by the self‐reported number of faculty at each of the following ranks: instructor, assistant professor, associate professor, full professor, and professor above scale/emeritus. In addition, a category of nonacademic track (eg, adjunct faculty, clinical associate) was included to capture hospitalists that did not fit into the traditional promotions categories. We did not distinguish between tenure‐track and nontenure‐track academic ranks. LAHP‐50 survey respondents reported the number of faculty in their group at each academic rank. Given that the majority of academic hospitalists hold a rank of assistant professor or lower,[6, 8, 9] and that the number of full professors was only 3% in the LAHP‐50 cohort, we combined the faculty at the associate and full professor ranks, defining successfully promoted faculty as the percent of hospitalists above the rank of assistant professor.
We created a new metric to assess scholarly output. We had considerable discussion of ways to assess the numbers of peer‐reviewed manuscripts generated by AHPs. However, the group had concerns about the feasibility of identification and attribution of authors to specific AHPs through literature searches. We considered examining only publications in the Journal of Hospital Medicine and the Journal of General Internal Medicine, but felt that this would exclude significant work published by hospitalists in fields of medical education or health services research that would more likely appear in alternate journals. Instead, we quantified scholarship based on the number of abstracts presented at national meetings. We focused on meetings of the SHM and SGIM as the primary professional societies representing hospital medicine. The group felt that even work published outside of the journals of our professional societies would likely be presented at those meetings. We used the following strategy: We reviewed research abstracts accepted for presentation as posters or oral abstracts at the 2010 and 2011 SHM national meetings, and research abstracts with a primary or secondary category of hospital medicine at the 2010 and 2011 SGIM national meetings. By including submissions at both SGIM and SHM meetings, we accounted for the fact that some programs may gravitate more to one society meeting or another. We did not include abstracts in the clinical vignettes or innovations categories. We tallied the number of abstracts by group affiliation of the authors for each of the 4 meetings above and created a cumulative total per group for the 2‐year period. Abstracts with authors from different AHPs were counted once for each individual group. Members of the study group reviewed abstracts from each of the meetings in pairs. Reviewers worked separately and compared tallies of results to ensure consistent tabulations. Internet searches were conducted to identify or confirm author affiliations if it was not apparent in the abstract author list. Abstract tallies were compiled without regard to whether programs had completed the LAHP‐50 survey; thus, we collected data on programs that did not respond to the LAHP‐50 survey.
Identification of the SCHOLAR Cohort
To identify our cohort of top‐performing AHPs, we combined the funding and promotions data from the LAHP‐50 sample with the abstract data. We limited our sample to adult hospital medicine groups to reduce heterogeneity. We created rank lists of programs in each category (grant funding, successful promotions, and scholarship), using data from the LAHP‐50 survey to rank programs on funding and promotions, and data from our abstract counts to rank on scholarship. We limited the top‐performing list in each category to 10 institutions as a cutoff. Because we set a threshold of at least $1 million in total funding, we identified only 9 top performing AHPs with regard to grant funding. We also calculated mean funding/FTE. We chose to rank programs only by funding/FTE rather than total funding per program to better account for group size. For successful promotions, we ranked programs by the percentage of senior faculty. For abstract counts, we included programs whose faculty presented abstracts at a minimum of 2 separate meetings, and ranked programs based on the total number of abstracts per group.
This process resulted in separate lists of top performing programs in each of the 3 domains we associated with academic success, arranged in descending order by grant dollars/FTE, percent of senior faculty, and abstract counts (Table 1). Seventeen different programs were represented across these 3 top 10 lists. One program appeared on all 3 lists, 8 programs appeared on 2 lists, and the remainder appeared on a single list (Table 2). Seven of these programs were identified solely based on abstract presentations, diversifying our top groups beyond only those who completed the LAHP‐50 survey. We considered all of these programs to represent high performance in academic hospital medicine. The group selected this inclusive approach because we recognized that any 1 metric was potentially limited, and we sought to identify diverse pathways to success.
| Funding | Promotions | Scholarship | |
|---|---|---|---|
| Grant $/FTE | Total Grant $ | Senior Faculty, No. (%) | Total Abstract Count |
| |||
| $1,409,090 | $15,500,000 | 3 (60%) | 23 |
| $1,000,000 | $9,000,000 | 3 (60%) | 21 |
| $750,000 | $8,000,000 | 4 (57%) | 20 |
| $478,609 | $6,700,535 | 9 (53%) | 15 |
| $347,826 | $3,000,000 | 8 (44%) | 11 |
| $86,956 | $3,000,000 | 14 (41%) | 11 |
| $66,666 | $2,000,000 | 17 (36%) | 10 |
| $46,153 | $1,500,000 | 9 (33%) | 10 |
| $38,461 | $1,000,000 | 2 (33%) | 9 |
| 4 (31%) | 9 | ||
| Selection Criteria for SCHOLAR Cohort | No. of Programs |
|---|---|
| |
| Abstracts, funding, and promotions | 1 |
| Abstracts plus promotions | 4 |
| Abstracts plus funding | 3 |
| Funding plus promotion | 1 |
| Funding only | 1 |
| Abstract only | 7 |
| Total | 17 |
| Top 10 abstract count | |
| 4 meetings | 2 |
| 3 meetings | 2 |
| 2 meetings | 6 |
The 17 unique adult AHPs appearing on at least 1 of the top 10 lists comprised the SCHOLAR cohort of programs that we studied in greater detail. Data reflecting program demographics were solicited directly from leaders of the AHPs identified in the SCHOLAR cohort, including size and age of program, reporting structure, number of faculty at various academic ranks (for programs that did not complete the LAHP‐50 survey), and number of faculty with fellowship training (defined as any postresidency fellowship program).
Subsequently, we performed comparative analyses between the programs in the SCHOLAR cohort to the general population of AHPs reflected by the LAHP‐50 sample. Because abstract presentations were not recorded in the original LAHP‐50 survey instrument, it was not possible to perform a benchmarking comparison for the scholarship domain.
Data Analysis
To measure the success of the SCHOLAR cohort we compared the grant funding and proportion of successfully promoted faculty at the SCHOLAR programs to those in the overall LAHP‐50 sample. Differences in mean and median grant funding were compared using t tests and Mann‐Whitney rank sum tests. Proportion of promoted faculty were compared using 2 tests. A 2‐tailed of 0.05 was used to test significance of differences.
RESULTS
Demographics
Among the AHPs in the SCHOLAR cohort, the mean program age was 13.2 years (range, 618 years), and the mean program size was 36 faculty (range, 1895; median, 28). On average, 15% of faculty members at SCHOLAR programs were fellowship trained (range, 0%37%). Reporting structure among the SCHOLAR programs was as follows: 53% were an independent division or section of the department of medicine; 29% were a section within general internal medicine, and 18% were an independent clinical group.
Grant Funding
Table 3 compares grant funding in the SCHOLAR programs to programs in the overall LAHP‐50 sample. Mean funding per group and mean funding per FTE were significantly higher in the SCHOLAR group than in the overall sample.
| Funding (Millions) | ||
|---|---|---|
| LAHP‐50 Overall Sample | SCHOLAR | |
| ||
| Median grant funding/AHP | 0.060 | 1.500* |
| Mean grant funding/AHP | 1.147 (015) | 3.984* (015) |
| Median grant funding/FTE | 0.004 | 0.038* |
| Mean grant funding/FTE | 0.095 (01.4) | 0.364* (01.4) |
Thirteen of the SCHOLAR programs were represented in the initial LAHP‐50, but 2 did not report a dollar amount for grants and contracts. Therefore, data for total grant funding were available for only 65% (11 of 17) of the programs in the SCHOLAR cohort. Of note, 28% of AHPs in the overall LAHP‐50 sample reported no external funding sources.
Faculty Promotion
Figure 1 demonstrates the proportion of faculty at various academic ranks. The percent of faculty above the rank of assistant professor in the SCHOLAR programs exceeded those in the overall LAHP‐50 by 5% (17.9% vs 12.8%, P = 0.01). Of note, 6% of the hospitalists at AHPs in the SCHOLAR programs were on nonfaculty tracks.
Scholarship
Mean abstract output over the 2‐year period measured was 10.8 (range, 323) in the SCHOLAR cohort. Because we did not collect these data for the LAHP‐50 group, comparative analyses were not possible.
DISCUSSION
Using a definition of academic success that incorporated metrics of grant funding, faculty promotion, and scholarly output, we identified a unique subset of successful AHPsthe SCHOLAR cohort. The programs represented in the SCHOLAR cohort were generally large and relatively mature. Despite this, the cohort consisted of mostly junior faculty, had a paucity of fellowship‐trained hospitalists, and not all reported grant funding.
Prior published work reported complementary findings.[6, 8, 9] A survey of 20 large, well‐established academic hospitalist programs in 2008 found that the majority of hospitalists were junior faculty with a limited publication portfolio. Of the 266 respondents in that study, 86% reported an academic rank at or below assistant professor; funding was not explored.[9] Our similar findings 4 years later add to this work by demonstrating trends over time, and suggest that progress toward creating successful pathways for academic advancement has been slow. In a 2012 survey of the SHM membership, 28% of hospitalists with academic appointments reported no current or future plans to engage in research.[8] These findings suggest that faculty in AHPs may define scholarship through nontraditional pathways, or in some cases choose not to pursue or prioritize scholarship altogether.
Our findings also add to the literature with regard to our assessment of funding, which was variable across the SCHOLAR group. The broad range of funding in the SCHOLAR programs for which we have data (grant dollars $0$15 million per program) suggests that opportunities to improve supported scholarship remain, even among a selected cohort of successful AHPs. The predominance of junior faculty in the SCHOLAR programs may be a reason for this variation. Junior faculty may be engaged in research with funding directed to senior mentors outside their AHP. Alternatively, they may pursue meaningful local hospital quality improvement or educational innovations not supported by external grants, or hold leadership roles in education, quality, or information technology that allow for advancement and promotion without external grant funding. As the scope and impact of these roles increases, senior leaders with alternate sources of support may rely less on research funds; this too may explain some of the differences. Our findings are congruent with results of a study that reviewed original research published by hospitalists, and concluded that the majority of hospitalist research was not externally funded.[8] Our approach for assessing grant funding by adjusting for FTE had the potential to inadvertently favor smaller well‐funded groups over larger ones; however, programs in our sample were similarly represented when ranked by funding/FTE or total grant dollars. As many successful AHPs do concentrate their research funding among a core of focused hospitalist researchers, our definition may not be the ideal metric for some programs.
We chose to define scholarship based on abstract output, rather than peer‐reviewed publications. Although this choice was necessary from a feasibility perspective, it may have excluded programs that prioritize peer‐reviewed publications over abstracts. Although we were unable to incorporate a search strategy to accurately and comprehensively track the publication output attributed specifically to hospitalist researchers and quantify it by program, others have since defined such an approach.[8] However, tracking abstracts theoretically allowed insights into a larger volume of innovative and creative work generated by top AHPs by potentially including work in the earlier stages of development.
We used a consensus‐based definition of success to define our SCHOLAR cohort. There are other ways to measure academic success, which if applied, may have yielded a different sample of programs. For example, over half of the original research articles published in the Journal of Hospital Medicine over a 7‐year span were generated from 5 academic centers.[8] This definition of success may be equally credible, though we note that 4 of these 5 programs were also included in the SCHOLAR cohort. We feel our broader approach was more reflective of the variety of pathways to success available to academic hospitalists. Before our metrics are applied as a benchmarking tool, however, they should ideally be combined with factors not measured in our study to ensure a more comprehensive or balanced reflection of academic success. Factors such as mentorship, level of hospitalist engagement,[10] prevalence of leadership opportunities, operational and fiscal infrastructure, and the impact of local quality, safety, and value efforts should be considered.
Comparison of successfully promoted faculty at AHPs across the country is inherently limited by the wide variation in promotion standards across different institutions; controlling for such differences was not possible with our methodology. For example, it appears that several programs with relatively few senior faculty may have met metrics leading to their inclusion in the SCHOLAR group because of their small program size. Future benchmarking efforts for promotion at AHPs should take scaling into account and consider both total number as well as percentage of senior faculty when evaluating success.
Our methodology has several limitations. Survey data were self‐reported and not independently validated, and as such are subject to recall and reporting biases. Response bias inherently excluded some AHPs that may have met our grant funding or promotions criteria had they participated in the initial LAHP‐50 survey, though we identified and included additional programs through our scholarship metric, increasing the representativeness of the SCHOLAR cohort. Given the dynamic nature of the field, the age of the data we relied upon for analysis limits the generalizability of our specific benchmarks to current practice. However, the development of academic success occurs over the long‐term, and published data on academic hospitalist productivity are consistent with this slower time course.[8] Despite these limitations, our data inform the general topic of gauging performance of AHPs, underscoring the challenges of developing and applying metrics of success, and highlight the variability of performance on selected metrics even among a relatively small group of 17 programs.
In conclusion, we have created a method to quantify academic success that may be useful to academic hospitalists and their group leaders as they set targets for improvement in the field. Even among our SCHOLAR cohort, room for ongoing improvement in development of funded scholarship and a core of senior faculty exists. Further investigation into the unique features of successful groups will offer insight to leaders in academic hospital medicine regarding infrastructure and processes that should be embraced to raise the bar for all AHPs. In addition, efforts to further define and validate nontraditional approaches to scholarship that allow for successful promotion at AHPs would be informative. We view our work less as a singular approach to benchmarking standards for AHPs, and more a call to action to continue efforts to balance scholarly activity and broad professional development of academic hospitalists with increasing clinical demands.
Acknowledgements
The authors thank all of the AHP leaders who participated in the SCHOLAR project. They also thank the Society of Hospital Medicine and Society of General Internal Medicine and the SHM Academic Committee and SGIM Academic Hospitalist Task Force for their support of this work.
Disclosures
The work reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.
- , , , , . Characteristics of primary care providers who adopted the hospitalist model from 2001 to 2009. J Hosp Med. 2015;10(2):75–82.
- , , , . Growth in the care of older patients by hospitalists in the United States. N Engl J Med. 2009;360(11):1102–1112.
- , , , , . Updating threshold‐based identification of hospitalists in 2012 Medicare pay data. J Hosp Med. 2016;11(1):45–47.
- , , , . Use of hospitalists by Medicare beneficiaries: a national picture. Medicare Medicaid Res Rev. 2014;4(2).
- , , , , , . Challenges and opportunities in Academic Hospital Medicine: report from the Academic Hospital Medicine Summit. J Hosp Med. 2009;4(4):240–246.
- , , , . Survey of US academic hospitalist leaders about mentorship and academic activities in hospitalist groups. J Hosp Med. 2011;6(1):5–9.
- , , , , , . The structure of hospital medicine programs at academic medical centers [abstract]. J Hosp Med. 2012;7(suppl 2):s92.
- , , , , . Research and publication trends in hospital medicine. J Hosp Med. 2014;9(3):148–154.
- , , , , , . Mentorship, productivity, and promotion among academic hospitalists. J Gen Intern Med. 2012;27(1):23–27.
- , , , et al. The key principles and characteristics of an effective hospital medicine group: an assessment guide for hospitals and hospitalists. J Hosp Med. 2014;9(2):123–128.
The structure and function of academic hospital medicine programs (AHPs) has evolved significantly with the growth of hospital medicine.[1, 2, 3, 4] Many AHPs formed in response to regulatory and financial changes, which drove demand for increased trainee oversight, improved clinical efficiency, and growth in nonteaching services staffed by hospitalists. Differences in local organizational contexts and needs have contributed to great variability in AHP program design and operations. As AHPs have become more established, the need to engage academic hospitalists in scholarship and activities that support professional development and promotion has been recognized. Defining sustainable and successful positions for academic hospitalists is a priority called for by leaders in the field.[5, 6]
In this rapidly evolving context, AHPs have employed a variety of approaches to organizing clinical and academic faculty roles, without guiding evidence or consensus‐based performance benchmarks. A number of AHPs have achieved success along traditional academic metrics of research, scholarship, and education. Currently, it is not known whether specific approaches to AHP organization, structure, or definition of faculty roles are associated with achievement of more traditional markers of academic success.
The Academic Committee of the Society of Hospital Medicine (SHM), and the Academic Hospitalist Task Force of the Society of General Internal Medicine (SGIM) had separately initiated projects to explore characteristics associated with success in AHPs. In 2012, these organizations combined efforts to jointly develop and implement the SCHOLAR (SuCcessful HOspitaLists in Academics and Research) project. The goals were to identify successful AHPs using objective criteria, and to then study those groups in greater detail to generate insights that would be broadly relevant to the field. Efforts to clarify the factors within AHPs linked to success by traditional academic metrics will benefit hospitalists, their leaders, and key stakeholders striving to achieve optimal balance between clinical and academic roles. We describe the initial work of the SCHOLAR project, our definitions of academic success in AHPs, and the characteristics of a cohort of exemplary AHPs who achieved the highest levels on these metrics.
METHODS
Defining Success
The 11 members of the SCHOLAR project held a variety of clinical and academic roles within a geographically diverse group of AHPs. We sought to create a functional definition of success applicable to AHPs. As no gold standard currently exists, we used a consensus process among task force members to arrive at a definition that was quantifiable, feasible, and meaningful. The first step was brainstorming on conference calls held 1 to 2 times monthly over 4 months. Potential defining characteristics that emerged from these discussions related to research, teaching, and administrative activities. When potential characteristics were proposed, we considered how to operationalize each one. Each characteristic was discussed until there was consensus from the entire group. Those around education and administration were the most complex, as many roles are locally driven and defined, and challenging to quantify. For this reason, we focused on promotion as a more global approach to assessing academic hospitalist success in these areas. Although criteria for academic advancement also vary across institutions, we felt that promotion generally reflected having met some threshold of academic success. We also wanted to recognize that scholarship occurs outside the context of funded research. Ultimately, 3 key domains emerged: research grant funding, faculty promotion, and scholarship.
After these 3 domains were identified, the group sought to define quantitative metrics to assess performance. These discussions occurred on subsequent calls over a 4‐month period. Between calls, group members gathered additional information to facilitate assessment of the feasibility of proposed metrics, reporting on progress via email. Again, group consensus was sought for each metric considered. Data on grant funding and successful promotions were available from a previous survey conducted through the SHM in 2011. Leaders from 170 AHPs were contacted, with 50 providing complete responses to the 21‐item questionnaire (see Supporting Information, Appendix 1, in the online version of this article). Results of the survey, heretofore referred to as the Leaders of Academic Hospitalist Programs survey (LAHP‐50), have been described elsewhere.[7] For the purposes of this study, we used the self‐reported data about grant funding and promotions contained in the survey to reflect the current state of the field. Although the survey response rate was approximately 30%, the survey was not anonymous, and many reputationally prominent academic hospitalist programs were represented. For these reasons, the group members felt that the survey results were relevant for the purposes of assessing academic success.
In the LAHP‐50, funding was defined as principal investigator or coinvestigator roles on federally and nonfederally funded research, clinical trials, internal grants, and any other extramurally funded projects. Mean and median funding for the overall sample was calculated. Through a separate question, each program's total faculty full‐time equivalent (FTE) count was reported, allowing us to adjust for group size by assessing both total funding per group and funding/FTE for each responding AHP.
Promotions were defined by the self‐reported number of faculty at each of the following ranks: instructor, assistant professor, associate professor, full professor, and professor above scale/emeritus. In addition, a category of nonacademic track (eg, adjunct faculty, clinical associate) was included to capture hospitalists that did not fit into the traditional promotions categories. We did not distinguish between tenure‐track and nontenure‐track academic ranks. LAHP‐50 survey respondents reported the number of faculty in their group at each academic rank. Given that the majority of academic hospitalists hold a rank of assistant professor or lower,[6, 8, 9] and that the number of full professors was only 3% in the LAHP‐50 cohort, we combined the faculty at the associate and full professor ranks, defining successfully promoted faculty as the percent of hospitalists above the rank of assistant professor.
We created a new metric to assess scholarly output. We had considerable discussion of ways to assess the numbers of peer‐reviewed manuscripts generated by AHPs. However, the group had concerns about the feasibility of identification and attribution of authors to specific AHPs through literature searches. We considered examining only publications in the Journal of Hospital Medicine and the Journal of General Internal Medicine, but felt that this would exclude significant work published by hospitalists in fields of medical education or health services research that would more likely appear in alternate journals. Instead, we quantified scholarship based on the number of abstracts presented at national meetings. We focused on meetings of the SHM and SGIM as the primary professional societies representing hospital medicine. The group felt that even work published outside of the journals of our professional societies would likely be presented at those meetings. We used the following strategy: We reviewed research abstracts accepted for presentation as posters or oral abstracts at the 2010 and 2011 SHM national meetings, and research abstracts with a primary or secondary category of hospital medicine at the 2010 and 2011 SGIM national meetings. By including submissions at both SGIM and SHM meetings, we accounted for the fact that some programs may gravitate more to one society meeting or another. We did not include abstracts in the clinical vignettes or innovations categories. We tallied the number of abstracts by group affiliation of the authors for each of the 4 meetings above and created a cumulative total per group for the 2‐year period. Abstracts with authors from different AHPs were counted once for each individual group. Members of the study group reviewed abstracts from each of the meetings in pairs. Reviewers worked separately and compared tallies of results to ensure consistent tabulations. Internet searches were conducted to identify or confirm author affiliations if it was not apparent in the abstract author list. Abstract tallies were compiled without regard to whether programs had completed the LAHP‐50 survey; thus, we collected data on programs that did not respond to the LAHP‐50 survey.
Identification of the SCHOLAR Cohort
To identify our cohort of top‐performing AHPs, we combined the funding and promotions data from the LAHP‐50 sample with the abstract data. We limited our sample to adult hospital medicine groups to reduce heterogeneity. We created rank lists of programs in each category (grant funding, successful promotions, and scholarship), using data from the LAHP‐50 survey to rank programs on funding and promotions, and data from our abstract counts to rank on scholarship. We limited the top‐performing list in each category to 10 institutions as a cutoff. Because we set a threshold of at least $1 million in total funding, we identified only 9 top performing AHPs with regard to grant funding. We also calculated mean funding/FTE. We chose to rank programs only by funding/FTE rather than total funding per program to better account for group size. For successful promotions, we ranked programs by the percentage of senior faculty. For abstract counts, we included programs whose faculty presented abstracts at a minimum of 2 separate meetings, and ranked programs based on the total number of abstracts per group.
This process resulted in separate lists of top performing programs in each of the 3 domains we associated with academic success, arranged in descending order by grant dollars/FTE, percent of senior faculty, and abstract counts (Table 1). Seventeen different programs were represented across these 3 top 10 lists. One program appeared on all 3 lists, 8 programs appeared on 2 lists, and the remainder appeared on a single list (Table 2). Seven of these programs were identified solely based on abstract presentations, diversifying our top groups beyond only those who completed the LAHP‐50 survey. We considered all of these programs to represent high performance in academic hospital medicine. The group selected this inclusive approach because we recognized that any 1 metric was potentially limited, and we sought to identify diverse pathways to success.
| Funding | Promotions | Scholarship | |
|---|---|---|---|
| Grant $/FTE | Total Grant $ | Senior Faculty, No. (%) | Total Abstract Count |
| |||
| $1,409,090 | $15,500,000 | 3 (60%) | 23 |
| $1,000,000 | $9,000,000 | 3 (60%) | 21 |
| $750,000 | $8,000,000 | 4 (57%) | 20 |
| $478,609 | $6,700,535 | 9 (53%) | 15 |
| $347,826 | $3,000,000 | 8 (44%) | 11 |
| $86,956 | $3,000,000 | 14 (41%) | 11 |
| $66,666 | $2,000,000 | 17 (36%) | 10 |
| $46,153 | $1,500,000 | 9 (33%) | 10 |
| $38,461 | $1,000,000 | 2 (33%) | 9 |
| 4 (31%) | 9 | ||
| Selection Criteria for SCHOLAR Cohort | No. of Programs |
|---|---|
| |
| Abstracts, funding, and promotions | 1 |
| Abstracts plus promotions | 4 |
| Abstracts plus funding | 3 |
| Funding plus promotion | 1 |
| Funding only | 1 |
| Abstract only | 7 |
| Total | 17 |
| Top 10 abstract count | |
| 4 meetings | 2 |
| 3 meetings | 2 |
| 2 meetings | 6 |
The 17 unique adult AHPs appearing on at least 1 of the top 10 lists comprised the SCHOLAR cohort of programs that we studied in greater detail. Data reflecting program demographics were solicited directly from leaders of the AHPs identified in the SCHOLAR cohort, including size and age of program, reporting structure, number of faculty at various academic ranks (for programs that did not complete the LAHP‐50 survey), and number of faculty with fellowship training (defined as any postresidency fellowship program).
Subsequently, we performed comparative analyses between the programs in the SCHOLAR cohort to the general population of AHPs reflected by the LAHP‐50 sample. Because abstract presentations were not recorded in the original LAHP‐50 survey instrument, it was not possible to perform a benchmarking comparison for the scholarship domain.
Data Analysis
To measure the success of the SCHOLAR cohort we compared the grant funding and proportion of successfully promoted faculty at the SCHOLAR programs to those in the overall LAHP‐50 sample. Differences in mean and median grant funding were compared using t tests and Mann‐Whitney rank sum tests. Proportion of promoted faculty were compared using 2 tests. A 2‐tailed of 0.05 was used to test significance of differences.
RESULTS
Demographics
Among the AHPs in the SCHOLAR cohort, the mean program age was 13.2 years (range, 618 years), and the mean program size was 36 faculty (range, 1895; median, 28). On average, 15% of faculty members at SCHOLAR programs were fellowship trained (range, 0%37%). Reporting structure among the SCHOLAR programs was as follows: 53% were an independent division or section of the department of medicine; 29% were a section within general internal medicine, and 18% were an independent clinical group.
Grant Funding
Table 3 compares grant funding in the SCHOLAR programs to programs in the overall LAHP‐50 sample. Mean funding per group and mean funding per FTE were significantly higher in the SCHOLAR group than in the overall sample.
| Funding (Millions) | ||
|---|---|---|
| LAHP‐50 Overall Sample | SCHOLAR | |
| ||
| Median grant funding/AHP | 0.060 | 1.500* |
| Mean grant funding/AHP | 1.147 (015) | 3.984* (015) |
| Median grant funding/FTE | 0.004 | 0.038* |
| Mean grant funding/FTE | 0.095 (01.4) | 0.364* (01.4) |
Thirteen of the SCHOLAR programs were represented in the initial LAHP‐50, but 2 did not report a dollar amount for grants and contracts. Therefore, data for total grant funding were available for only 65% (11 of 17) of the programs in the SCHOLAR cohort. Of note, 28% of AHPs in the overall LAHP‐50 sample reported no external funding sources.
Faculty Promotion
Figure 1 demonstrates the proportion of faculty at various academic ranks. The percent of faculty above the rank of assistant professor in the SCHOLAR programs exceeded those in the overall LAHP‐50 by 5% (17.9% vs 12.8%, P = 0.01). Of note, 6% of the hospitalists at AHPs in the SCHOLAR programs were on nonfaculty tracks.
Scholarship
Mean abstract output over the 2‐year period measured was 10.8 (range, 323) in the SCHOLAR cohort. Because we did not collect these data for the LAHP‐50 group, comparative analyses were not possible.
DISCUSSION
Using a definition of academic success that incorporated metrics of grant funding, faculty promotion, and scholarly output, we identified a unique subset of successful AHPsthe SCHOLAR cohort. The programs represented in the SCHOLAR cohort were generally large and relatively mature. Despite this, the cohort consisted of mostly junior faculty, had a paucity of fellowship‐trained hospitalists, and not all reported grant funding.
Prior published work reported complementary findings.[6, 8, 9] A survey of 20 large, well‐established academic hospitalist programs in 2008 found that the majority of hospitalists were junior faculty with a limited publication portfolio. Of the 266 respondents in that study, 86% reported an academic rank at or below assistant professor; funding was not explored.[9] Our similar findings 4 years later add to this work by demonstrating trends over time, and suggest that progress toward creating successful pathways for academic advancement has been slow. In a 2012 survey of the SHM membership, 28% of hospitalists with academic appointments reported no current or future plans to engage in research.[8] These findings suggest that faculty in AHPs may define scholarship through nontraditional pathways, or in some cases choose not to pursue or prioritize scholarship altogether.
Our findings also add to the literature with regard to our assessment of funding, which was variable across the SCHOLAR group. The broad range of funding in the SCHOLAR programs for which we have data (grant dollars $0$15 million per program) suggests that opportunities to improve supported scholarship remain, even among a selected cohort of successful AHPs. The predominance of junior faculty in the SCHOLAR programs may be a reason for this variation. Junior faculty may be engaged in research with funding directed to senior mentors outside their AHP. Alternatively, they may pursue meaningful local hospital quality improvement or educational innovations not supported by external grants, or hold leadership roles in education, quality, or information technology that allow for advancement and promotion without external grant funding. As the scope and impact of these roles increases, senior leaders with alternate sources of support may rely less on research funds; this too may explain some of the differences. Our findings are congruent with results of a study that reviewed original research published by hospitalists, and concluded that the majority of hospitalist research was not externally funded.[8] Our approach for assessing grant funding by adjusting for FTE had the potential to inadvertently favor smaller well‐funded groups over larger ones; however, programs in our sample were similarly represented when ranked by funding/FTE or total grant dollars. As many successful AHPs do concentrate their research funding among a core of focused hospitalist researchers, our definition may not be the ideal metric for some programs.
We chose to define scholarship based on abstract output, rather than peer‐reviewed publications. Although this choice was necessary from a feasibility perspective, it may have excluded programs that prioritize peer‐reviewed publications over abstracts. Although we were unable to incorporate a search strategy to accurately and comprehensively track the publication output attributed specifically to hospitalist researchers and quantify it by program, others have since defined such an approach.[8] However, tracking abstracts theoretically allowed insights into a larger volume of innovative and creative work generated by top AHPs by potentially including work in the earlier stages of development.
We used a consensus‐based definition of success to define our SCHOLAR cohort. There are other ways to measure academic success, which if applied, may have yielded a different sample of programs. For example, over half of the original research articles published in the Journal of Hospital Medicine over a 7‐year span were generated from 5 academic centers.[8] This definition of success may be equally credible, though we note that 4 of these 5 programs were also included in the SCHOLAR cohort. We feel our broader approach was more reflective of the variety of pathways to success available to academic hospitalists. Before our metrics are applied as a benchmarking tool, however, they should ideally be combined with factors not measured in our study to ensure a more comprehensive or balanced reflection of academic success. Factors such as mentorship, level of hospitalist engagement,[10] prevalence of leadership opportunities, operational and fiscal infrastructure, and the impact of local quality, safety, and value efforts should be considered.
Comparison of successfully promoted faculty at AHPs across the country is inherently limited by the wide variation in promotion standards across different institutions; controlling for such differences was not possible with our methodology. For example, it appears that several programs with relatively few senior faculty may have met metrics leading to their inclusion in the SCHOLAR group because of their small program size. Future benchmarking efforts for promotion at AHPs should take scaling into account and consider both total number as well as percentage of senior faculty when evaluating success.
Our methodology has several limitations. Survey data were self‐reported and not independently validated, and as such are subject to recall and reporting biases. Response bias inherently excluded some AHPs that may have met our grant funding or promotions criteria had they participated in the initial LAHP‐50 survey, though we identified and included additional programs through our scholarship metric, increasing the representativeness of the SCHOLAR cohort. Given the dynamic nature of the field, the age of the data we relied upon for analysis limits the generalizability of our specific benchmarks to current practice. However, the development of academic success occurs over the long‐term, and published data on academic hospitalist productivity are consistent with this slower time course.[8] Despite these limitations, our data inform the general topic of gauging performance of AHPs, underscoring the challenges of developing and applying metrics of success, and highlight the variability of performance on selected metrics even among a relatively small group of 17 programs.
In conclusion, we have created a method to quantify academic success that may be useful to academic hospitalists and their group leaders as they set targets for improvement in the field. Even among our SCHOLAR cohort, room for ongoing improvement in development of funded scholarship and a core of senior faculty exists. Further investigation into the unique features of successful groups will offer insight to leaders in academic hospital medicine regarding infrastructure and processes that should be embraced to raise the bar for all AHPs. In addition, efforts to further define and validate nontraditional approaches to scholarship that allow for successful promotion at AHPs would be informative. We view our work less as a singular approach to benchmarking standards for AHPs, and more a call to action to continue efforts to balance scholarly activity and broad professional development of academic hospitalists with increasing clinical demands.
Acknowledgements
The authors thank all of the AHP leaders who participated in the SCHOLAR project. They also thank the Society of Hospital Medicine and Society of General Internal Medicine and the SHM Academic Committee and SGIM Academic Hospitalist Task Force for their support of this work.
Disclosures
The work reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.
The structure and function of academic hospital medicine programs (AHPs) has evolved significantly with the growth of hospital medicine.[1, 2, 3, 4] Many AHPs formed in response to regulatory and financial changes, which drove demand for increased trainee oversight, improved clinical efficiency, and growth in nonteaching services staffed by hospitalists. Differences in local organizational contexts and needs have contributed to great variability in AHP program design and operations. As AHPs have become more established, the need to engage academic hospitalists in scholarship and activities that support professional development and promotion has been recognized. Defining sustainable and successful positions for academic hospitalists is a priority called for by leaders in the field.[5, 6]
In this rapidly evolving context, AHPs have employed a variety of approaches to organizing clinical and academic faculty roles, without guiding evidence or consensus‐based performance benchmarks. A number of AHPs have achieved success along traditional academic metrics of research, scholarship, and education. Currently, it is not known whether specific approaches to AHP organization, structure, or definition of faculty roles are associated with achievement of more traditional markers of academic success.
The Academic Committee of the Society of Hospital Medicine (SHM), and the Academic Hospitalist Task Force of the Society of General Internal Medicine (SGIM) had separately initiated projects to explore characteristics associated with success in AHPs. In 2012, these organizations combined efforts to jointly develop and implement the SCHOLAR (SuCcessful HOspitaLists in Academics and Research) project. The goals were to identify successful AHPs using objective criteria, and to then study those groups in greater detail to generate insights that would be broadly relevant to the field. Efforts to clarify the factors within AHPs linked to success by traditional academic metrics will benefit hospitalists, their leaders, and key stakeholders striving to achieve optimal balance between clinical and academic roles. We describe the initial work of the SCHOLAR project, our definitions of academic success in AHPs, and the characteristics of a cohort of exemplary AHPs who achieved the highest levels on these metrics.
METHODS
Defining Success
The 11 members of the SCHOLAR project held a variety of clinical and academic roles within a geographically diverse group of AHPs. We sought to create a functional definition of success applicable to AHPs. As no gold standard currently exists, we used a consensus process among task force members to arrive at a definition that was quantifiable, feasible, and meaningful. The first step was brainstorming on conference calls held 1 to 2 times monthly over 4 months. Potential defining characteristics that emerged from these discussions related to research, teaching, and administrative activities. When potential characteristics were proposed, we considered how to operationalize each one. Each characteristic was discussed until there was consensus from the entire group. Those around education and administration were the most complex, as many roles are locally driven and defined, and challenging to quantify. For this reason, we focused on promotion as a more global approach to assessing academic hospitalist success in these areas. Although criteria for academic advancement also vary across institutions, we felt that promotion generally reflected having met some threshold of academic success. We also wanted to recognize that scholarship occurs outside the context of funded research. Ultimately, 3 key domains emerged: research grant funding, faculty promotion, and scholarship.
After these 3 domains were identified, the group sought to define quantitative metrics to assess performance. These discussions occurred on subsequent calls over a 4‐month period. Between calls, group members gathered additional information to facilitate assessment of the feasibility of proposed metrics, reporting on progress via email. Again, group consensus was sought for each metric considered. Data on grant funding and successful promotions were available from a previous survey conducted through the SHM in 2011. Leaders from 170 AHPs were contacted, with 50 providing complete responses to the 21‐item questionnaire (see Supporting Information, Appendix 1, in the online version of this article). Results of the survey, heretofore referred to as the Leaders of Academic Hospitalist Programs survey (LAHP‐50), have been described elsewhere.[7] For the purposes of this study, we used the self‐reported data about grant funding and promotions contained in the survey to reflect the current state of the field. Although the survey response rate was approximately 30%, the survey was not anonymous, and many reputationally prominent academic hospitalist programs were represented. For these reasons, the group members felt that the survey results were relevant for the purposes of assessing academic success.
In the LAHP‐50, funding was defined as principal investigator or coinvestigator roles on federally and nonfederally funded research, clinical trials, internal grants, and any other extramurally funded projects. Mean and median funding for the overall sample was calculated. Through a separate question, each program's total faculty full‐time equivalent (FTE) count was reported, allowing us to adjust for group size by assessing both total funding per group and funding/FTE for each responding AHP.
Promotions were defined by the self‐reported number of faculty at each of the following ranks: instructor, assistant professor, associate professor, full professor, and professor above scale/emeritus. In addition, a category of nonacademic track (eg, adjunct faculty, clinical associate) was included to capture hospitalists that did not fit into the traditional promotions categories. We did not distinguish between tenure‐track and nontenure‐track academic ranks. LAHP‐50 survey respondents reported the number of faculty in their group at each academic rank. Given that the majority of academic hospitalists hold a rank of assistant professor or lower,[6, 8, 9] and that the number of full professors was only 3% in the LAHP‐50 cohort, we combined the faculty at the associate and full professor ranks, defining successfully promoted faculty as the percent of hospitalists above the rank of assistant professor.
We created a new metric to assess scholarly output. We had considerable discussion of ways to assess the numbers of peer‐reviewed manuscripts generated by AHPs. However, the group had concerns about the feasibility of identification and attribution of authors to specific AHPs through literature searches. We considered examining only publications in the Journal of Hospital Medicine and the Journal of General Internal Medicine, but felt that this would exclude significant work published by hospitalists in fields of medical education or health services research that would more likely appear in alternate journals. Instead, we quantified scholarship based on the number of abstracts presented at national meetings. We focused on meetings of the SHM and SGIM as the primary professional societies representing hospital medicine. The group felt that even work published outside of the journals of our professional societies would likely be presented at those meetings. We used the following strategy: We reviewed research abstracts accepted for presentation as posters or oral abstracts at the 2010 and 2011 SHM national meetings, and research abstracts with a primary or secondary category of hospital medicine at the 2010 and 2011 SGIM national meetings. By including submissions at both SGIM and SHM meetings, we accounted for the fact that some programs may gravitate more to one society meeting or another. We did not include abstracts in the clinical vignettes or innovations categories. We tallied the number of abstracts by group affiliation of the authors for each of the 4 meetings above and created a cumulative total per group for the 2‐year period. Abstracts with authors from different AHPs were counted once for each individual group. Members of the study group reviewed abstracts from each of the meetings in pairs. Reviewers worked separately and compared tallies of results to ensure consistent tabulations. Internet searches were conducted to identify or confirm author affiliations if it was not apparent in the abstract author list. Abstract tallies were compiled without regard to whether programs had completed the LAHP‐50 survey; thus, we collected data on programs that did not respond to the LAHP‐50 survey.
Identification of the SCHOLAR Cohort
To identify our cohort of top‐performing AHPs, we combined the funding and promotions data from the LAHP‐50 sample with the abstract data. We limited our sample to adult hospital medicine groups to reduce heterogeneity. We created rank lists of programs in each category (grant funding, successful promotions, and scholarship), using data from the LAHP‐50 survey to rank programs on funding and promotions, and data from our abstract counts to rank on scholarship. We limited the top‐performing list in each category to 10 institutions as a cutoff. Because we set a threshold of at least $1 million in total funding, we identified only 9 top performing AHPs with regard to grant funding. We also calculated mean funding/FTE. We chose to rank programs only by funding/FTE rather than total funding per program to better account for group size. For successful promotions, we ranked programs by the percentage of senior faculty. For abstract counts, we included programs whose faculty presented abstracts at a minimum of 2 separate meetings, and ranked programs based on the total number of abstracts per group.
This process resulted in separate lists of top performing programs in each of the 3 domains we associated with academic success, arranged in descending order by grant dollars/FTE, percent of senior faculty, and abstract counts (Table 1). Seventeen different programs were represented across these 3 top 10 lists. One program appeared on all 3 lists, 8 programs appeared on 2 lists, and the remainder appeared on a single list (Table 2). Seven of these programs were identified solely based on abstract presentations, diversifying our top groups beyond only those who completed the LAHP‐50 survey. We considered all of these programs to represent high performance in academic hospital medicine. The group selected this inclusive approach because we recognized that any 1 metric was potentially limited, and we sought to identify diverse pathways to success.
| Funding | Promotions | Scholarship | |
|---|---|---|---|
| Grant $/FTE | Total Grant $ | Senior Faculty, No. (%) | Total Abstract Count |
| |||
| $1,409,090 | $15,500,000 | 3 (60%) | 23 |
| $1,000,000 | $9,000,000 | 3 (60%) | 21 |
| $750,000 | $8,000,000 | 4 (57%) | 20 |
| $478,609 | $6,700,535 | 9 (53%) | 15 |
| $347,826 | $3,000,000 | 8 (44%) | 11 |
| $86,956 | $3,000,000 | 14 (41%) | 11 |
| $66,666 | $2,000,000 | 17 (36%) | 10 |
| $46,153 | $1,500,000 | 9 (33%) | 10 |
| $38,461 | $1,000,000 | 2 (33%) | 9 |
| 4 (31%) | 9 | ||
| Selection Criteria for SCHOLAR Cohort | No. of Programs |
|---|---|
| |
| Abstracts, funding, and promotions | 1 |
| Abstracts plus promotions | 4 |
| Abstracts plus funding | 3 |
| Funding plus promotion | 1 |
| Funding only | 1 |
| Abstract only | 7 |
| Total | 17 |
| Top 10 abstract count | |
| 4 meetings | 2 |
| 3 meetings | 2 |
| 2 meetings | 6 |
The 17 unique adult AHPs appearing on at least 1 of the top 10 lists comprised the SCHOLAR cohort of programs that we studied in greater detail. Data reflecting program demographics were solicited directly from leaders of the AHPs identified in the SCHOLAR cohort, including size and age of program, reporting structure, number of faculty at various academic ranks (for programs that did not complete the LAHP‐50 survey), and number of faculty with fellowship training (defined as any postresidency fellowship program).
Subsequently, we performed comparative analyses between the programs in the SCHOLAR cohort to the general population of AHPs reflected by the LAHP‐50 sample. Because abstract presentations were not recorded in the original LAHP‐50 survey instrument, it was not possible to perform a benchmarking comparison for the scholarship domain.
Data Analysis
To measure the success of the SCHOLAR cohort we compared the grant funding and proportion of successfully promoted faculty at the SCHOLAR programs to those in the overall LAHP‐50 sample. Differences in mean and median grant funding were compared using t tests and Mann‐Whitney rank sum tests. Proportion of promoted faculty were compared using 2 tests. A 2‐tailed of 0.05 was used to test significance of differences.
RESULTS
Demographics
Among the AHPs in the SCHOLAR cohort, the mean program age was 13.2 years (range, 618 years), and the mean program size was 36 faculty (range, 1895; median, 28). On average, 15% of faculty members at SCHOLAR programs were fellowship trained (range, 0%37%). Reporting structure among the SCHOLAR programs was as follows: 53% were an independent division or section of the department of medicine; 29% were a section within general internal medicine, and 18% were an independent clinical group.
Grant Funding
Table 3 compares grant funding in the SCHOLAR programs to programs in the overall LAHP‐50 sample. Mean funding per group and mean funding per FTE were significantly higher in the SCHOLAR group than in the overall sample.
| Funding (Millions) | ||
|---|---|---|
| LAHP‐50 Overall Sample | SCHOLAR | |
| ||
| Median grant funding/AHP | 0.060 | 1.500* |
| Mean grant funding/AHP | 1.147 (015) | 3.984* (015) |
| Median grant funding/FTE | 0.004 | 0.038* |
| Mean grant funding/FTE | 0.095 (01.4) | 0.364* (01.4) |
Thirteen of the SCHOLAR programs were represented in the initial LAHP‐50, but 2 did not report a dollar amount for grants and contracts. Therefore, data for total grant funding were available for only 65% (11 of 17) of the programs in the SCHOLAR cohort. Of note, 28% of AHPs in the overall LAHP‐50 sample reported no external funding sources.
Faculty Promotion
Figure 1 demonstrates the proportion of faculty at various academic ranks. The percent of faculty above the rank of assistant professor in the SCHOLAR programs exceeded those in the overall LAHP‐50 by 5% (17.9% vs 12.8%, P = 0.01). Of note, 6% of the hospitalists at AHPs in the SCHOLAR programs were on nonfaculty tracks.
Scholarship
Mean abstract output over the 2‐year period measured was 10.8 (range, 323) in the SCHOLAR cohort. Because we did not collect these data for the LAHP‐50 group, comparative analyses were not possible.
DISCUSSION
Using a definition of academic success that incorporated metrics of grant funding, faculty promotion, and scholarly output, we identified a unique subset of successful AHPsthe SCHOLAR cohort. The programs represented in the SCHOLAR cohort were generally large and relatively mature. Despite this, the cohort consisted of mostly junior faculty, had a paucity of fellowship‐trained hospitalists, and not all reported grant funding.
Prior published work reported complementary findings.[6, 8, 9] A survey of 20 large, well‐established academic hospitalist programs in 2008 found that the majority of hospitalists were junior faculty with a limited publication portfolio. Of the 266 respondents in that study, 86% reported an academic rank at or below assistant professor; funding was not explored.[9] Our similar findings 4 years later add to this work by demonstrating trends over time, and suggest that progress toward creating successful pathways for academic advancement has been slow. In a 2012 survey of the SHM membership, 28% of hospitalists with academic appointments reported no current or future plans to engage in research.[8] These findings suggest that faculty in AHPs may define scholarship through nontraditional pathways, or in some cases choose not to pursue or prioritize scholarship altogether.
Our findings also add to the literature with regard to our assessment of funding, which was variable across the SCHOLAR group. The broad range of funding in the SCHOLAR programs for which we have data (grant dollars $0$15 million per program) suggests that opportunities to improve supported scholarship remain, even among a selected cohort of successful AHPs. The predominance of junior faculty in the SCHOLAR programs may be a reason for this variation. Junior faculty may be engaged in research with funding directed to senior mentors outside their AHP. Alternatively, they may pursue meaningful local hospital quality improvement or educational innovations not supported by external grants, or hold leadership roles in education, quality, or information technology that allow for advancement and promotion without external grant funding. As the scope and impact of these roles increases, senior leaders with alternate sources of support may rely less on research funds; this too may explain some of the differences. Our findings are congruent with results of a study that reviewed original research published by hospitalists, and concluded that the majority of hospitalist research was not externally funded.[8] Our approach for assessing grant funding by adjusting for FTE had the potential to inadvertently favor smaller well‐funded groups over larger ones; however, programs in our sample were similarly represented when ranked by funding/FTE or total grant dollars. As many successful AHPs do concentrate their research funding among a core of focused hospitalist researchers, our definition may not be the ideal metric for some programs.
We chose to define scholarship based on abstract output, rather than peer‐reviewed publications. Although this choice was necessary from a feasibility perspective, it may have excluded programs that prioritize peer‐reviewed publications over abstracts. Although we were unable to incorporate a search strategy to accurately and comprehensively track the publication output attributed specifically to hospitalist researchers and quantify it by program, others have since defined such an approach.[8] However, tracking abstracts theoretically allowed insights into a larger volume of innovative and creative work generated by top AHPs by potentially including work in the earlier stages of development.
We used a consensus‐based definition of success to define our SCHOLAR cohort. There are other ways to measure academic success, which if applied, may have yielded a different sample of programs. For example, over half of the original research articles published in the Journal of Hospital Medicine over a 7‐year span were generated from 5 academic centers.[8] This definition of success may be equally credible, though we note that 4 of these 5 programs were also included in the SCHOLAR cohort. We feel our broader approach was more reflective of the variety of pathways to success available to academic hospitalists. Before our metrics are applied as a benchmarking tool, however, they should ideally be combined with factors not measured in our study to ensure a more comprehensive or balanced reflection of academic success. Factors such as mentorship, level of hospitalist engagement,[10] prevalence of leadership opportunities, operational and fiscal infrastructure, and the impact of local quality, safety, and value efforts should be considered.
Comparison of successfully promoted faculty at AHPs across the country is inherently limited by the wide variation in promotion standards across different institutions; controlling for such differences was not possible with our methodology. For example, it appears that several programs with relatively few senior faculty may have met metrics leading to their inclusion in the SCHOLAR group because of their small program size. Future benchmarking efforts for promotion at AHPs should take scaling into account and consider both total number as well as percentage of senior faculty when evaluating success.
Our methodology has several limitations. Survey data were self‐reported and not independently validated, and as such are subject to recall and reporting biases. Response bias inherently excluded some AHPs that may have met our grant funding or promotions criteria had they participated in the initial LAHP‐50 survey, though we identified and included additional programs through our scholarship metric, increasing the representativeness of the SCHOLAR cohort. Given the dynamic nature of the field, the age of the data we relied upon for analysis limits the generalizability of our specific benchmarks to current practice. However, the development of academic success occurs over the long‐term, and published data on academic hospitalist productivity are consistent with this slower time course.[8] Despite these limitations, our data inform the general topic of gauging performance of AHPs, underscoring the challenges of developing and applying metrics of success, and highlight the variability of performance on selected metrics even among a relatively small group of 17 programs.
In conclusion, we have created a method to quantify academic success that may be useful to academic hospitalists and their group leaders as they set targets for improvement in the field. Even among our SCHOLAR cohort, room for ongoing improvement in development of funded scholarship and a core of senior faculty exists. Further investigation into the unique features of successful groups will offer insight to leaders in academic hospital medicine regarding infrastructure and processes that should be embraced to raise the bar for all AHPs. In addition, efforts to further define and validate nontraditional approaches to scholarship that allow for successful promotion at AHPs would be informative. We view our work less as a singular approach to benchmarking standards for AHPs, and more a call to action to continue efforts to balance scholarly activity and broad professional development of academic hospitalists with increasing clinical demands.
Acknowledgements
The authors thank all of the AHP leaders who participated in the SCHOLAR project. They also thank the Society of Hospital Medicine and Society of General Internal Medicine and the SHM Academic Committee and SGIM Academic Hospitalist Task Force for their support of this work.
Disclosures
The work reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The authors report no conflicts of interest.
- , , , , . Characteristics of primary care providers who adopted the hospitalist model from 2001 to 2009. J Hosp Med. 2015;10(2):75–82.
- , , , . Growth in the care of older patients by hospitalists in the United States. N Engl J Med. 2009;360(11):1102–1112.
- , , , , . Updating threshold‐based identification of hospitalists in 2012 Medicare pay data. J Hosp Med. 2016;11(1):45–47.
- , , , . Use of hospitalists by Medicare beneficiaries: a national picture. Medicare Medicaid Res Rev. 2014;4(2).
- , , , , , . Challenges and opportunities in Academic Hospital Medicine: report from the Academic Hospital Medicine Summit. J Hosp Med. 2009;4(4):240–246.
- , , , . Survey of US academic hospitalist leaders about mentorship and academic activities in hospitalist groups. J Hosp Med. 2011;6(1):5–9.
- , , , , , . The structure of hospital medicine programs at academic medical centers [abstract]. J Hosp Med. 2012;7(suppl 2):s92.
- , , , , . Research and publication trends in hospital medicine. J Hosp Med. 2014;9(3):148–154.
- , , , , , . Mentorship, productivity, and promotion among academic hospitalists. J Gen Intern Med. 2012;27(1):23–27.
- , , , et al. The key principles and characteristics of an effective hospital medicine group: an assessment guide for hospitals and hospitalists. J Hosp Med. 2014;9(2):123–128.
- , , , , . Characteristics of primary care providers who adopted the hospitalist model from 2001 to 2009. J Hosp Med. 2015;10(2):75–82.
- , , , . Growth in the care of older patients by hospitalists in the United States. N Engl J Med. 2009;360(11):1102–1112.
- , , , , . Updating threshold‐based identification of hospitalists in 2012 Medicare pay data. J Hosp Med. 2016;11(1):45–47.
- , , , . Use of hospitalists by Medicare beneficiaries: a national picture. Medicare Medicaid Res Rev. 2014;4(2).
- , , , , , . Challenges and opportunities in Academic Hospital Medicine: report from the Academic Hospital Medicine Summit. J Hosp Med. 2009;4(4):240–246.
- , , , . Survey of US academic hospitalist leaders about mentorship and academic activities in hospitalist groups. J Hosp Med. 2011;6(1):5–9.
- , , , , , . The structure of hospital medicine programs at academic medical centers [abstract]. J Hosp Med. 2012;7(suppl 2):s92.
- , , , , . Research and publication trends in hospital medicine. J Hosp Med. 2014;9(3):148–154.
- , , , , , . Mentorship, productivity, and promotion among academic hospitalists. J Gen Intern Med. 2012;27(1):23–27.
- , , , et al. The key principles and characteristics of an effective hospital medicine group: an assessment guide for hospitals and hospitalists. J Hosp Med. 2014;9(2):123–128.
Caught red‐handed
A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.
Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.
His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.
The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.
Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.
These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.
Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.
Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.
Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.
The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.
The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.
DISCUSSION
TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]
| Diagnostic Criteria* | This Case |
|---|---|
| |
| Fever: Temperature 102.0F | Fever: 105.3F on admission |
| Rash: Diffuse macular erythroderma | Diffuse morbilliform rash with progression to confluent erythroderma |
| Desquamation of rash: occurs 12 weeks following rash onset | Desquamation 12 days after discharge |
| Hypotension: SBP 90 mm Hg for adults | Intermittent |
| Multisystem involvement, 3 of the following: | 4 organ systems definitively involved |
| GI: vomiting or diarrhea at disease onset | Vomiting and abdominal pain |
| Muscular: severe myalgias, or creatine phosphokinase >2 times the upper limit of normal | |
| Mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia | |
| Renal: BUN or Cr >2 times the upper limit of normal, or pyuria without evidence of infection | |
| Hepatic: total bilirubin, AST, or ALT levels >2 times the upper limit of normal | AST and ALT peaked at 128IU/L and 94 IU/L |
| Hematologic: platelets <100,000/mm3 | Platelet nadir of 80,000/mm3 |
| CNS: disorientation or altered consciousness without focal neurologic signs | Disorientation and somnolence |
| Probable case: 4 out of 5 clinical criteria present | |
| Confirmed case: 5 out of 5 clinical criteria present, or patient dies before desquamation can occur | |
A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.
In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]
Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.
This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.
KEY POINTS
- When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
- TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
- The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.
Disclosure
Nothing to report.
- . Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin. 2013;29:651–675.
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- Centers for Disease Control and Prevention. National Notifiable Diseases Surveillance System. Toxic shock syndrome (other than Streptococcal) (TSS) 2011 Case Definition. Available at: http://wwwn.cdc.gov/nndss/conditions/toxic‐shock‐syndrome‐other‐than‐streptococcal/case‐definition/2011. Accessed June 4, 2015.
- Centers for Disease Control and Prevention. Update: toxic‐shock syndrome—United States. MMWR Morb Mortal Wkly Rep. 1983;32(30):398–400.
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- , , , et al. Toxic‐shock syndrome in menstruating women: association with tampon use and staphylococcus aureus and clinical features in 52 cases. N Engl J Med. 1980;303(25):1436–1442.
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- , , , et al. One in five mortality in non‐menstrual toxic shock syndrome versus no mortality in menstrual cases in a balanced French series of 55 cases. Eur J Clin Microbio Infect Dis. 2008;27(1):37–43.
- , . Gram‐positive toxic shock syndromes. Lancet Infect Dis. 2009;9(5):281–290.
A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.
Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.
His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.
The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.
Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.
These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.
Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.
Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.
Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.
The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.
The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.
DISCUSSION
TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]
| Diagnostic Criteria* | This Case |
|---|---|
| |
| Fever: Temperature 102.0F | Fever: 105.3F on admission |
| Rash: Diffuse macular erythroderma | Diffuse morbilliform rash with progression to confluent erythroderma |
| Desquamation of rash: occurs 12 weeks following rash onset | Desquamation 12 days after discharge |
| Hypotension: SBP 90 mm Hg for adults | Intermittent |
| Multisystem involvement, 3 of the following: | 4 organ systems definitively involved |
| GI: vomiting or diarrhea at disease onset | Vomiting and abdominal pain |
| Muscular: severe myalgias, or creatine phosphokinase >2 times the upper limit of normal | |
| Mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia | |
| Renal: BUN or Cr >2 times the upper limit of normal, or pyuria without evidence of infection | |
| Hepatic: total bilirubin, AST, or ALT levels >2 times the upper limit of normal | AST and ALT peaked at 128IU/L and 94 IU/L |
| Hematologic: platelets <100,000/mm3 | Platelet nadir of 80,000/mm3 |
| CNS: disorientation or altered consciousness without focal neurologic signs | Disorientation and somnolence |
| Probable case: 4 out of 5 clinical criteria present | |
| Confirmed case: 5 out of 5 clinical criteria present, or patient dies before desquamation can occur | |
A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.
In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]
Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.
This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.
KEY POINTS
- When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
- TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
- The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.
Disclosure
Nothing to report.
A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.
Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.
His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.
The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.
Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.
These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.
Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.
Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.
Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.
The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.
The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.
DISCUSSION
TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]
| Diagnostic Criteria* | This Case |
|---|---|
| |
| Fever: Temperature 102.0F | Fever: 105.3F on admission |
| Rash: Diffuse macular erythroderma | Diffuse morbilliform rash with progression to confluent erythroderma |
| Desquamation of rash: occurs 12 weeks following rash onset | Desquamation 12 days after discharge |
| Hypotension: SBP 90 mm Hg for adults | Intermittent |
| Multisystem involvement, 3 of the following: | 4 organ systems definitively involved |
| GI: vomiting or diarrhea at disease onset | Vomiting and abdominal pain |
| Muscular: severe myalgias, or creatine phosphokinase >2 times the upper limit of normal | |
| Mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia | |
| Renal: BUN or Cr >2 times the upper limit of normal, or pyuria without evidence of infection | |
| Hepatic: total bilirubin, AST, or ALT levels >2 times the upper limit of normal | AST and ALT peaked at 128IU/L and 94 IU/L |
| Hematologic: platelets <100,000/mm3 | Platelet nadir of 80,000/mm3 |
| CNS: disorientation or altered consciousness without focal neurologic signs | Disorientation and somnolence |
| Probable case: 4 out of 5 clinical criteria present | |
| Confirmed case: 5 out of 5 clinical criteria present, or patient dies before desquamation can occur | |
A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.
In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]
Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.
This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.
KEY POINTS
- When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
- TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
- The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.
Disclosure
Nothing to report.
- . Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin. 2013;29:651–675.
- . The toxic shock syndromes. Infect Dis Clin North Am. 1996;10(4):727–746.
- Centers for Disease Control and Prevention. National Notifiable Diseases Surveillance System. Toxic shock syndrome (other than Streptococcal) (TSS) 2011 Case Definition. Available at: http://wwwn.cdc.gov/nndss/conditions/toxic‐shock‐syndrome‐other‐than‐streptococcal/case‐definition/2011. Accessed June 4, 2015.
- Centers for Disease Control and Prevention. Update: toxic‐shock syndrome—United States. MMWR Morb Mortal Wkly Rep. 1983;32(30):398–400.
- , , , , , . Toxic shock syndrome in the United States: surveillance update, 1979–1996. Emerg Infect Dis. 1999;5(6):807–810.
- . Fever and rash. Infect Dis Clin North Am. 1996;10(1):101–110.
- , , , et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS One. 2011;6(8):e22997.
- , , , et al. Toxic‐shock syndrome in menstruating women: association with tampon use and staphylococcus aureus and clinical features in 52 cases. N Engl J Med. 1980;303(25):1436–1442.
- , , , . Toxic‐shock syndrome—epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med. 1980;303:1429–1435.
- , . Evaluating the febrile patient with a rash. Am Fam Physician. 2000;62(4):804–816.
- . Toxic shock syndrome: broadening the differential diagnosis. J Am Board Fam Pract. 2001;14(2):131–136.
- , , , . Spatial clustering by disease severity among reported Rocky Mountain spotted fever cases in the United States, 2001–2005. Am J Trop Med Hyg. 2009;80(1):72–77.
- , , , et al. One in five mortality in non‐menstrual toxic shock syndrome versus no mortality in menstrual cases in a balanced French series of 55 cases. Eur J Clin Microbio Infect Dis. 2008;27(1):37–43.
- , . Gram‐positive toxic shock syndromes. Lancet Infect Dis. 2009;9(5):281–290.
- . Toxic shock syndrome: major advances in pathogenesis, but not treatment. Crit Care Clin. 2013;29:651–675.
- . The toxic shock syndromes. Infect Dis Clin North Am. 1996;10(4):727–746.
- Centers for Disease Control and Prevention. National Notifiable Diseases Surveillance System. Toxic shock syndrome (other than Streptococcal) (TSS) 2011 Case Definition. Available at: http://wwwn.cdc.gov/nndss/conditions/toxic‐shock‐syndrome‐other‐than‐streptococcal/case‐definition/2011. Accessed June 4, 2015.
- Centers for Disease Control and Prevention. Update: toxic‐shock syndrome—United States. MMWR Morb Mortal Wkly Rep. 1983;32(30):398–400.
- , , , , , . Toxic shock syndrome in the United States: surveillance update, 1979–1996. Emerg Infect Dis. 1999;5(6):807–810.
- . Fever and rash. Infect Dis Clin North Am. 1996;10(1):101–110.
- , , , et al. Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics. PLoS One. 2011;6(8):e22997.
- , , , et al. Toxic‐shock syndrome in menstruating women: association with tampon use and staphylococcus aureus and clinical features in 52 cases. N Engl J Med. 1980;303(25):1436–1442.
- , , , . Toxic‐shock syndrome—epidemiologic features, recurrence, risk factors, and prevention. N Engl J Med. 1980;303:1429–1435.
- , . Evaluating the febrile patient with a rash. Am Fam Physician. 2000;62(4):804–816.
- . Toxic shock syndrome: broadening the differential diagnosis. J Am Board Fam Pract. 2001;14(2):131–136.
- , , , . Spatial clustering by disease severity among reported Rocky Mountain spotted fever cases in the United States, 2001–2005. Am J Trop Med Hyg. 2009;80(1):72–77.
- , , , et al. One in five mortality in non‐menstrual toxic shock syndrome versus no mortality in menstrual cases in a balanced French series of 55 cases. Eur J Clin Microbio Infect Dis. 2008;27(1):37–43.
- , . Gram‐positive toxic shock syndromes. Lancet Infect Dis. 2009;9(5):281–290.
Can patients with infectious endocarditis be safely anticoagulated?
Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.
Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.
Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.
AVAILABLE EVIDENCE IS SCARCE AND MIXED
Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.
In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.
How great is the benefit or the potential harm?
Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.
In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.11–13 Snygg-Martin et al11 and Rasmussen et al12 found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.
These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.
Similarly, Anavekar et al14 showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.15
A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).16
Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,8 but not seen in a study by Rasmussen et al.12
Continuing anticoagulation is an individualized decision
The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.
Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).1–3
TAKE-HOME POINTS
- Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
- In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
- Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
- If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
- If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132:1435–1486.
- Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis. Rev Esp Cardiol (Engl Ed) 2016; 69:69.
- Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141:e576S–e600S.
- Delahaye JP, Poncet P, Malquarti V, Beaune J, Garé JP, Mann JM. Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J 1990; 11:1074–1078.
- Loewe L. The combined use of anti-infectives and anticoagulants in the treatment of subacute bacterial endocarditis. Bull N Y Acad Med 1945; 21:59–86.
- Priest WS, Smith JM, McGee GC. The effect of anticoagulants on the penicillin therapy and the pathologic lesions of subacute bacterial endocarditis. N Engl J Med 1946; 235:699–706.
- Pruitt AA, Rubin RH, Karchmer AW, Duncan GW. Neurologic complications of bacterial endocarditis. Medicine 1978; 57:329–343.
- Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med 1999; 159:473–475.
- Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis. Circulation 1978; 57:1004–1007.
- Schulz R, Werner GS, Fuchs JB, et al. Clinical outcome and echocardiographic findings of native and prosthetic valve endocarditis in the 1990’s. Eur Heart J 1996; 17:281–288.
- Snygg-Martin U, Rasmussen RV, Hassager C, Bruun NE, Andersson R, Olaison L. Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis. Eur J Clin Microbiol Infect Dis 2011; 30:151–157.
- Rasmussen RV, Snygg-Martin U, Olaison L, et al. Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe? Cardiology 2009; 114:284–291.
- Yau JW, Lee P, Wilson A, Jenkins AJ. Prosthetic valve endocarditis: what is the evidence for anticoagulant therapy? Intern Med J 2011; 41:795–797.
- Anavekar NS, Tleyjeh IM, Mirzoyev Z, et al. Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis 2007; 44:1180–1186.
- Chan KL, Dumesnil JG, Cujec B, et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 2003; 42:775–780.
- Garcia-Cabrera E, Fernández-Hidalgo N, Almirante B, et al. Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation 2013; 127:2272–2284.
- Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005; 112:69–75.
Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.
Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.
Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.
AVAILABLE EVIDENCE IS SCARCE AND MIXED
Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.
In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.
How great is the benefit or the potential harm?
Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.
In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.11–13 Snygg-Martin et al11 and Rasmussen et al12 found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.
These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.
Similarly, Anavekar et al14 showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.15
A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).16
Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,8 but not seen in a study by Rasmussen et al.12
Continuing anticoagulation is an individualized decision
The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.
Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).1–3
TAKE-HOME POINTS
- Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
- In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
- Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
- If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
- If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.
Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.
Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.
Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.
AVAILABLE EVIDENCE IS SCARCE AND MIXED
Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.
In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.
How great is the benefit or the potential harm?
Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.
In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.11–13 Snygg-Martin et al11 and Rasmussen et al12 found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.
These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.
Similarly, Anavekar et al14 showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.15
A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).16
Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,8 but not seen in a study by Rasmussen et al.12
Continuing anticoagulation is an individualized decision
The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.
Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).1–3
TAKE-HOME POINTS
- Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
- In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
- Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
- If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
- If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132:1435–1486.
- Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis. Rev Esp Cardiol (Engl Ed) 2016; 69:69.
- Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141:e576S–e600S.
- Delahaye JP, Poncet P, Malquarti V, Beaune J, Garé JP, Mann JM. Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J 1990; 11:1074–1078.
- Loewe L. The combined use of anti-infectives and anticoagulants in the treatment of subacute bacterial endocarditis. Bull N Y Acad Med 1945; 21:59–86.
- Priest WS, Smith JM, McGee GC. The effect of anticoagulants on the penicillin therapy and the pathologic lesions of subacute bacterial endocarditis. N Engl J Med 1946; 235:699–706.
- Pruitt AA, Rubin RH, Karchmer AW, Duncan GW. Neurologic complications of bacterial endocarditis. Medicine 1978; 57:329–343.
- Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med 1999; 159:473–475.
- Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis. Circulation 1978; 57:1004–1007.
- Schulz R, Werner GS, Fuchs JB, et al. Clinical outcome and echocardiographic findings of native and prosthetic valve endocarditis in the 1990’s. Eur Heart J 1996; 17:281–288.
- Snygg-Martin U, Rasmussen RV, Hassager C, Bruun NE, Andersson R, Olaison L. Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis. Eur J Clin Microbiol Infect Dis 2011; 30:151–157.
- Rasmussen RV, Snygg-Martin U, Olaison L, et al. Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe? Cardiology 2009; 114:284–291.
- Yau JW, Lee P, Wilson A, Jenkins AJ. Prosthetic valve endocarditis: what is the evidence for anticoagulant therapy? Intern Med J 2011; 41:795–797.
- Anavekar NS, Tleyjeh IM, Mirzoyev Z, et al. Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis 2007; 44:1180–1186.
- Chan KL, Dumesnil JG, Cujec B, et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 2003; 42:775–780.
- Garcia-Cabrera E, Fernández-Hidalgo N, Almirante B, et al. Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation 2013; 127:2272–2284.
- Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005; 112:69–75.
- Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132:1435–1486.
- Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis. Rev Esp Cardiol (Engl Ed) 2016; 69:69.
- Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141:e576S–e600S.
- Delahaye JP, Poncet P, Malquarti V, Beaune J, Garé JP, Mann JM. Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J 1990; 11:1074–1078.
- Loewe L. The combined use of anti-infectives and anticoagulants in the treatment of subacute bacterial endocarditis. Bull N Y Acad Med 1945; 21:59–86.
- Priest WS, Smith JM, McGee GC. The effect of anticoagulants on the penicillin therapy and the pathologic lesions of subacute bacterial endocarditis. N Engl J Med 1946; 235:699–706.
- Pruitt AA, Rubin RH, Karchmer AW, Duncan GW. Neurologic complications of bacterial endocarditis. Medicine 1978; 57:329–343.
- Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med 1999; 159:473–475.
- Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis. Circulation 1978; 57:1004–1007.
- Schulz R, Werner GS, Fuchs JB, et al. Clinical outcome and echocardiographic findings of native and prosthetic valve endocarditis in the 1990’s. Eur Heart J 1996; 17:281–288.
- Snygg-Martin U, Rasmussen RV, Hassager C, Bruun NE, Andersson R, Olaison L. Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis. Eur J Clin Microbiol Infect Dis 2011; 30:151–157.
- Rasmussen RV, Snygg-Martin U, Olaison L, et al. Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe? Cardiology 2009; 114:284–291.
- Yau JW, Lee P, Wilson A, Jenkins AJ. Prosthetic valve endocarditis: what is the evidence for anticoagulant therapy? Intern Med J 2011; 41:795–797.
- Anavekar NS, Tleyjeh IM, Mirzoyev Z, et al. Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis 2007; 44:1180–1186.
- Chan KL, Dumesnil JG, Cujec B, et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 2003; 42:775–780.
- Garcia-Cabrera E, Fernández-Hidalgo N, Almirante B, et al. Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation 2013; 127:2272–2284.
- Thuny F, Di Salvo G, Belliard O, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005; 112:69–75.
