A 62-year-old man with severe chronic obstructive pulmonary disease (COPD; forced expiratory volume during the first second [FEV1] 40% predicted) and type 2 diabetes mellitus presented to a Veterans Affairs emergency department (ED) with a steadily worsening cough of 4-months’ duration. He also reported subjective fevers, sputum production, shortness of breath, and unintentional 20-pound weight loss. He denied chills, chest pain, nausea, or vomiting.

Cough is classified as acute, subacute, or chronic based on duration of less than 3 weeks, between 3-8 weeks, and greater than 8 weeks, respectively. Common causes of chronic cough include bronchitis, acid reflux, cough-variant asthma, and a side effect of angiotensin converting enzyme inhibitors. Unintentional weight loss suggests a serious disorder, including indolent infection, end-stage COPD, malignancy, and autoimmune causes. Among patients with chronic bronchitis, the microbiology of sputum is often mixed with commensal respiratory flora, including Streptococcus pneumoniae and Haemophilus species. When these organisms are not recovered in sputa, or when patients fail to respond to empiric treatment, the differential diagnosis should be broadened to include pulmonary tuberculosis, nontuberculous mycobacterial infection, lung abscess, pulmonary nocardiosis, or pertussis.

An exposure and social history can focus the differential. For example, coccidioidomycosis or histoplasmosis may present indolently, but have distinct geographic distributions. Bird fanciers may acquire hypersensitivity pneumonitis, psittacosis, or cryptococcosis. Risk factors including smoking history, corticosteroid use, uncontrolled diabetes, and ill contacts should be assessed.

He was discharged from the ED twice in the last 2 weeks after presenting with similar symptoms. On each occasion, he was treated for presumed COPD exacerbations with nebulized albuterol and ipratropium, methylprednisolone followed by oral prednisone, and azithromycin, which did not lead to improvement. Over the last 3 days, he developed lower extremity edema, orthopnea, and dyspnea at rest. He reported worsening fatigue, night sweats, and anorexia. He denied any sick contacts.

Two diagnostic issues have emerged. His edema, orthopnea, and dyspnea at rest suggest a new cause of hypervolemia, perhaps caused by sodium retention from corticosteroids, pulmonary edema from valvular or myocardial disease, or renal failure. More concerning is that he has been treated with azithromycin twice recently but still has night sweats, fatigue, and anorexia. The presence of weight loss despite extracellular volume accumulation suggests an indolent systemic illness. Infection with macrolide-resistant organisms, such as nocardia, mycobacteria, or endemic mycoses, remains high on the differential diagnosis.

His past medical history included hypertension, untreated chronic hepatitis C, tobacco dependence, alcohol use disorder, and extraction of 8 decayed teeth 2 months earlier. He served in a noncombat role during the Vietnam War. He consumed 12 beers weekly with a remote history of alcoholism which required rehabilitation, reported a 50 pack-year smoking history, and denied intravenous (IV) drug use. He lived with an appropriately vaccinated dog and denied recent insect or animal exposures. He had a cat that passed away from an unknown illness 3 years prior. He was in a monogamous relationship with his girlfriend of 35 years. His father had coronary disease. His medications included glyburide, hydrochlorothiazide, lisinopril, theophylline, and meloxicam. Chronic cough, weight loss, diabetes, alcoholism, and history of dental disease raise concern for lung abscess. Oral microbiota such as Streptococcus viridans and Actinomycetes are usually harmless, but when aspirated repeatedly, such as during alcohol intoxication, may evolve into a lung abscess via bronchogenic spread. The combination of unintentional weight loss and smoking history raises concern for lung malignancy. Small cell lung cancer can present with paraneoplastic Cushing’s syndrome and could explain the patient’s volume overload. Finally, human immunodeficiency virus (HIV) serostatus should be determined in all adult patients.

His temperature was 37 °C, blood pressure 161/69 mm Hg, pulse 104 beats per minute, respiratory rate 20 breaths per minute, and oxygen saturation was 95% on room air. On examination, he was an unkempt, ill-appearing man. He had poor dentition, but no oral ulcers or petechiae. Pulmonary exam revealed diffuse rhonchi and scattered wheezes. He developed dyspnea after speaking 2 sentences. Cardiovascular exam showed regular tachycardia, normal S1 and S2 heart sounds, and both an S3 and S4 gallop. A grade III/VI holosystolic murmur at the left lower sternal border with apical radiation, and an early, grade III/IV diastolic murmur at the right upper sternal border were present. Neck exam showed jugular venous distention (JVD) 8 cm above the right clavicle. Lower extremities showed symmetric 3+ pitting edema to the knees. His abdomen was soft, nondistended, and without hepatosplenomegaly. There was no lymphadenopathy. Skin exam showed small, healed excoriations on his anterior shins, forearms, and knuckles. There were no petechiae, Janeway lesions, or Osler’s nodes.

These exam findings change the differential substantially. New regurgitant murmurs strongly suggest infective endocarditis (IE). A diastolic murmur is never normal and suggests aortic regurgitation. The holosystolic murmur with apical radiation suggests mitral regurgitation. Cutaneous stigmata should always be sought, but are found in fewer than half of cases of subacute IE, and their absence does not rule out this diagnosis. Disheveled hygiene and excoriations suggest a skin source of infection, and poor dentition is concerning for an oral source. For the moment, the source does not matter. His clinical condition is serious: tachycardia, JVD, edema, and two-sentence dyspnea indicate congestive heart failure. Even before labs and imaging return, inpatient admission is warranted.

Serum sodium concentration was 140 mEq/L, potassium 3.7 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, blood urea nitrogen (BUN) 26 mg/dL, creatinine 0.8 mg/dL, glucose 120 mg/dL, and calcium 9.0 mg/dL. The white blood cell count was 7100/µL, hemoglobin 11.8 g/dL, and platelet count 101 K/µL. Brain natriuretic peptide (BNP) was 785 pg/mL (reference range 0-100 pg/mL), aspartate aminotransferase 77 U/L, alanine aminotransferase 57 U/L, alkaline phosphatase 125 U/L, total bilirubin 0.8 mg/dL, total protein 7.7 g/dL, and albumin 3.7 g/dL. Erythrocyte sedimentation (ESR) rate was 38 mm/hour (reference range 0-25 mm/hour) and C-reactive protein (CRP) 0.62 mg/dL (reference range <1.0 mg/dL). Cardiac troponins were 0.03 ng/mL (reference range <0.04 ng/mL). Screening for HIV was negative. Urinalysis showed trace blood by dipstick, but no glucose, protein, dysmorphic red blood cells, or casts. Two sets of peripheral blood cultures were drawn. Two sets of blood cultures from his previous ED visits were negative (drawn 6 and 14 days prior).

These laboratory values are nonspecific, and the differential remains unchanged, with top concern for IE, then lung abscess. Ideally, 3 sets of cultures drawn greater than 12 hours apart should be obtained because the likelihood of pathogen detection rises with the volume of blood tested. Thrombocytopenia and microscopic hematuria suggest microangiopathic hemolytic anemia, and a peripheral blood smear should be examined for schistocytes. Glomerulonephritis from immune complex deposition can occur in IE, but is unlikely with a normal serum creatinine and lack of proteinuria, dysmorphic red blood cells, or casts. The elevated BNP suggests cardiac strain due to a regurgitant valve. ESR and CRP are rarely helpful in this situation, and perhaps previous treatment with azithromycin and steroids prevented significant elevation.

Due to concern for IE, blood cultures were repeated, and IV vancomycin, IV ceftriaxone, and IV gentamicin were initiated. Azithromycin and prednisone were discontinued. His respiratory status continued to improve with IV furosemide, albuterol, ipratropium, and supportive care.

TTE inadequately visualizes the mitral valve, but is useful for tricuspid valve assessment because the right ventricle is closer to the chest wall. Transesophageal echocardiography (TEE) is indicated for a more detailed assessment of the left heart valves for vegetations and perivalvar abscesses. The new regurgitant murmurs satisfy a major criterion of the modified Duke criteria, and valvar vegetations suggests IE. He does not yet fulfill the other major modified Duke criterion for IE, nor does he satisfy enough minor criteria because there are no diagnostic vascular, microbiologic, or immunologic phenomena. However, no diagnostic rubric is perfect, and these results should not supersede clinical judgment. Despite the absence of positive cultures, the concern for bacterial IE remains high. The absence of embolic phenomena fits best with subacute rather than acute IE. Three negative blood cultures to date suggest a fastidious organism is responsible, although oral flora remain on the differential.

There is rarely a need to “hold” blood cultures for prolonged periods because modern instruments typically yield positive results within 7 days for most bacteria, including the HACEK group. Blood culture-negative endocarditis (BCNE) is considered when 3 sets of cultures are negative for at least 5 days. In this situation, one should consider other microorganisms based on the patient’s exposure history. Only certain species with complex growth requirements, such as Brucella and Bartonella, require prolonged holds. Revisiting his exposure history would be helpful in deciding whether serologic testing warranted. If he recalls exposure to parturient animals, then Coxiella is worth pursuing; if he has been bitten by lice, then B. quintana rises as a possibility; if the scratches on his limbs are from recent cat scratches, then B. henselae becomes more likely. Both C. burnetti and Bartonella endocarditis might be partially treated by his courses of azithromycin, confounding the picture.

If the infectious work-up is ultimately negative, one could then consider other etiologies of endocarditis, such as nonbacterial thrombotic endocarditis, which is seen in the context of malignancy and systemic lupus erythematosus (Libman-Sacks endocarditis). Other mimickers of IE include myxomatous valve degeneration, ruptured mitral chordae, and eosinophilic heart disease (Löffler’s endocarditis).

A transesophageal echocardiogram confirmed the presence of small echodensities on the aortic valve’s right and left coronary cusps, consistent with vegetations. The vegetation on the anterior leaflet of the mitral valve from the TTE also showed an aneurysm with a small perforation (Figure 2).

The combination of aortic regurgitation and the mitral valve aneurysm supports IE, because the aortic regurgitant jet directly strikes the anterior mitral valve leaflet, seeding the valve with infection from the aortic cusps. A positive serum PCR is diagnostic, but if it had been negative or unavailable, the serology would remain very helpful. In this context, the elevated IgG titer implicates B. henselae, the agent responsible for cat scratch disease (CSD). Out of context, these titers would not be diagnostic, because anti-Bartonella IgG may be increased due to a prior subclinical episode of CSD. Anti-Bartonella IgM is an unreliable indicator of recent infection because it may wane within weeks, and this IgG titer is higher than what is observed with most remote infections.

Revisiting previous cat exposure is warranted. He lost his cat to an illness 3 years prior, however it would be appropriate to inquire about other animals, such as a stray kitten with fleas, which his skin scratches suggest. Up to 50% of all cats in flea endemic regions harbor Bartonella and are asymptomatic. Rarely, dogs can serve as reservoirs of this organism, with a presumed transmission route via flea, louse, or tick. Regardless of the route of infection, treatment should be focused on B. henselae IE.

Azithromycin can treat CSD, and its use for his presumed COPD exacerbation may have temporized his infection. However, azithromycin monotherapy is not recommended for B. henselae IE. Treatment is usually with 2 antibiotics, including an aminoglycoside (gentamicin) for the first 2 weeks, combined with either a tetracycline, a macrolide, or a beta-lactam for a minimum of 4-6 weeks. Oral rifampin can be considered if gentamicin is not tolerated. After completing IV treatment, an additional 6 months of oral doxycycline or azithromycin should be considered, especially for those who have not undergone valve surgery.

His symptoms are compatible with subacute IE, which is typically more difficult to diagnose than acute IE due to its insidious onset. He meets criteria for blood culture negative IE based on 3 sets of negative blood cultures for greater than 5 days and major criteria for IE. The pathologic changes are consistent with B. henselae infection.

The incidence of IE in the United States is 40,000 cases per year¹ with an in-hospital mortality of 15%-20% and a 1-year mortality of up to 40%.^2,3 Five to 20% of patients with IE never develop positive blood cultures⁴ due to receipt of antibiotics prior to culture, inadequate microbiologic testing, or infection caused by noncultivable bacteria (eg, Tropheryma whipplei), fastidious extracellular bacteria (eg, HACEK group and nutritionally variant streptococci), or by intracellular pathogens with complex nutrient requirements (eg, Bartonella, Chlamydia, Brucella, or Coxiella). Previous administration of antibiotics reduces the likelihood of isolating an organism by 35%-40%.⁵ Patients meeting criteria for BCNE should prompt consideration of serologic testing. The most prevalent pathogens vary globally, and incidence data in the US is scarce. Worldwide, the majority of BCNE cases are caused by Coxiella, Bartonella, and Brucella species.^6,7

When clinical suspicion for IE remains high despite negative cultures, detailed history can uncover clues and guide additional testing. For example, contact with contaminated milk products or farm animals are associated with Brucella, Coxiella, and Erysipelothrix species IE.^7,8 Bartonella species are zoonotic gram-negative bacilli with a tropism for endothelial cells and are transmitted by arthropod vectors (ie, fleas, lice, ticks, and sandflies), cat scratches, or cat bites. Bartonella may account for 3%-4% of all cases of IE, most of which are due to B. henselae and B. quintana.^{7, 9} Underlying heart valve disease, alcoholism, cirrhosis, and homelessness are associated with B. henselae endocarditis.¹⁰

Diagnostic criteria are lacking for B. henselae IE, and the modified Duke criteria is of limited utility for diagnosing Bartonella IE because blood cultures are often negative and echocardiographic evidence of vegetation is not always apparent. Serology plays a critical role in the diagnosis of Bartonella infections. The addition of positive serology, Western blot or PCR for B. henselae and B. quintana as a major criterion in the modified Duke criteria for IE has been proposed but has not yet been formally accepted.⁹ For B. henselae IE, an IgG titer of ≥1:800 has been recommended as a cutoff for subacute IE because it combines a high specificity and positive predictive value along with reasonable sensitivity and negative predictive value in this situation.⁹ The humoral immune response rises over time, and thus acute IE due to Bartonella may not generate a substantial IgG titer. Interestingly, because of the indolent nature of this pathogen, most cases of IE present once IgG titers have begun to rise. Serum PCR testing has shown a sensitivity and specificity of 58% and 100%, respectively.¹¹ Isolation by blood culture requires specific growth media and prolonged incubation, with a sensitivity as low as 20% and 30% for blood and tissue, respectively.¹⁰ The microbiology laboratory should be notified of suspected Bartonella to intensify efforts to cultivate this organism. If infection with Coxiella or Brucella is suspected, the lab should also be informed, both to increase diagnostic yield and to trigger enhanced biosafety precautions when handling the specimens. Despite attempts to optimize the yield, up to 75% of Bartonella IE may remain culture negative,^12,13 making it difficult to meet the current major modified Duke criterion of positive blood cultures. H&E staining of valve tissue infected with Bartonella commonly reveals increased inflammation, fibrosis, and calcified granulomas relative to endocarditis from other causes.¹⁴ The Warthin-Starry silver stain can identify small, darkly staining bacteria in more than 75% of Bartonella endocarditis; however, this stain is not specific for Bartonella species.⁹

This case highlights the challenge of diagnosing subacute IE because this patient received antibiotics and steroids prior to presentation, clouding the clinical picture. Although he did not exhibit textbook signs of endocarditis, his symptoms (new onset heart failure and new regurgitant murmurs) prioritized the diagnosis. The combination of elevated serum titers, positive PCR, valve granulomas and abscesses on TEE, and pathology findings led the discussant to the correct diagnosis. Scratching beneath the surface revealed his penchant for cats, but this was only considered a key epidemiological feature later in his clinical course.

• Subacute IE typically presents with indolent constitutional symptoms over a course of weeks to months, whereas acute IE causes a rapid onset of fevers, rigors, and is more likely to exhibit embolic phenomena.
• Epidemiologic features specific to Bartonella species include alcoholism, cirrhosis, dog or cat exposure, homelessness, and body lice, and should be considered in suspected cases of BCNE.
• If suspicion for endocarditis remains high and animal exposure is elicited, then serologic and PCR testing for fastidious organisms should be strongly considered. The most common causes of BCNE include Coxiella, Bartonella, and Brucella species.
• The modified Duke criteria do not incorporate Bartonella within the diagnostic schema. Presentation is usually late and often requires valve replacement.

Acknowledgments

The authors thank Dr. Michael Pfeiffer from the Pennsylvania State Hershey Heart and Vascular Institute for providing his expertise in diagnostic echocardiography.

Disclosure

There are no conflicts of interest or financial disclosures to report.

A 62-year-old man with severe chronic obstructive pulmonary disease (COPD; forced expiratory volume during the first second [FEV1] 40% predicted) and type 2 diabetes mellitus presented to a Veterans Affairs emergency department (ED) with a steadily worsening cough of 4-months’ duration. He also reported subjective fevers, sputum production, shortness of breath, and unintentional 20-pound weight loss. He denied chills, chest pain, nausea, or vomiting.

Cough is classified as acute, subacute, or chronic based on duration of less than 3 weeks, between 3-8 weeks, and greater than 8 weeks, respectively. Common causes of chronic cough include bronchitis, acid reflux, cough-variant asthma, and a side effect of angiotensin converting enzyme inhibitors. Unintentional weight loss suggests a serious disorder, including indolent infection, end-stage COPD, malignancy, and autoimmune causes. Among patients with chronic bronchitis, the microbiology of sputum is often mixed with commensal respiratory flora, including Streptococcus pneumoniae and Haemophilus species. When these organisms are not recovered in sputa, or when patients fail to respond to empiric treatment, the differential diagnosis should be broadened to include pulmonary tuberculosis, nontuberculous mycobacterial infection, lung abscess, pulmonary nocardiosis, or pertussis.

An exposure and social history can focus the differential. For example, coccidioidomycosis or histoplasmosis may present indolently, but have distinct geographic distributions. Bird fanciers may acquire hypersensitivity pneumonitis, psittacosis, or cryptococcosis. Risk factors including smoking history, corticosteroid use, uncontrolled diabetes, and ill contacts should be assessed.

He was discharged from the ED twice in the last 2 weeks after presenting with similar symptoms. On each occasion, he was treated for presumed COPD exacerbations with nebulized albuterol and ipratropium, methylprednisolone followed by oral prednisone, and azithromycin, which did not lead to improvement. Over the last 3 days, he developed lower extremity edema, orthopnea, and dyspnea at rest. He reported worsening fatigue, night sweats, and anorexia. He denied any sick contacts.

Two diagnostic issues have emerged. His edema, orthopnea, and dyspnea at rest suggest a new cause of hypervolemia, perhaps caused by sodium retention from corticosteroids, pulmonary edema from valvular or myocardial disease, or renal failure. More concerning is that he has been treated with azithromycin twice recently but still has night sweats, fatigue, and anorexia. The presence of weight loss despite extracellular volume accumulation suggests an indolent systemic illness. Infection with macrolide-resistant organisms, such as nocardia, mycobacteria, or endemic mycoses, remains high on the differential diagnosis.

His past medical history included hypertension, untreated chronic hepatitis C, tobacco dependence, alcohol use disorder, and extraction of 8 decayed teeth 2 months earlier. He served in a noncombat role during the Vietnam War. He consumed 12 beers weekly with a remote history of alcoholism which required rehabilitation, reported a 50 pack-year smoking history, and denied intravenous (IV) drug use. He lived with an appropriately vaccinated dog and denied recent insect or animal exposures. He had a cat that passed away from an unknown illness 3 years prior. He was in a monogamous relationship with his girlfriend of 35 years. His father had coronary disease. His medications included glyburide, hydrochlorothiazide, lisinopril, theophylline, and meloxicam. Chronic cough, weight loss, diabetes, alcoholism, and history of dental disease raise concern for lung abscess. Oral microbiota such as Streptococcus viridans and Actinomycetes are usually harmless, but when aspirated repeatedly, such as during alcohol intoxication, may evolve into a lung abscess via bronchogenic spread. The combination of unintentional weight loss and smoking history raises concern for lung malignancy. Small cell lung cancer can present with paraneoplastic Cushing’s syndrome and could explain the patient’s volume overload. Finally, human immunodeficiency virus (HIV) serostatus should be determined in all adult patients.

His temperature was 37 °C, blood pressure 161/69 mm Hg, pulse 104 beats per minute, respiratory rate 20 breaths per minute, and oxygen saturation was 95% on room air. On examination, he was an unkempt, ill-appearing man. He had poor dentition, but no oral ulcers or petechiae. Pulmonary exam revealed diffuse rhonchi and scattered wheezes. He developed dyspnea after speaking 2 sentences. Cardiovascular exam showed regular tachycardia, normal S1 and S2 heart sounds, and both an S3 and S4 gallop. A grade III/VI holosystolic murmur at the left lower sternal border with apical radiation, and an early, grade III/IV diastolic murmur at the right upper sternal border were present. Neck exam showed jugular venous distention (JVD) 8 cm above the right clavicle. Lower extremities showed symmetric 3+ pitting edema to the knees. His abdomen was soft, nondistended, and without hepatosplenomegaly. There was no lymphadenopathy. Skin exam showed small, healed excoriations on his anterior shins, forearms, and knuckles. There were no petechiae, Janeway lesions, or Osler’s nodes.

These exam findings change the differential substantially. New regurgitant murmurs strongly suggest infective endocarditis (IE). A diastolic murmur is never normal and suggests aortic regurgitation. The holosystolic murmur with apical radiation suggests mitral regurgitation. Cutaneous stigmata should always be sought, but are found in fewer than half of cases of subacute IE, and their absence does not rule out this diagnosis. Disheveled hygiene and excoriations suggest a skin source of infection, and poor dentition is concerning for an oral source. For the moment, the source does not matter. His clinical condition is serious: tachycardia, JVD, edema, and two-sentence dyspnea indicate congestive heart failure. Even before labs and imaging return, inpatient admission is warranted.

Serum sodium concentration was 140 mEq/L, potassium 3.7 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, blood urea nitrogen (BUN) 26 mg/dL, creatinine 0.8 mg/dL, glucose 120 mg/dL, and calcium 9.0 mg/dL. The white blood cell count was 7100/µL, hemoglobin 11.8 g/dL, and platelet count 101 K/µL. Brain natriuretic peptide (BNP) was 785 pg/mL (reference range 0-100 pg/mL), aspartate aminotransferase 77 U/L, alanine aminotransferase 57 U/L, alkaline phosphatase 125 U/L, total bilirubin 0.8 mg/dL, total protein 7.7 g/dL, and albumin 3.7 g/dL. Erythrocyte sedimentation (ESR) rate was 38 mm/hour (reference range 0-25 mm/hour) and C-reactive protein (CRP) 0.62 mg/dL (reference range <1.0 mg/dL). Cardiac troponins were 0.03 ng/mL (reference range <0.04 ng/mL). Screening for HIV was negative. Urinalysis showed trace blood by dipstick, but no glucose, protein, dysmorphic red blood cells, or casts. Two sets of peripheral blood cultures were drawn. Two sets of blood cultures from his previous ED visits were negative (drawn 6 and 14 days prior).

These laboratory values are nonspecific, and the differential remains unchanged, with top concern for IE, then lung abscess. Ideally, 3 sets of cultures drawn greater than 12 hours apart should be obtained because the likelihood of pathogen detection rises with the volume of blood tested. Thrombocytopenia and microscopic hematuria suggest microangiopathic hemolytic anemia, and a peripheral blood smear should be examined for schistocytes. Glomerulonephritis from immune complex deposition can occur in IE, but is unlikely with a normal serum creatinine and lack of proteinuria, dysmorphic red blood cells, or casts. The elevated BNP suggests cardiac strain due to a regurgitant valve. ESR and CRP are rarely helpful in this situation, and perhaps previous treatment with azithromycin and steroids prevented significant elevation.

Due to concern for IE, blood cultures were repeated, and IV vancomycin, IV ceftriaxone, and IV gentamicin were initiated. Azithromycin and prednisone were discontinued. His respiratory status continued to improve with IV furosemide, albuterol, ipratropium, and supportive care.

TTE inadequately visualizes the mitral valve, but is useful for tricuspid valve assessment because the right ventricle is closer to the chest wall. Transesophageal echocardiography (TEE) is indicated for a more detailed assessment of the left heart valves for vegetations and perivalvar abscesses. The new regurgitant murmurs satisfy a major criterion of the modified Duke criteria, and valvar vegetations suggests IE. He does not yet fulfill the other major modified Duke criterion for IE, nor does he satisfy enough minor criteria because there are no diagnostic vascular, microbiologic, or immunologic phenomena. However, no diagnostic rubric is perfect, and these results should not supersede clinical judgment. Despite the absence of positive cultures, the concern for bacterial IE remains high. The absence of embolic phenomena fits best with subacute rather than acute IE. Three negative blood cultures to date suggest a fastidious organism is responsible, although oral flora remain on the differential.

There is rarely a need to “hold” blood cultures for prolonged periods because modern instruments typically yield positive results within 7 days for most bacteria, including the HACEK group. Blood culture-negative endocarditis (BCNE) is considered when 3 sets of cultures are negative for at least 5 days. In this situation, one should consider other microorganisms based on the patient’s exposure history. Only certain species with complex growth requirements, such as Brucella and Bartonella, require prolonged holds. Revisiting his exposure history would be helpful in deciding whether serologic testing warranted. If he recalls exposure to parturient animals, then Coxiella is worth pursuing; if he has been bitten by lice, then B. quintana rises as a possibility; if the scratches on his limbs are from recent cat scratches, then B. henselae becomes more likely. Both C. burnetti and Bartonella endocarditis might be partially treated by his courses of azithromycin, confounding the picture.

If the infectious work-up is ultimately negative, one could then consider other etiologies of endocarditis, such as nonbacterial thrombotic endocarditis, which is seen in the context of malignancy and systemic lupus erythematosus (Libman-Sacks endocarditis). Other mimickers of IE include myxomatous valve degeneration, ruptured mitral chordae, and eosinophilic heart disease (Löffler’s endocarditis).

A transesophageal echocardiogram confirmed the presence of small echodensities on the aortic valve’s right and left coronary cusps, consistent with vegetations. The vegetation on the anterior leaflet of the mitral valve from the TTE also showed an aneurysm with a small perforation (Figure 2).

The combination of aortic regurgitation and the mitral valve aneurysm supports IE, because the aortic regurgitant jet directly strikes the anterior mitral valve leaflet, seeding the valve with infection from the aortic cusps. A positive serum PCR is diagnostic, but if it had been negative or unavailable, the serology would remain very helpful. In this context, the elevated IgG titer implicates B. henselae, the agent responsible for cat scratch disease (CSD). Out of context, these titers would not be diagnostic, because anti-Bartonella IgG may be increased due to a prior subclinical episode of CSD. Anti-Bartonella IgM is an unreliable indicator of recent infection because it may wane within weeks, and this IgG titer is higher than what is observed with most remote infections.

Revisiting previous cat exposure is warranted. He lost his cat to an illness 3 years prior, however it would be appropriate to inquire about other animals, such as a stray kitten with fleas, which his skin scratches suggest. Up to 50% of all cats in flea endemic regions harbor Bartonella and are asymptomatic. Rarely, dogs can serve as reservoirs of this organism, with a presumed transmission route via flea, louse, or tick. Regardless of the route of infection, treatment should be focused on B. henselae IE.

Azithromycin can treat CSD, and its use for his presumed COPD exacerbation may have temporized his infection. However, azithromycin monotherapy is not recommended for B. henselae IE. Treatment is usually with 2 antibiotics, including an aminoglycoside (gentamicin) for the first 2 weeks, combined with either a tetracycline, a macrolide, or a beta-lactam for a minimum of 4-6 weeks. Oral rifampin can be considered if gentamicin is not tolerated. After completing IV treatment, an additional 6 months of oral doxycycline or azithromycin should be considered, especially for those who have not undergone valve surgery.

His symptoms are compatible with subacute IE, which is typically more difficult to diagnose than acute IE due to its insidious onset. He meets criteria for blood culture negative IE based on 3 sets of negative blood cultures for greater than 5 days and major criteria for IE. The pathologic changes are consistent with B. henselae infection.

The incidence of IE in the United States is 40,000 cases per year¹ with an in-hospital mortality of 15%-20% and a 1-year mortality of up to 40%.^2,3 Five to 20% of patients with IE never develop positive blood cultures⁴ due to receipt of antibiotics prior to culture, inadequate microbiologic testing, or infection caused by noncultivable bacteria (eg, Tropheryma whipplei), fastidious extracellular bacteria (eg, HACEK group and nutritionally variant streptococci), or by intracellular pathogens with complex nutrient requirements (eg, Bartonella, Chlamydia, Brucella, or Coxiella). Previous administration of antibiotics reduces the likelihood of isolating an organism by 35%-40%.⁵ Patients meeting criteria for BCNE should prompt consideration of serologic testing. The most prevalent pathogens vary globally, and incidence data in the US is scarce. Worldwide, the majority of BCNE cases are caused by Coxiella, Bartonella, and Brucella species.^6,7

When clinical suspicion for IE remains high despite negative cultures, detailed history can uncover clues and guide additional testing. For example, contact with contaminated milk products or farm animals are associated with Brucella, Coxiella, and Erysipelothrix species IE.^7,8 Bartonella species are zoonotic gram-negative bacilli with a tropism for endothelial cells and are transmitted by arthropod vectors (ie, fleas, lice, ticks, and sandflies), cat scratches, or cat bites. Bartonella may account for 3%-4% of all cases of IE, most of which are due to B. henselae and B. quintana.^{7, 9} Underlying heart valve disease, alcoholism, cirrhosis, and homelessness are associated with B. henselae endocarditis.¹⁰

Diagnostic criteria are lacking for B. henselae IE, and the modified Duke criteria is of limited utility for diagnosing Bartonella IE because blood cultures are often negative and echocardiographic evidence of vegetation is not always apparent. Serology plays a critical role in the diagnosis of Bartonella infections. The addition of positive serology, Western blot or PCR for B. henselae and B. quintana as a major criterion in the modified Duke criteria for IE has been proposed but has not yet been formally accepted.⁹ For B. henselae IE, an IgG titer of ≥1:800 has been recommended as a cutoff for subacute IE because it combines a high specificity and positive predictive value along with reasonable sensitivity and negative predictive value in this situation.⁹ The humoral immune response rises over time, and thus acute IE due to Bartonella may not generate a substantial IgG titer. Interestingly, because of the indolent nature of this pathogen, most cases of IE present once IgG titers have begun to rise. Serum PCR testing has shown a sensitivity and specificity of 58% and 100%, respectively.¹¹ Isolation by blood culture requires specific growth media and prolonged incubation, with a sensitivity as low as 20% and 30% for blood and tissue, respectively.¹⁰ The microbiology laboratory should be notified of suspected Bartonella to intensify efforts to cultivate this organism. If infection with Coxiella or Brucella is suspected, the lab should also be informed, both to increase diagnostic yield and to trigger enhanced biosafety precautions when handling the specimens. Despite attempts to optimize the yield, up to 75% of Bartonella IE may remain culture negative,^12,13 making it difficult to meet the current major modified Duke criterion of positive blood cultures. H&E staining of valve tissue infected with Bartonella commonly reveals increased inflammation, fibrosis, and calcified granulomas relative to endocarditis from other causes.¹⁴ The Warthin-Starry silver stain can identify small, darkly staining bacteria in more than 75% of Bartonella endocarditis; however, this stain is not specific for Bartonella species.⁹

This case highlights the challenge of diagnosing subacute IE because this patient received antibiotics and steroids prior to presentation, clouding the clinical picture. Although he did not exhibit textbook signs of endocarditis, his symptoms (new onset heart failure and new regurgitant murmurs) prioritized the diagnosis. The combination of elevated serum titers, positive PCR, valve granulomas and abscesses on TEE, and pathology findings led the discussant to the correct diagnosis. Scratching beneath the surface revealed his penchant for cats, but this was only considered a key epidemiological feature later in his clinical course.

• Subacute IE typically presents with indolent constitutional symptoms over a course of weeks to months, whereas acute IE causes a rapid onset of fevers, rigors, and is more likely to exhibit embolic phenomena.
• Epidemiologic features specific to Bartonella species include alcoholism, cirrhosis, dog or cat exposure, homelessness, and body lice, and should be considered in suspected cases of BCNE.
• If suspicion for endocarditis remains high and animal exposure is elicited, then serologic and PCR testing for fastidious organisms should be strongly considered. The most common causes of BCNE include Coxiella, Bartonella, and Brucella species.
• The modified Duke criteria do not incorporate Bartonella within the diagnostic schema. Presentation is usually late and often requires valve replacement.

Acknowledgments

The authors thank Dr. Michael Pfeiffer from the Pennsylvania State Hershey Heart and Vascular Institute for providing his expertise in diagnostic echocardiography.

Disclosure

There are no conflicts of interest or financial disclosures to report.

A 62-year-old man with severe chronic obstructive pulmonary disease (COPD; forced expiratory volume during the first second [FEV1] 40% predicted) and type 2 diabetes mellitus presented to a Veterans Affairs emergency department (ED) with a steadily worsening cough of 4-months’ duration. He also reported subjective fevers, sputum production, shortness of breath, and unintentional 20-pound weight loss. He denied chills, chest pain, nausea, or vomiting.

Cough is classified as acute, subacute, or chronic based on duration of less than 3 weeks, between 3-8 weeks, and greater than 8 weeks, respectively. Common causes of chronic cough include bronchitis, acid reflux, cough-variant asthma, and a side effect of angiotensin converting enzyme inhibitors. Unintentional weight loss suggests a serious disorder, including indolent infection, end-stage COPD, malignancy, and autoimmune causes. Among patients with chronic bronchitis, the microbiology of sputum is often mixed with commensal respiratory flora, including Streptococcus pneumoniae and Haemophilus species. When these organisms are not recovered in sputa, or when patients fail to respond to empiric treatment, the differential diagnosis should be broadened to include pulmonary tuberculosis, nontuberculous mycobacterial infection, lung abscess, pulmonary nocardiosis, or pertussis.

An exposure and social history can focus the differential. For example, coccidioidomycosis or histoplasmosis may present indolently, but have distinct geographic distributions. Bird fanciers may acquire hypersensitivity pneumonitis, psittacosis, or cryptococcosis. Risk factors including smoking history, corticosteroid use, uncontrolled diabetes, and ill contacts should be assessed.

He was discharged from the ED twice in the last 2 weeks after presenting with similar symptoms. On each occasion, he was treated for presumed COPD exacerbations with nebulized albuterol and ipratropium, methylprednisolone followed by oral prednisone, and azithromycin, which did not lead to improvement. Over the last 3 days, he developed lower extremity edema, orthopnea, and dyspnea at rest. He reported worsening fatigue, night sweats, and anorexia. He denied any sick contacts.

Two diagnostic issues have emerged. His edema, orthopnea, and dyspnea at rest suggest a new cause of hypervolemia, perhaps caused by sodium retention from corticosteroids, pulmonary edema from valvular or myocardial disease, or renal failure. More concerning is that he has been treated with azithromycin twice recently but still has night sweats, fatigue, and anorexia. The presence of weight loss despite extracellular volume accumulation suggests an indolent systemic illness. Infection with macrolide-resistant organisms, such as nocardia, mycobacteria, or endemic mycoses, remains high on the differential diagnosis.

His past medical history included hypertension, untreated chronic hepatitis C, tobacco dependence, alcohol use disorder, and extraction of 8 decayed teeth 2 months earlier. He served in a noncombat role during the Vietnam War. He consumed 12 beers weekly with a remote history of alcoholism which required rehabilitation, reported a 50 pack-year smoking history, and denied intravenous (IV) drug use. He lived with an appropriately vaccinated dog and denied recent insect or animal exposures. He had a cat that passed away from an unknown illness 3 years prior. He was in a monogamous relationship with his girlfriend of 35 years. His father had coronary disease. His medications included glyburide, hydrochlorothiazide, lisinopril, theophylline, and meloxicam. Chronic cough, weight loss, diabetes, alcoholism, and history of dental disease raise concern for lung abscess. Oral microbiota such as Streptococcus viridans and Actinomycetes are usually harmless, but when aspirated repeatedly, such as during alcohol intoxication, may evolve into a lung abscess via bronchogenic spread. The combination of unintentional weight loss and smoking history raises concern for lung malignancy. Small cell lung cancer can present with paraneoplastic Cushing’s syndrome and could explain the patient’s volume overload. Finally, human immunodeficiency virus (HIV) serostatus should be determined in all adult patients.

His temperature was 37 °C, blood pressure 161/69 mm Hg, pulse 104 beats per minute, respiratory rate 20 breaths per minute, and oxygen saturation was 95% on room air. On examination, he was an unkempt, ill-appearing man. He had poor dentition, but no oral ulcers or petechiae. Pulmonary exam revealed diffuse rhonchi and scattered wheezes. He developed dyspnea after speaking 2 sentences. Cardiovascular exam showed regular tachycardia, normal S1 and S2 heart sounds, and both an S3 and S4 gallop. A grade III/VI holosystolic murmur at the left lower sternal border with apical radiation, and an early, grade III/IV diastolic murmur at the right upper sternal border were present. Neck exam showed jugular venous distention (JVD) 8 cm above the right clavicle. Lower extremities showed symmetric 3+ pitting edema to the knees. His abdomen was soft, nondistended, and without hepatosplenomegaly. There was no lymphadenopathy. Skin exam showed small, healed excoriations on his anterior shins, forearms, and knuckles. There were no petechiae, Janeway lesions, or Osler’s nodes.

These exam findings change the differential substantially. New regurgitant murmurs strongly suggest infective endocarditis (IE). A diastolic murmur is never normal and suggests aortic regurgitation. The holosystolic murmur with apical radiation suggests mitral regurgitation. Cutaneous stigmata should always be sought, but are found in fewer than half of cases of subacute IE, and their absence does not rule out this diagnosis. Disheveled hygiene and excoriations suggest a skin source of infection, and poor dentition is concerning for an oral source. For the moment, the source does not matter. His clinical condition is serious: tachycardia, JVD, edema, and two-sentence dyspnea indicate congestive heart failure. Even before labs and imaging return, inpatient admission is warranted.

Serum sodium concentration was 140 mEq/L, potassium 3.7 mEq/L, chloride 103 mEq/L, bicarbonate 30 mEq/L, blood urea nitrogen (BUN) 26 mg/dL, creatinine 0.8 mg/dL, glucose 120 mg/dL, and calcium 9.0 mg/dL. The white blood cell count was 7100/µL, hemoglobin 11.8 g/dL, and platelet count 101 K/µL. Brain natriuretic peptide (BNP) was 785 pg/mL (reference range 0-100 pg/mL), aspartate aminotransferase 77 U/L, alanine aminotransferase 57 U/L, alkaline phosphatase 125 U/L, total bilirubin 0.8 mg/dL, total protein 7.7 g/dL, and albumin 3.7 g/dL. Erythrocyte sedimentation (ESR) rate was 38 mm/hour (reference range 0-25 mm/hour) and C-reactive protein (CRP) 0.62 mg/dL (reference range <1.0 mg/dL). Cardiac troponins were 0.03 ng/mL (reference range <0.04 ng/mL). Screening for HIV was negative. Urinalysis showed trace blood by dipstick, but no glucose, protein, dysmorphic red blood cells, or casts. Two sets of peripheral blood cultures were drawn. Two sets of blood cultures from his previous ED visits were negative (drawn 6 and 14 days prior).

These laboratory values are nonspecific, and the differential remains unchanged, with top concern for IE, then lung abscess. Ideally, 3 sets of cultures drawn greater than 12 hours apart should be obtained because the likelihood of pathogen detection rises with the volume of blood tested. Thrombocytopenia and microscopic hematuria suggest microangiopathic hemolytic anemia, and a peripheral blood smear should be examined for schistocytes. Glomerulonephritis from immune complex deposition can occur in IE, but is unlikely with a normal serum creatinine and lack of proteinuria, dysmorphic red blood cells, or casts. The elevated BNP suggests cardiac strain due to a regurgitant valve. ESR and CRP are rarely helpful in this situation, and perhaps previous treatment with azithromycin and steroids prevented significant elevation.

Due to concern for IE, blood cultures were repeated, and IV vancomycin, IV ceftriaxone, and IV gentamicin were initiated. Azithromycin and prednisone were discontinued. His respiratory status continued to improve with IV furosemide, albuterol, ipratropium, and supportive care.

TTE inadequately visualizes the mitral valve, but is useful for tricuspid valve assessment because the right ventricle is closer to the chest wall. Transesophageal echocardiography (TEE) is indicated for a more detailed assessment of the left heart valves for vegetations and perivalvar abscesses. The new regurgitant murmurs satisfy a major criterion of the modified Duke criteria, and valvar vegetations suggests IE. He does not yet fulfill the other major modified Duke criterion for IE, nor does he satisfy enough minor criteria because there are no diagnostic vascular, microbiologic, or immunologic phenomena. However, no diagnostic rubric is perfect, and these results should not supersede clinical judgment. Despite the absence of positive cultures, the concern for bacterial IE remains high. The absence of embolic phenomena fits best with subacute rather than acute IE. Three negative blood cultures to date suggest a fastidious organism is responsible, although oral flora remain on the differential.

There is rarely a need to “hold” blood cultures for prolonged periods because modern instruments typically yield positive results within 7 days for most bacteria, including the HACEK group. Blood culture-negative endocarditis (BCNE) is considered when 3 sets of cultures are negative for at least 5 days. In this situation, one should consider other microorganisms based on the patient’s exposure history. Only certain species with complex growth requirements, such as Brucella and Bartonella, require prolonged holds. Revisiting his exposure history would be helpful in deciding whether serologic testing warranted. If he recalls exposure to parturient animals, then Coxiella is worth pursuing; if he has been bitten by lice, then B. quintana rises as a possibility; if the scratches on his limbs are from recent cat scratches, then B. henselae becomes more likely. Both C. burnetti and Bartonella endocarditis might be partially treated by his courses of azithromycin, confounding the picture.

If the infectious work-up is ultimately negative, one could then consider other etiologies of endocarditis, such as nonbacterial thrombotic endocarditis, which is seen in the context of malignancy and systemic lupus erythematosus (Libman-Sacks endocarditis). Other mimickers of IE include myxomatous valve degeneration, ruptured mitral chordae, and eosinophilic heart disease (Löffler’s endocarditis).

A transesophageal echocardiogram confirmed the presence of small echodensities on the aortic valve’s right and left coronary cusps, consistent with vegetations. The vegetation on the anterior leaflet of the mitral valve from the TTE also showed an aneurysm with a small perforation (Figure 2).

The combination of aortic regurgitation and the mitral valve aneurysm supports IE, because the aortic regurgitant jet directly strikes the anterior mitral valve leaflet, seeding the valve with infection from the aortic cusps. A positive serum PCR is diagnostic, but if it had been negative or unavailable, the serology would remain very helpful. In this context, the elevated IgG titer implicates B. henselae, the agent responsible for cat scratch disease (CSD). Out of context, these titers would not be diagnostic, because anti-Bartonella IgG may be increased due to a prior subclinical episode of CSD. Anti-Bartonella IgM is an unreliable indicator of recent infection because it may wane within weeks, and this IgG titer is higher than what is observed with most remote infections.

Revisiting previous cat exposure is warranted. He lost his cat to an illness 3 years prior, however it would be appropriate to inquire about other animals, such as a stray kitten with fleas, which his skin scratches suggest. Up to 50% of all cats in flea endemic regions harbor Bartonella and are asymptomatic. Rarely, dogs can serve as reservoirs of this organism, with a presumed transmission route via flea, louse, or tick. Regardless of the route of infection, treatment should be focused on B. henselae IE.

Azithromycin can treat CSD, and its use for his presumed COPD exacerbation may have temporized his infection. However, azithromycin monotherapy is not recommended for B. henselae IE. Treatment is usually with 2 antibiotics, including an aminoglycoside (gentamicin) for the first 2 weeks, combined with either a tetracycline, a macrolide, or a beta-lactam for a minimum of 4-6 weeks. Oral rifampin can be considered if gentamicin is not tolerated. After completing IV treatment, an additional 6 months of oral doxycycline or azithromycin should be considered, especially for those who have not undergone valve surgery.

His symptoms are compatible with subacute IE, which is typically more difficult to diagnose than acute IE due to its insidious onset. He meets criteria for blood culture negative IE based on 3 sets of negative blood cultures for greater than 5 days and major criteria for IE. The pathologic changes are consistent with B. henselae infection.

The incidence of IE in the United States is 40,000 cases per year¹ with an in-hospital mortality of 15%-20% and a 1-year mortality of up to 40%.^2,3 Five to 20% of patients with IE never develop positive blood cultures⁴ due to receipt of antibiotics prior to culture, inadequate microbiologic testing, or infection caused by noncultivable bacteria (eg, Tropheryma whipplei), fastidious extracellular bacteria (eg, HACEK group and nutritionally variant streptococci), or by intracellular pathogens with complex nutrient requirements (eg, Bartonella, Chlamydia, Brucella, or Coxiella). Previous administration of antibiotics reduces the likelihood of isolating an organism by 35%-40%.⁵ Patients meeting criteria for BCNE should prompt consideration of serologic testing. The most prevalent pathogens vary globally, and incidence data in the US is scarce. Worldwide, the majority of BCNE cases are caused by Coxiella, Bartonella, and Brucella species.^6,7

When clinical suspicion for IE remains high despite negative cultures, detailed history can uncover clues and guide additional testing. For example, contact with contaminated milk products or farm animals are associated with Brucella, Coxiella, and Erysipelothrix species IE.^7,8 Bartonella species are zoonotic gram-negative bacilli with a tropism for endothelial cells and are transmitted by arthropod vectors (ie, fleas, lice, ticks, and sandflies), cat scratches, or cat bites. Bartonella may account for 3%-4% of all cases of IE, most of which are due to B. henselae and B. quintana.^{7, 9} Underlying heart valve disease, alcoholism, cirrhosis, and homelessness are associated with B. henselae endocarditis.¹⁰

Diagnostic criteria are lacking for B. henselae IE, and the modified Duke criteria is of limited utility for diagnosing Bartonella IE because blood cultures are often negative and echocardiographic evidence of vegetation is not always apparent. Serology plays a critical role in the diagnosis of Bartonella infections. The addition of positive serology, Western blot or PCR for B. henselae and B. quintana as a major criterion in the modified Duke criteria for IE has been proposed but has not yet been formally accepted.⁹ For B. henselae IE, an IgG titer of ≥1:800 has been recommended as a cutoff for subacute IE because it combines a high specificity and positive predictive value along with reasonable sensitivity and negative predictive value in this situation.⁹ The humoral immune response rises over time, and thus acute IE due to Bartonella may not generate a substantial IgG titer. Interestingly, because of the indolent nature of this pathogen, most cases of IE present once IgG titers have begun to rise. Serum PCR testing has shown a sensitivity and specificity of 58% and 100%, respectively.¹¹ Isolation by blood culture requires specific growth media and prolonged incubation, with a sensitivity as low as 20% and 30% for blood and tissue, respectively.¹⁰ The microbiology laboratory should be notified of suspected Bartonella to intensify efforts to cultivate this organism. If infection with Coxiella or Brucella is suspected, the lab should also be informed, both to increase diagnostic yield and to trigger enhanced biosafety precautions when handling the specimens. Despite attempts to optimize the yield, up to 75% of Bartonella IE may remain culture negative,^12,13 making it difficult to meet the current major modified Duke criterion of positive blood cultures. H&E staining of valve tissue infected with Bartonella commonly reveals increased inflammation, fibrosis, and calcified granulomas relative to endocarditis from other causes.¹⁴ The Warthin-Starry silver stain can identify small, darkly staining bacteria in more than 75% of Bartonella endocarditis; however, this stain is not specific for Bartonella species.⁹

This case highlights the challenge of diagnosing subacute IE because this patient received antibiotics and steroids prior to presentation, clouding the clinical picture. Although he did not exhibit textbook signs of endocarditis, his symptoms (new onset heart failure and new regurgitant murmurs) prioritized the diagnosis. The combination of elevated serum titers, positive PCR, valve granulomas and abscesses on TEE, and pathology findings led the discussant to the correct diagnosis. Scratching beneath the surface revealed his penchant for cats, but this was only considered a key epidemiological feature later in his clinical course.

• Subacute IE typically presents with indolent constitutional symptoms over a course of weeks to months, whereas acute IE causes a rapid onset of fevers, rigors, and is more likely to exhibit embolic phenomena.
• Epidemiologic features specific to Bartonella species include alcoholism, cirrhosis, dog or cat exposure, homelessness, and body lice, and should be considered in suspected cases of BCNE.
• If suspicion for endocarditis remains high and animal exposure is elicited, then serologic and PCR testing for fastidious organisms should be strongly considered. The most common causes of BCNE include Coxiella, Bartonella, and Brucella species.
• The modified Duke criteria do not incorporate Bartonella within the diagnostic schema. Presentation is usually late and often requires valve replacement.

Acknowledgments

The authors thank Dr. Michael Pfeiffer from the Pennsylvania State Hershey Heart and Vascular Institute for providing his expertise in diagnostic echocardiography.

Disclosure

There are no conflicts of interest or financial disclosures to report.

Answer: C
 

Rationale

The patient has ascending cholangitis. After stabilization and initiation of antibiotics, the next most appropriate step is ERCP. The patient is high risk for postsphincterotomy bleeding as he is on three antithrombotic agents. The most prudent course of action is ERCP with stent placement. ERCP and stent placement is not contraindicated in patients on antithrombotic agents. This will allow for confirmation of the diagnosis as well as therapy for the obstruction. Once the patient has recovered, he can return on an elective basis, off antithrombotic agents, for definitive management of the common bile duct stone. MRCP would allow for a diagnosis; however, it is not therapeutic, and in the setting of cholangitis, management of the obstruction is necessary. Continued medical management neither provides information regarding diagnosis nor treats the obstruction. Percutaneous biliary drain would provide appropriate drainage but, as he is at a high risk for bleeding, ERCP with stent placement is a better therapeutic option in this patient.
 

References

1. Committee, ASGE Standards of Practice, et al. Management of anti-thrombotic agents for endoscopic procedures. Gastrointest Endosc. 2009;70(6):1060-70.

2. Boustiere C., Veitch A., Vanbiervliet G., et al. Endoscopy and antiplatelet agents. Endoscopy. 2011;43(5):445-61.

[email protected]

Answer: C
 

Rationale

The patient has ascending cholangitis. After stabilization and initiation of antibiotics, the next most appropriate step is ERCP. The patient is high risk for postsphincterotomy bleeding as he is on three antithrombotic agents. The most prudent course of action is ERCP with stent placement. ERCP and stent placement is not contraindicated in patients on antithrombotic agents. This will allow for confirmation of the diagnosis as well as therapy for the obstruction. Once the patient has recovered, he can return on an elective basis, off antithrombotic agents, for definitive management of the common bile duct stone. MRCP would allow for a diagnosis; however, it is not therapeutic, and in the setting of cholangitis, management of the obstruction is necessary. Continued medical management neither provides information regarding diagnosis nor treats the obstruction. Percutaneous biliary drain would provide appropriate drainage but, as he is at a high risk for bleeding, ERCP with stent placement is a better therapeutic option in this patient.
 

References

1. Committee, ASGE Standards of Practice, et al. Management of anti-thrombotic agents for endoscopic procedures. Gastrointest Endosc. 2009;70(6):1060-70.

2. Boustiere C., Veitch A., Vanbiervliet G., et al. Endoscopy and antiplatelet agents. Endoscopy. 2011;43(5):445-61.

[email protected]

Answer: C
 

Rationale

The patient has ascending cholangitis. After stabilization and initiation of antibiotics, the next most appropriate step is ERCP. The patient is high risk for postsphincterotomy bleeding as he is on three antithrombotic agents. The most prudent course of action is ERCP with stent placement. ERCP and stent placement is not contraindicated in patients on antithrombotic agents. This will allow for confirmation of the diagnosis as well as therapy for the obstruction. Once the patient has recovered, he can return on an elective basis, off antithrombotic agents, for definitive management of the common bile duct stone. MRCP would allow for a diagnosis; however, it is not therapeutic, and in the setting of cholangitis, management of the obstruction is necessary. Continued medical management neither provides information regarding diagnosis nor treats the obstruction. Percutaneous biliary drain would provide appropriate drainage but, as he is at a high risk for bleeding, ERCP with stent placement is a better therapeutic option in this patient.
 

References

1. Committee, ASGE Standards of Practice, et al. Management of anti-thrombotic agents for endoscopic procedures. Gastrointest Endosc. 2009;70(6):1060-70.

2. Boustiere C., Veitch A., Vanbiervliet G., et al. Endoscopy and antiplatelet agents. Endoscopy. 2011;43(5):445-61.

[email protected]

Answer: B

Rationale

Hypergastrinemia is normally a physiologic response to hypochlorhydria. When hypergastrinemia occurs in the setting of acidic gastric pH, it is considered inappropriate. Gastrinoma is a component of MEN-1 syndrome that results in abnormal gastrin release and acid hypersecretion. Gastric outlet obstruction may lead to stomach distention and persistent stimulation by retained food, causing increased gastrin release and acid secretion. Chronic renal failure leads to a decrease in clearance of gastrin from the circulation, resulting in hypergastrinemia. This increase in circulating gastrin results in stimulation of parietal cells to release acid into the gastric lumen. Therefore, the hypergastrinemia associated with chronic renal failure is inappropriate, given the high serum gastrin level despite low intragastric pH. Retained antrum results when a small portion of antrum is left attached to the duodenal bulb (afferent loop) during a Billroth II surgical procedure. As a result, the G cells from the retained antrum are displaced from the stomach and excluded from the inhibitory effects of gastric acid. The lack of negative feedback leads to persistently high gastrin release and resultant acid production. H. pylori pangastritis results in suppression of acid secretion, leading to a high intragastric pH. Therefore, it represents an appropriate cause for hypergastrinemia.

Reference

1. Murugesan S.V., Varro A., Pritchard D.M. Review article: Strategies to determine whether hypergastrinaemia is due to Zollinger-Ellison syndrome rather than a more common benign cause. Aliment Pharmacol Ther. 2009;29:1055-68.

Answer: B

Rationale

Hypergastrinemia is normally a physiologic response to hypochlorhydria. When hypergastrinemia occurs in the setting of acidic gastric pH, it is considered inappropriate. Gastrinoma is a component of MEN-1 syndrome that results in abnormal gastrin release and acid hypersecretion. Gastric outlet obstruction may lead to stomach distention and persistent stimulation by retained food, causing increased gastrin release and acid secretion. Chronic renal failure leads to a decrease in clearance of gastrin from the circulation, resulting in hypergastrinemia. This increase in circulating gastrin results in stimulation of parietal cells to release acid into the gastric lumen. Therefore, the hypergastrinemia associated with chronic renal failure is inappropriate, given the high serum gastrin level despite low intragastric pH. Retained antrum results when a small portion of antrum is left attached to the duodenal bulb (afferent loop) during a Billroth II surgical procedure. As a result, the G cells from the retained antrum are displaced from the stomach and excluded from the inhibitory effects of gastric acid. The lack of negative feedback leads to persistently high gastrin release and resultant acid production. H. pylori pangastritis results in suppression of acid secretion, leading to a high intragastric pH. Therefore, it represents an appropriate cause for hypergastrinemia.

Reference

1. Murugesan S.V., Varro A., Pritchard D.M. Review article: Strategies to determine whether hypergastrinaemia is due to Zollinger-Ellison syndrome rather than a more common benign cause. Aliment Pharmacol Ther. 2009;29:1055-68.

Answer: B

Rationale

Hypergastrinemia is normally a physiologic response to hypochlorhydria. When hypergastrinemia occurs in the setting of acidic gastric pH, it is considered inappropriate. Gastrinoma is a component of MEN-1 syndrome that results in abnormal gastrin release and acid hypersecretion. Gastric outlet obstruction may lead to stomach distention and persistent stimulation by retained food, causing increased gastrin release and acid secretion. Chronic renal failure leads to a decrease in clearance of gastrin from the circulation, resulting in hypergastrinemia. This increase in circulating gastrin results in stimulation of parietal cells to release acid into the gastric lumen. Therefore, the hypergastrinemia associated with chronic renal failure is inappropriate, given the high serum gastrin level despite low intragastric pH. Retained antrum results when a small portion of antrum is left attached to the duodenal bulb (afferent loop) during a Billroth II surgical procedure. As a result, the G cells from the retained antrum are displaced from the stomach and excluded from the inhibitory effects of gastric acid. The lack of negative feedback leads to persistently high gastrin release and resultant acid production. H. pylori pangastritis results in suppression of acid secretion, leading to a high intragastric pH. Therefore, it represents an appropriate cause for hypergastrinemia.

Reference

1. Murugesan S.V., Varro A., Pritchard D.M. Review article: Strategies to determine whether hypergastrinaemia is due to Zollinger-Ellison syndrome rather than a more common benign cause. Aliment Pharmacol Ther. 2009;29:1055-68.

Neurofibromatosis (NF) is an autosomal dominant genetic neurocutaneous disorder. There are eight subtypes of NF: NF type 1-7 and NF-NOS, or not otherwise specified. Neurofibromatosis type 1 (NF-1), or von Recklinghausen disease, is the most common and is a result of a genetic mutation on chromosome 17 that is involved in producing a protein called neurofibromin. Neurofibromin is a tumor suppressor that suppresses products of ras proto-oncogenes. When it is absent, tumor progression may occur. 

Courtesy Dr. Parteek Singla and Dr. Donna Bilu Martin

Von Recklinghausen NF-1 appears in childhood, usually by age 10. Diagnosis requires the presence of at least 2 of the following 7 criteria:
•Six or more café au lait macules measuring 5 mm in diameter or greater in prepubertal children and measuring greater than 15 mm in postpubertal children.
•Axillary or inguinal freckling (Crowe’s sign).
•Two or more neurofibromas or one plexiform neurofibroma.
•Optic nerve glioma.
•Two or more iris hamartomas (Lisch nodules).
•Sphenoid dysplasia or long-bone abnormalities, such as pseudoarthrosis.
•First degree relative with NF-1.

The diagnosis is usually made via physical examination. Supportive tests include an ophthalmologic exam to detect Lisch nodules and cataracts. A neurological evaluation is essential. Imaging examinations can identify bony abnormalities and tumor growths. Also, genetic testing to identify genetic mutations can be performed.

Dr. Donna Bilu Martin

Neurofibromatosis type 2 results from a genetic mutation located on chromosome 22 that produces a protein called merlin and occurs in adolescence. Acoustic or vestibular neuromas may occur; these interfere with the transmission of sound and maintaining balance. Symptoms include gradual hearing loss, tinnitus, poor balance, and headaches. Radiosurgery and cochlear implants have shown a role for symptomatic treatment in patients with NF-2. 

This case and photo were submitted by Parteek Singla, MD, of the division of dermatology at Washington University and Barnes Jewish Hospital, both in St. Louis, and by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected]. 
 

Neurofibromatosis (NF) is an autosomal dominant genetic neurocutaneous disorder. There are eight subtypes of NF: NF type 1-7 and NF-NOS, or not otherwise specified. Neurofibromatosis type 1 (NF-1), or von Recklinghausen disease, is the most common and is a result of a genetic mutation on chromosome 17 that is involved in producing a protein called neurofibromin. Neurofibromin is a tumor suppressor that suppresses products of ras proto-oncogenes. When it is absent, tumor progression may occur. 

Courtesy Dr. Parteek Singla and Dr. Donna Bilu Martin

Von Recklinghausen NF-1 appears in childhood, usually by age 10. Diagnosis requires the presence of at least 2 of the following 7 criteria:
•Six or more café au lait macules measuring 5 mm in diameter or greater in prepubertal children and measuring greater than 15 mm in postpubertal children.
•Axillary or inguinal freckling (Crowe’s sign).
•Two or more neurofibromas or one plexiform neurofibroma.
•Optic nerve glioma.
•Two or more iris hamartomas (Lisch nodules).
•Sphenoid dysplasia or long-bone abnormalities, such as pseudoarthrosis.
•First degree relative with NF-1.

The diagnosis is usually made via physical examination. Supportive tests include an ophthalmologic exam to detect Lisch nodules and cataracts. A neurological evaluation is essential. Imaging examinations can identify bony abnormalities and tumor growths. Also, genetic testing to identify genetic mutations can be performed.

Dr. Donna Bilu Martin

Neurofibromatosis type 2 results from a genetic mutation located on chromosome 22 that produces a protein called merlin and occurs in adolescence. Acoustic or vestibular neuromas may occur; these interfere with the transmission of sound and maintaining balance. Symptoms include gradual hearing loss, tinnitus, poor balance, and headaches. Radiosurgery and cochlear implants have shown a role for symptomatic treatment in patients with NF-2. 

This case and photo were submitted by Parteek Singla, MD, of the division of dermatology at Washington University and Barnes Jewish Hospital, both in St. Louis, and by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected]. 
 

Neurofibromatosis (NF) is an autosomal dominant genetic neurocutaneous disorder. There are eight subtypes of NF: NF type 1-7 and NF-NOS, or not otherwise specified. Neurofibromatosis type 1 (NF-1), or von Recklinghausen disease, is the most common and is a result of a genetic mutation on chromosome 17 that is involved in producing a protein called neurofibromin. Neurofibromin is a tumor suppressor that suppresses products of ras proto-oncogenes. When it is absent, tumor progression may occur. 

Courtesy Dr. Parteek Singla and Dr. Donna Bilu Martin

Von Recklinghausen NF-1 appears in childhood, usually by age 10. Diagnosis requires the presence of at least 2 of the following 7 criteria:
•Six or more café au lait macules measuring 5 mm in diameter or greater in prepubertal children and measuring greater than 15 mm in postpubertal children.
•Axillary or inguinal freckling (Crowe’s sign).
•Two or more neurofibromas or one plexiform neurofibroma.
•Optic nerve glioma.
•Two or more iris hamartomas (Lisch nodules).
•Sphenoid dysplasia or long-bone abnormalities, such as pseudoarthrosis.
•First degree relative with NF-1.

The diagnosis is usually made via physical examination. Supportive tests include an ophthalmologic exam to detect Lisch nodules and cataracts. A neurological evaluation is essential. Imaging examinations can identify bony abnormalities and tumor growths. Also, genetic testing to identify genetic mutations can be performed.

Dr. Donna Bilu Martin

Neurofibromatosis type 2 results from a genetic mutation located on chromosome 22 that produces a protein called merlin and occurs in adolescence. Acoustic or vestibular neuromas may occur; these interfere with the transmission of sound and maintaining balance. Symptoms include gradual hearing loss, tinnitus, poor balance, and headaches. Radiosurgery and cochlear implants have shown a role for symptomatic treatment in patients with NF-2. 

This case and photo were submitted by Parteek Singla, MD, of the division of dermatology at Washington University and Barnes Jewish Hospital, both in St. Louis, and by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected]. 
 

Increases in hepatitis C–related inpatient stays for baby boomers from 2005 to 2014 far outpaced those of older adults, while younger adults saw their admissions drop over that period, according to the Agency for Healthcare Research and Quality.

For the baby boomers (adults aged 52-72 years), the rate of inpatient stays involving hepatitis C with or without hepatitis B, HIV, or alcoholic liver disease rose from 300.7 per 100,000 population in 2005 to 503.1 per 100,000 in 2014 – an increase of over 67%. For patients aged 73 years and older, that rate went from 104.4 in 2005 to 117.1 in 2014, which translates to a 12% increase, and for patients aged 18-51 years, it dropped 15%, from 182.5 to 155.4, the AHRQ said in a statistical brief.

[email protected]

Increases in hepatitis C–related inpatient stays for baby boomers from 2005 to 2014 far outpaced those of older adults, while younger adults saw their admissions drop over that period, according to the Agency for Healthcare Research and Quality.

For the baby boomers (adults aged 52-72 years), the rate of inpatient stays involving hepatitis C with or without hepatitis B, HIV, or alcoholic liver disease rose from 300.7 per 100,000 population in 2005 to 503.1 per 100,000 in 2014 – an increase of over 67%. For patients aged 73 years and older, that rate went from 104.4 in 2005 to 117.1 in 2014, which translates to a 12% increase, and for patients aged 18-51 years, it dropped 15%, from 182.5 to 155.4, the AHRQ said in a statistical brief.

[email protected]

Increases in hepatitis C–related inpatient stays for baby boomers from 2005 to 2014 far outpaced those of older adults, while younger adults saw their admissions drop over that period, according to the Agency for Healthcare Research and Quality.

For the baby boomers (adults aged 52-72 years), the rate of inpatient stays involving hepatitis C with or without hepatitis B, HIV, or alcoholic liver disease rose from 300.7 per 100,000 population in 2005 to 503.1 per 100,000 in 2014 – an increase of over 67%. For patients aged 73 years and older, that rate went from 104.4 in 2005 to 117.1 in 2014, which translates to a 12% increase, and for patients aged 18-51 years, it dropped 15%, from 182.5 to 155.4, the AHRQ said in a statistical brief.

[email protected]

Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.

A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.

“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”

Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.

To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.

Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.

Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”

The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.

SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
 

Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.

A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.

“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”

Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.

To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.

Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.

Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”

The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.

SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
 

Pediatric patients with relapsing remitting multiple sclerosis (MS) had fewer relapses after receiving the oral drug fingolimod when compared with patients who received intramuscular interferon beta-1a in the randomized, double-blind PARADIGMS study, suggesting that the sphingosine-1-phosphate receptor modulator could offer a new treatment option to patients younger than 18 years.

A new agent in this patient population is particularly important because most children and adolescents have the relapsing remitting form of the disease, and generally experience a relapse rate that is two to three times higher than that seen in people with adult-onset multiple sclerosis.

“These results indicate that fingolimod is more effective than the current standard of care, beta-interferon, in patients aged 10-17 and is a consideration for treatment in teenagers,” said Dr. Chitnis, director of the Partners Pediatric MS Center at the MassGeneral Hospital for Children, Boston. “The overall safety profile was reasonable, and there were no new major adverse events observed in comparison to adult studies.”

Participants were primarily Caucasian (92%) and female (62%). The mean age of each group at randomization was similar: 15.2 years in the fingolimod group and 15.4 years in the interferon beta-1a group. Disease duration since onset of first symptom was shorter in the fingolimod patients, a mean of 1.9 years, compared with a mean 2.4 years in the interferon beta-1a patients. At baseline, patients in both groups reported a mean 1.5 relapses in the previous year and a median Expanded Disability Status Scale (EDSS) score of 1.5.

To be included in the study, the children and teenagers had to have an EDSS score of 0 to 5.5; one or more relapses in the past year or two relapses in the previous two years; or MRI evidence of one or more gadolinium-enhancing lesions in the 6 months prior to trial randomization.

Fingolimod (Gilenya) is approved for the first-line treatment of relapsing forms of MS in adults in the United States. It is not yet FDA-approved for treatment of pediatric patients.

Dr. Chitnis said she was somewhat surprised by the strength of the findings in the PARADIGMS study. “These results showed very strong efficacy in young patients. However, as this study was being conducted, our group looked in more detail at the young adult subpopulation in the pivotal fingolimod adult studies, there was an improved effect in younger adults [those younger than 20 or younger than 30], compared to the entire group. Thus, one could extrapolate that the effects in adolescents would follow and show even greater efficacy.”

The study was sponsored by Novartis, the maker of fingolimod. Dr. Chitnis and nearly all of her coauthors disclosed financial ties to Novartis. Three authors are employees of Novartis.

SOURCE: Chitnis T et al. ACTRIMS Forum 2018, Abstract P025.
 

A proposed metric to quantify the impact of an antimicrobial stewardship program (ASP) is using changes in the antibiotic days of therapy (DOT) per 1000 patient-days, which is the total number of days any dose of an antibiotic is administered during a specified time period, standardized by the number of patient-days.¹ Although DOT is useful for comparing antibiotic use among hospitals or time periods, this metric is a composite result of an ASP’s often multifaceted approach to improving antibiotic use. Thus, DOT provides a loose estimate of the direct impact of specific ASP activities and does not quantify the amount of antibiotics directly avoided or direct cost savings on the patient level. To ameliorate this, we reviewed our institution’s ASP prospective audit and feedback (PAF) and applied a novel metric, days of therapy avoided (DOTA), to calculate the number of antibiotic days avoided that directly result from our ASP’s actions targeting antibiotic stoppage. From DOTA, we also calculate attributable cost savings.

To quantify the direct impact of PAF, DOTA (Table) was calculated. Antibiotic costs avoided were calculated by multiplying the average wholesale price (AWP) per day (range: $0.44-$534; mean: $67.85) by DOTA. This calculation was done twice under 2 assumptions: that PAF led to the prevention of (1) 1 more day of antibiotic prescription and (2) the remainder of the documented or assumed LOT.

Over 4 years, the ASP made 1594 interventions to stop antibiotics. Accepted interventions totaled 1151 (72%): 513 (44.5%) for NI and 638 (55.4%) for TC, involving 431 and 575 unique patients, respectively. Nearly half (45.8%) of the NI interventions targeted asymptomatic bacteriuria, whereas respiratory tract infections were the most common (42.2%) indication for the TC intervention.

Under the most conservative assumption that each accepted PAF recommendation avoided 1 day of unnecessary antibiotics, we estimated a total of 1151 DOTA; 690 (59.9%) were intravenous antibiotics. The average DOT on which the PAF note was written was 3.07 ± 1.69 for NI and 6.38 ± 2.73 for TC. A planned LOT was documented for only 36.7% of the courses. On the basis of documented or assumed LOT, we estimate that the NI and TC interventions led to between 1077 and 2826 DOTA and between 397 and 1598 DOTA, respectively. Potential fluoroquinolone DOTA ranged from 300 to 1126; for third- and fourth-generation cephalosporins, there were 314 to 1017 DOTA.

Using the conservative estimate of 1151 DOTA, the costs avoided totaled $16,700, which includes $10,700 for intravenous antibiotics. When the AWP per day of each antibiotic was applied to the remaining LOTs avoided, the maximum potential cost savings was $67,100. Additional cost savings may have been realized if indirect expenses, such as pharmacy preparation and nursing administration time or costs of medical supplies, were evaluated.

We investigated DOTA as a measure of the direct patient-level and intervention-specific impact of an ASP’s PAF. DOTA may be useful for ASPs with limited access to an electronic record or electronically generated DOT reports because DOTA and cost savings can be tracked manually and prospectively with each accepted intervention. DOTA can also help ASPs identify which clinical conditions are responsible for the most antibiotic overuse, and thus may benefit from the development of clinical treatment guidelines. We found that the highest yield areas for DOTA were targeting asymptomatic bacteriuria (NI) and respiratory infections (TC). In doing so, these have also succeeded in reducing high-risk, broad-spectrum antimicrobials, such as fluoroquinolones and advanced-generation cephalosporins. Further research is needed to assess if DOTA correlates with other ASP metrics and clinical outcomes; however, current evidence supports that reducing unnecessary antibiotic use is fundamental to reducing antibiotic resistance and adverse events.¹⁰

The limitations of measuring DOTA include time consumption, particularly if not collected prospectively. However, we make several conclusions. ASP PAF stopping antibiotics was well accepted and reduced antibiotic use. Second, calculating DOTA requires little technology and only knowledge of the planned LOT and drug costs. DOTA also identifies which infectious indications to focus PAF efforts on and gain the greatest impact. Overall, DOTA is a simple, useful, and promising measurement of the direct antibiotic and economic impacts of specific ASP PAF and warrants further investigation as an ASP metric.

Acknowledgments

The authors thank the patients and RGH staff, particularly the departments of infectious diseases, pharmacy, and internal medicine, for their support.

Disclosure

The authors declare no conflicts of interest. This study was previously presented in poster form at the Society for Healthcare Epidemiology of America Spring Conference in St. Louis, Missouri (March 29-31, 2017).

A proposed metric to quantify the impact of an antimicrobial stewardship program (ASP) is using changes in the antibiotic days of therapy (DOT) per 1000 patient-days, which is the total number of days any dose of an antibiotic is administered during a specified time period, standardized by the number of patient-days.¹ Although DOT is useful for comparing antibiotic use among hospitals or time periods, this metric is a composite result of an ASP’s often multifaceted approach to improving antibiotic use. Thus, DOT provides a loose estimate of the direct impact of specific ASP activities and does not quantify the amount of antibiotics directly avoided or direct cost savings on the patient level. To ameliorate this, we reviewed our institution’s ASP prospective audit and feedback (PAF) and applied a novel metric, days of therapy avoided (DOTA), to calculate the number of antibiotic days avoided that directly result from our ASP’s actions targeting antibiotic stoppage. From DOTA, we also calculate attributable cost savings.

To quantify the direct impact of PAF, DOTA (Table) was calculated. Antibiotic costs avoided were calculated by multiplying the average wholesale price (AWP) per day (range: $0.44-$534; mean: $67.85) by DOTA. This calculation was done twice under 2 assumptions: that PAF led to the prevention of (1) 1 more day of antibiotic prescription and (2) the remainder of the documented or assumed LOT.

Over 4 years, the ASP made 1594 interventions to stop antibiotics. Accepted interventions totaled 1151 (72%): 513 (44.5%) for NI and 638 (55.4%) for TC, involving 431 and 575 unique patients, respectively. Nearly half (45.8%) of the NI interventions targeted asymptomatic bacteriuria, whereas respiratory tract infections were the most common (42.2%) indication for the TC intervention.

Under the most conservative assumption that each accepted PAF recommendation avoided 1 day of unnecessary antibiotics, we estimated a total of 1151 DOTA; 690 (59.9%) were intravenous antibiotics. The average DOT on which the PAF note was written was 3.07 ± 1.69 for NI and 6.38 ± 2.73 for TC. A planned LOT was documented for only 36.7% of the courses. On the basis of documented or assumed LOT, we estimate that the NI and TC interventions led to between 1077 and 2826 DOTA and between 397 and 1598 DOTA, respectively. Potential fluoroquinolone DOTA ranged from 300 to 1126; for third- and fourth-generation cephalosporins, there were 314 to 1017 DOTA.

Using the conservative estimate of 1151 DOTA, the costs avoided totaled $16,700, which includes $10,700 for intravenous antibiotics. When the AWP per day of each antibiotic was applied to the remaining LOTs avoided, the maximum potential cost savings was $67,100. Additional cost savings may have been realized if indirect expenses, such as pharmacy preparation and nursing administration time or costs of medical supplies, were evaluated.

We investigated DOTA as a measure of the direct patient-level and intervention-specific impact of an ASP’s PAF. DOTA may be useful for ASPs with limited access to an electronic record or electronically generated DOT reports because DOTA and cost savings can be tracked manually and prospectively with each accepted intervention. DOTA can also help ASPs identify which clinical conditions are responsible for the most antibiotic overuse, and thus may benefit from the development of clinical treatment guidelines. We found that the highest yield areas for DOTA were targeting asymptomatic bacteriuria (NI) and respiratory infections (TC). In doing so, these have also succeeded in reducing high-risk, broad-spectrum antimicrobials, such as fluoroquinolones and advanced-generation cephalosporins. Further research is needed to assess if DOTA correlates with other ASP metrics and clinical outcomes; however, current evidence supports that reducing unnecessary antibiotic use is fundamental to reducing antibiotic resistance and adverse events.¹⁰

The limitations of measuring DOTA include time consumption, particularly if not collected prospectively. However, we make several conclusions. ASP PAF stopping antibiotics was well accepted and reduced antibiotic use. Second, calculating DOTA requires little technology and only knowledge of the planned LOT and drug costs. DOTA also identifies which infectious indications to focus PAF efforts on and gain the greatest impact. Overall, DOTA is a simple, useful, and promising measurement of the direct antibiotic and economic impacts of specific ASP PAF and warrants further investigation as an ASP metric.

Acknowledgments

The authors thank the patients and RGH staff, particularly the departments of infectious diseases, pharmacy, and internal medicine, for their support.

Disclosure

The authors declare no conflicts of interest. This study was previously presented in poster form at the Society for Healthcare Epidemiology of America Spring Conference in St. Louis, Missouri (March 29-31, 2017).

A proposed metric to quantify the impact of an antimicrobial stewardship program (ASP) is using changes in the antibiotic days of therapy (DOT) per 1000 patient-days, which is the total number of days any dose of an antibiotic is administered during a specified time period, standardized by the number of patient-days.¹ Although DOT is useful for comparing antibiotic use among hospitals or time periods, this metric is a composite result of an ASP’s often multifaceted approach to improving antibiotic use. Thus, DOT provides a loose estimate of the direct impact of specific ASP activities and does not quantify the amount of antibiotics directly avoided or direct cost savings on the patient level. To ameliorate this, we reviewed our institution’s ASP prospective audit and feedback (PAF) and applied a novel metric, days of therapy avoided (DOTA), to calculate the number of antibiotic days avoided that directly result from our ASP’s actions targeting antibiotic stoppage. From DOTA, we also calculate attributable cost savings.

To quantify the direct impact of PAF, DOTA (Table) was calculated. Antibiotic costs avoided were calculated by multiplying the average wholesale price (AWP) per day (range: $0.44-$534; mean: $67.85) by DOTA. This calculation was done twice under 2 assumptions: that PAF led to the prevention of (1) 1 more day of antibiotic prescription and (2) the remainder of the documented or assumed LOT.

Over 4 years, the ASP made 1594 interventions to stop antibiotics. Accepted interventions totaled 1151 (72%): 513 (44.5%) for NI and 638 (55.4%) for TC, involving 431 and 575 unique patients, respectively. Nearly half (45.8%) of the NI interventions targeted asymptomatic bacteriuria, whereas respiratory tract infections were the most common (42.2%) indication for the TC intervention.

Under the most conservative assumption that each accepted PAF recommendation avoided 1 day of unnecessary antibiotics, we estimated a total of 1151 DOTA; 690 (59.9%) were intravenous antibiotics. The average DOT on which the PAF note was written was 3.07 ± 1.69 for NI and 6.38 ± 2.73 for TC. A planned LOT was documented for only 36.7% of the courses. On the basis of documented or assumed LOT, we estimate that the NI and TC interventions led to between 1077 and 2826 DOTA and between 397 and 1598 DOTA, respectively. Potential fluoroquinolone DOTA ranged from 300 to 1126; for third- and fourth-generation cephalosporins, there were 314 to 1017 DOTA.

Using the conservative estimate of 1151 DOTA, the costs avoided totaled $16,700, which includes $10,700 for intravenous antibiotics. When the AWP per day of each antibiotic was applied to the remaining LOTs avoided, the maximum potential cost savings was $67,100. Additional cost savings may have been realized if indirect expenses, such as pharmacy preparation and nursing administration time or costs of medical supplies, were evaluated.

We investigated DOTA as a measure of the direct patient-level and intervention-specific impact of an ASP’s PAF. DOTA may be useful for ASPs with limited access to an electronic record or electronically generated DOT reports because DOTA and cost savings can be tracked manually and prospectively with each accepted intervention. DOTA can also help ASPs identify which clinical conditions are responsible for the most antibiotic overuse, and thus may benefit from the development of clinical treatment guidelines. We found that the highest yield areas for DOTA were targeting asymptomatic bacteriuria (NI) and respiratory infections (TC). In doing so, these have also succeeded in reducing high-risk, broad-spectrum antimicrobials, such as fluoroquinolones and advanced-generation cephalosporins. Further research is needed to assess if DOTA correlates with other ASP metrics and clinical outcomes; however, current evidence supports that reducing unnecessary antibiotic use is fundamental to reducing antibiotic resistance and adverse events.¹⁰

The limitations of measuring DOTA include time consumption, particularly if not collected prospectively. However, we make several conclusions. ASP PAF stopping antibiotics was well accepted and reduced antibiotic use. Second, calculating DOTA requires little technology and only knowledge of the planned LOT and drug costs. DOTA also identifies which infectious indications to focus PAF efforts on and gain the greatest impact. Overall, DOTA is a simple, useful, and promising measurement of the direct antibiotic and economic impacts of specific ASP PAF and warrants further investigation as an ASP metric.

Acknowledgments

The authors thank the patients and RGH staff, particularly the departments of infectious diseases, pharmacy, and internal medicine, for their support.

Disclosure

The authors declare no conflicts of interest. This study was previously presented in poster form at the Society for Healthcare Epidemiology of America Spring Conference in St. Louis, Missouri (March 29-31, 2017).

Immune checkpoint inhibitors (ICIs), a form of immunotherapy, have changed the management of cancer since their introduction in 2011.¹ They were initially tested on melanoma.² Their use in the advanced stages of the disease demonstrated a 2-year survival of 18% compared with 5% by using other therapies.³ Similar results were observed in nonsmall cell lung carcinoma (NSCLC); the overall survival benefit was 3 months with the use of ICIs compared with traditional chemotherapy (42% and 24% at 1 year, respectively).⁴ Antitumor activity has also been seen in the treatment of other malignancies, including renal cell carcinoma,⁵ bladder carcinoma,^6,7 head and neck carcinoma,⁸ colorectal cancer,⁹ Hodgkin lymphoma,¹⁰ and, more recently, hepatocellular carcinoma.¹¹ The use of ICIs has also been linked to serious complications.¹² Although the skin, kidneys, lungs, and endocrine and nervous systems may be affected, complications of the gastrointestinal (GI) tract are frequent and can be life-threatening.^12-16 We performed a thorough review of the literature to familiarize hospitalists with the mechanism of action and uses of ICIs, the clinical presentation of their GI toxicity, and the current recommendations regarding diagnosis and treatment.

A 66-year-old man was admitted to our institution with a 1-week history of severe, diffuse abdominal pain and profuse watery diarrhea. He reported having more than 8 watery bowel movements per day and denied fever, recent travel, ill contacts, or ingestion of undercooked food. He had a history of metastatic melanoma and was undergoing treatment with both nivolumab and ipilimumab; the drugs were started 6 weeks prior to presentation. Physical examination revealed a heart rate of 110 beats/minute while supine and 123 beats/minute while standing, blood pressure of 112/69 mm Hg while supine and 92/62 mm Hg while standing, and a temperature of 37.2°C. He was in mild distress and had dry oral mucosa. Abdominal examination revealed hyperactive bowel sounds and mild diffuse abdominal tenderness with no guarding or rebound. His extremities were cool, but peripheral pulses were present. Initial laboratory results included a hemoglobin level of 15.3 g/dL (range 12.0-16.0 mg/dL), white blood cell count 14.2 × 10⁹/L (range 4.5-11.0 × 10⁹/L), and platelet count 236 × 10⁹/L (range 150-400 × 10⁹/L); other test results included a sodium level of 130 mmol/L (range 135-145 mmol/L), potassium 2.3 mmol/L (range 3.5-5.5 mmol/L), serum creatinine 2.2 mg/dL (range 0.8-1.3 mg/dL), blood urea nitrogen 72 mg/dL (range 8-21 mg/dL), and serum venous lactate 5.9 mmol/L (range 0.9-1.7 mmol/L).

T-cell lymphocytes play a pivotal role in acquired immunity, but their function requires an appropriate balance between stimulatory and inhibitory signals to prevent autoimmunity.¹⁷ Immune checkpoint molecules are used by the immune system to assist with this balance.¹⁸ Although several of these molecules exist, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are among the most widely studied.¹²

Because of the sustained T-cell activation, ICIs have been associated with autoimmune-like toxicities known as immune-related adverse events (irAEs).^19,31 Because the PD-1/PD-L1 pathway is more tumor-specific than the CTLA-4 pathway,^21-23 there is a higher incidence of serious irAEs seen with ipilimumab, reported to be around 27%.^18,22 Furthermore, the risk of developing irAEs is dose-dependent and can increase up to 55% when anti-CTLA-4 are used with other ICIs such as nivolumab.^13,32-34

The skin and GI tract are the most commonly involved organs.^14-16 Skin is affected in 50% of patients receiving ipilimumab and 40% of patients on nivolumab or pembrolizumab, often in the form of a rash or pruritus.^12,35-37 The rash is often described as faintly erythematous, reticular, and maculopapular and typically affects the trunk and extremities.³⁸ Importantly, these events usually occur within the first 2 weeks of treatment, and fewer than 5% are severe.^12,36,39 A higher percentage of severe adverse events occurs in the GI tract, with a reported incidence of 12%.^3,14,36,39

Colitis, defined by either the presence of symptoms or radiologic findings suggestive of inflammation, occurs less often than diarrhea alone, with a reported incidence of 2.3%.^37,43 This incidence increases to almost 12% when anti-CTLA-4 and anti-PD-1/PD-L1 are combined.³² Colitis symptoms include abdominal pain (20%), nausea and vomiting (15%), fever (12%), and, less often, bloody diarrhea or rectal bleeding.^19,20 Colitis severity is graded according to the CTCAE (Table 2).⁴² Most patients have mild colitis (grade 1 or 2).¹⁹ The risk for developing severe colitis (grade 3 or higher) is almost 10 times higher with the use of anti-CTLA-4 compared with anti-PD-1/PD-L1 agents.⁴³ Patients with severe disease are at risk of developing life-threatening complications, such as ileus, toxic megacolon, bowel ischemia, necrosis, or even perforation, which has been reported in up to 5% of patients with colitis because of ipilimumab.^13,17

Based on the patient’s symptoms, physical findings, and temporal relationship to ICI therapy, he was believed to have immune-mediated colitis. Stool studies, including those looking for ova and parasites, Clostridium difficile polymerase chain reaction (PCR), and stool cultures were negative.

In a patient undergoing ICI treatment who has diarrhea, the initial assessment should exclude C. difficile and Salmonella by stool culture, PCR, or pathogenic antigens.¹⁹ Cytomegalovirus reactivation should also be considered. Immune-mediated colitis and infection can coexist; thus, a positive infectious etiology does not rule out the presence of immune colitis or vice versa.⁴⁴ Fecal calprotectin, a marker of neutrophil-associated inflammation, is nonspecific for ICI-induced colitis; however, it may help to distinguish inflammatory from noninflammatory diarrhea.^33,45

No clear guideline exists for the use of abdominal imaging. Some experts suggest using computed tomography in patients with severe, persistent, or progressive symptoms in order to exclude bowel obstruction, toxic megacolon, or perforation.^19,46

In patients with typical symptoms, and after infectious etiologies are ruled out, empiric use of corticosteroids can be initiated without an endoscopic evaluation, which is not necessary to establish a diagnosis and rarely changes management.^12,37,47 In patients with atypical presentations or for whom the diagnosis remains in question, endoscopic evaluation with biopsies may be required. Macroscopic findings may be similar to those seen with inflammatory bowel disease (IBD), including erythema, edema, ulceration, granularity, or loss of vascular pattern. Although immune-mediated colitis affects the descending colon more often than IBD, this feature and any macroscopic findings are insufficient to make this distinction.^20,36 Furthermore, the lack of macroscopic abnormalities does not rule out immune-mediated colitis.²⁰

When endoscopic biopsies are obtained, histologic findings for anti-CTLA-4 medications (eg, ipilimumab) usually follow 3 patterns: neutrophilic infiltrate (46%), lymphocytic infiltrate (15%), and mixed infiltrate (38%).⁴¹ Other findings include crypt abscesses and tissue destruction.²⁰ No biopsy-specific pattern has been described with anti-PD-1/PD-L1 medications, such as nivolumab or pembrolizumab.¹⁸ A normal colonic tissue does not exclude the presence of an irAE, as cases of isolated ileitis⁴⁸ or enteritis⁴⁹ without colitis can also occur.

The patient was started on intravenous (IV) methylprednisolone 2 mg/kg twice a day. After 48 hours, he still had more than 7 episodes of diarrhea per day, so he was treated with 1 dose of infliximab 5 mg/kg without stopping corticosteroids. Within 72 hours, the patient’s abdominal pain improved and his diarrhea stopped. He was discharged on an 8-week taper of prednisone starting at 1 mg/kg/day, pneumocystis pneumonia (PCP) prophylaxis was started, and ICI therapy was discontinued indefinitely.

Management of grade 1 and 2 colitis is mainly supportive, consisting of fluid and electrolyte replacement, the American Dietetic Association colitis diet, and antimotility agents, such as loperamide, oral diphenoxylate hydrochloride, or atropine sulfate.^36,37 Persistent grade 2 symptoms (lasting >3 days), should prompt initiation of 0.5 to 1 mg/kg/day of oral prednisone or an equivalent.¹⁹ If symptoms do not improve with oral corticosteroids, patient hospitalization for IV corticosteroids should be considered.³⁷ Importantly, opioids and antidiarrheals may mask the pain and severity of symptoms and, therefore, should be used cautiously.¹⁹

Patients with grade 3 and 4 colitis (≥7 stools per day, severe abdominal pain, or complications) require the use of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or an equivalent.¹⁵ Patients who fail to respond to prednisone alone may benefit from the addition of oral budesonide at a dose of 9 to 12 mg/day.⁵⁰ In severe cases of colitis, hospitalization may be necessary for IV hydration, electrolyte replacement, and IV methylprednisolone at a starting dose of 2 mg/kg twice a day for 1 to 2 days before transitioning to oral corticosteroids.^12,15 Though improvement is usually noted within the first 2 weeks of treatment, prednisone should be slowly tapered over a period of 4 to 8 weeks to ensure complete healing and prevent relapse.^20,36 Patients who receive an equivalent dose of prednisone 20 mg daily during a period of 4 weeks or more should receive PCP prophylaxis.⁵¹ Some patients fail to respond to IV corticosteroids despite adequate dosing. Many of these patients have severe disease, possibly because of delayed recognition and initiation of treatment.¹⁹ As with IBD, the addition of infliximab to corticosteroids at 5 mg/kg as a single dose is usually successful for this population subset.^52-54 Although a response is seen within 1 to 3 days,⁴¹ some patients benefit from an additional dose of infliximab 2 weeks after the initial dose.¹⁹ If sepsis or perforation is suspected at any point, corticosteroids or infliximab should be avoided and antibiotics should be started immediately.^15,19 Patients with a medically unresponsive disease may require partial or complete colectomy.²⁰ The use of prophylactic budesonide to prevent diarrhea or colitis has not been proven effective and should not be used.⁵⁵ Despite complications, mortality from colitis has markedly decreased given the increased awareness of this adverse event, reduction in the time to recognition and treatment, and increased adherence to corticosteroids.¹²

Treating physicians may be delayed in starting appropriate therapy because patients are concerned that using corticosteroids will negatively impact immunotherapy efficacy. Current evidence shows that the use of temporary immunosuppression to treat irAEs does not affect overall survival, efficacy, or time to treatment failure of the ICI.^12,56 Restarting ICI therapy is a complex decision and should always be individualized. In grade 1 and 2 colitis, ICI therapy is typically restarted after symptoms have improved.⁵ In grade 3 and 4 colitis, ICI therapy is often permanently discontinued.²⁰

ICIs have not only increased our understanding of the biology of cancer, but they have also improved survival in advanced stages of malignancies like melanoma, NSCLC, and renal cell carcinoma. The expanding use of these medications increases the likelihood that healthcare providers will encounter patients experiencing their adverse events.

Immune-mediated GI adverse events include a wide range of symptoms, from mild diarrhea to severe colitis complicated by perforation and death. Diagnosis requires exclusion of an infectious process. Early recognition and treatment with corticosteroids or another immunosuppressant such as infliximab hastens recovery and decreases complications and mortality. Treatment should be started within 5 days of symptom onset. Corticosteroids should be slowly tapered for no less than 4 weeks to prevent relapse and PCP prophylaxis administered in appropriate patients. Restarting ICI therapy may be considered in cases of mild colitis, but in severe cases, ICI therapy is usually discontinued.

Disclosure

Julian Marin-Acevedo, Dana Harris, and M. Caroline Burton have no conflicts of interest or funding sources to declare.

Immune checkpoint inhibitors (ICIs), a form of immunotherapy, have changed the management of cancer since their introduction in 2011.¹ They were initially tested on melanoma.² Their use in the advanced stages of the disease demonstrated a 2-year survival of 18% compared with 5% by using other therapies.³ Similar results were observed in nonsmall cell lung carcinoma (NSCLC); the overall survival benefit was 3 months with the use of ICIs compared with traditional chemotherapy (42% and 24% at 1 year, respectively).⁴ Antitumor activity has also been seen in the treatment of other malignancies, including renal cell carcinoma,⁵ bladder carcinoma,^6,7 head and neck carcinoma,⁸ colorectal cancer,⁹ Hodgkin lymphoma,¹⁰ and, more recently, hepatocellular carcinoma.¹¹ The use of ICIs has also been linked to serious complications.¹² Although the skin, kidneys, lungs, and endocrine and nervous systems may be affected, complications of the gastrointestinal (GI) tract are frequent and can be life-threatening.^12-16 We performed a thorough review of the literature to familiarize hospitalists with the mechanism of action and uses of ICIs, the clinical presentation of their GI toxicity, and the current recommendations regarding diagnosis and treatment.

A 66-year-old man was admitted to our institution with a 1-week history of severe, diffuse abdominal pain and profuse watery diarrhea. He reported having more than 8 watery bowel movements per day and denied fever, recent travel, ill contacts, or ingestion of undercooked food. He had a history of metastatic melanoma and was undergoing treatment with both nivolumab and ipilimumab; the drugs were started 6 weeks prior to presentation. Physical examination revealed a heart rate of 110 beats/minute while supine and 123 beats/minute while standing, blood pressure of 112/69 mm Hg while supine and 92/62 mm Hg while standing, and a temperature of 37.2°C. He was in mild distress and had dry oral mucosa. Abdominal examination revealed hyperactive bowel sounds and mild diffuse abdominal tenderness with no guarding or rebound. His extremities were cool, but peripheral pulses were present. Initial laboratory results included a hemoglobin level of 15.3 g/dL (range 12.0-16.0 mg/dL), white blood cell count 14.2 × 10⁹/L (range 4.5-11.0 × 10⁹/L), and platelet count 236 × 10⁹/L (range 150-400 × 10⁹/L); other test results included a sodium level of 130 mmol/L (range 135-145 mmol/L), potassium 2.3 mmol/L (range 3.5-5.5 mmol/L), serum creatinine 2.2 mg/dL (range 0.8-1.3 mg/dL), blood urea nitrogen 72 mg/dL (range 8-21 mg/dL), and serum venous lactate 5.9 mmol/L (range 0.9-1.7 mmol/L).

T-cell lymphocytes play a pivotal role in acquired immunity, but their function requires an appropriate balance between stimulatory and inhibitory signals to prevent autoimmunity.¹⁷ Immune checkpoint molecules are used by the immune system to assist with this balance.¹⁸ Although several of these molecules exist, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are among the most widely studied.¹²

Because of the sustained T-cell activation, ICIs have been associated with autoimmune-like toxicities known as immune-related adverse events (irAEs).^19,31 Because the PD-1/PD-L1 pathway is more tumor-specific than the CTLA-4 pathway,^21-23 there is a higher incidence of serious irAEs seen with ipilimumab, reported to be around 27%.^18,22 Furthermore, the risk of developing irAEs is dose-dependent and can increase up to 55% when anti-CTLA-4 are used with other ICIs such as nivolumab.^13,32-34

The skin and GI tract are the most commonly involved organs.^14-16 Skin is affected in 50% of patients receiving ipilimumab and 40% of patients on nivolumab or pembrolizumab, often in the form of a rash or pruritus.^12,35-37 The rash is often described as faintly erythematous, reticular, and maculopapular and typically affects the trunk and extremities.³⁸ Importantly, these events usually occur within the first 2 weeks of treatment, and fewer than 5% are severe.^12,36,39 A higher percentage of severe adverse events occurs in the GI tract, with a reported incidence of 12%.^3,14,36,39

Colitis, defined by either the presence of symptoms or radiologic findings suggestive of inflammation, occurs less often than diarrhea alone, with a reported incidence of 2.3%.^37,43 This incidence increases to almost 12% when anti-CTLA-4 and anti-PD-1/PD-L1 are combined.³² Colitis symptoms include abdominal pain (20%), nausea and vomiting (15%), fever (12%), and, less often, bloody diarrhea or rectal bleeding.^19,20 Colitis severity is graded according to the CTCAE (Table 2).⁴² Most patients have mild colitis (grade 1 or 2).¹⁹ The risk for developing severe colitis (grade 3 or higher) is almost 10 times higher with the use of anti-CTLA-4 compared with anti-PD-1/PD-L1 agents.⁴³ Patients with severe disease are at risk of developing life-threatening complications, such as ileus, toxic megacolon, bowel ischemia, necrosis, or even perforation, which has been reported in up to 5% of patients with colitis because of ipilimumab.^13,17

Based on the patient’s symptoms, physical findings, and temporal relationship to ICI therapy, he was believed to have immune-mediated colitis. Stool studies, including those looking for ova and parasites, Clostridium difficile polymerase chain reaction (PCR), and stool cultures were negative.

In a patient undergoing ICI treatment who has diarrhea, the initial assessment should exclude C. difficile and Salmonella by stool culture, PCR, or pathogenic antigens.¹⁹ Cytomegalovirus reactivation should also be considered. Immune-mediated colitis and infection can coexist; thus, a positive infectious etiology does not rule out the presence of immune colitis or vice versa.⁴⁴ Fecal calprotectin, a marker of neutrophil-associated inflammation, is nonspecific for ICI-induced colitis; however, it may help to distinguish inflammatory from noninflammatory diarrhea.^33,45

No clear guideline exists for the use of abdominal imaging. Some experts suggest using computed tomography in patients with severe, persistent, or progressive symptoms in order to exclude bowel obstruction, toxic megacolon, or perforation.^19,46

In patients with typical symptoms, and after infectious etiologies are ruled out, empiric use of corticosteroids can be initiated without an endoscopic evaluation, which is not necessary to establish a diagnosis and rarely changes management.^12,37,47 In patients with atypical presentations or for whom the diagnosis remains in question, endoscopic evaluation with biopsies may be required. Macroscopic findings may be similar to those seen with inflammatory bowel disease (IBD), including erythema, edema, ulceration, granularity, or loss of vascular pattern. Although immune-mediated colitis affects the descending colon more often than IBD, this feature and any macroscopic findings are insufficient to make this distinction.^20,36 Furthermore, the lack of macroscopic abnormalities does not rule out immune-mediated colitis.²⁰

When endoscopic biopsies are obtained, histologic findings for anti-CTLA-4 medications (eg, ipilimumab) usually follow 3 patterns: neutrophilic infiltrate (46%), lymphocytic infiltrate (15%), and mixed infiltrate (38%).⁴¹ Other findings include crypt abscesses and tissue destruction.²⁰ No biopsy-specific pattern has been described with anti-PD-1/PD-L1 medications, such as nivolumab or pembrolizumab.¹⁸ A normal colonic tissue does not exclude the presence of an irAE, as cases of isolated ileitis⁴⁸ or enteritis⁴⁹ without colitis can also occur.

The patient was started on intravenous (IV) methylprednisolone 2 mg/kg twice a day. After 48 hours, he still had more than 7 episodes of diarrhea per day, so he was treated with 1 dose of infliximab 5 mg/kg without stopping corticosteroids. Within 72 hours, the patient’s abdominal pain improved and his diarrhea stopped. He was discharged on an 8-week taper of prednisone starting at 1 mg/kg/day, pneumocystis pneumonia (PCP) prophylaxis was started, and ICI therapy was discontinued indefinitely.

Management of grade 1 and 2 colitis is mainly supportive, consisting of fluid and electrolyte replacement, the American Dietetic Association colitis diet, and antimotility agents, such as loperamide, oral diphenoxylate hydrochloride, or atropine sulfate.^36,37 Persistent grade 2 symptoms (lasting >3 days), should prompt initiation of 0.5 to 1 mg/kg/day of oral prednisone or an equivalent.¹⁹ If symptoms do not improve with oral corticosteroids, patient hospitalization for IV corticosteroids should be considered.³⁷ Importantly, opioids and antidiarrheals may mask the pain and severity of symptoms and, therefore, should be used cautiously.¹⁹

Patients with grade 3 and 4 colitis (≥7 stools per day, severe abdominal pain, or complications) require the use of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or an equivalent.¹⁵ Patients who fail to respond to prednisone alone may benefit from the addition of oral budesonide at a dose of 9 to 12 mg/day.⁵⁰ In severe cases of colitis, hospitalization may be necessary for IV hydration, electrolyte replacement, and IV methylprednisolone at a starting dose of 2 mg/kg twice a day for 1 to 2 days before transitioning to oral corticosteroids.^12,15 Though improvement is usually noted within the first 2 weeks of treatment, prednisone should be slowly tapered over a period of 4 to 8 weeks to ensure complete healing and prevent relapse.^20,36 Patients who receive an equivalent dose of prednisone 20 mg daily during a period of 4 weeks or more should receive PCP prophylaxis.⁵¹ Some patients fail to respond to IV corticosteroids despite adequate dosing. Many of these patients have severe disease, possibly because of delayed recognition and initiation of treatment.¹⁹ As with IBD, the addition of infliximab to corticosteroids at 5 mg/kg as a single dose is usually successful for this population subset.^52-54 Although a response is seen within 1 to 3 days,⁴¹ some patients benefit from an additional dose of infliximab 2 weeks after the initial dose.¹⁹ If sepsis or perforation is suspected at any point, corticosteroids or infliximab should be avoided and antibiotics should be started immediately.^15,19 Patients with a medically unresponsive disease may require partial or complete colectomy.²⁰ The use of prophylactic budesonide to prevent diarrhea or colitis has not been proven effective and should not be used.⁵⁵ Despite complications, mortality from colitis has markedly decreased given the increased awareness of this adverse event, reduction in the time to recognition and treatment, and increased adherence to corticosteroids.¹²

Treating physicians may be delayed in starting appropriate therapy because patients are concerned that using corticosteroids will negatively impact immunotherapy efficacy. Current evidence shows that the use of temporary immunosuppression to treat irAEs does not affect overall survival, efficacy, or time to treatment failure of the ICI.^12,56 Restarting ICI therapy is a complex decision and should always be individualized. In grade 1 and 2 colitis, ICI therapy is typically restarted after symptoms have improved.⁵ In grade 3 and 4 colitis, ICI therapy is often permanently discontinued.²⁰

ICIs have not only increased our understanding of the biology of cancer, but they have also improved survival in advanced stages of malignancies like melanoma, NSCLC, and renal cell carcinoma. The expanding use of these medications increases the likelihood that healthcare providers will encounter patients experiencing their adverse events.

Immune-mediated GI adverse events include a wide range of symptoms, from mild diarrhea to severe colitis complicated by perforation and death. Diagnosis requires exclusion of an infectious process. Early recognition and treatment with corticosteroids or another immunosuppressant such as infliximab hastens recovery and decreases complications and mortality. Treatment should be started within 5 days of symptom onset. Corticosteroids should be slowly tapered for no less than 4 weeks to prevent relapse and PCP prophylaxis administered in appropriate patients. Restarting ICI therapy may be considered in cases of mild colitis, but in severe cases, ICI therapy is usually discontinued.

Disclosure

Julian Marin-Acevedo, Dana Harris, and M. Caroline Burton have no conflicts of interest or funding sources to declare.

Immune checkpoint inhibitors (ICIs), a form of immunotherapy, have changed the management of cancer since their introduction in 2011.¹ They were initially tested on melanoma.² Their use in the advanced stages of the disease demonstrated a 2-year survival of 18% compared with 5% by using other therapies.³ Similar results were observed in nonsmall cell lung carcinoma (NSCLC); the overall survival benefit was 3 months with the use of ICIs compared with traditional chemotherapy (42% and 24% at 1 year, respectively).⁴ Antitumor activity has also been seen in the treatment of other malignancies, including renal cell carcinoma,⁵ bladder carcinoma,^6,7 head and neck carcinoma,⁸ colorectal cancer,⁹ Hodgkin lymphoma,¹⁰ and, more recently, hepatocellular carcinoma.¹¹ The use of ICIs has also been linked to serious complications.¹² Although the skin, kidneys, lungs, and endocrine and nervous systems may be affected, complications of the gastrointestinal (GI) tract are frequent and can be life-threatening.^12-16 We performed a thorough review of the literature to familiarize hospitalists with the mechanism of action and uses of ICIs, the clinical presentation of their GI toxicity, and the current recommendations regarding diagnosis and treatment.

A 66-year-old man was admitted to our institution with a 1-week history of severe, diffuse abdominal pain and profuse watery diarrhea. He reported having more than 8 watery bowel movements per day and denied fever, recent travel, ill contacts, or ingestion of undercooked food. He had a history of metastatic melanoma and was undergoing treatment with both nivolumab and ipilimumab; the drugs were started 6 weeks prior to presentation. Physical examination revealed a heart rate of 110 beats/minute while supine and 123 beats/minute while standing, blood pressure of 112/69 mm Hg while supine and 92/62 mm Hg while standing, and a temperature of 37.2°C. He was in mild distress and had dry oral mucosa. Abdominal examination revealed hyperactive bowel sounds and mild diffuse abdominal tenderness with no guarding or rebound. His extremities were cool, but peripheral pulses were present. Initial laboratory results included a hemoglobin level of 15.3 g/dL (range 12.0-16.0 mg/dL), white blood cell count 14.2 × 10⁹/L (range 4.5-11.0 × 10⁹/L), and platelet count 236 × 10⁹/L (range 150-400 × 10⁹/L); other test results included a sodium level of 130 mmol/L (range 135-145 mmol/L), potassium 2.3 mmol/L (range 3.5-5.5 mmol/L), serum creatinine 2.2 mg/dL (range 0.8-1.3 mg/dL), blood urea nitrogen 72 mg/dL (range 8-21 mg/dL), and serum venous lactate 5.9 mmol/L (range 0.9-1.7 mmol/L).

T-cell lymphocytes play a pivotal role in acquired immunity, but their function requires an appropriate balance between stimulatory and inhibitory signals to prevent autoimmunity.¹⁷ Immune checkpoint molecules are used by the immune system to assist with this balance.¹⁸ Although several of these molecules exist, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are among the most widely studied.¹²

Because of the sustained T-cell activation, ICIs have been associated with autoimmune-like toxicities known as immune-related adverse events (irAEs).^19,31 Because the PD-1/PD-L1 pathway is more tumor-specific than the CTLA-4 pathway,^21-23 there is a higher incidence of serious irAEs seen with ipilimumab, reported to be around 27%.^18,22 Furthermore, the risk of developing irAEs is dose-dependent and can increase up to 55% when anti-CTLA-4 are used with other ICIs such as nivolumab.^13,32-34

The skin and GI tract are the most commonly involved organs.^14-16 Skin is affected in 50% of patients receiving ipilimumab and 40% of patients on nivolumab or pembrolizumab, often in the form of a rash or pruritus.^12,35-37 The rash is often described as faintly erythematous, reticular, and maculopapular and typically affects the trunk and extremities.³⁸ Importantly, these events usually occur within the first 2 weeks of treatment, and fewer than 5% are severe.^12,36,39 A higher percentage of severe adverse events occurs in the GI tract, with a reported incidence of 12%.^3,14,36,39

Colitis, defined by either the presence of symptoms or radiologic findings suggestive of inflammation, occurs less often than diarrhea alone, with a reported incidence of 2.3%.^37,43 This incidence increases to almost 12% when anti-CTLA-4 and anti-PD-1/PD-L1 are combined.³² Colitis symptoms include abdominal pain (20%), nausea and vomiting (15%), fever (12%), and, less often, bloody diarrhea or rectal bleeding.^19,20 Colitis severity is graded according to the CTCAE (Table 2).⁴² Most patients have mild colitis (grade 1 or 2).¹⁹ The risk for developing severe colitis (grade 3 or higher) is almost 10 times higher with the use of anti-CTLA-4 compared with anti-PD-1/PD-L1 agents.⁴³ Patients with severe disease are at risk of developing life-threatening complications, such as ileus, toxic megacolon, bowel ischemia, necrosis, or even perforation, which has been reported in up to 5% of patients with colitis because of ipilimumab.^13,17

Based on the patient’s symptoms, physical findings, and temporal relationship to ICI therapy, he was believed to have immune-mediated colitis. Stool studies, including those looking for ova and parasites, Clostridium difficile polymerase chain reaction (PCR), and stool cultures were negative.

In a patient undergoing ICI treatment who has diarrhea, the initial assessment should exclude C. difficile and Salmonella by stool culture, PCR, or pathogenic antigens.¹⁹ Cytomegalovirus reactivation should also be considered. Immune-mediated colitis and infection can coexist; thus, a positive infectious etiology does not rule out the presence of immune colitis or vice versa.⁴⁴ Fecal calprotectin, a marker of neutrophil-associated inflammation, is nonspecific for ICI-induced colitis; however, it may help to distinguish inflammatory from noninflammatory diarrhea.^33,45

No clear guideline exists for the use of abdominal imaging. Some experts suggest using computed tomography in patients with severe, persistent, or progressive symptoms in order to exclude bowel obstruction, toxic megacolon, or perforation.^19,46

In patients with typical symptoms, and after infectious etiologies are ruled out, empiric use of corticosteroids can be initiated without an endoscopic evaluation, which is not necessary to establish a diagnosis and rarely changes management.^12,37,47 In patients with atypical presentations or for whom the diagnosis remains in question, endoscopic evaluation with biopsies may be required. Macroscopic findings may be similar to those seen with inflammatory bowel disease (IBD), including erythema, edema, ulceration, granularity, or loss of vascular pattern. Although immune-mediated colitis affects the descending colon more often than IBD, this feature and any macroscopic findings are insufficient to make this distinction.^20,36 Furthermore, the lack of macroscopic abnormalities does not rule out immune-mediated colitis.²⁰

When endoscopic biopsies are obtained, histologic findings for anti-CTLA-4 medications (eg, ipilimumab) usually follow 3 patterns: neutrophilic infiltrate (46%), lymphocytic infiltrate (15%), and mixed infiltrate (38%).⁴¹ Other findings include crypt abscesses and tissue destruction.²⁰ No biopsy-specific pattern has been described with anti-PD-1/PD-L1 medications, such as nivolumab or pembrolizumab.¹⁸ A normal colonic tissue does not exclude the presence of an irAE, as cases of isolated ileitis⁴⁸ or enteritis⁴⁹ without colitis can also occur.

The patient was started on intravenous (IV) methylprednisolone 2 mg/kg twice a day. After 48 hours, he still had more than 7 episodes of diarrhea per day, so he was treated with 1 dose of infliximab 5 mg/kg without stopping corticosteroids. Within 72 hours, the patient’s abdominal pain improved and his diarrhea stopped. He was discharged on an 8-week taper of prednisone starting at 1 mg/kg/day, pneumocystis pneumonia (PCP) prophylaxis was started, and ICI therapy was discontinued indefinitely.

Management of grade 1 and 2 colitis is mainly supportive, consisting of fluid and electrolyte replacement, the American Dietetic Association colitis diet, and antimotility agents, such as loperamide, oral diphenoxylate hydrochloride, or atropine sulfate.^36,37 Persistent grade 2 symptoms (lasting >3 days), should prompt initiation of 0.5 to 1 mg/kg/day of oral prednisone or an equivalent.¹⁹ If symptoms do not improve with oral corticosteroids, patient hospitalization for IV corticosteroids should be considered.³⁷ Importantly, opioids and antidiarrheals may mask the pain and severity of symptoms and, therefore, should be used cautiously.¹⁹

Patients with grade 3 and 4 colitis (≥7 stools per day, severe abdominal pain, or complications) require the use of systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or an equivalent.¹⁵ Patients who fail to respond to prednisone alone may benefit from the addition of oral budesonide at a dose of 9 to 12 mg/day.⁵⁰ In severe cases of colitis, hospitalization may be necessary for IV hydration, electrolyte replacement, and IV methylprednisolone at a starting dose of 2 mg/kg twice a day for 1 to 2 days before transitioning to oral corticosteroids.^12,15 Though improvement is usually noted within the first 2 weeks of treatment, prednisone should be slowly tapered over a period of 4 to 8 weeks to ensure complete healing and prevent relapse.^20,36 Patients who receive an equivalent dose of prednisone 20 mg daily during a period of 4 weeks or more should receive PCP prophylaxis.⁵¹ Some patients fail to respond to IV corticosteroids despite adequate dosing. Many of these patients have severe disease, possibly because of delayed recognition and initiation of treatment.¹⁹ As with IBD, the addition of infliximab to corticosteroids at 5 mg/kg as a single dose is usually successful for this population subset.^52-54 Although a response is seen within 1 to 3 days,⁴¹ some patients benefit from an additional dose of infliximab 2 weeks after the initial dose.¹⁹ If sepsis or perforation is suspected at any point, corticosteroids or infliximab should be avoided and antibiotics should be started immediately.^15,19 Patients with a medically unresponsive disease may require partial or complete colectomy.²⁰ The use of prophylactic budesonide to prevent diarrhea or colitis has not been proven effective and should not be used.⁵⁵ Despite complications, mortality from colitis has markedly decreased given the increased awareness of this adverse event, reduction in the time to recognition and treatment, and increased adherence to corticosteroids.¹²

Treating physicians may be delayed in starting appropriate therapy because patients are concerned that using corticosteroids will negatively impact immunotherapy efficacy. Current evidence shows that the use of temporary immunosuppression to treat irAEs does not affect overall survival, efficacy, or time to treatment failure of the ICI.^12,56 Restarting ICI therapy is a complex decision and should always be individualized. In grade 1 and 2 colitis, ICI therapy is typically restarted after symptoms have improved.⁵ In grade 3 and 4 colitis, ICI therapy is often permanently discontinued.²⁰

ICIs have not only increased our understanding of the biology of cancer, but they have also improved survival in advanced stages of malignancies like melanoma, NSCLC, and renal cell carcinoma. The expanding use of these medications increases the likelihood that healthcare providers will encounter patients experiencing their adverse events.

Immune-mediated GI adverse events include a wide range of symptoms, from mild diarrhea to severe colitis complicated by perforation and death. Diagnosis requires exclusion of an infectious process. Early recognition and treatment with corticosteroids or another immunosuppressant such as infliximab hastens recovery and decreases complications and mortality. Treatment should be started within 5 days of symptom onset. Corticosteroids should be slowly tapered for no less than 4 weeks to prevent relapse and PCP prophylaxis administered in appropriate patients. Restarting ICI therapy may be considered in cases of mild colitis, but in severe cases, ICI therapy is usually discontinued.

Disclosure

Julian Marin-Acevedo, Dana Harris, and M. Caroline Burton have no conflicts of interest or funding sources to declare.

Venous thromboembolism (VTE) prophylaxis is an important consideration for every older adult admitted to the hospital¹ but should not be prescribed to all patients. Use of anticoagulants (specifically low-molecular-weight heparin, low-dose unfractionated heparin, and fondaparinux) when not medically indicated may be harmful, especially for older adults who on average have more chronic conditions,¹ take more potentially interacting medications,² and have higher risks of bleeding.³ The American College of Chest Physicians (ACCP) Ninth Edition Guidelines for Antithrombotic Therapy and Prevention of Thrombosis explicitly recommend a risk-stratification approach using the Padua Prediction Score (PPS) to select those patients most likely to benefit from VTE prophylaxis.^4,5 This study aimed to describe the use of risk stratification and pharmacologic VTE prophylaxis use in a population of medically ill, hospitalized older patients.

We conducted a retrospective cohort study using data from patients aged 70 years or older admitted to Duke University Hospital general medicine services between January 1, 2014, to December 31, 2014. The PPS variables, 11 in total, are each weighed and sum to a score that stratifies patients into either high or low risk for VTE occurrence.⁵ Manual chart abstraction was performed using the electronic health record (EHR) to determine each patient’s PPS, inpatient pharmacologic VTE prophylaxis use, and contraindications to VTE prophylaxis. Descriptive statistics are presented for the important confounders/covariates, VTE risk, and VTE prophylaxis use.

Of the total eligible cohort (N = 1399), 400 patients were randomly selected for manual chart review; 89 of these patients were not eligible because they were on anticoagulation upon admission, leaving n = 311 patients in the analytic sample. Mean age for the sample was 80.6 years (standard deviation [SD]: 7.3); 42% were male and 34% were African American, and median length of stay was 4.0 days. The overall mean PPS for the sample was 3.6 (SD 1.8), resulting in 59% (n = 182) defined as “low risk.” Reasons for admission, median length of stay, and aspirin use did not differ between the risk groups.

Pharmacological VTE prophylaxis was present in 74% (134 out of 182) of low-risk patients and 71% (92 out of 129) of high-risk patients (Figure). In both low- and high-risk patients who received pharmacological VTE prophylaxis, over 90% had the therapy initiated within 24 hours of admission, and it was continued for over 60% of their hospital days.

We found no association between PPS and use of anticoagulants for VTE prophylaxis, suggesting that risk stratification is not being used to guide clinical decision-making. There are several barriers to implementing guideline directed use of VTE risk stratification. First, there is a lack of consensus on which VTE risk assessment tool is best to use with medically ill, hospitalized patients. While the ACCP Ninth Edition Guidelines support the use of the PPS, the American College of Physicians does not recommend a specific tool for VTE risk assessment.^5,6 Although other risk stratification tools exist, concordance between these tools has not been well studied.⁷ Second, manual calculation of the PPS can be cumbersome, error prone, and disruptive to the clinical workflow. Automated data extraction leveraging existing structured data elements in the EHR may be particularly attractive to many health systems striving to use EHRs to improve care. Designing and testing automatically populated VTE risk stratification tools may facilitate translation of evidence-based guidelines into routine clinical practice. Lastly, a key barrier is clinician education and awareness about these tools. Adding risk stratification tools to admission order sets is one way to increase clinician awareness and has been shown to decrease inappropriate VTE prophylaxis use.⁸ High-quality studies that use implementation science to promote uptake and efficacy of risk stratification tools into clinical practice are urgently needed.

Our study has several limitations. First, this was a single-site study at an academic center, which may limit generalizability of the findings. However, our design enabled us to look at other specific patient-level data that is typically not available in larger databases. Second, determination of PPS is limited to data available in the EHR, resulting in measurement error and possibly the underreporting of risk factors. Finally, due to feasibility and the low probability of VTE, we did not collect data on long-term VTE outcome and were unable to determine the impact that inappropriate VTE prophylaxis use has in low-risk hospitalized older adults.

In summary, we found poor adherence to risk stratification guidelines among medically ill, hospitalized older adults, resulting in overuse of anticoagulants for VTE prophylaxis. Automating risk stratification tools and incorporating results into order sets may ensure that adequate prophylaxis is used for patients who need it, while minimizing excess prophylaxis in those who do not.

Acknowledgments

The authors would like to thank Shenglan Li from Research Triangle Institute for her assistance in the data programming and database creation.

Disclosure

The authors have no conflicts of interest to report. This study was funded by the National Institute on Aging (NIA) GEMSSTAR Award (NIA R03AG048007) and the Duke Older Americans Independence Center (NIA P30 AG028716–01). This work was also supported by the Duke University Internal Medicine Chair’s Award, the Duke University Hartford Center of Excellence, and the Center of Innovation for Health Services Research in Primary Care (CIN 13-410) at the Durham VA Health Care System. This work was conducted while Dr. Pavon was supported by the T. Franklin Williams Scholars Program. Dr. Colón-Emeric is supported by K24 AG049077-01A1. The funding sources had no role in the design and conduct of the study; analysis or interpretation of the data; preparation or final approval of the manuscript before publication, and decision to submit the manuscript for publication. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of Duke University or the Department of Veterans Affairs.

Venous thromboembolism (VTE) prophylaxis is an important consideration for every older adult admitted to the hospital¹ but should not be prescribed to all patients. Use of anticoagulants (specifically low-molecular-weight heparin, low-dose unfractionated heparin, and fondaparinux) when not medically indicated may be harmful, especially for older adults who on average have more chronic conditions,¹ take more potentially interacting medications,² and have higher risks of bleeding.³ The American College of Chest Physicians (ACCP) Ninth Edition Guidelines for Antithrombotic Therapy and Prevention of Thrombosis explicitly recommend a risk-stratification approach using the Padua Prediction Score (PPS) to select those patients most likely to benefit from VTE prophylaxis.^4,5 This study aimed to describe the use of risk stratification and pharmacologic VTE prophylaxis use in a population of medically ill, hospitalized older patients.

We conducted a retrospective cohort study using data from patients aged 70 years or older admitted to Duke University Hospital general medicine services between January 1, 2014, to December 31, 2014. The PPS variables, 11 in total, are each weighed and sum to a score that stratifies patients into either high or low risk for VTE occurrence.⁵ Manual chart abstraction was performed using the electronic health record (EHR) to determine each patient’s PPS, inpatient pharmacologic VTE prophylaxis use, and contraindications to VTE prophylaxis. Descriptive statistics are presented for the important confounders/covariates, VTE risk, and VTE prophylaxis use.

Of the total eligible cohort (N = 1399), 400 patients were randomly selected for manual chart review; 89 of these patients were not eligible because they were on anticoagulation upon admission, leaving n = 311 patients in the analytic sample. Mean age for the sample was 80.6 years (standard deviation [SD]: 7.3); 42% were male and 34% were African American, and median length of stay was 4.0 days. The overall mean PPS for the sample was 3.6 (SD 1.8), resulting in 59% (n = 182) defined as “low risk.” Reasons for admission, median length of stay, and aspirin use did not differ between the risk groups.

Pharmacological VTE prophylaxis was present in 74% (134 out of 182) of low-risk patients and 71% (92 out of 129) of high-risk patients (Figure). In both low- and high-risk patients who received pharmacological VTE prophylaxis, over 90% had the therapy initiated within 24 hours of admission, and it was continued for over 60% of their hospital days.

We found no association between PPS and use of anticoagulants for VTE prophylaxis, suggesting that risk stratification is not being used to guide clinical decision-making. There are several barriers to implementing guideline directed use of VTE risk stratification. First, there is a lack of consensus on which VTE risk assessment tool is best to use with medically ill, hospitalized patients. While the ACCP Ninth Edition Guidelines support the use of the PPS, the American College of Physicians does not recommend a specific tool for VTE risk assessment.^5,6 Although other risk stratification tools exist, concordance between these tools has not been well studied.⁷ Second, manual calculation of the PPS can be cumbersome, error prone, and disruptive to the clinical workflow. Automated data extraction leveraging existing structured data elements in the EHR may be particularly attractive to many health systems striving to use EHRs to improve care. Designing and testing automatically populated VTE risk stratification tools may facilitate translation of evidence-based guidelines into routine clinical practice. Lastly, a key barrier is clinician education and awareness about these tools. Adding risk stratification tools to admission order sets is one way to increase clinician awareness and has been shown to decrease inappropriate VTE prophylaxis use.⁸ High-quality studies that use implementation science to promote uptake and efficacy of risk stratification tools into clinical practice are urgently needed.

Our study has several limitations. First, this was a single-site study at an academic center, which may limit generalizability of the findings. However, our design enabled us to look at other specific patient-level data that is typically not available in larger databases. Second, determination of PPS is limited to data available in the EHR, resulting in measurement error and possibly the underreporting of risk factors. Finally, due to feasibility and the low probability of VTE, we did not collect data on long-term VTE outcome and were unable to determine the impact that inappropriate VTE prophylaxis use has in low-risk hospitalized older adults.

In summary, we found poor adherence to risk stratification guidelines among medically ill, hospitalized older adults, resulting in overuse of anticoagulants for VTE prophylaxis. Automating risk stratification tools and incorporating results into order sets may ensure that adequate prophylaxis is used for patients who need it, while minimizing excess prophylaxis in those who do not.

Acknowledgments

The authors would like to thank Shenglan Li from Research Triangle Institute for her assistance in the data programming and database creation.

Disclosure

The authors have no conflicts of interest to report. This study was funded by the National Institute on Aging (NIA) GEMSSTAR Award (NIA R03AG048007) and the Duke Older Americans Independence Center (NIA P30 AG028716–01). This work was also supported by the Duke University Internal Medicine Chair’s Award, the Duke University Hartford Center of Excellence, and the Center of Innovation for Health Services Research in Primary Care (CIN 13-410) at the Durham VA Health Care System. This work was conducted while Dr. Pavon was supported by the T. Franklin Williams Scholars Program. Dr. Colón-Emeric is supported by K24 AG049077-01A1. The funding sources had no role in the design and conduct of the study; analysis or interpretation of the data; preparation or final approval of the manuscript before publication, and decision to submit the manuscript for publication. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of Duke University or the Department of Veterans Affairs.

Venous thromboembolism (VTE) prophylaxis is an important consideration for every older adult admitted to the hospital¹ but should not be prescribed to all patients. Use of anticoagulants (specifically low-molecular-weight heparin, low-dose unfractionated heparin, and fondaparinux) when not medically indicated may be harmful, especially for older adults who on average have more chronic conditions,¹ take more potentially interacting medications,² and have higher risks of bleeding.³ The American College of Chest Physicians (ACCP) Ninth Edition Guidelines for Antithrombotic Therapy and Prevention of Thrombosis explicitly recommend a risk-stratification approach using the Padua Prediction Score (PPS) to select those patients most likely to benefit from VTE prophylaxis.^4,5 This study aimed to describe the use of risk stratification and pharmacologic VTE prophylaxis use in a population of medically ill, hospitalized older patients.

We conducted a retrospective cohort study using data from patients aged 70 years or older admitted to Duke University Hospital general medicine services between January 1, 2014, to December 31, 2014. The PPS variables, 11 in total, are each weighed and sum to a score that stratifies patients into either high or low risk for VTE occurrence.⁵ Manual chart abstraction was performed using the electronic health record (EHR) to determine each patient’s PPS, inpatient pharmacologic VTE prophylaxis use, and contraindications to VTE prophylaxis. Descriptive statistics are presented for the important confounders/covariates, VTE risk, and VTE prophylaxis use.

Of the total eligible cohort (N = 1399), 400 patients were randomly selected for manual chart review; 89 of these patients were not eligible because they were on anticoagulation upon admission, leaving n = 311 patients in the analytic sample. Mean age for the sample was 80.6 years (standard deviation [SD]: 7.3); 42% were male and 34% were African American, and median length of stay was 4.0 days. The overall mean PPS for the sample was 3.6 (SD 1.8), resulting in 59% (n = 182) defined as “low risk.” Reasons for admission, median length of stay, and aspirin use did not differ between the risk groups.

Pharmacological VTE prophylaxis was present in 74% (134 out of 182) of low-risk patients and 71% (92 out of 129) of high-risk patients (Figure). In both low- and high-risk patients who received pharmacological VTE prophylaxis, over 90% had the therapy initiated within 24 hours of admission, and it was continued for over 60% of their hospital days.

We found no association between PPS and use of anticoagulants for VTE prophylaxis, suggesting that risk stratification is not being used to guide clinical decision-making. There are several barriers to implementing guideline directed use of VTE risk stratification. First, there is a lack of consensus on which VTE risk assessment tool is best to use with medically ill, hospitalized patients. While the ACCP Ninth Edition Guidelines support the use of the PPS, the American College of Physicians does not recommend a specific tool for VTE risk assessment.^5,6 Although other risk stratification tools exist, concordance between these tools has not been well studied.⁷ Second, manual calculation of the PPS can be cumbersome, error prone, and disruptive to the clinical workflow. Automated data extraction leveraging existing structured data elements in the EHR may be particularly attractive to many health systems striving to use EHRs to improve care. Designing and testing automatically populated VTE risk stratification tools may facilitate translation of evidence-based guidelines into routine clinical practice. Lastly, a key barrier is clinician education and awareness about these tools. Adding risk stratification tools to admission order sets is one way to increase clinician awareness and has been shown to decrease inappropriate VTE prophylaxis use.⁸ High-quality studies that use implementation science to promote uptake and efficacy of risk stratification tools into clinical practice are urgently needed.

Our study has several limitations. First, this was a single-site study at an academic center, which may limit generalizability of the findings. However, our design enabled us to look at other specific patient-level data that is typically not available in larger databases. Second, determination of PPS is limited to data available in the EHR, resulting in measurement error and possibly the underreporting of risk factors. Finally, due to feasibility and the low probability of VTE, we did not collect data on long-term VTE outcome and were unable to determine the impact that inappropriate VTE prophylaxis use has in low-risk hospitalized older adults.

In summary, we found poor adherence to risk stratification guidelines among medically ill, hospitalized older adults, resulting in overuse of anticoagulants for VTE prophylaxis. Automating risk stratification tools and incorporating results into order sets may ensure that adequate prophylaxis is used for patients who need it, while minimizing excess prophylaxis in those who do not.

Acknowledgments

The authors would like to thank Shenglan Li from Research Triangle Institute for her assistance in the data programming and database creation.

Disclosure

The authors have no conflicts of interest to report. This study was funded by the National Institute on Aging (NIA) GEMSSTAR Award (NIA R03AG048007) and the Duke Older Americans Independence Center (NIA P30 AG028716–01). This work was also supported by the Duke University Internal Medicine Chair’s Award, the Duke University Hartford Center of Excellence, and the Center of Innovation for Health Services Research in Primary Care (CIN 13-410) at the Durham VA Health Care System. This work was conducted while Dr. Pavon was supported by the T. Franklin Williams Scholars Program. Dr. Colón-Emeric is supported by K24 AG049077-01A1. The funding sources had no role in the design and conduct of the study; analysis or interpretation of the data; preparation or final approval of the manuscript before publication, and decision to submit the manuscript for publication. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of Duke University or the Department of Veterans Affairs.

The ethos of medicine has shifted from paternalistic, physician-driven care to patient autonomy and engagement, in which the physician shares information and advises.^1-3 Although there are ethical, legal, and practical reasons to respect patient preferences,^1-4 patient engagement also fosters quality and safety⁵ and may improve clinical outcomes.^5-8 Patients whose preferences are respected are more likely to trust their doctor, feel empowered, and adhere to treatments.⁹

Providers may partner with patients through shared decision-making (SDM).^10,11 Several SDM models describe the process of providers and patients balancing evidence, preferences and context to arrive at a clinical decision.^12-15 The National Academy of Medicine and the American Academy of Pediatrics has called for more SDM,^16,17 including when clinical evidence is limited,² equally beneficial options exist,¹⁸ clinical stakes are high,¹⁹ and even with deferential patients.²⁰ Despite its value, SDM does not reliably occur^21,22 and SDM training is often unavailable.⁴ Clinical decision tools, patient education aids, and various training interventions have shown promising, although inconsistent results.^{23, 24}

Little is known about SDM in inpatient settings where unique patient, clinician, and environmental factors may influence SDM. This study describes the quality and possible predictors of inpatient SDM during attending rounds in 4 academic training settings. Although SDM may occur anytime during a hospitalization, attending rounds present a valuable opportunity for SDM observation given their centrality to inpatient care and teaching.^25,26 Because attending physicians bear ultimate responsibility for patient management, we examined whether SDM performance varies among attendings within each service. In addition, we tested the hypothesis that service-level, team-level, and patient-level features explain variation in SDM quality more than individual attending physicians. Finally, we compared peer-observer perspectives of SDM behaviors with patient and/or guardian perspectives.

Study Design and Setting

This cross-sectional, observational study examined the diversity of SDM practice within and between 4 inpatient services during attending rounds, including the internal medicine and pediatrics services at Stanford University and the University of California, San Francisco (UCSF). Both institutions provide quaternary care to diverse patient populations with approximately half enrolled in Medicare and/or Medicaid.

One institution had 42 internal medicine (Med-1) and 15 pediatric hospitalists (Peds-1) compared to 8 internal medicine (Med-2) and 12 pediatric hospitalists (Peds-2) at the second location. Both pediatric services used family-centered rounds that included discussions between the patients’ families and the whole team. One medicine service used a similar rounding model that did not necessarily involve the patients’ families. In contrast, the smaller medicine service typically began rounds by discussing all patients in a conference room and then visiting select patients afterwards.

From August 2014 to November 2014, peer observers gathered data on team SDM behaviors during attending rounds. After the rounding team departed, nonphysician interviewers surveyed consenting patients’ (or guardians’) views of the SDM experience, yielding paired evaluations for a subset of SDM encounters. Institutional review board approval was obtained from Stanford University and UCSF.

Participants and Inclusion Criteria

Attending physicians were hospitalists who supervised rounds at least 1 month per year, and did not include those conducting the study. All provided verbal assent to be observed on 3 days within a 7-day period. While team composition varied as needed (eg, to include the nurse, pharmacist, interpreter, etc), we restricted study observations to those teams with an attending and at least one learner (eg, resident, intern, medical student) to capture the influence of attending physicians in their training role. Because services vary in number of attendings on staff, rounds assigned per attending, and patients per round, it was not possible to enroll equal sample sizes per service in the study.

Nonintensive care unit patients who were deemed medically stable by the team were eligible for peer observation and participation in a subsequent patient interview once during the study period. Pediatric patients were invited for an interview if they were between 13 and 21 years old and had the option of having a parent or guardian present; if the pediatric patients were less than 13 years old or they were not interested in being interviewed, then their parents or guardians were invited to be interviewed. Interpreters were on rounds, and thus, non-English participants were able to participate in the peer observations, but could not participate in patient interviews because interpreters were not available during afternoons for study purposes. Consent was obtained from all participating patients and/or guardians.

Data Collection

Round and Patient Characteristics

Peer observers recorded rounding, team, and patient characteristics using a standardized form. Rounding data included date, attending name, duration of rounds, and patient census. Patient level data included the decision(s) discussed, the seniority of the clinician leading the discussion, team composition, minutes spent discussing the patient (both with the patient and/or guardian and total time), hospitalization week, and patient’s primary language. Additional patient data obtained from electronic health records included age, gender, race, ethnicity, date of admission, and admitting diagnosis.

SDM Measures

Peer-observed SDM behaviors were quantified per patient encounter using the 9-item Rochester Participatory Decision-Making Scale (RPAD), with credit given for SDM behaviors exhibited by anyone on the rounding team (team-level metric).²⁷ Each item was scored on a 3-point scale (0 = absent, 0.5 = partial, and 1 = present) for a maximum of 9 points, with higher scores indicating higher-quality SDM (Peer-RPAD Score). We created semistructured patient interview guides by adapting each RPAD item into layperson language (Patient-RPAD Score) and adding open-ended questions to assess the patient experience.

Peer-Observer Training

Eight peer-observers (7 hospitalists and 1 palliative care physician) were trained to perform RPAD ratings using videos of patient encounters. Initially, raters viewed videos together and discussed ratings for each RPAD item. The observers incorporated behavioral anchors and clinical examples into the development of an RPAD rating guide, which they subsequently used to independently score 4 videos from an online medical communication library.²⁸ These scores were discussed to resolve any differences before 4 additional videos were independently viewed, scored, and compared. Interrater reliability was achieved when the standard deviation of summed SDM scores across raters was less than 1 for all 4 videos.

Patient Interviewers

Interviewers were English-speaking volunteers without formal medical training. They were educated in hospital etiquette by a physician and in administering patient interviews through peer-to-peer role playing and an observation and feedback interview with at least 1 patient.

Data Analysis

The analysis set included every unique patient with whom a medical decision was made by an eligible clinical team. To account for the nested study design (patient-level scores within rounds, rounds within attending, and attendings within service), we used mixed-effects models to estimate mean (summary or item) RPAD score by levels of fixed covariate(s). The models included random effects accounting for attending-level and round-level correlations among scores via variance components, and allowing the attending-level random effect to differ by service. Analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). We used descriptive statistics to summarize round- and patient-level characteristics.

SDM Variation by Attending and Service

Box plots were used to summarize raw patient-level, Peer-RPAD scores by service and attending. By using the methods described above, we estimated the mean score overall and by service. In both models, we examined the statistical significance of service-specific variation in attending-level random effects by using likelihood-ratio test (LRT) to compare models.

SDM Variation by Round and Patient Characteristics

We used the models described above to identify covariates associated with Peer-RPAD scores. We fit univariate models separately for each covariate, then fit 2 multivariable models, including (1) all covariates and (2) all effects significant in either model at P ≤ .20 according to F tests. For uniformity of presentation, we express continuous covariates categorically; however, we report P values based on continuous versions. Means generated by the multivariable models were calculated at the mean values of all other covariates in model.

Patient-Level RPAD Data

A subsample of patients completed semistructured interviews with analogous RPAD questions. To identify possible selection bias in the full sample, we summarized response rates by service and patient language and modeled Peer-RPAD scores by interview response status. Among responders, we estimated the mean Peer-RPAD and Patient-RPAD scores and their paired differences and correlations, testing for non-zero correlations via the Spearman rank test.

All Patient Encounters

The median duration of rounding sessions was 1.8 hours, median patient census was 9, and median patient encounter was 13 minutes. The duration of rounds and minutes per patient were longest at Med-2 and shortest at Peds-1. See Table 1 for other team characteristics.

Peer Evaluations of SDM Encounters

Characteristics of Patients

Teams spent a median of 13 minutes per SDM encounter, which was not higher than the round median. SDM topics discussed included 47% treatment, 15% diagnostic, 30% both treatment and diagnostic, and 7% other.

Variation in SDM Quality Among Attending Physicians

Overall Peer-RPAD Scores were normally distributed. After adjusting for the nested study design, the overall mean (standard error) score was 4.16 (0.11). Score variability among attendings differed significantly by service (LRT P = .0067). For example, raw scores were lower and more variable among attending physicians at Med-2 than other among attendings in other services (see Appendix Figure in Supporting Information). However, when service was included in the model as a fixed effect, mean scores varied significantly, from 3.0 at Med-2 to 4.7 at Med-1 (P < .0001), but the random variation among attendings no longer differed significantly by service (P = .13). This finding supports the hypothesis that service-level influences are stronger than influences of individual attending physicians, that is, that variation between services exceeded variation among attendings within service.

Aspects of SDM That Are More Prevalent on Rounds

Rounds and Patient Characteristics Associated With Peer-RPAD Scores

Patient-RPAD Results: Dissimilar Perspectives of Patients and/or Guardians and Physician Observers

Among responders, mean Patient-RPAD scores were 6.8 to 7.1 for medicine services and 7.6 to 7.8 for pediatric services (P = .01). The overall mean Patient-RPAD score, 7.46, was significantly greater than the paired Peer-RPAD score by 3.5 (P = .011); however, correlations were not statistically significantly different from 0 (by service, each P > .12).

To understand drivers of the differences between Peer-RPAD and Patient-RPAD scores, we analyzed findings by item. Each mean patient-item score exceeded its peer counterpart (P ≤ .01; panel B of Figure). Peer-item scores fell below 33% on 2 items (Items 9 and 4) and only exceeded 67% on 2 items (Items 1 and 6), whereas patient-item scores ranged from 60% (Item 8) to 97% (Item 7). Three paired differences exceeded 50% (Items 9, 4, and 7) and 3 were below 20% (Items 6, 8 and 1), underlying the lack of correlation between peer and patient scores.

In this multisite study of SDM during inpatient attending rounds, SDM quality, specific SDM behaviors, and factors contributing to SDM were identified. Our study found an adjusted overall Peer-RPAD Score of 4.4 out of 9, and found the following 3 SDM elements most needing improvement according to trained peer observers: (1) “Checking understanding of the patient’s perspective”, (2) “Examining barriers to follow-through with the treatment plan”, and (3) “Asking if the patient has questions.” Areas of strength included explaining the clinical issue or nature of the decision and matching medical language to the patient’s level of understanding, with each rated highly by both peer-observers and patients. Broadly speaking, physicians were skillful in delivering information to patients but failed to solicit input from patients. Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient’s hospital stay, and amount of time rounding with each patient.

Patients similarly found that physicians could improve their abilities to elicit information from patients and families, noting the 3 lowest patient-rated SDM elements were as follows: (1) asking open-ended questions, (2) discussing alternatives or uncertainties, and (3) discussing barriers to treatment plan follow through. Overall, patients and guardians perceived the quantity and quality of SDM on rounds more favorably than peer observers, which is consistent with other studies of patient perceptions of communication. ^29-31 It is possible that patient ratings are more influenced by demand characteristics, fear of negatively impacting their patient-provider relationships, and conflation of overall satisfaction with quality of communication.³² This difference in patient perception of SDM is worthy of further study.

Prior work has revealed that SDM may occur infrequently during inpatient rounds.¹¹ This study further elucidates specific SDM behaviors used along with univariate and multivariate modeling to explore possible contributing factors. The strengths and weaknesses found were similar at all 4 services and the influence of the service was more important than variability across attendings. This study’s findings are similar to a study by Shields et al.,³³ in which the findings in a geographically different outpatient setting 10 years earlier suggesting global and enduring challenges to SDM. To our knowledge, this is the first published study to characterize inpatient SDM behaviors and may serve as the basis for future interventions.

Although the item-level components were ranked similarly across services, on average the summary Peer-RPAD score was lowest at Med-2, where we observed high variability within and between attendings, and was highest at Med-1, where variability was low. Med-2 carried the highest caseload and held the longest rounds, while Med-1 carried the lowest caseload, suggesting that modifiable burdens may hamper SDM performance. Prior studies suggest that patients are often selected based on teaching opportunities, immediate medical need and being newly admitted.³⁴ The high scores at Med-1 may reflect that service’s prediscussion of patients during card-flipping rounds or their selection of which patients to round on as a team. Consistent with prior studies^29,35 of SDM and the family-centered rounding model, which includes the involvement of nurses, respiratory therapists, pharmacists, case managers, social workers, and interpreters on rounds, both pediatrics services showed higher SDM scores.

In contrast to prior studies,^34,36 team size and number of learners did not affect SDM performance, nor did decision type. Despite teams having up to 17 members, 8 learners, and 14 complex patients, SDM scores did not vary significantly by team. Nonetheless, trends were in the directions expected: Scores tended to decrease as the team size or the percentage of trainees grew, and increased with the seniority of the presenting physician. Interestingly, SDM performance decreased with round-average minutes per patient, which may be measuring on-going intensity across cases that leads to exhaustion. Statistically significant patient factors for increased SDM included longer duration of patient encounters, second week of hospital stay, and female patient gender. Although we anticipated that the high number of decisions made early in hospitalization would facilitate higher SDM scores, continuity and stronger patient-provider relationships may enhance SDM.³⁶ We report service-specific team and patient characteristics, in addition to SDM findings in anticipation that some readers will identify with 1 service more than others.

This study has several important limitations. First, our peer observers were not blinded and primarily observed encounters at their own site. To minimize bias, observers periodically rated videos to recalibrate RPAD scoring. Second, additional SDM conversations with a patient and/or guardian may have occurred outside of rounds and were not captured, and poor patient recall may have affected Patient-RPAD scores despite interviewer prompts and timeliness of interviews within 12 hours of rounds. Third, there might have been a selection bias for the one service who selected a smaller number of patients to see, compared with the three other services that performed bedside rounds on all patients. It is possible that attending physicians selected patients who were deemed most able to have SDM conversations, thus affecting RPAD scores on that service. Fourth, study services had fewer patients on average than other academic hospitals (median 9, range 3-14), which might limit its generalizability. Last, as in any observational study, there is always the possibility of the Hawthorne effect. However, neither teams nor patients knew the study objectives.

Nevertheless, important findings emerged through the use of RPAD Scores to evaluate inpatient SDM practices. In particular, we found that to increase SDM quality in inpatient settings, practitioners should (1) check their understanding of the patient’s perspective, (2) examine barriers to follow-through with the treatment plan, and (3) ask if the patient has questions. Variation among services remained very influential after adjusting for team and patient characteristics, which suggests that “climate” or service culture should be targeted by an intervention, rather than individual attendings or subgroups defined by team or patient characteristics. Notably, team size, number of learners, patient census, and type of decision being made did not affect SDM performance, suggesting that even large, busy services can perform SDM if properly trained.

Acknowledgments

The authors thank the patients, families, pediatric and internal medicine residents, and hospitalists at Stanford School of Medicine and University of California, San Francisco School of Medicine for their participation in this study. We would also like to thank the student volunteers who collected patient perspectives on the encounters.

Disclosure 

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an NIH/NCCIH grant R25 AT006573.

The ethos of medicine has shifted from paternalistic, physician-driven care to patient autonomy and engagement, in which the physician shares information and advises.^1-3 Although there are ethical, legal, and practical reasons to respect patient preferences,^1-4 patient engagement also fosters quality and safety⁵ and may improve clinical outcomes.^5-8 Patients whose preferences are respected are more likely to trust their doctor, feel empowered, and adhere to treatments.⁹

Providers may partner with patients through shared decision-making (SDM).^10,11 Several SDM models describe the process of providers and patients balancing evidence, preferences and context to arrive at a clinical decision.^12-15 The National Academy of Medicine and the American Academy of Pediatrics has called for more SDM,^16,17 including when clinical evidence is limited,² equally beneficial options exist,¹⁸ clinical stakes are high,¹⁹ and even with deferential patients.²⁰ Despite its value, SDM does not reliably occur^21,22 and SDM training is often unavailable.⁴ Clinical decision tools, patient education aids, and various training interventions have shown promising, although inconsistent results.^{23, 24}

Little is known about SDM in inpatient settings where unique patient, clinician, and environmental factors may influence SDM. This study describes the quality and possible predictors of inpatient SDM during attending rounds in 4 academic training settings. Although SDM may occur anytime during a hospitalization, attending rounds present a valuable opportunity for SDM observation given their centrality to inpatient care and teaching.^25,26 Because attending physicians bear ultimate responsibility for patient management, we examined whether SDM performance varies among attendings within each service. In addition, we tested the hypothesis that service-level, team-level, and patient-level features explain variation in SDM quality more than individual attending physicians. Finally, we compared peer-observer perspectives of SDM behaviors with patient and/or guardian perspectives.

Study Design and Setting

This cross-sectional, observational study examined the diversity of SDM practice within and between 4 inpatient services during attending rounds, including the internal medicine and pediatrics services at Stanford University and the University of California, San Francisco (UCSF). Both institutions provide quaternary care to diverse patient populations with approximately half enrolled in Medicare and/or Medicaid.

One institution had 42 internal medicine (Med-1) and 15 pediatric hospitalists (Peds-1) compared to 8 internal medicine (Med-2) and 12 pediatric hospitalists (Peds-2) at the second location. Both pediatric services used family-centered rounds that included discussions between the patients’ families and the whole team. One medicine service used a similar rounding model that did not necessarily involve the patients’ families. In contrast, the smaller medicine service typically began rounds by discussing all patients in a conference room and then visiting select patients afterwards.

From August 2014 to November 2014, peer observers gathered data on team SDM behaviors during attending rounds. After the rounding team departed, nonphysician interviewers surveyed consenting patients’ (or guardians’) views of the SDM experience, yielding paired evaluations for a subset of SDM encounters. Institutional review board approval was obtained from Stanford University and UCSF.

Participants and Inclusion Criteria

Attending physicians were hospitalists who supervised rounds at least 1 month per year, and did not include those conducting the study. All provided verbal assent to be observed on 3 days within a 7-day period. While team composition varied as needed (eg, to include the nurse, pharmacist, interpreter, etc), we restricted study observations to those teams with an attending and at least one learner (eg, resident, intern, medical student) to capture the influence of attending physicians in their training role. Because services vary in number of attendings on staff, rounds assigned per attending, and patients per round, it was not possible to enroll equal sample sizes per service in the study.

Nonintensive care unit patients who were deemed medically stable by the team were eligible for peer observation and participation in a subsequent patient interview once during the study period. Pediatric patients were invited for an interview if they were between 13 and 21 years old and had the option of having a parent or guardian present; if the pediatric patients were less than 13 years old or they were not interested in being interviewed, then their parents or guardians were invited to be interviewed. Interpreters were on rounds, and thus, non-English participants were able to participate in the peer observations, but could not participate in patient interviews because interpreters were not available during afternoons for study purposes. Consent was obtained from all participating patients and/or guardians.

Data Collection

Round and Patient Characteristics

Peer observers recorded rounding, team, and patient characteristics using a standardized form. Rounding data included date, attending name, duration of rounds, and patient census. Patient level data included the decision(s) discussed, the seniority of the clinician leading the discussion, team composition, minutes spent discussing the patient (both with the patient and/or guardian and total time), hospitalization week, and patient’s primary language. Additional patient data obtained from electronic health records included age, gender, race, ethnicity, date of admission, and admitting diagnosis.

SDM Measures

Peer-observed SDM behaviors were quantified per patient encounter using the 9-item Rochester Participatory Decision-Making Scale (RPAD), with credit given for SDM behaviors exhibited by anyone on the rounding team (team-level metric).²⁷ Each item was scored on a 3-point scale (0 = absent, 0.5 = partial, and 1 = present) for a maximum of 9 points, with higher scores indicating higher-quality SDM (Peer-RPAD Score). We created semistructured patient interview guides by adapting each RPAD item into layperson language (Patient-RPAD Score) and adding open-ended questions to assess the patient experience.

Peer-Observer Training

Eight peer-observers (7 hospitalists and 1 palliative care physician) were trained to perform RPAD ratings using videos of patient encounters. Initially, raters viewed videos together and discussed ratings for each RPAD item. The observers incorporated behavioral anchors and clinical examples into the development of an RPAD rating guide, which they subsequently used to independently score 4 videos from an online medical communication library.²⁸ These scores were discussed to resolve any differences before 4 additional videos were independently viewed, scored, and compared. Interrater reliability was achieved when the standard deviation of summed SDM scores across raters was less than 1 for all 4 videos.

Patient Interviewers

Interviewers were English-speaking volunteers without formal medical training. They were educated in hospital etiquette by a physician and in administering patient interviews through peer-to-peer role playing and an observation and feedback interview with at least 1 patient.

Data Analysis

The analysis set included every unique patient with whom a medical decision was made by an eligible clinical team. To account for the nested study design (patient-level scores within rounds, rounds within attending, and attendings within service), we used mixed-effects models to estimate mean (summary or item) RPAD score by levels of fixed covariate(s). The models included random effects accounting for attending-level and round-level correlations among scores via variance components, and allowing the attending-level random effect to differ by service. Analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). We used descriptive statistics to summarize round- and patient-level characteristics.

SDM Variation by Attending and Service

Box plots were used to summarize raw patient-level, Peer-RPAD scores by service and attending. By using the methods described above, we estimated the mean score overall and by service. In both models, we examined the statistical significance of service-specific variation in attending-level random effects by using likelihood-ratio test (LRT) to compare models.

SDM Variation by Round and Patient Characteristics

We used the models described above to identify covariates associated with Peer-RPAD scores. We fit univariate models separately for each covariate, then fit 2 multivariable models, including (1) all covariates and (2) all effects significant in either model at P ≤ .20 according to F tests. For uniformity of presentation, we express continuous covariates categorically; however, we report P values based on continuous versions. Means generated by the multivariable models were calculated at the mean values of all other covariates in model.

Patient-Level RPAD Data

A subsample of patients completed semistructured interviews with analogous RPAD questions. To identify possible selection bias in the full sample, we summarized response rates by service and patient language and modeled Peer-RPAD scores by interview response status. Among responders, we estimated the mean Peer-RPAD and Patient-RPAD scores and their paired differences and correlations, testing for non-zero correlations via the Spearman rank test.

All Patient Encounters

The median duration of rounding sessions was 1.8 hours, median patient census was 9, and median patient encounter was 13 minutes. The duration of rounds and minutes per patient were longest at Med-2 and shortest at Peds-1. See Table 1 for other team characteristics.

Peer Evaluations of SDM Encounters

Characteristics of Patients

Teams spent a median of 13 minutes per SDM encounter, which was not higher than the round median. SDM topics discussed included 47% treatment, 15% diagnostic, 30% both treatment and diagnostic, and 7% other.

Variation in SDM Quality Among Attending Physicians

Overall Peer-RPAD Scores were normally distributed. After adjusting for the nested study design, the overall mean (standard error) score was 4.16 (0.11). Score variability among attendings differed significantly by service (LRT P = .0067). For example, raw scores were lower and more variable among attending physicians at Med-2 than other among attendings in other services (see Appendix Figure in Supporting Information). However, when service was included in the model as a fixed effect, mean scores varied significantly, from 3.0 at Med-2 to 4.7 at Med-1 (P < .0001), but the random variation among attendings no longer differed significantly by service (P = .13). This finding supports the hypothesis that service-level influences are stronger than influences of individual attending physicians, that is, that variation between services exceeded variation among attendings within service.

Aspects of SDM That Are More Prevalent on Rounds

Rounds and Patient Characteristics Associated With Peer-RPAD Scores

Patient-RPAD Results: Dissimilar Perspectives of Patients and/or Guardians and Physician Observers

Among responders, mean Patient-RPAD scores were 6.8 to 7.1 for medicine services and 7.6 to 7.8 for pediatric services (P = .01). The overall mean Patient-RPAD score, 7.46, was significantly greater than the paired Peer-RPAD score by 3.5 (P = .011); however, correlations were not statistically significantly different from 0 (by service, each P > .12).

To understand drivers of the differences between Peer-RPAD and Patient-RPAD scores, we analyzed findings by item. Each mean patient-item score exceeded its peer counterpart (P ≤ .01; panel B of Figure). Peer-item scores fell below 33% on 2 items (Items 9 and 4) and only exceeded 67% on 2 items (Items 1 and 6), whereas patient-item scores ranged from 60% (Item 8) to 97% (Item 7). Three paired differences exceeded 50% (Items 9, 4, and 7) and 3 were below 20% (Items 6, 8 and 1), underlying the lack of correlation between peer and patient scores.

In this multisite study of SDM during inpatient attending rounds, SDM quality, specific SDM behaviors, and factors contributing to SDM were identified. Our study found an adjusted overall Peer-RPAD Score of 4.4 out of 9, and found the following 3 SDM elements most needing improvement according to trained peer observers: (1) “Checking understanding of the patient’s perspective”, (2) “Examining barriers to follow-through with the treatment plan”, and (3) “Asking if the patient has questions.” Areas of strength included explaining the clinical issue or nature of the decision and matching medical language to the patient’s level of understanding, with each rated highly by both peer-observers and patients. Broadly speaking, physicians were skillful in delivering information to patients but failed to solicit input from patients. Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient’s hospital stay, and amount of time rounding with each patient.

Patients similarly found that physicians could improve their abilities to elicit information from patients and families, noting the 3 lowest patient-rated SDM elements were as follows: (1) asking open-ended questions, (2) discussing alternatives or uncertainties, and (3) discussing barriers to treatment plan follow through. Overall, patients and guardians perceived the quantity and quality of SDM on rounds more favorably than peer observers, which is consistent with other studies of patient perceptions of communication. ^29-31 It is possible that patient ratings are more influenced by demand characteristics, fear of negatively impacting their patient-provider relationships, and conflation of overall satisfaction with quality of communication.³² This difference in patient perception of SDM is worthy of further study.

Prior work has revealed that SDM may occur infrequently during inpatient rounds.¹¹ This study further elucidates specific SDM behaviors used along with univariate and multivariate modeling to explore possible contributing factors. The strengths and weaknesses found were similar at all 4 services and the influence of the service was more important than variability across attendings. This study’s findings are similar to a study by Shields et al.,³³ in which the findings in a geographically different outpatient setting 10 years earlier suggesting global and enduring challenges to SDM. To our knowledge, this is the first published study to characterize inpatient SDM behaviors and may serve as the basis for future interventions.

Although the item-level components were ranked similarly across services, on average the summary Peer-RPAD score was lowest at Med-2, where we observed high variability within and between attendings, and was highest at Med-1, where variability was low. Med-2 carried the highest caseload and held the longest rounds, while Med-1 carried the lowest caseload, suggesting that modifiable burdens may hamper SDM performance. Prior studies suggest that patients are often selected based on teaching opportunities, immediate medical need and being newly admitted.³⁴ The high scores at Med-1 may reflect that service’s prediscussion of patients during card-flipping rounds or their selection of which patients to round on as a team. Consistent with prior studies^29,35 of SDM and the family-centered rounding model, which includes the involvement of nurses, respiratory therapists, pharmacists, case managers, social workers, and interpreters on rounds, both pediatrics services showed higher SDM scores.

In contrast to prior studies,^34,36 team size and number of learners did not affect SDM performance, nor did decision type. Despite teams having up to 17 members, 8 learners, and 14 complex patients, SDM scores did not vary significantly by team. Nonetheless, trends were in the directions expected: Scores tended to decrease as the team size or the percentage of trainees grew, and increased with the seniority of the presenting physician. Interestingly, SDM performance decreased with round-average minutes per patient, which may be measuring on-going intensity across cases that leads to exhaustion. Statistically significant patient factors for increased SDM included longer duration of patient encounters, second week of hospital stay, and female patient gender. Although we anticipated that the high number of decisions made early in hospitalization would facilitate higher SDM scores, continuity and stronger patient-provider relationships may enhance SDM.³⁶ We report service-specific team and patient characteristics, in addition to SDM findings in anticipation that some readers will identify with 1 service more than others.

This study has several important limitations. First, our peer observers were not blinded and primarily observed encounters at their own site. To minimize bias, observers periodically rated videos to recalibrate RPAD scoring. Second, additional SDM conversations with a patient and/or guardian may have occurred outside of rounds and were not captured, and poor patient recall may have affected Patient-RPAD scores despite interviewer prompts and timeliness of interviews within 12 hours of rounds. Third, there might have been a selection bias for the one service who selected a smaller number of patients to see, compared with the three other services that performed bedside rounds on all patients. It is possible that attending physicians selected patients who were deemed most able to have SDM conversations, thus affecting RPAD scores on that service. Fourth, study services had fewer patients on average than other academic hospitals (median 9, range 3-14), which might limit its generalizability. Last, as in any observational study, there is always the possibility of the Hawthorne effect. However, neither teams nor patients knew the study objectives.

Nevertheless, important findings emerged through the use of RPAD Scores to evaluate inpatient SDM practices. In particular, we found that to increase SDM quality in inpatient settings, practitioners should (1) check their understanding of the patient’s perspective, (2) examine barriers to follow-through with the treatment plan, and (3) ask if the patient has questions. Variation among services remained very influential after adjusting for team and patient characteristics, which suggests that “climate” or service culture should be targeted by an intervention, rather than individual attendings or subgroups defined by team or patient characteristics. Notably, team size, number of learners, patient census, and type of decision being made did not affect SDM performance, suggesting that even large, busy services can perform SDM if properly trained.

Acknowledgments

The authors thank the patients, families, pediatric and internal medicine residents, and hospitalists at Stanford School of Medicine and University of California, San Francisco School of Medicine for their participation in this study. We would also like to thank the student volunteers who collected patient perspectives on the encounters.

Disclosure 

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an NIH/NCCIH grant R25 AT006573.

The ethos of medicine has shifted from paternalistic, physician-driven care to patient autonomy and engagement, in which the physician shares information and advises.^1-3 Although there are ethical, legal, and practical reasons to respect patient preferences,^1-4 patient engagement also fosters quality and safety⁵ and may improve clinical outcomes.^5-8 Patients whose preferences are respected are more likely to trust their doctor, feel empowered, and adhere to treatments.⁹

Providers may partner with patients through shared decision-making (SDM).^10,11 Several SDM models describe the process of providers and patients balancing evidence, preferences and context to arrive at a clinical decision.^12-15 The National Academy of Medicine and the American Academy of Pediatrics has called for more SDM,^16,17 including when clinical evidence is limited,² equally beneficial options exist,¹⁸ clinical stakes are high,¹⁹ and even with deferential patients.²⁰ Despite its value, SDM does not reliably occur^21,22 and SDM training is often unavailable.⁴ Clinical decision tools, patient education aids, and various training interventions have shown promising, although inconsistent results.^{23, 24}

Little is known about SDM in inpatient settings where unique patient, clinician, and environmental factors may influence SDM. This study describes the quality and possible predictors of inpatient SDM during attending rounds in 4 academic training settings. Although SDM may occur anytime during a hospitalization, attending rounds present a valuable opportunity for SDM observation given their centrality to inpatient care and teaching.^25,26 Because attending physicians bear ultimate responsibility for patient management, we examined whether SDM performance varies among attendings within each service. In addition, we tested the hypothesis that service-level, team-level, and patient-level features explain variation in SDM quality more than individual attending physicians. Finally, we compared peer-observer perspectives of SDM behaviors with patient and/or guardian perspectives.

Study Design and Setting

This cross-sectional, observational study examined the diversity of SDM practice within and between 4 inpatient services during attending rounds, including the internal medicine and pediatrics services at Stanford University and the University of California, San Francisco (UCSF). Both institutions provide quaternary care to diverse patient populations with approximately half enrolled in Medicare and/or Medicaid.

One institution had 42 internal medicine (Med-1) and 15 pediatric hospitalists (Peds-1) compared to 8 internal medicine (Med-2) and 12 pediatric hospitalists (Peds-2) at the second location. Both pediatric services used family-centered rounds that included discussions between the patients’ families and the whole team. One medicine service used a similar rounding model that did not necessarily involve the patients’ families. In contrast, the smaller medicine service typically began rounds by discussing all patients in a conference room and then visiting select patients afterwards.

From August 2014 to November 2014, peer observers gathered data on team SDM behaviors during attending rounds. After the rounding team departed, nonphysician interviewers surveyed consenting patients’ (or guardians’) views of the SDM experience, yielding paired evaluations for a subset of SDM encounters. Institutional review board approval was obtained from Stanford University and UCSF.

Participants and Inclusion Criteria

Attending physicians were hospitalists who supervised rounds at least 1 month per year, and did not include those conducting the study. All provided verbal assent to be observed on 3 days within a 7-day period. While team composition varied as needed (eg, to include the nurse, pharmacist, interpreter, etc), we restricted study observations to those teams with an attending and at least one learner (eg, resident, intern, medical student) to capture the influence of attending physicians in their training role. Because services vary in number of attendings on staff, rounds assigned per attending, and patients per round, it was not possible to enroll equal sample sizes per service in the study.

Nonintensive care unit patients who were deemed medically stable by the team were eligible for peer observation and participation in a subsequent patient interview once during the study period. Pediatric patients were invited for an interview if they were between 13 and 21 years old and had the option of having a parent or guardian present; if the pediatric patients were less than 13 years old or they were not interested in being interviewed, then their parents or guardians were invited to be interviewed. Interpreters were on rounds, and thus, non-English participants were able to participate in the peer observations, but could not participate in patient interviews because interpreters were not available during afternoons for study purposes. Consent was obtained from all participating patients and/or guardians.

Data Collection

Round and Patient Characteristics

Peer observers recorded rounding, team, and patient characteristics using a standardized form. Rounding data included date, attending name, duration of rounds, and patient census. Patient level data included the decision(s) discussed, the seniority of the clinician leading the discussion, team composition, minutes spent discussing the patient (both with the patient and/or guardian and total time), hospitalization week, and patient’s primary language. Additional patient data obtained from electronic health records included age, gender, race, ethnicity, date of admission, and admitting diagnosis.

SDM Measures

Peer-observed SDM behaviors were quantified per patient encounter using the 9-item Rochester Participatory Decision-Making Scale (RPAD), with credit given for SDM behaviors exhibited by anyone on the rounding team (team-level metric).²⁷ Each item was scored on a 3-point scale (0 = absent, 0.5 = partial, and 1 = present) for a maximum of 9 points, with higher scores indicating higher-quality SDM (Peer-RPAD Score). We created semistructured patient interview guides by adapting each RPAD item into layperson language (Patient-RPAD Score) and adding open-ended questions to assess the patient experience.

Peer-Observer Training

Eight peer-observers (7 hospitalists and 1 palliative care physician) were trained to perform RPAD ratings using videos of patient encounters. Initially, raters viewed videos together and discussed ratings for each RPAD item. The observers incorporated behavioral anchors and clinical examples into the development of an RPAD rating guide, which they subsequently used to independently score 4 videos from an online medical communication library.²⁸ These scores were discussed to resolve any differences before 4 additional videos were independently viewed, scored, and compared. Interrater reliability was achieved when the standard deviation of summed SDM scores across raters was less than 1 for all 4 videos.

Patient Interviewers

Interviewers were English-speaking volunteers without formal medical training. They were educated in hospital etiquette by a physician and in administering patient interviews through peer-to-peer role playing and an observation and feedback interview with at least 1 patient.

Data Analysis

The analysis set included every unique patient with whom a medical decision was made by an eligible clinical team. To account for the nested study design (patient-level scores within rounds, rounds within attending, and attendings within service), we used mixed-effects models to estimate mean (summary or item) RPAD score by levels of fixed covariate(s). The models included random effects accounting for attending-level and round-level correlations among scores via variance components, and allowing the attending-level random effect to differ by service. Analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC). We used descriptive statistics to summarize round- and patient-level characteristics.

SDM Variation by Attending and Service

Box plots were used to summarize raw patient-level, Peer-RPAD scores by service and attending. By using the methods described above, we estimated the mean score overall and by service. In both models, we examined the statistical significance of service-specific variation in attending-level random effects by using likelihood-ratio test (LRT) to compare models.

SDM Variation by Round and Patient Characteristics

We used the models described above to identify covariates associated with Peer-RPAD scores. We fit univariate models separately for each covariate, then fit 2 multivariable models, including (1) all covariates and (2) all effects significant in either model at P ≤ .20 according to F tests. For uniformity of presentation, we express continuous covariates categorically; however, we report P values based on continuous versions. Means generated by the multivariable models were calculated at the mean values of all other covariates in model.

Patient-Level RPAD Data

A subsample of patients completed semistructured interviews with analogous RPAD questions. To identify possible selection bias in the full sample, we summarized response rates by service and patient language and modeled Peer-RPAD scores by interview response status. Among responders, we estimated the mean Peer-RPAD and Patient-RPAD scores and their paired differences and correlations, testing for non-zero correlations via the Spearman rank test.

All Patient Encounters

The median duration of rounding sessions was 1.8 hours, median patient census was 9, and median patient encounter was 13 minutes. The duration of rounds and minutes per patient were longest at Med-2 and shortest at Peds-1. See Table 1 for other team characteristics.

Peer Evaluations of SDM Encounters

Characteristics of Patients

Teams spent a median of 13 minutes per SDM encounter, which was not higher than the round median. SDM topics discussed included 47% treatment, 15% diagnostic, 30% both treatment and diagnostic, and 7% other.

Variation in SDM Quality Among Attending Physicians

Overall Peer-RPAD Scores were normally distributed. After adjusting for the nested study design, the overall mean (standard error) score was 4.16 (0.11). Score variability among attendings differed significantly by service (LRT P = .0067). For example, raw scores were lower and more variable among attending physicians at Med-2 than other among attendings in other services (see Appendix Figure in Supporting Information). However, when service was included in the model as a fixed effect, mean scores varied significantly, from 3.0 at Med-2 to 4.7 at Med-1 (P < .0001), but the random variation among attendings no longer differed significantly by service (P = .13). This finding supports the hypothesis that service-level influences are stronger than influences of individual attending physicians, that is, that variation between services exceeded variation among attendings within service.

Aspects of SDM That Are More Prevalent on Rounds

Rounds and Patient Characteristics Associated With Peer-RPAD Scores

Patient-RPAD Results: Dissimilar Perspectives of Patients and/or Guardians and Physician Observers

Among responders, mean Patient-RPAD scores were 6.8 to 7.1 for medicine services and 7.6 to 7.8 for pediatric services (P = .01). The overall mean Patient-RPAD score, 7.46, was significantly greater than the paired Peer-RPAD score by 3.5 (P = .011); however, correlations were not statistically significantly different from 0 (by service, each P > .12).

To understand drivers of the differences between Peer-RPAD and Patient-RPAD scores, we analyzed findings by item. Each mean patient-item score exceeded its peer counterpart (P ≤ .01; panel B of Figure). Peer-item scores fell below 33% on 2 items (Items 9 and 4) and only exceeded 67% on 2 items (Items 1 and 6), whereas patient-item scores ranged from 60% (Item 8) to 97% (Item 7). Three paired differences exceeded 50% (Items 9, 4, and 7) and 3 were below 20% (Items 6, 8 and 1), underlying the lack of correlation between peer and patient scores.

In this multisite study of SDM during inpatient attending rounds, SDM quality, specific SDM behaviors, and factors contributing to SDM were identified. Our study found an adjusted overall Peer-RPAD Score of 4.4 out of 9, and found the following 3 SDM elements most needing improvement according to trained peer observers: (1) “Checking understanding of the patient’s perspective”, (2) “Examining barriers to follow-through with the treatment plan”, and (3) “Asking if the patient has questions.” Areas of strength included explaining the clinical issue or nature of the decision and matching medical language to the patient’s level of understanding, with each rated highly by both peer-observers and patients. Broadly speaking, physicians were skillful in delivering information to patients but failed to solicit input from patients. Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient’s hospital stay, and amount of time rounding with each patient.

Patients similarly found that physicians could improve their abilities to elicit information from patients and families, noting the 3 lowest patient-rated SDM elements were as follows: (1) asking open-ended questions, (2) discussing alternatives or uncertainties, and (3) discussing barriers to treatment plan follow through. Overall, patients and guardians perceived the quantity and quality of SDM on rounds more favorably than peer observers, which is consistent with other studies of patient perceptions of communication. ^29-31 It is possible that patient ratings are more influenced by demand characteristics, fear of negatively impacting their patient-provider relationships, and conflation of overall satisfaction with quality of communication.³² This difference in patient perception of SDM is worthy of further study.

Prior work has revealed that SDM may occur infrequently during inpatient rounds.¹¹ This study further elucidates specific SDM behaviors used along with univariate and multivariate modeling to explore possible contributing factors. The strengths and weaknesses found were similar at all 4 services and the influence of the service was more important than variability across attendings. This study’s findings are similar to a study by Shields et al.,³³ in which the findings in a geographically different outpatient setting 10 years earlier suggesting global and enduring challenges to SDM. To our knowledge, this is the first published study to characterize inpatient SDM behaviors and may serve as the basis for future interventions.

Although the item-level components were ranked similarly across services, on average the summary Peer-RPAD score was lowest at Med-2, where we observed high variability within and between attendings, and was highest at Med-1, where variability was low. Med-2 carried the highest caseload and held the longest rounds, while Med-1 carried the lowest caseload, suggesting that modifiable burdens may hamper SDM performance. Prior studies suggest that patients are often selected based on teaching opportunities, immediate medical need and being newly admitted.³⁴ The high scores at Med-1 may reflect that service’s prediscussion of patients during card-flipping rounds or their selection of which patients to round on as a team. Consistent with prior studies^29,35 of SDM and the family-centered rounding model, which includes the involvement of nurses, respiratory therapists, pharmacists, case managers, social workers, and interpreters on rounds, both pediatrics services showed higher SDM scores.

In contrast to prior studies,^34,36 team size and number of learners did not affect SDM performance, nor did decision type. Despite teams having up to 17 members, 8 learners, and 14 complex patients, SDM scores did not vary significantly by team. Nonetheless, trends were in the directions expected: Scores tended to decrease as the team size or the percentage of trainees grew, and increased with the seniority of the presenting physician. Interestingly, SDM performance decreased with round-average minutes per patient, which may be measuring on-going intensity across cases that leads to exhaustion. Statistically significant patient factors for increased SDM included longer duration of patient encounters, second week of hospital stay, and female patient gender. Although we anticipated that the high number of decisions made early in hospitalization would facilitate higher SDM scores, continuity and stronger patient-provider relationships may enhance SDM.³⁶ We report service-specific team and patient characteristics, in addition to SDM findings in anticipation that some readers will identify with 1 service more than others.

This study has several important limitations. First, our peer observers were not blinded and primarily observed encounters at their own site. To minimize bias, observers periodically rated videos to recalibrate RPAD scoring. Second, additional SDM conversations with a patient and/or guardian may have occurred outside of rounds and were not captured, and poor patient recall may have affected Patient-RPAD scores despite interviewer prompts and timeliness of interviews within 12 hours of rounds. Third, there might have been a selection bias for the one service who selected a smaller number of patients to see, compared with the three other services that performed bedside rounds on all patients. It is possible that attending physicians selected patients who were deemed most able to have SDM conversations, thus affecting RPAD scores on that service. Fourth, study services had fewer patients on average than other academic hospitals (median 9, range 3-14), which might limit its generalizability. Last, as in any observational study, there is always the possibility of the Hawthorne effect. However, neither teams nor patients knew the study objectives.

Nevertheless, important findings emerged through the use of RPAD Scores to evaluate inpatient SDM practices. In particular, we found that to increase SDM quality in inpatient settings, practitioners should (1) check their understanding of the patient’s perspective, (2) examine barriers to follow-through with the treatment plan, and (3) ask if the patient has questions. Variation among services remained very influential after adjusting for team and patient characteristics, which suggests that “climate” or service culture should be targeted by an intervention, rather than individual attendings or subgroups defined by team or patient characteristics. Notably, team size, number of learners, patient census, and type of decision being made did not affect SDM performance, suggesting that even large, busy services can perform SDM if properly trained.

Acknowledgments

The authors thank the patients, families, pediatric and internal medicine residents, and hospitalists at Stanford School of Medicine and University of California, San Francisco School of Medicine for their participation in this study. We would also like to thank the student volunteers who collected patient perspectives on the encounters.

Disclosure 

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an NIH/NCCIH grant R25 AT006573.