A 59‐year‐old man with a history of hypertension was admitted with 6 months of shortness of breath, night sweats, and debilitating fatigue. His symptoms were initially mild and would persist for weeks at a time, after which he would feel better for several days. Over the 2 weeks prior to admission his symptoms had progressed, and he had become dyspneic with minimal exertion.

Progressive dyspnea has a broad differential that includes diseases of the heart (eg, congestive heart failure, aortic stenosis, constrictive pericarditis), lung (eg, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, pleural effusion), and blood (eg, anemia).

Night sweats suggest an inflammatory condition, but do not help prioritize infection, malignancy, or autoimmunity. Any of those conditions can be relapsing and remitting, at least in their early phases, but the return to normalcy raises the possibility of hypersensitivity pneumonitis from a periodic exposure.

The 6‐month duration makes typical bacterial and viral infections less likely and suggests indolent infections such as mycobacteria, fungi, or human immunodeficiency virus. Lymphoma or chronic leukemia could cause dyspnea through pleural or pulmonary involvement or from anemia. Autoimmune conditions such as systemic lupus erythematosus or adult Still's disease could also present with this course.

On admission, he described progressive orthopnea, lower extremity edema, and a 15‐lb weight gain. He denied chest pain or palpitations. His symptoms did not correlate with environmental or occupational exposures. He had been diagnosed with essential hypertension a few years earlier but was not taking any medications. He worked as an editor for a newspaper and had traveled throughout California. He never used tobacco and drank alcohol in moderation. He previously smoked marijuana. His father died of Alzheimer's disease, and his mother and 2 siblings were healthy.

Orthopnea, lower extremity edema, and weight gain suggest volume overload, which can result from heart failure, cirrhosis, renal failure, or nephrotic syndrome. The untreated hypertension is a principal risk factor for heart failure. Subacute bacterial endocarditis is an important consideration in a patient with suspected heart failure and night sweats. Travel through the central valley of California may have exposed him to coccidiodomycosis, which can cause chronic pulmonary and extrapulmonary infection.

Physical examination revealed a chronically ill‐appearing man in mild respiratory distress. His temperature was 37.2C, heart rate was 83 bpm, and blood pressure was 168/81 mm Hg. His oxygen saturation was 97% with a respiratory rate of 17 while breathing ambient air. Bilateral chemosis was present. He had crackles at the lung bases. There was a 2/6 systolic murmur loudest at the left lower sternal border with apical radiation. His jugular venous pressure was 2 cm above the sternal angle at 45. He had mild pitting edema of both lower extremities. His abdomen was soft and nondistended. He demonstrated full range of motion of all extremities and had no rashes. He was alert and oriented to person, place, and time. There were no cranial nerve deficits. His strength, sensation and coordination were intact, and he had a normal gait.

Chemosis (conjunctival edema) usually represents conjunctival irritation from an allergic, infectious, or toxic process. It can also be seen in cases of increased ophthalmic venous pressure such as hyperthyroid ophthalmopathy, superior vena cava syndrome, or carotid‐cavernous sinus fistula. The crackles, weight gain, borderline jugular venous distention, and edema suggest some systemic volume overload, but not enough to produce chemosis.

The location and timing of the murmur suggests regurgitation through the mitral or tricuspid valve, a ventricular septal defect, or hypertrophic cardiomyopathy. Tricuspid regurgitation may indicate pulmonary hypertension with right ventricular failure. Despite the absence of fever, subacute bacterial endocarditis remains a concern.

Laboratory evaluation revealed a white blood cell count of 9600/L, hemoglobin of 8.7 g/dL, and platelet count of 522,000/L. Mean corpuscular volume was 88 fL. Serum chemistries were normal; serum creatinine was 1.2 mg/dL. Serum albumin was 2.6 g/dL. A urinalysis was normal. An electrocardiogram demonstrated normal sinus rhythm and left ventricular hypertrophy (LVH). A chest x‐ray revealed interstitial edema and small bilateral pleural effusions. A transthoracic echocardiogram demonstrated normal left ventricular systolic function, an ejection fraction of 65%, mild LVH, and mild diastolic dysfunction. Mild mitral regurgitation, a mildly dilated left atrium, and a minimal pericardial effusion were also noted. A renal ultrasound revealed an atrophic left kidney without arterial flow. He was treated with diuretics for presumed heart failure related to diastolic dysfunction. His dyspnea partially improved, and he was discharged.

Heart failure with preserved ejection fraction may be contributing to his dyspnea but is unlikely to be entirely explanatory given the laboratory abnormalities. The absence of valvular vegetations on transthoracic echocardiogram lowers the probability of bacterial endocarditis. The interstitial pulmonary markings may represent pulmonary edema but alternatively could reflect interstitial lung disease, lymphangitic spread of cancer, infection (eg, Pneumocystis jiroveci), or diffuse alveolar hemorrhage.

Anemia may also be contributing to his dyspnea. There is no evidence of bleeding on history, examination, or imaging. Hemolysis is unlikely given the absence of jaundice, splenomegaly, or a known predisposing condition. The normocytic anemia may also arise from chronic inflammation. Severe anemia can cause high output heart failure, but usually the hemoglobin level is much lower and the echocardiogram would have suggestive findings. Thrombocytosis suggests inflammation, a primary myeloproliferative disorder, or severe iron deficiency (not suspected here). His hypoalbuminemia is further evidence of chronic inflammation especially in the absence of nephropathy, hepatopathy, or a protein‐losing enteropathy.

An atrophic kidney may be congenital or result from long‐standing unilateral renal ischemia, infection, or obstruction. Diminished arterial flow in a middle‐aged man with hypertension may simply reflect atherosclerotic renal artery stenosis, but mass effect within the left renal artery from thrombus, infection, or cancer cannot be ruled out.

Four weeks later he was readmitted for progressive dyspnea and persistent night sweats. He was afebrile, fatigued, and in marked respiratory distress. The remainder of his physical examination was unchanged. Laboratory evaluation revealed a white blood cell count of 20,000/L with neutrophilic predominance, hemoglobin of 11 g/dL, and platelet count of 614,000/L. Creatinine was 1.4 mg/dL. Erythrocyte sedimentation rate (ESR) was greater than 100 mm/h, and C‐reactive protein (CRP) was 44 mg/L. Blood cultures were negative. Chest x‐ray (Figure 1) revealed persistent interstitial edema and increased bilateral pleural effusions.

Figure 1

Although clinical and radiologic features continue to suggest heart failure, the marked respiratory distress and persistent chest x‐ray abnormalities imply that a superimposed process is affecting the lungs. The night sweats, neutrophilia, and elevated ESR and CRP strongly suggest an inflammatory state from infection, malignancy, or autoimmunity.

A computed tomography (CT) scan of the lungs would help assess for interstitial lung disease, lymphangitic carcinomatosis and septic emboli. Blood cultures should be repeated to definitively exclude subacute endocarditis. A peripheral blood smear is needed to evaluate for hematologic malignancy. Finally, human immunodeficiency virus antibody testing is indicated.

CT of the abdomen and pelvis demonstrated left renal artery stenosis, an atrophic left kidney, right kidney edema with mild perinephric stranding, and mild‐to‐moderate right hydroureter without an obstructing mass or calculus. There was mild splenomegaly and mesenteric lymphadenopathy up to 3 cm in diameter. The distal thoracic and suprarenal abdominal aorta had crescentic high‐density wall thickening. There were small sclerotic densities of the proximal femora, pelvic girdle, and thoracolumbar spine (Figure 2). Contrast chest CT demonstrated severe wall thickening of his entire thoracic aorta. There was also cardiomegaly, mild interlobular septal thickening, small bilateral pleural effusions, a 3.2‐cm right upper lobe paratracheal lymph node, and nodular pleural thickening (Figure 3).

Figure 2

Figure 3

Diffuse aortopathy is caused by inflammatory, infectious, or infiltrative processes. Large vessel vasculitides such as Behet's disease, giant cell arteritis, and Takayasu's arteritis are unlikely, as the patient lacks the associated clinical findings or epidemiology. Imaging does not reveal preexisting aortic pathology, such as an aneurysm or atherosclerotic plaque, which could predispose him to bacterial endovascular infection.

Urinary system dilation without an obvious obstruction could be explained by retroperitoneal fibrosis. Generalized lymphadenopathy, (suspected) retroperitoneal fibrosis, sclerotic bone lesions, and cardiopulmonary disease collectively suggest a widespread infiltrative process. Lymphoma may lead to lymphadenopathy and bone lesions but would not explain the aortopathy. He lacks risk factors for infections like tuberculosis or tertiary syphilis, a well‐known cause of aortopathy in the past.

Widespread multisystem involvement invites consideration of nonmalignant, noninfectious infiltrative disorders such as immunoglobulin G4‐related disease (IgG4‐RD), histiocytoses such as Erdheim‐Chester disease (ECD), systemic mastocytosis (SM), and sarcoidosis. ECD is a disorder of non‐Langerhans histiocytes that infiltrate the aorta, bones, retroperitoneum, lungs, myocardium, and periorbital structures. Perinephric stranding is sometimes seen in this condition. The lymphoplasmacytes in IgG4‐RD and noncaseating granulomas of sarcoidosis infiltrate many of the same organs. Common sites infiltrated by mast cells in SM include the bone and lymph nodes. Among these diseases, ECD and IgG4‐RD more commonly manifest with aortic and retroperitoneal infiltration and thus are prioritized on this differential diagnosis.

A positron emission tomography (PET) scan revealed abnormal fluordeoxyglucose uptake involving the thoracic aorta, right apical pleural surface, perinephric soft tissue, and various marrow spaces. Core needle biopsy of a sclerotic lesion in the right ischium demonstrated focal marrow replacement by a fibrohistiocytic process. No malignant cells or pathogenic organisms were identified. Biopsy of the right kidney revealed chronic interstitial nephritis with features of megalocytic interstitial nephritis (histiocytic inflammation) and arteriolar nephrosclerosis. A transbronchial biopsy demonstrated alveolar tissue with focal intra‐alveolar hemorrhage and organization, but no malignancy, atypia, or pathogenic organisms.

The biopsy results do not support infection, lymphoma, or carcinoma. The absence of noncaseating granulomas and mastocytes on multiple biopsies essentially rules out sarcoidosis and SM, respectively. None of the characteristic pathologic features of IgG4‐RDlymphoplasmacytic infiltrate, obliterative phlebitis, and fibrosiswere observed. The pulmonary pathology points to injury, but not the underlying cause. The bone and kidney tissue samples reveal histiocytic infiltration.

The abnormalities of the aorta, bone, lung, kidney, and retroperitoneum can be explained by the diffuse histiocytic involvement seen in ECD. The perinephric stranding detected on CT and perinephric inflammation on the PET scan may reflect the hairy kidney of ECD, which is a result of histiocytic infiltration. It is possible that the chemosis relates to exophthalmos from histiocytic orbital infiltrates. Sensitivity for detecting orbital pathology on a PET scan is limited because of the high signal from the adjacent brain.

ECD should be distinguished from Langerhans cell histiocytosis (LCH) by immunohistologic staining and microscopic characteristics of the histiocytes. LCH usually does not involve the aorta, and it more commonly involves the skin.

Serum IgG4 was within normal limits, and immunohistochemical staining of pathology specimens for IgG4 was negative. The BRAF V600E mutation, which is present in the majority of patients with ECD, was detected in a subsequent right perinephric biopsy specimen. The patient was diagnosed with ECD.

Prednisone and pegylated interferon‐ led to a rapid improvement in his symptoms. As the prednisone was tapered, he developed bilateral periorbital swelling. Magnetic resonance imaging (MRI) revealed well‐circumscribed, intraorbital soft tissue masses with partial encasement of his optic nerves and superior ophthalmic veins, as well as infiltration of his transverse sinuses, consistent with intracranial manifestations of ECD. There was no evidence of pituitary, hypothalamic, or other brain parenchymal infiltration. His dyspnea, night sweats, and hypertension improved; however, 3 months into therapy he developed an extensive rash. Interferon was discontinued. Vemurafinib, a serine kinase inhibitor that targets the BRAF mutation, was prescribed with subsequent resolution of the rash.

COMMENTARY

This patient suffered from a chronic, progressive, inflammatory illness. Although the disease initially appeared to be confined to the heart and lungs, laboratory testing signaled a more systemic condition, and subsequent imaging demonstrated involvement of a disparate group of organs. Subacute disease processes with elevated markers of inflammation and diffuse organ involvement often fall into 1 of 3 categories: infectious, autoimmune, or neoplastic. The histiocytoses inhabit a fourth and easily overlooked category that can be described as infiltrative. Infiltrative diseases are a heterogeneous group of conditions that cause illness when cells or substances not normally found in tissues lead to organ dysfunction.

Although traditional teaching has focused on sarcoidosis, amyloidosis, and hemochromatosis as the primary representatives of this category, the medical literature describes a number of other infiltrative disease processes. IgG4‐RD is a fibroinflammatory disorder characterized by space‐occupying lesions, a lymphoplasmacytic infiltrate of IgG4‐positive plasma cells, and storiform (matted and irregularly whorled microscopic pattern) fibrosis.[1] IgG4‐RD, like sarcoidosis, blurs the categorical line between infiltrative and autoimmune diseases. Other infiltrative cellular disorders, such as histiocytosis and mastocytosis, exist on a spectrum between monoclonal proliferation and neoplastic invasion.

The histiocytoses represent a diverse group of disorders with an evolving nomenclature, characterized by localized or diffuse infiltration of macrophages, monocytes, and dendritic cells (Table 1). ECD is a rare, non‐Langerhans histiocytosis characterized by excessive recruitment and activation of histiocytes through kinase signaling pathways.[2, 3] Immunohistochemical staining for CD68, CD163, and Factor XIIIa, with lack of staining for CD1a, S100, and CD207, supports the diagnosis.[3] Mutations in the BRAF V600E gene (a protein kinase involved in cell proliferation) represent the most likely etiology of this overactivation. An estimated 38% to 100% of patients with ECD harbor this mutation, with detection rates influenced by the sensitivity of testing techniques.[3] The serine kinase inhibitor vemurafinib targets this mutation, and early experience with this agent in ECD demonstrates encouraging results.[4]

ECD presents heterogeneously, occurring most commonly between the ages of 40 and 70 years. Nonspecific symptoms include weakness, fatigue, fever, chills, weight loss, and night sweats. Typical sites of involvement include the bone, central nervous system, cardiovascular system, lungs, and retroperitoneum. Bone involvement is nearly universal, and bone pain is the most common presenting symptom. Symmetric diaphyseal and metaphyseal osteosclerotic lesions may be seen on x‐rays, bone scan, PET, CT, and MRI.[3] Approximately 50% of patients have extraskeletal involvement at diagnosis.[5] Neurologic manifestations may result from invasion of histiocytes into the facial bones, orbits, meninges, and intracranial vessels, as eventually developed in this patient. Diabetes insipidus is the most common neurologic manifestation of ECD, followed by exophthalmos, cerebellar ataxia, panhypopituitarism, and papilledema.[6, 7] Approximately 75% of patients eventually suffer from cardiovascular disease, including hypertension, congestive heart failure, acute myocardial infarction, valvular dysfunction, pericardial infiltration, and cardiac tamponade.[8] Vascular involvement includes perivascular infiltration and periaortic fibrosis, resulting in the coated aorta seen in 20% of patients with ECD.[3] Pulmonary manifestations of ECD include interstitial, pleural, and consolidative lung disease. A review of high‐resolution chest CTs of patients with ECD demonstrated that greater than half had evidence of parenchymal lung disease, with interlobular septal thickening being the most common finding.[9] Infiltration and fibrosis of retroperitoneal structures is common. Infiltration of perinephric fat creates irregular renal borders, appearing radiographically as hairy kidneys.

Arriving at the diagnosis in this case proved to be challenging because the early presentation was consistent with congestive heart failure. As the patient's conditioned deteriorated, imaging suggested multisystem involvement. It was the extensive aortopathy in particularnot the less specific bone, kidney, lymph node, or pulmonary findingsthat allowed the clinicians to hone the extensive differential diagnosis. The coated aorta is a finding that has been strongly associated with ECD; few other conditions coat the aorta in a similar fashion.[10] In most mysteries, the perpetrator's coat conceals his identity; however, in this story the coat gave it away.

KEY LEARNING POINTS

1. Subacute, inflammatory, multiorgan disease is usually explained by 3 categoriesinfection, autoimmunity, and neoplasiabut a fourth category, infiltrative disorders, sometimes warrants consideration.
2. ECD presents heterogeneously, ranging from localized disease to widespread organ infiltration. The classic presentation includes bone pain, diabetes insipidus, and exophthalmos.
3. Characteristic radiological findings that suggest ECD include long bone osteosclerosis, a coated aorta from periaortic infiltration, and hairy kidneys from perinephric infiltration.

Disclosure

Nothing to report

A 59‐year‐old man with a history of hypertension was admitted with 6 months of shortness of breath, night sweats, and debilitating fatigue. His symptoms were initially mild and would persist for weeks at a time, after which he would feel better for several days. Over the 2 weeks prior to admission his symptoms had progressed, and he had become dyspneic with minimal exertion.

Progressive dyspnea has a broad differential that includes diseases of the heart (eg, congestive heart failure, aortic stenosis, constrictive pericarditis), lung (eg, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, pleural effusion), and blood (eg, anemia).

Night sweats suggest an inflammatory condition, but do not help prioritize infection, malignancy, or autoimmunity. Any of those conditions can be relapsing and remitting, at least in their early phases, but the return to normalcy raises the possibility of hypersensitivity pneumonitis from a periodic exposure.

The 6‐month duration makes typical bacterial and viral infections less likely and suggests indolent infections such as mycobacteria, fungi, or human immunodeficiency virus. Lymphoma or chronic leukemia could cause dyspnea through pleural or pulmonary involvement or from anemia. Autoimmune conditions such as systemic lupus erythematosus or adult Still's disease could also present with this course.

On admission, he described progressive orthopnea, lower extremity edema, and a 15‐lb weight gain. He denied chest pain or palpitations. His symptoms did not correlate with environmental or occupational exposures. He had been diagnosed with essential hypertension a few years earlier but was not taking any medications. He worked as an editor for a newspaper and had traveled throughout California. He never used tobacco and drank alcohol in moderation. He previously smoked marijuana. His father died of Alzheimer's disease, and his mother and 2 siblings were healthy.

Orthopnea, lower extremity edema, and weight gain suggest volume overload, which can result from heart failure, cirrhosis, renal failure, or nephrotic syndrome. The untreated hypertension is a principal risk factor for heart failure. Subacute bacterial endocarditis is an important consideration in a patient with suspected heart failure and night sweats. Travel through the central valley of California may have exposed him to coccidiodomycosis, which can cause chronic pulmonary and extrapulmonary infection.

Physical examination revealed a chronically ill‐appearing man in mild respiratory distress. His temperature was 37.2C, heart rate was 83 bpm, and blood pressure was 168/81 mm Hg. His oxygen saturation was 97% with a respiratory rate of 17 while breathing ambient air. Bilateral chemosis was present. He had crackles at the lung bases. There was a 2/6 systolic murmur loudest at the left lower sternal border with apical radiation. His jugular venous pressure was 2 cm above the sternal angle at 45. He had mild pitting edema of both lower extremities. His abdomen was soft and nondistended. He demonstrated full range of motion of all extremities and had no rashes. He was alert and oriented to person, place, and time. There were no cranial nerve deficits. His strength, sensation and coordination were intact, and he had a normal gait.

Chemosis (conjunctival edema) usually represents conjunctival irritation from an allergic, infectious, or toxic process. It can also be seen in cases of increased ophthalmic venous pressure such as hyperthyroid ophthalmopathy, superior vena cava syndrome, or carotid‐cavernous sinus fistula. The crackles, weight gain, borderline jugular venous distention, and edema suggest some systemic volume overload, but not enough to produce chemosis.

The location and timing of the murmur suggests regurgitation through the mitral or tricuspid valve, a ventricular septal defect, or hypertrophic cardiomyopathy. Tricuspid regurgitation may indicate pulmonary hypertension with right ventricular failure. Despite the absence of fever, subacute bacterial endocarditis remains a concern.

Laboratory evaluation revealed a white blood cell count of 9600/L, hemoglobin of 8.7 g/dL, and platelet count of 522,000/L. Mean corpuscular volume was 88 fL. Serum chemistries were normal; serum creatinine was 1.2 mg/dL. Serum albumin was 2.6 g/dL. A urinalysis was normal. An electrocardiogram demonstrated normal sinus rhythm and left ventricular hypertrophy (LVH). A chest x‐ray revealed interstitial edema and small bilateral pleural effusions. A transthoracic echocardiogram demonstrated normal left ventricular systolic function, an ejection fraction of 65%, mild LVH, and mild diastolic dysfunction. Mild mitral regurgitation, a mildly dilated left atrium, and a minimal pericardial effusion were also noted. A renal ultrasound revealed an atrophic left kidney without arterial flow. He was treated with diuretics for presumed heart failure related to diastolic dysfunction. His dyspnea partially improved, and he was discharged.

Heart failure with preserved ejection fraction may be contributing to his dyspnea but is unlikely to be entirely explanatory given the laboratory abnormalities. The absence of valvular vegetations on transthoracic echocardiogram lowers the probability of bacterial endocarditis. The interstitial pulmonary markings may represent pulmonary edema but alternatively could reflect interstitial lung disease, lymphangitic spread of cancer, infection (eg, Pneumocystis jiroveci), or diffuse alveolar hemorrhage.

Anemia may also be contributing to his dyspnea. There is no evidence of bleeding on history, examination, or imaging. Hemolysis is unlikely given the absence of jaundice, splenomegaly, or a known predisposing condition. The normocytic anemia may also arise from chronic inflammation. Severe anemia can cause high output heart failure, but usually the hemoglobin level is much lower and the echocardiogram would have suggestive findings. Thrombocytosis suggests inflammation, a primary myeloproliferative disorder, or severe iron deficiency (not suspected here). His hypoalbuminemia is further evidence of chronic inflammation especially in the absence of nephropathy, hepatopathy, or a protein‐losing enteropathy.

An atrophic kidney may be congenital or result from long‐standing unilateral renal ischemia, infection, or obstruction. Diminished arterial flow in a middle‐aged man with hypertension may simply reflect atherosclerotic renal artery stenosis, but mass effect within the left renal artery from thrombus, infection, or cancer cannot be ruled out.

Four weeks later he was readmitted for progressive dyspnea and persistent night sweats. He was afebrile, fatigued, and in marked respiratory distress. The remainder of his physical examination was unchanged. Laboratory evaluation revealed a white blood cell count of 20,000/L with neutrophilic predominance, hemoglobin of 11 g/dL, and platelet count of 614,000/L. Creatinine was 1.4 mg/dL. Erythrocyte sedimentation rate (ESR) was greater than 100 mm/h, and C‐reactive protein (CRP) was 44 mg/L. Blood cultures were negative. Chest x‐ray (Figure 1) revealed persistent interstitial edema and increased bilateral pleural effusions.

Figure 1

Although clinical and radiologic features continue to suggest heart failure, the marked respiratory distress and persistent chest x‐ray abnormalities imply that a superimposed process is affecting the lungs. The night sweats, neutrophilia, and elevated ESR and CRP strongly suggest an inflammatory state from infection, malignancy, or autoimmunity.

A computed tomography (CT) scan of the lungs would help assess for interstitial lung disease, lymphangitic carcinomatosis and septic emboli. Blood cultures should be repeated to definitively exclude subacute endocarditis. A peripheral blood smear is needed to evaluate for hematologic malignancy. Finally, human immunodeficiency virus antibody testing is indicated.

CT of the abdomen and pelvis demonstrated left renal artery stenosis, an atrophic left kidney, right kidney edema with mild perinephric stranding, and mild‐to‐moderate right hydroureter without an obstructing mass or calculus. There was mild splenomegaly and mesenteric lymphadenopathy up to 3 cm in diameter. The distal thoracic and suprarenal abdominal aorta had crescentic high‐density wall thickening. There were small sclerotic densities of the proximal femora, pelvic girdle, and thoracolumbar spine (Figure 2). Contrast chest CT demonstrated severe wall thickening of his entire thoracic aorta. There was also cardiomegaly, mild interlobular septal thickening, small bilateral pleural effusions, a 3.2‐cm right upper lobe paratracheal lymph node, and nodular pleural thickening (Figure 3).

Figure 2

Figure 3

Diffuse aortopathy is caused by inflammatory, infectious, or infiltrative processes. Large vessel vasculitides such as Behet's disease, giant cell arteritis, and Takayasu's arteritis are unlikely, as the patient lacks the associated clinical findings or epidemiology. Imaging does not reveal preexisting aortic pathology, such as an aneurysm or atherosclerotic plaque, which could predispose him to bacterial endovascular infection.

Urinary system dilation without an obvious obstruction could be explained by retroperitoneal fibrosis. Generalized lymphadenopathy, (suspected) retroperitoneal fibrosis, sclerotic bone lesions, and cardiopulmonary disease collectively suggest a widespread infiltrative process. Lymphoma may lead to lymphadenopathy and bone lesions but would not explain the aortopathy. He lacks risk factors for infections like tuberculosis or tertiary syphilis, a well‐known cause of aortopathy in the past.

Widespread multisystem involvement invites consideration of nonmalignant, noninfectious infiltrative disorders such as immunoglobulin G4‐related disease (IgG4‐RD), histiocytoses such as Erdheim‐Chester disease (ECD), systemic mastocytosis (SM), and sarcoidosis. ECD is a disorder of non‐Langerhans histiocytes that infiltrate the aorta, bones, retroperitoneum, lungs, myocardium, and periorbital structures. Perinephric stranding is sometimes seen in this condition. The lymphoplasmacytes in IgG4‐RD and noncaseating granulomas of sarcoidosis infiltrate many of the same organs. Common sites infiltrated by mast cells in SM include the bone and lymph nodes. Among these diseases, ECD and IgG4‐RD more commonly manifest with aortic and retroperitoneal infiltration and thus are prioritized on this differential diagnosis.

A positron emission tomography (PET) scan revealed abnormal fluordeoxyglucose uptake involving the thoracic aorta, right apical pleural surface, perinephric soft tissue, and various marrow spaces. Core needle biopsy of a sclerotic lesion in the right ischium demonstrated focal marrow replacement by a fibrohistiocytic process. No malignant cells or pathogenic organisms were identified. Biopsy of the right kidney revealed chronic interstitial nephritis with features of megalocytic interstitial nephritis (histiocytic inflammation) and arteriolar nephrosclerosis. A transbronchial biopsy demonstrated alveolar tissue with focal intra‐alveolar hemorrhage and organization, but no malignancy, atypia, or pathogenic organisms.

The biopsy results do not support infection, lymphoma, or carcinoma. The absence of noncaseating granulomas and mastocytes on multiple biopsies essentially rules out sarcoidosis and SM, respectively. None of the characteristic pathologic features of IgG4‐RDlymphoplasmacytic infiltrate, obliterative phlebitis, and fibrosiswere observed. The pulmonary pathology points to injury, but not the underlying cause. The bone and kidney tissue samples reveal histiocytic infiltration.

The abnormalities of the aorta, bone, lung, kidney, and retroperitoneum can be explained by the diffuse histiocytic involvement seen in ECD. The perinephric stranding detected on CT and perinephric inflammation on the PET scan may reflect the hairy kidney of ECD, which is a result of histiocytic infiltration. It is possible that the chemosis relates to exophthalmos from histiocytic orbital infiltrates. Sensitivity for detecting orbital pathology on a PET scan is limited because of the high signal from the adjacent brain.

ECD should be distinguished from Langerhans cell histiocytosis (LCH) by immunohistologic staining and microscopic characteristics of the histiocytes. LCH usually does not involve the aorta, and it more commonly involves the skin.

Serum IgG4 was within normal limits, and immunohistochemical staining of pathology specimens for IgG4 was negative. The BRAF V600E mutation, which is present in the majority of patients with ECD, was detected in a subsequent right perinephric biopsy specimen. The patient was diagnosed with ECD.

Prednisone and pegylated interferon‐ led to a rapid improvement in his symptoms. As the prednisone was tapered, he developed bilateral periorbital swelling. Magnetic resonance imaging (MRI) revealed well‐circumscribed, intraorbital soft tissue masses with partial encasement of his optic nerves and superior ophthalmic veins, as well as infiltration of his transverse sinuses, consistent with intracranial manifestations of ECD. There was no evidence of pituitary, hypothalamic, or other brain parenchymal infiltration. His dyspnea, night sweats, and hypertension improved; however, 3 months into therapy he developed an extensive rash. Interferon was discontinued. Vemurafinib, a serine kinase inhibitor that targets the BRAF mutation, was prescribed with subsequent resolution of the rash.

COMMENTARY

This patient suffered from a chronic, progressive, inflammatory illness. Although the disease initially appeared to be confined to the heart and lungs, laboratory testing signaled a more systemic condition, and subsequent imaging demonstrated involvement of a disparate group of organs. Subacute disease processes with elevated markers of inflammation and diffuse organ involvement often fall into 1 of 3 categories: infectious, autoimmune, or neoplastic. The histiocytoses inhabit a fourth and easily overlooked category that can be described as infiltrative. Infiltrative diseases are a heterogeneous group of conditions that cause illness when cells or substances not normally found in tissues lead to organ dysfunction.

Although traditional teaching has focused on sarcoidosis, amyloidosis, and hemochromatosis as the primary representatives of this category, the medical literature describes a number of other infiltrative disease processes. IgG4‐RD is a fibroinflammatory disorder characterized by space‐occupying lesions, a lymphoplasmacytic infiltrate of IgG4‐positive plasma cells, and storiform (matted and irregularly whorled microscopic pattern) fibrosis.[1] IgG4‐RD, like sarcoidosis, blurs the categorical line between infiltrative and autoimmune diseases. Other infiltrative cellular disorders, such as histiocytosis and mastocytosis, exist on a spectrum between monoclonal proliferation and neoplastic invasion.

The histiocytoses represent a diverse group of disorders with an evolving nomenclature, characterized by localized or diffuse infiltration of macrophages, monocytes, and dendritic cells (Table 1). ECD is a rare, non‐Langerhans histiocytosis characterized by excessive recruitment and activation of histiocytes through kinase signaling pathways.[2, 3] Immunohistochemical staining for CD68, CD163, and Factor XIIIa, with lack of staining for CD1a, S100, and CD207, supports the diagnosis.[3] Mutations in the BRAF V600E gene (a protein kinase involved in cell proliferation) represent the most likely etiology of this overactivation. An estimated 38% to 100% of patients with ECD harbor this mutation, with detection rates influenced by the sensitivity of testing techniques.[3] The serine kinase inhibitor vemurafinib targets this mutation, and early experience with this agent in ECD demonstrates encouraging results.[4]

ECD presents heterogeneously, occurring most commonly between the ages of 40 and 70 years. Nonspecific symptoms include weakness, fatigue, fever, chills, weight loss, and night sweats. Typical sites of involvement include the bone, central nervous system, cardiovascular system, lungs, and retroperitoneum. Bone involvement is nearly universal, and bone pain is the most common presenting symptom. Symmetric diaphyseal and metaphyseal osteosclerotic lesions may be seen on x‐rays, bone scan, PET, CT, and MRI.[3] Approximately 50% of patients have extraskeletal involvement at diagnosis.[5] Neurologic manifestations may result from invasion of histiocytes into the facial bones, orbits, meninges, and intracranial vessels, as eventually developed in this patient. Diabetes insipidus is the most common neurologic manifestation of ECD, followed by exophthalmos, cerebellar ataxia, panhypopituitarism, and papilledema.[6, 7] Approximately 75% of patients eventually suffer from cardiovascular disease, including hypertension, congestive heart failure, acute myocardial infarction, valvular dysfunction, pericardial infiltration, and cardiac tamponade.[8] Vascular involvement includes perivascular infiltration and periaortic fibrosis, resulting in the coated aorta seen in 20% of patients with ECD.[3] Pulmonary manifestations of ECD include interstitial, pleural, and consolidative lung disease. A review of high‐resolution chest CTs of patients with ECD demonstrated that greater than half had evidence of parenchymal lung disease, with interlobular septal thickening being the most common finding.[9] Infiltration and fibrosis of retroperitoneal structures is common. Infiltration of perinephric fat creates irregular renal borders, appearing radiographically as hairy kidneys.

Arriving at the diagnosis in this case proved to be challenging because the early presentation was consistent with congestive heart failure. As the patient's conditioned deteriorated, imaging suggested multisystem involvement. It was the extensive aortopathy in particularnot the less specific bone, kidney, lymph node, or pulmonary findingsthat allowed the clinicians to hone the extensive differential diagnosis. The coated aorta is a finding that has been strongly associated with ECD; few other conditions coat the aorta in a similar fashion.[10] In most mysteries, the perpetrator's coat conceals his identity; however, in this story the coat gave it away.

KEY LEARNING POINTS

1. Subacute, inflammatory, multiorgan disease is usually explained by 3 categoriesinfection, autoimmunity, and neoplasiabut a fourth category, infiltrative disorders, sometimes warrants consideration.
2. ECD presents heterogeneously, ranging from localized disease to widespread organ infiltration. The classic presentation includes bone pain, diabetes insipidus, and exophthalmos.
3. Characteristic radiological findings that suggest ECD include long bone osteosclerosis, a coated aorta from periaortic infiltration, and hairy kidneys from perinephric infiltration.

Disclosure

Nothing to report

A 59‐year‐old man with a history of hypertension was admitted with 6 months of shortness of breath, night sweats, and debilitating fatigue. His symptoms were initially mild and would persist for weeks at a time, after which he would feel better for several days. Over the 2 weeks prior to admission his symptoms had progressed, and he had become dyspneic with minimal exertion.

Progressive dyspnea has a broad differential that includes diseases of the heart (eg, congestive heart failure, aortic stenosis, constrictive pericarditis), lung (eg, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, pleural effusion), and blood (eg, anemia).

Night sweats suggest an inflammatory condition, but do not help prioritize infection, malignancy, or autoimmunity. Any of those conditions can be relapsing and remitting, at least in their early phases, but the return to normalcy raises the possibility of hypersensitivity pneumonitis from a periodic exposure.

The 6‐month duration makes typical bacterial and viral infections less likely and suggests indolent infections such as mycobacteria, fungi, or human immunodeficiency virus. Lymphoma or chronic leukemia could cause dyspnea through pleural or pulmonary involvement or from anemia. Autoimmune conditions such as systemic lupus erythematosus or adult Still's disease could also present with this course.

On admission, he described progressive orthopnea, lower extremity edema, and a 15‐lb weight gain. He denied chest pain or palpitations. His symptoms did not correlate with environmental or occupational exposures. He had been diagnosed with essential hypertension a few years earlier but was not taking any medications. He worked as an editor for a newspaper and had traveled throughout California. He never used tobacco and drank alcohol in moderation. He previously smoked marijuana. His father died of Alzheimer's disease, and his mother and 2 siblings were healthy.

Orthopnea, lower extremity edema, and weight gain suggest volume overload, which can result from heart failure, cirrhosis, renal failure, or nephrotic syndrome. The untreated hypertension is a principal risk factor for heart failure. Subacute bacterial endocarditis is an important consideration in a patient with suspected heart failure and night sweats. Travel through the central valley of California may have exposed him to coccidiodomycosis, which can cause chronic pulmonary and extrapulmonary infection.

Physical examination revealed a chronically ill‐appearing man in mild respiratory distress. His temperature was 37.2C, heart rate was 83 bpm, and blood pressure was 168/81 mm Hg. His oxygen saturation was 97% with a respiratory rate of 17 while breathing ambient air. Bilateral chemosis was present. He had crackles at the lung bases. There was a 2/6 systolic murmur loudest at the left lower sternal border with apical radiation. His jugular venous pressure was 2 cm above the sternal angle at 45. He had mild pitting edema of both lower extremities. His abdomen was soft and nondistended. He demonstrated full range of motion of all extremities and had no rashes. He was alert and oriented to person, place, and time. There were no cranial nerve deficits. His strength, sensation and coordination were intact, and he had a normal gait.

Chemosis (conjunctival edema) usually represents conjunctival irritation from an allergic, infectious, or toxic process. It can also be seen in cases of increased ophthalmic venous pressure such as hyperthyroid ophthalmopathy, superior vena cava syndrome, or carotid‐cavernous sinus fistula. The crackles, weight gain, borderline jugular venous distention, and edema suggest some systemic volume overload, but not enough to produce chemosis.

The location and timing of the murmur suggests regurgitation through the mitral or tricuspid valve, a ventricular septal defect, or hypertrophic cardiomyopathy. Tricuspid regurgitation may indicate pulmonary hypertension with right ventricular failure. Despite the absence of fever, subacute bacterial endocarditis remains a concern.

Laboratory evaluation revealed a white blood cell count of 9600/L, hemoglobin of 8.7 g/dL, and platelet count of 522,000/L. Mean corpuscular volume was 88 fL. Serum chemistries were normal; serum creatinine was 1.2 mg/dL. Serum albumin was 2.6 g/dL. A urinalysis was normal. An electrocardiogram demonstrated normal sinus rhythm and left ventricular hypertrophy (LVH). A chest x‐ray revealed interstitial edema and small bilateral pleural effusions. A transthoracic echocardiogram demonstrated normal left ventricular systolic function, an ejection fraction of 65%, mild LVH, and mild diastolic dysfunction. Mild mitral regurgitation, a mildly dilated left atrium, and a minimal pericardial effusion were also noted. A renal ultrasound revealed an atrophic left kidney without arterial flow. He was treated with diuretics for presumed heart failure related to diastolic dysfunction. His dyspnea partially improved, and he was discharged.

Heart failure with preserved ejection fraction may be contributing to his dyspnea but is unlikely to be entirely explanatory given the laboratory abnormalities. The absence of valvular vegetations on transthoracic echocardiogram lowers the probability of bacterial endocarditis. The interstitial pulmonary markings may represent pulmonary edema but alternatively could reflect interstitial lung disease, lymphangitic spread of cancer, infection (eg, Pneumocystis jiroveci), or diffuse alveolar hemorrhage.

Anemia may also be contributing to his dyspnea. There is no evidence of bleeding on history, examination, or imaging. Hemolysis is unlikely given the absence of jaundice, splenomegaly, or a known predisposing condition. The normocytic anemia may also arise from chronic inflammation. Severe anemia can cause high output heart failure, but usually the hemoglobin level is much lower and the echocardiogram would have suggestive findings. Thrombocytosis suggests inflammation, a primary myeloproliferative disorder, or severe iron deficiency (not suspected here). His hypoalbuminemia is further evidence of chronic inflammation especially in the absence of nephropathy, hepatopathy, or a protein‐losing enteropathy.

An atrophic kidney may be congenital or result from long‐standing unilateral renal ischemia, infection, or obstruction. Diminished arterial flow in a middle‐aged man with hypertension may simply reflect atherosclerotic renal artery stenosis, but mass effect within the left renal artery from thrombus, infection, or cancer cannot be ruled out.

Four weeks later he was readmitted for progressive dyspnea and persistent night sweats. He was afebrile, fatigued, and in marked respiratory distress. The remainder of his physical examination was unchanged. Laboratory evaluation revealed a white blood cell count of 20,000/L with neutrophilic predominance, hemoglobin of 11 g/dL, and platelet count of 614,000/L. Creatinine was 1.4 mg/dL. Erythrocyte sedimentation rate (ESR) was greater than 100 mm/h, and C‐reactive protein (CRP) was 44 mg/L. Blood cultures were negative. Chest x‐ray (Figure 1) revealed persistent interstitial edema and increased bilateral pleural effusions.

Figure 1

Although clinical and radiologic features continue to suggest heart failure, the marked respiratory distress and persistent chest x‐ray abnormalities imply that a superimposed process is affecting the lungs. The night sweats, neutrophilia, and elevated ESR and CRP strongly suggest an inflammatory state from infection, malignancy, or autoimmunity.

A computed tomography (CT) scan of the lungs would help assess for interstitial lung disease, lymphangitic carcinomatosis and septic emboli. Blood cultures should be repeated to definitively exclude subacute endocarditis. A peripheral blood smear is needed to evaluate for hematologic malignancy. Finally, human immunodeficiency virus antibody testing is indicated.

CT of the abdomen and pelvis demonstrated left renal artery stenosis, an atrophic left kidney, right kidney edema with mild perinephric stranding, and mild‐to‐moderate right hydroureter without an obstructing mass or calculus. There was mild splenomegaly and mesenteric lymphadenopathy up to 3 cm in diameter. The distal thoracic and suprarenal abdominal aorta had crescentic high‐density wall thickening. There were small sclerotic densities of the proximal femora, pelvic girdle, and thoracolumbar spine (Figure 2). Contrast chest CT demonstrated severe wall thickening of his entire thoracic aorta. There was also cardiomegaly, mild interlobular septal thickening, small bilateral pleural effusions, a 3.2‐cm right upper lobe paratracheal lymph node, and nodular pleural thickening (Figure 3).

Figure 2

Figure 3

Diffuse aortopathy is caused by inflammatory, infectious, or infiltrative processes. Large vessel vasculitides such as Behet's disease, giant cell arteritis, and Takayasu's arteritis are unlikely, as the patient lacks the associated clinical findings or epidemiology. Imaging does not reveal preexisting aortic pathology, such as an aneurysm or atherosclerotic plaque, which could predispose him to bacterial endovascular infection.

Urinary system dilation without an obvious obstruction could be explained by retroperitoneal fibrosis. Generalized lymphadenopathy, (suspected) retroperitoneal fibrosis, sclerotic bone lesions, and cardiopulmonary disease collectively suggest a widespread infiltrative process. Lymphoma may lead to lymphadenopathy and bone lesions but would not explain the aortopathy. He lacks risk factors for infections like tuberculosis or tertiary syphilis, a well‐known cause of aortopathy in the past.

Widespread multisystem involvement invites consideration of nonmalignant, noninfectious infiltrative disorders such as immunoglobulin G4‐related disease (IgG4‐RD), histiocytoses such as Erdheim‐Chester disease (ECD), systemic mastocytosis (SM), and sarcoidosis. ECD is a disorder of non‐Langerhans histiocytes that infiltrate the aorta, bones, retroperitoneum, lungs, myocardium, and periorbital structures. Perinephric stranding is sometimes seen in this condition. The lymphoplasmacytes in IgG4‐RD and noncaseating granulomas of sarcoidosis infiltrate many of the same organs. Common sites infiltrated by mast cells in SM include the bone and lymph nodes. Among these diseases, ECD and IgG4‐RD more commonly manifest with aortic and retroperitoneal infiltration and thus are prioritized on this differential diagnosis.

A positron emission tomography (PET) scan revealed abnormal fluordeoxyglucose uptake involving the thoracic aorta, right apical pleural surface, perinephric soft tissue, and various marrow spaces. Core needle biopsy of a sclerotic lesion in the right ischium demonstrated focal marrow replacement by a fibrohistiocytic process. No malignant cells or pathogenic organisms were identified. Biopsy of the right kidney revealed chronic interstitial nephritis with features of megalocytic interstitial nephritis (histiocytic inflammation) and arteriolar nephrosclerosis. A transbronchial biopsy demonstrated alveolar tissue with focal intra‐alveolar hemorrhage and organization, but no malignancy, atypia, or pathogenic organisms.

The biopsy results do not support infection, lymphoma, or carcinoma. The absence of noncaseating granulomas and mastocytes on multiple biopsies essentially rules out sarcoidosis and SM, respectively. None of the characteristic pathologic features of IgG4‐RDlymphoplasmacytic infiltrate, obliterative phlebitis, and fibrosiswere observed. The pulmonary pathology points to injury, but not the underlying cause. The bone and kidney tissue samples reveal histiocytic infiltration.

The abnormalities of the aorta, bone, lung, kidney, and retroperitoneum can be explained by the diffuse histiocytic involvement seen in ECD. The perinephric stranding detected on CT and perinephric inflammation on the PET scan may reflect the hairy kidney of ECD, which is a result of histiocytic infiltration. It is possible that the chemosis relates to exophthalmos from histiocytic orbital infiltrates. Sensitivity for detecting orbital pathology on a PET scan is limited because of the high signal from the adjacent brain.

ECD should be distinguished from Langerhans cell histiocytosis (LCH) by immunohistologic staining and microscopic characteristics of the histiocytes. LCH usually does not involve the aorta, and it more commonly involves the skin.

Serum IgG4 was within normal limits, and immunohistochemical staining of pathology specimens for IgG4 was negative. The BRAF V600E mutation, which is present in the majority of patients with ECD, was detected in a subsequent right perinephric biopsy specimen. The patient was diagnosed with ECD.

Prednisone and pegylated interferon‐ led to a rapid improvement in his symptoms. As the prednisone was tapered, he developed bilateral periorbital swelling. Magnetic resonance imaging (MRI) revealed well‐circumscribed, intraorbital soft tissue masses with partial encasement of his optic nerves and superior ophthalmic veins, as well as infiltration of his transverse sinuses, consistent with intracranial manifestations of ECD. There was no evidence of pituitary, hypothalamic, or other brain parenchymal infiltration. His dyspnea, night sweats, and hypertension improved; however, 3 months into therapy he developed an extensive rash. Interferon was discontinued. Vemurafinib, a serine kinase inhibitor that targets the BRAF mutation, was prescribed with subsequent resolution of the rash.

COMMENTARY

This patient suffered from a chronic, progressive, inflammatory illness. Although the disease initially appeared to be confined to the heart and lungs, laboratory testing signaled a more systemic condition, and subsequent imaging demonstrated involvement of a disparate group of organs. Subacute disease processes with elevated markers of inflammation and diffuse organ involvement often fall into 1 of 3 categories: infectious, autoimmune, or neoplastic. The histiocytoses inhabit a fourth and easily overlooked category that can be described as infiltrative. Infiltrative diseases are a heterogeneous group of conditions that cause illness when cells or substances not normally found in tissues lead to organ dysfunction.

Although traditional teaching has focused on sarcoidosis, amyloidosis, and hemochromatosis as the primary representatives of this category, the medical literature describes a number of other infiltrative disease processes. IgG4‐RD is a fibroinflammatory disorder characterized by space‐occupying lesions, a lymphoplasmacytic infiltrate of IgG4‐positive plasma cells, and storiform (matted and irregularly whorled microscopic pattern) fibrosis.[1] IgG4‐RD, like sarcoidosis, blurs the categorical line between infiltrative and autoimmune diseases. Other infiltrative cellular disorders, such as histiocytosis and mastocytosis, exist on a spectrum between monoclonal proliferation and neoplastic invasion.

The histiocytoses represent a diverse group of disorders with an evolving nomenclature, characterized by localized or diffuse infiltration of macrophages, monocytes, and dendritic cells (Table 1). ECD is a rare, non‐Langerhans histiocytosis characterized by excessive recruitment and activation of histiocytes through kinase signaling pathways.[2, 3] Immunohistochemical staining for CD68, CD163, and Factor XIIIa, with lack of staining for CD1a, S100, and CD207, supports the diagnosis.[3] Mutations in the BRAF V600E gene (a protein kinase involved in cell proliferation) represent the most likely etiology of this overactivation. An estimated 38% to 100% of patients with ECD harbor this mutation, with detection rates influenced by the sensitivity of testing techniques.[3] The serine kinase inhibitor vemurafinib targets this mutation, and early experience with this agent in ECD demonstrates encouraging results.[4]

ECD presents heterogeneously, occurring most commonly between the ages of 40 and 70 years. Nonspecific symptoms include weakness, fatigue, fever, chills, weight loss, and night sweats. Typical sites of involvement include the bone, central nervous system, cardiovascular system, lungs, and retroperitoneum. Bone involvement is nearly universal, and bone pain is the most common presenting symptom. Symmetric diaphyseal and metaphyseal osteosclerotic lesions may be seen on x‐rays, bone scan, PET, CT, and MRI.[3] Approximately 50% of patients have extraskeletal involvement at diagnosis.[5] Neurologic manifestations may result from invasion of histiocytes into the facial bones, orbits, meninges, and intracranial vessels, as eventually developed in this patient. Diabetes insipidus is the most common neurologic manifestation of ECD, followed by exophthalmos, cerebellar ataxia, panhypopituitarism, and papilledema.[6, 7] Approximately 75% of patients eventually suffer from cardiovascular disease, including hypertension, congestive heart failure, acute myocardial infarction, valvular dysfunction, pericardial infiltration, and cardiac tamponade.[8] Vascular involvement includes perivascular infiltration and periaortic fibrosis, resulting in the coated aorta seen in 20% of patients with ECD.[3] Pulmonary manifestations of ECD include interstitial, pleural, and consolidative lung disease. A review of high‐resolution chest CTs of patients with ECD demonstrated that greater than half had evidence of parenchymal lung disease, with interlobular septal thickening being the most common finding.[9] Infiltration and fibrosis of retroperitoneal structures is common. Infiltration of perinephric fat creates irregular renal borders, appearing radiographically as hairy kidneys.

Arriving at the diagnosis in this case proved to be challenging because the early presentation was consistent with congestive heart failure. As the patient's conditioned deteriorated, imaging suggested multisystem involvement. It was the extensive aortopathy in particularnot the less specific bone, kidney, lymph node, or pulmonary findingsthat allowed the clinicians to hone the extensive differential diagnosis. The coated aorta is a finding that has been strongly associated with ECD; few other conditions coat the aorta in a similar fashion.[10] In most mysteries, the perpetrator's coat conceals his identity; however, in this story the coat gave it away.

KEY LEARNING POINTS

1. Subacute, inflammatory, multiorgan disease is usually explained by 3 categoriesinfection, autoimmunity, and neoplasiabut a fourth category, infiltrative disorders, sometimes warrants consideration.
2. ECD presents heterogeneously, ranging from localized disease to widespread organ infiltration. The classic presentation includes bone pain, diabetes insipidus, and exophthalmos.
3. Characteristic radiological findings that suggest ECD include long bone osteosclerosis, a coated aorta from periaortic infiltration, and hairy kidneys from perinephric infiltration.

Disclosure

Nothing to report

Cirrhosis is a leading cause of death in the United States. In 2010, cirrhosis resulted in an estimated 49,500 deaths, which represented a significant increase from 35,500 deaths 2 decades ago.[1] Cirrhotic patients are susceptible to numerous disease‐specific complications including ascites, esophageal varices, hepatic encephalopathy (HE), and hepatorenal syndrome (HRS).[2]

Esophageal varices develop in approximately 50% of patient with cirrhosis, and their presence correlates with the severity of liver disease.[3] In cirrhotic patients, esophageal variceal bleeding (EVB) occurs at an annual rate of 5% to 15% and results in substantial morbidity and mortality.[3] Utilizing US national data, Jamal et al. reported a decline in the rate of hospitalizations related to EVB from 1988 to 2002.[4] However, recent large‐scale studies relating to the epidemiology of EVB are lacking. We conducted a retrospective analysis using a national US database to study the differences in demographic characteristics, rate of complications, outcomes, and temporal trends in hospitalized cirrhotic patients with and without EVB.

METHODS

We utilized biennial data (20022012) from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample using methods described earlier.[5] Initially, we extracted all entries with any discharge diagnosis of cirrhosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM] codes: 571.2, 571.5, 571.6) in adult patients ages 18 years and older.[6] Within this cirrhotic population, we next extracted all entries with any discharge diagnosis of EVB (ICD‐9‐CM codes: 456.0., 456.20).[6] Population‐based rates relating to hospital discharges were reported as per 100,000 population/year.

The outcome variables of interest were in‐hospital mortality, total charges (rounded to the nearest $1000) and length of stay (LOS). Demographic details and hospital characteristics were also extracted. Cases were queried for complications well recognized in cirrhotic patients. These included urinary tract infection (UTI) (ICD‐9‐CM codes: 1122, 59010‐11, 5902‐03, 59080‐81, 5950, 5970, 5990), skin and subcutaneous tissue infections (SSCI) (ICD‐9‐CM codes: 680‐82, 684, 686), spontaneous bacterial peritonitis (SBP) (ICD‐9‐CM codes: 56723, 5672), Clostridium difficile infection (ICD‐9‐CM code: 00845), or pneumonia (ICD‐9‐CM codes: 480‐83, 487).[6] Also queried were HE (ICD‐9‐CM code: 572.2)[7] and HRS (ICD‐9‐CM code: 572.4).[8] Comorbid conditions were assessed using the Elixhauser comorbidity index minus the presence of liver disorders but including alcohol abuse.[9]

Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). To determine the independent association of EVB on outcome variables, we performed case‐control matching (EVB vs no EVB). We used high‐dimensional propensity scores in a 1:5 matching ratio with a greedy matching algorithm generated by regression analysis of patients with EVB based on demographics details (age, gender, insurance status), comorbid conditions, alcohol abuse, infections as detailed above, HE, and HRS. The ² test and the Mann‐Whitney U test compared categorical and continuous variables. For trend analysis, we used the Cochrane‐Armitage test. The threshold for significance for all analyses was P<0.01.

RESULTS

In 2012, there were 570,020 hospital discharges related to cirrhosis in patients 18 years of age and older. Within this cohort, EVB occurred in 32,945 discharges (5.78%). Table 1 details differences between cirrhotic patients with and without EVB. Comparatively, patients with EVB were younger (median age 55 years, interquartile range [IQR] 13 years vs median age 58 years, IQR 15 years; P<0.01), more likely to be male (70.1% vs 60.4%; P<0.01), and without health insurance (21.0% vs 12.50%; P<0.01). Minor differences between the 2 groups were observed in respect to hospital region, location, teaching status, and household income quartile. There was no difference in the number of comorbid conditions (median 4 comorbid conditions in each group).

Patients with EVB suffered a significantly higher rate of alcohol abuse (63.90% vs 48.80%; P<0.01). EVB was also associated with an overall lower incidence of infection (13.50% vs 24.10%; P<0.01). Specifically, the greatest difference in rates of infection were observed for UTI (6.90% vs 13.10%; P<0.01) and SSCI (1.70% vs 6.30%; P<0.01). Also, patients with EVB demonstrated a small, yet significant increased incidence of HE (18.80% vs 17.70%; P<0.01) and HRS (4.30% vs 3.70%; P<0.01).

Cirrhotic patients with EVB demonstrated worse overall outcomes compared to their counterparts without EVB. This manifested in an unadjusted higher mortality rate (9.90% vs 5.80%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $28,000 [IQR $39,000]; P<0.01). LOS between the 2 groups did not differ (median 4 days). After adjusting for demographic differences, complications, and comorbid conditions, EVB in patients with cirrhosis continued to be independently associated with a higher mortality rate (10.00% vs 5.00%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $26,000 [IQR $34,000]; P<0.01). Again, LOS was similar for the 2 groups (median 4 days).

Between the years 2002 and 2012, the number of hospital discharges related to cirrhosis increased from 337,956 to 570,220 (P<0.01). Concurrently, the incidence of EVB in this population declined from 8.60% to 5.78% (Figure 1), representing an overall decrease of 33.0% with a significant decreased trend (P<0.01).

Figure 1

We also calculated population‐adjusted hospitalization rates for discharges related to cirrhosis and EVB. The rate of cirrhosis‐related discharges continued to demonstrate an increased trend from 157.42/100,000 population in 2002 to 237.43/100,000 population in 2012 (P<0.01). However, no significant trend was observed for EVB‐related hospital discharges in the same period of time (13.60/100,000 population in 2002 to 13.72/100,000 population in 2012; P=0.91).

DISCUSSION

Our results indicated a significantly higher rate of alcohol abuse in cirrhotic patients with EVB. Alcohol consumption is an independent risk factor for esophageal variceal bleeding.[10, 11] Continued alcohol consumption not only increases the risk for development of varices but may also precipitate variceal rupture.[10] Other risk factors associated with EVB in this study (younger age, male, lower economic status) are likely related to a higher incidence of alcohol abuse in this demographic.[12]

Patients with EVB were also noted to have a lower overall incidence of infection, especially UTI and SSCI. The use of broad‐spectrum antibiotics decreases mortality from secondary infection and improves the prognosis of cirrhotic patients with EVB.[13, 14] The American Association for the Study of Liver Diseases recommends the use of third‐generation cephalosporins in the setting of EVB.[3] The widespread adoption of this in clinical practice may have contributed to a decreased rate of infection in patients with EVB. The difference in the incidence rates of HE and HRS, although statistically significant, were small, and likely the consequence of the large numbers involved in our study.

Our results also indicate that cirrhotic patients with EVB were twice as likely to die compared to matched counterparts without EVB. The increased mortality associated with EVB could be related to hemorrhagic/hypovolemic shock and cardiovascular collapse, aspiration into airway, multiorgan dysfunction due to poor perfusion, infections including SBP, and HE. Although prior studies have demonstrated the relationship between EVB and increased mortality, typically they have been restricted to small single‐center studies involving fewer than 200 patients.[6, 7, 8, 9] Cirrhotic patients with EVB also incurred significantly higher hospital charges compared to matched counterparts. Interestingly, the hospital LOS did not differ between the 2 groups. Intensive care and procedural costs were likely a major contributor to the higher charges; cirrhotic patients with EVB underwent a median of 3 procedures (IQR 2) during their hospital stay compared to a median of 1 procedure (IQR 3) for cirrhotic patients without EVB (P<0.01; data not shown).

In contrast to trends from earlier decades,[4] the population‐adjusted rate of EVB‐related hospital discharges did not change significantly from 2002 to 2012. However, these data are confounded in their interpretation by a substantial increase in the prevalence of cirrhosis in the United States during the same time period.[15] Therefore, it may be more meaningful to state that there was a contemporaneous decline in EVB‐related hospital discharges when considered in the context of a complicating rate in hospitalized cirrhotic patients. These results are consistent with a recent single‐center study[16] and are very likely the fruition of intensive screening programs with primary and secondary prophylaxis for EVB involving esophageal variceal ligation and pharmacotherapy (‐blockers) as well as the increased acceptance of transjugular intrahepatic portosystemic shunt placement.[17, 18, 19]

There are limitations to our study. First, we relied exclusively on ICD‐9‐CM codes for case identification. Second, there is a nonavailability of data pertaining to Model for End‐Stage Liver Disease score calculations, medication, and antibiotic usage. Third, the Nationwide Inpatient Sample database does not allow for distinguishing individual patients with repeat admissions. Finally, our results represent a weighted estimate of national data.

CONCLUSION

EVB in cirrhotic patients was associated with significantly higher mortality and increased hospital charges. Also, the rate of EVB‐related hospital discharges as a complicating factor in patients with cirrhosis declined significantly during the decade 2002 to 2012. This likely reflects the ongoing effectiveness of primary and secondary prophylaxis.

Cirrhosis is a leading cause of death in the United States. In 2010, cirrhosis resulted in an estimated 49,500 deaths, which represented a significant increase from 35,500 deaths 2 decades ago.[1] Cirrhotic patients are susceptible to numerous disease‐specific complications including ascites, esophageal varices, hepatic encephalopathy (HE), and hepatorenal syndrome (HRS).[2]

Esophageal varices develop in approximately 50% of patient with cirrhosis, and their presence correlates with the severity of liver disease.[3] In cirrhotic patients, esophageal variceal bleeding (EVB) occurs at an annual rate of 5% to 15% and results in substantial morbidity and mortality.[3] Utilizing US national data, Jamal et al. reported a decline in the rate of hospitalizations related to EVB from 1988 to 2002.[4] However, recent large‐scale studies relating to the epidemiology of EVB are lacking. We conducted a retrospective analysis using a national US database to study the differences in demographic characteristics, rate of complications, outcomes, and temporal trends in hospitalized cirrhotic patients with and without EVB.

METHODS

We utilized biennial data (20022012) from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample using methods described earlier.[5] Initially, we extracted all entries with any discharge diagnosis of cirrhosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM] codes: 571.2, 571.5, 571.6) in adult patients ages 18 years and older.[6] Within this cirrhotic population, we next extracted all entries with any discharge diagnosis of EVB (ICD‐9‐CM codes: 456.0., 456.20).[6] Population‐based rates relating to hospital discharges were reported as per 100,000 population/year.

The outcome variables of interest were in‐hospital mortality, total charges (rounded to the nearest $1000) and length of stay (LOS). Demographic details and hospital characteristics were also extracted. Cases were queried for complications well recognized in cirrhotic patients. These included urinary tract infection (UTI) (ICD‐9‐CM codes: 1122, 59010‐11, 5902‐03, 59080‐81, 5950, 5970, 5990), skin and subcutaneous tissue infections (SSCI) (ICD‐9‐CM codes: 680‐82, 684, 686), spontaneous bacterial peritonitis (SBP) (ICD‐9‐CM codes: 56723, 5672), Clostridium difficile infection (ICD‐9‐CM code: 00845), or pneumonia (ICD‐9‐CM codes: 480‐83, 487).[6] Also queried were HE (ICD‐9‐CM code: 572.2)[7] and HRS (ICD‐9‐CM code: 572.4).[8] Comorbid conditions were assessed using the Elixhauser comorbidity index minus the presence of liver disorders but including alcohol abuse.[9]

Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). To determine the independent association of EVB on outcome variables, we performed case‐control matching (EVB vs no EVB). We used high‐dimensional propensity scores in a 1:5 matching ratio with a greedy matching algorithm generated by regression analysis of patients with EVB based on demographics details (age, gender, insurance status), comorbid conditions, alcohol abuse, infections as detailed above, HE, and HRS. The ² test and the Mann‐Whitney U test compared categorical and continuous variables. For trend analysis, we used the Cochrane‐Armitage test. The threshold for significance for all analyses was P<0.01.

RESULTS

In 2012, there were 570,020 hospital discharges related to cirrhosis in patients 18 years of age and older. Within this cohort, EVB occurred in 32,945 discharges (5.78%). Table 1 details differences between cirrhotic patients with and without EVB. Comparatively, patients with EVB were younger (median age 55 years, interquartile range [IQR] 13 years vs median age 58 years, IQR 15 years; P<0.01), more likely to be male (70.1% vs 60.4%; P<0.01), and without health insurance (21.0% vs 12.50%; P<0.01). Minor differences between the 2 groups were observed in respect to hospital region, location, teaching status, and household income quartile. There was no difference in the number of comorbid conditions (median 4 comorbid conditions in each group).

Patients with EVB suffered a significantly higher rate of alcohol abuse (63.90% vs 48.80%; P<0.01). EVB was also associated with an overall lower incidence of infection (13.50% vs 24.10%; P<0.01). Specifically, the greatest difference in rates of infection were observed for UTI (6.90% vs 13.10%; P<0.01) and SSCI (1.70% vs 6.30%; P<0.01). Also, patients with EVB demonstrated a small, yet significant increased incidence of HE (18.80% vs 17.70%; P<0.01) and HRS (4.30% vs 3.70%; P<0.01).

Cirrhotic patients with EVB demonstrated worse overall outcomes compared to their counterparts without EVB. This manifested in an unadjusted higher mortality rate (9.90% vs 5.80%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $28,000 [IQR $39,000]; P<0.01). LOS between the 2 groups did not differ (median 4 days). After adjusting for demographic differences, complications, and comorbid conditions, EVB in patients with cirrhosis continued to be independently associated with a higher mortality rate (10.00% vs 5.00%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $26,000 [IQR $34,000]; P<0.01). Again, LOS was similar for the 2 groups (median 4 days).

Between the years 2002 and 2012, the number of hospital discharges related to cirrhosis increased from 337,956 to 570,220 (P<0.01). Concurrently, the incidence of EVB in this population declined from 8.60% to 5.78% (Figure 1), representing an overall decrease of 33.0% with a significant decreased trend (P<0.01).

Figure 1

We also calculated population‐adjusted hospitalization rates for discharges related to cirrhosis and EVB. The rate of cirrhosis‐related discharges continued to demonstrate an increased trend from 157.42/100,000 population in 2002 to 237.43/100,000 population in 2012 (P<0.01). However, no significant trend was observed for EVB‐related hospital discharges in the same period of time (13.60/100,000 population in 2002 to 13.72/100,000 population in 2012; P=0.91).

DISCUSSION

Our results indicated a significantly higher rate of alcohol abuse in cirrhotic patients with EVB. Alcohol consumption is an independent risk factor for esophageal variceal bleeding.[10, 11] Continued alcohol consumption not only increases the risk for development of varices but may also precipitate variceal rupture.[10] Other risk factors associated with EVB in this study (younger age, male, lower economic status) are likely related to a higher incidence of alcohol abuse in this demographic.[12]

Patients with EVB were also noted to have a lower overall incidence of infection, especially UTI and SSCI. The use of broad‐spectrum antibiotics decreases mortality from secondary infection and improves the prognosis of cirrhotic patients with EVB.[13, 14] The American Association for the Study of Liver Diseases recommends the use of third‐generation cephalosporins in the setting of EVB.[3] The widespread adoption of this in clinical practice may have contributed to a decreased rate of infection in patients with EVB. The difference in the incidence rates of HE and HRS, although statistically significant, were small, and likely the consequence of the large numbers involved in our study.

Our results also indicate that cirrhotic patients with EVB were twice as likely to die compared to matched counterparts without EVB. The increased mortality associated with EVB could be related to hemorrhagic/hypovolemic shock and cardiovascular collapse, aspiration into airway, multiorgan dysfunction due to poor perfusion, infections including SBP, and HE. Although prior studies have demonstrated the relationship between EVB and increased mortality, typically they have been restricted to small single‐center studies involving fewer than 200 patients.[6, 7, 8, 9] Cirrhotic patients with EVB also incurred significantly higher hospital charges compared to matched counterparts. Interestingly, the hospital LOS did not differ between the 2 groups. Intensive care and procedural costs were likely a major contributor to the higher charges; cirrhotic patients with EVB underwent a median of 3 procedures (IQR 2) during their hospital stay compared to a median of 1 procedure (IQR 3) for cirrhotic patients without EVB (P<0.01; data not shown).

In contrast to trends from earlier decades,[4] the population‐adjusted rate of EVB‐related hospital discharges did not change significantly from 2002 to 2012. However, these data are confounded in their interpretation by a substantial increase in the prevalence of cirrhosis in the United States during the same time period.[15] Therefore, it may be more meaningful to state that there was a contemporaneous decline in EVB‐related hospital discharges when considered in the context of a complicating rate in hospitalized cirrhotic patients. These results are consistent with a recent single‐center study[16] and are very likely the fruition of intensive screening programs with primary and secondary prophylaxis for EVB involving esophageal variceal ligation and pharmacotherapy (‐blockers) as well as the increased acceptance of transjugular intrahepatic portosystemic shunt placement.[17, 18, 19]

There are limitations to our study. First, we relied exclusively on ICD‐9‐CM codes for case identification. Second, there is a nonavailability of data pertaining to Model for End‐Stage Liver Disease score calculations, medication, and antibiotic usage. Third, the Nationwide Inpatient Sample database does not allow for distinguishing individual patients with repeat admissions. Finally, our results represent a weighted estimate of national data.

CONCLUSION

EVB in cirrhotic patients was associated with significantly higher mortality and increased hospital charges. Also, the rate of EVB‐related hospital discharges as a complicating factor in patients with cirrhosis declined significantly during the decade 2002 to 2012. This likely reflects the ongoing effectiveness of primary and secondary prophylaxis.

Cirrhosis is a leading cause of death in the United States. In 2010, cirrhosis resulted in an estimated 49,500 deaths, which represented a significant increase from 35,500 deaths 2 decades ago.[1] Cirrhotic patients are susceptible to numerous disease‐specific complications including ascites, esophageal varices, hepatic encephalopathy (HE), and hepatorenal syndrome (HRS).[2]

Esophageal varices develop in approximately 50% of patient with cirrhosis, and their presence correlates with the severity of liver disease.[3] In cirrhotic patients, esophageal variceal bleeding (EVB) occurs at an annual rate of 5% to 15% and results in substantial morbidity and mortality.[3] Utilizing US national data, Jamal et al. reported a decline in the rate of hospitalizations related to EVB from 1988 to 2002.[4] However, recent large‐scale studies relating to the epidemiology of EVB are lacking. We conducted a retrospective analysis using a national US database to study the differences in demographic characteristics, rate of complications, outcomes, and temporal trends in hospitalized cirrhotic patients with and without EVB.

METHODS

We utilized biennial data (20022012) from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample using methods described earlier.[5] Initially, we extracted all entries with any discharge diagnosis of cirrhosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM] codes: 571.2, 571.5, 571.6) in adult patients ages 18 years and older.[6] Within this cirrhotic population, we next extracted all entries with any discharge diagnosis of EVB (ICD‐9‐CM codes: 456.0., 456.20).[6] Population‐based rates relating to hospital discharges were reported as per 100,000 population/year.

The outcome variables of interest were in‐hospital mortality, total charges (rounded to the nearest $1000) and length of stay (LOS). Demographic details and hospital characteristics were also extracted. Cases were queried for complications well recognized in cirrhotic patients. These included urinary tract infection (UTI) (ICD‐9‐CM codes: 1122, 59010‐11, 5902‐03, 59080‐81, 5950, 5970, 5990), skin and subcutaneous tissue infections (SSCI) (ICD‐9‐CM codes: 680‐82, 684, 686), spontaneous bacterial peritonitis (SBP) (ICD‐9‐CM codes: 56723, 5672), Clostridium difficile infection (ICD‐9‐CM code: 00845), or pneumonia (ICD‐9‐CM codes: 480‐83, 487).[6] Also queried were HE (ICD‐9‐CM code: 572.2)[7] and HRS (ICD‐9‐CM code: 572.4).[8] Comorbid conditions were assessed using the Elixhauser comorbidity index minus the presence of liver disorders but including alcohol abuse.[9]

Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). To determine the independent association of EVB on outcome variables, we performed case‐control matching (EVB vs no EVB). We used high‐dimensional propensity scores in a 1:5 matching ratio with a greedy matching algorithm generated by regression analysis of patients with EVB based on demographics details (age, gender, insurance status), comorbid conditions, alcohol abuse, infections as detailed above, HE, and HRS. The ² test and the Mann‐Whitney U test compared categorical and continuous variables. For trend analysis, we used the Cochrane‐Armitage test. The threshold for significance for all analyses was P<0.01.

RESULTS

In 2012, there were 570,020 hospital discharges related to cirrhosis in patients 18 years of age and older. Within this cohort, EVB occurred in 32,945 discharges (5.78%). Table 1 details differences between cirrhotic patients with and without EVB. Comparatively, patients with EVB were younger (median age 55 years, interquartile range [IQR] 13 years vs median age 58 years, IQR 15 years; P<0.01), more likely to be male (70.1% vs 60.4%; P<0.01), and without health insurance (21.0% vs 12.50%; P<0.01). Minor differences between the 2 groups were observed in respect to hospital region, location, teaching status, and household income quartile. There was no difference in the number of comorbid conditions (median 4 comorbid conditions in each group).

Patients with EVB suffered a significantly higher rate of alcohol abuse (63.90% vs 48.80%; P<0.01). EVB was also associated with an overall lower incidence of infection (13.50% vs 24.10%; P<0.01). Specifically, the greatest difference in rates of infection were observed for UTI (6.90% vs 13.10%; P<0.01) and SSCI (1.70% vs 6.30%; P<0.01). Also, patients with EVB demonstrated a small, yet significant increased incidence of HE (18.80% vs 17.70%; P<0.01) and HRS (4.30% vs 3.70%; P<0.01).

Cirrhotic patients with EVB demonstrated worse overall outcomes compared to their counterparts without EVB. This manifested in an unadjusted higher mortality rate (9.90% vs 5.80%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $28,000 [IQR $39,000]; P<0.01). LOS between the 2 groups did not differ (median 4 days). After adjusting for demographic differences, complications, and comorbid conditions, EVB in patients with cirrhosis continued to be independently associated with a higher mortality rate (10.00% vs 5.00%; P<0.01) and increased hospital charges (median $41,000 [IQR $49,000] vs $26,000 [IQR $34,000]; P<0.01). Again, LOS was similar for the 2 groups (median 4 days).

Between the years 2002 and 2012, the number of hospital discharges related to cirrhosis increased from 337,956 to 570,220 (P<0.01). Concurrently, the incidence of EVB in this population declined from 8.60% to 5.78% (Figure 1), representing an overall decrease of 33.0% with a significant decreased trend (P<0.01).

Figure 1

We also calculated population‐adjusted hospitalization rates for discharges related to cirrhosis and EVB. The rate of cirrhosis‐related discharges continued to demonstrate an increased trend from 157.42/100,000 population in 2002 to 237.43/100,000 population in 2012 (P<0.01). However, no significant trend was observed for EVB‐related hospital discharges in the same period of time (13.60/100,000 population in 2002 to 13.72/100,000 population in 2012; P=0.91).

DISCUSSION

Our results indicated a significantly higher rate of alcohol abuse in cirrhotic patients with EVB. Alcohol consumption is an independent risk factor for esophageal variceal bleeding.[10, 11] Continued alcohol consumption not only increases the risk for development of varices but may also precipitate variceal rupture.[10] Other risk factors associated with EVB in this study (younger age, male, lower economic status) are likely related to a higher incidence of alcohol abuse in this demographic.[12]

Patients with EVB were also noted to have a lower overall incidence of infection, especially UTI and SSCI. The use of broad‐spectrum antibiotics decreases mortality from secondary infection and improves the prognosis of cirrhotic patients with EVB.[13, 14] The American Association for the Study of Liver Diseases recommends the use of third‐generation cephalosporins in the setting of EVB.[3] The widespread adoption of this in clinical practice may have contributed to a decreased rate of infection in patients with EVB. The difference in the incidence rates of HE and HRS, although statistically significant, were small, and likely the consequence of the large numbers involved in our study.

Our results also indicate that cirrhotic patients with EVB were twice as likely to die compared to matched counterparts without EVB. The increased mortality associated with EVB could be related to hemorrhagic/hypovolemic shock and cardiovascular collapse, aspiration into airway, multiorgan dysfunction due to poor perfusion, infections including SBP, and HE. Although prior studies have demonstrated the relationship between EVB and increased mortality, typically they have been restricted to small single‐center studies involving fewer than 200 patients.[6, 7, 8, 9] Cirrhotic patients with EVB also incurred significantly higher hospital charges compared to matched counterparts. Interestingly, the hospital LOS did not differ between the 2 groups. Intensive care and procedural costs were likely a major contributor to the higher charges; cirrhotic patients with EVB underwent a median of 3 procedures (IQR 2) during their hospital stay compared to a median of 1 procedure (IQR 3) for cirrhotic patients without EVB (P<0.01; data not shown).

In contrast to trends from earlier decades,[4] the population‐adjusted rate of EVB‐related hospital discharges did not change significantly from 2002 to 2012. However, these data are confounded in their interpretation by a substantial increase in the prevalence of cirrhosis in the United States during the same time period.[15] Therefore, it may be more meaningful to state that there was a contemporaneous decline in EVB‐related hospital discharges when considered in the context of a complicating rate in hospitalized cirrhotic patients. These results are consistent with a recent single‐center study[16] and are very likely the fruition of intensive screening programs with primary and secondary prophylaxis for EVB involving esophageal variceal ligation and pharmacotherapy (‐blockers) as well as the increased acceptance of transjugular intrahepatic portosystemic shunt placement.[17, 18, 19]

There are limitations to our study. First, we relied exclusively on ICD‐9‐CM codes for case identification. Second, there is a nonavailability of data pertaining to Model for End‐Stage Liver Disease score calculations, medication, and antibiotic usage. Third, the Nationwide Inpatient Sample database does not allow for distinguishing individual patients with repeat admissions. Finally, our results represent a weighted estimate of national data.

CONCLUSION

EVB in cirrhotic patients was associated with significantly higher mortality and increased hospital charges. Also, the rate of EVB‐related hospital discharges as a complicating factor in patients with cirrhosis declined significantly during the decade 2002 to 2012. This likely reflects the ongoing effectiveness of primary and secondary prophylaxis.

The recently published article by Schouten et al.[1] showed no difference in measured patient outcomes with the use of face‐to‐face handoffs. The authors bring several potential explanations for this observation, all of which might be relevant. Another potential explanation could be the human brain's very predisposition for cognitive biases, and face‐to‐face interaction only increases this possibility. The "framing effect" is a cognitive bias when people make decisions differently depending how information is presented, and "anchoring" describes the human tendency to rely heavily on the first piece of information provided. In our case, the daytime physicians who received face‐to‐face handoffs could have been biased with additional information provided and how this information was provided, and this could have increased the rate of measured adverse patient outcome for this group, eliminating the between group difference. More research is needed to study the influence of the cognitive biases in the medical field.

The recently published article by Schouten et al.[1] showed no difference in measured patient outcomes with the use of face‐to‐face handoffs. The authors bring several potential explanations for this observation, all of which might be relevant. Another potential explanation could be the human brain's very predisposition for cognitive biases, and face‐to‐face interaction only increases this possibility. The "framing effect" is a cognitive bias when people make decisions differently depending how information is presented, and "anchoring" describes the human tendency to rely heavily on the first piece of information provided. In our case, the daytime physicians who received face‐to‐face handoffs could have been biased with additional information provided and how this information was provided, and this could have increased the rate of measured adverse patient outcome for this group, eliminating the between group difference. More research is needed to study the influence of the cognitive biases in the medical field.

The recently published article by Schouten et al.[1] showed no difference in measured patient outcomes with the use of face‐to‐face handoffs. The authors bring several potential explanations for this observation, all of which might be relevant. Another potential explanation could be the human brain's very predisposition for cognitive biases, and face‐to‐face interaction only increases this possibility. The "framing effect" is a cognitive bias when people make decisions differently depending how information is presented, and "anchoring" describes the human tendency to rely heavily on the first piece of information provided. In our case, the daytime physicians who received face‐to‐face handoffs could have been biased with additional information provided and how this information was provided, and this could have increased the rate of measured adverse patient outcome for this group, eliminating the between group difference. More research is needed to study the influence of the cognitive biases in the medical field.

As a practicing hospitalist, I enjoyed the recently published research article by Schouten et al.[1] Their findings are not surprising to our hospitalist group. We evolved over the years from mandatory face‐to‐face or verbal handoffs to secured e‐mail communications. The night physician transfers care through a secured hospital‐provided email by 7 _am. This information is supplemented by a phone call, originating from the day hospitalist on an as‐needed basis. This system works best for most community hospitalist programs, because it provides flexibility, improved communication, and saves a lot of time. In the era of electronic medical records and constantly updated tests results, a face‐to‐face communication is less important. We used to spend 45 to 60 minutes on the handoffs, sometimes even longer due to people being late or not answering phone calls right away. It squeezed time out of patient encounters. The accepting day hospitalist needed to review electronic records (including dictated history and physical information if completed) during the course of the day regardless of the sign out from the night physician. Now, the information flow is smoother and it leaves more time for patient encounters. The day hospitalist keeps printed e‐mail with him or her so that information is readily accessible.

For the relatively smaller community hospitalist groups, it is difficult to ensure that all hospitalists will be available for the face‐to‐face handoffs. The hospitalist who is supposed to take sign‐outs could also be on call for the admissions or responsible for codes or rapid responses, which may interrupt or delay the sign‐out process. The Society of Hospital Medicine recommends both written and verbal sign‐outs.[2] This goal could be achieved more efficiently by the model followed by our group as discussed above. The verbal component could be over the phone rather than face‐to‐face meetings.

As a practicing hospitalist, I enjoyed the recently published research article by Schouten et al.[1] Their findings are not surprising to our hospitalist group. We evolved over the years from mandatory face‐to‐face or verbal handoffs to secured e‐mail communications. The night physician transfers care through a secured hospital‐provided email by 7 _am. This information is supplemented by a phone call, originating from the day hospitalist on an as‐needed basis. This system works best for most community hospitalist programs, because it provides flexibility, improved communication, and saves a lot of time. In the era of electronic medical records and constantly updated tests results, a face‐to‐face communication is less important. We used to spend 45 to 60 minutes on the handoffs, sometimes even longer due to people being late or not answering phone calls right away. It squeezed time out of patient encounters. The accepting day hospitalist needed to review electronic records (including dictated history and physical information if completed) during the course of the day regardless of the sign out from the night physician. Now, the information flow is smoother and it leaves more time for patient encounters. The day hospitalist keeps printed e‐mail with him or her so that information is readily accessible.

For the relatively smaller community hospitalist groups, it is difficult to ensure that all hospitalists will be available for the face‐to‐face handoffs. The hospitalist who is supposed to take sign‐outs could also be on call for the admissions or responsible for codes or rapid responses, which may interrupt or delay the sign‐out process. The Society of Hospital Medicine recommends both written and verbal sign‐outs.[2] This goal could be achieved more efficiently by the model followed by our group as discussed above. The verbal component could be over the phone rather than face‐to‐face meetings.

As a practicing hospitalist, I enjoyed the recently published research article by Schouten et al.[1] Their findings are not surprising to our hospitalist group. We evolved over the years from mandatory face‐to‐face or verbal handoffs to secured e‐mail communications. The night physician transfers care through a secured hospital‐provided email by 7 _am. This information is supplemented by a phone call, originating from the day hospitalist on an as‐needed basis. This system works best for most community hospitalist programs, because it provides flexibility, improved communication, and saves a lot of time. In the era of electronic medical records and constantly updated tests results, a face‐to‐face communication is less important. We used to spend 45 to 60 minutes on the handoffs, sometimes even longer due to people being late or not answering phone calls right away. It squeezed time out of patient encounters. The accepting day hospitalist needed to review electronic records (including dictated history and physical information if completed) during the course of the day regardless of the sign out from the night physician. Now, the information flow is smoother and it leaves more time for patient encounters. The day hospitalist keeps printed e‐mail with him or her so that information is readily accessible.

For the relatively smaller community hospitalist groups, it is difficult to ensure that all hospitalists will be available for the face‐to‐face handoffs. The hospitalist who is supposed to take sign‐outs could also be on call for the admissions or responsible for codes or rapid responses, which may interrupt or delay the sign‐out process. The Society of Hospital Medicine recommends both written and verbal sign‐outs.[2] This goal could be achieved more efficiently by the model followed by our group as discussed above. The verbal component could be over the phone rather than face‐to‐face meetings.