Reza Sedighi Manesh, MD

DISCUSSION

KEY TEACHING POINTS

DISCUSSION

KEY TEACHING POINTS

DISCUSSION

KEY TEACHING POINTS

A 57‐year‐old man presented to an emergency department with 1 month of progressive, bilateral lower extremity pain and weakness.

The first step in evaluating weakness is to determine whether it is objective (ie, decreased muscle strength due to pathology along the neuromuscular axis) or subjective. The sensation of weakness without loss of muscle strength may result from a debilitating chronic disease (eg, congestive heart failure, anemia, or chronic obstructive pulmonary disease). In patients with true lower extremity weakness it is prudent to assess for a myelopathy with a focused history and exam that includes assessment of bowel or bladder impairment and anal reflex. The presence of pain along with weakness might suggest disease of the muscle itself. A myopathy may arise from an infectious (eg, influenza), inflammatory (eg, polymyositis), endocrine (eg, hypothyroidism), or drug‐related (eg, statin) process.

The patient described 1 month of generalized weakness and pain in his lower extremities, which had worsened progressively to the point where ambulation was difficult. He was able to rise from a seated position using his arms for assistance, but had difficulty balancing in a standing position without assistance. The pain also involved both of his knees and increased with weight bearing. He also complained of bilateral lower extremity numbness and paresthesias, which had been migrating proximally from his toes over several months. He denied any recent trauma to his legs or back.

These symmetrical, distal sensory deficits favor a peripheral neuropathy over a myopathy, with neuropathic pain and arthralgia causing his impaired ability to ambulate or remain standing. In polyneuropathy, the type of nerve involvement (sensory vs motor) and pathology (axonal vs demyelinating) helps prioritize the differential. In developed countries, the most common causes of polyneuropathy are diabetes mellitus and alcohol. However, the tempo of his disease broadens the possibilities to include acute inflammatory demyelinating polyneuropathy, paraneoplastic syndrome (eg, monoclonal gammopathy), an autoimmune process (eg, rheumatoid arthritis, vasculitis), and heavy metal toxicity such as lead poisoning.

He had no history of chronic medical illness or hospitalizations and took no medications. His social history was notable for a history of alcohol abuse. For the past several years, he had only been drinking 1 to 2 beers daily due to cost, but had a history of more significant alcohol abuse in the distant past. He smoked 1 pack of tobacco per day, and denied illicit drug use. He denied any sexual activity or recent travel. He lived in a van, and had been homeless for over 10 years.

His socioeconomic status adds a layer of complexity to the case. Human immunodeficiency virus and hepatitis C virus (HCV) are more prevalent in the homeless and are associated with polyneuropathy. His lack of funds may drive him to drink illegally distilled alcohol, which can cause polyneuropathy through lead or arsenic toxicity. Excessive smoking could be linked to a peripheral neuropathy through a paraneoplastic syndrome (eg, small cell lung cancer).

Alcohol causes polyneuropathy through toxic effects on nerves and may be playing a role in his polyneuropathy, but the rapid pace and severity suggests an additional process. Alcoholism can be associated with deficiency of various B vitamins, such as thiamine, pyridoxine, and cobalamin, which can cause polyneuropathy. In alcoholics who are hospitalized, thiamine should be administered prior to glucose to decrease risk of Wernicke encephalopathy.

His temperature was 38.0C, heart rate 93 beats/min, blood pressure 121/60 mm Hg, respiratory rate 14/min, with an oxygen saturation of 97% on ambient air. He appeared cachectic and disheveled. He had moist mucous membranes, poor dentition with missing teeth, and no mucosal bleeding or oropharyngeal erythema. His cardiac exam revealed no murmurs, rubs, or gallops. His lungs were clear. His abdominal exam was benign, without masses or tenderness. His skin exam (Figure 1) was notable for nonpalpable petechiae on his anterior shins and thighs up to his buttocks. His extremity exam was significant for diffuse tenderness to light palpation on both lower extremities, a large indurated tender ecchymosis 15 15 cm behind the right knee, and another ecchymosis 6 8 cm behind the left knee. His dorsalis pedis and anterior tibialis pulses were appreciated by Doppler but not by palpation. He had decreased sensation to light touch of his bilateral feet to his ankles. Strength exam was challenging to assess secondary to posterior leg pain, but he demonstrated 4/5 strength of his hip flexors, quadriceps, and plantar flexors of the foot. His upper extremity strength and sensory exam were normal. Examination of the cranial nerves was normal. He had 2+ patellar and Achilles reflexes. Gait could not be adequately assessed.

Figure 1

Petechiae manifest as a nonblanchable rash caused by extravasated red blood cells. Common etiologies include quantitative or qualitative platelet defects, disseminated intravascular coagulopathy, trauma, and vasculitis. Cirrhosis from alcohol leading to thrombocytopenia and petechial rash is unlikely given no other stigmata of liver disease such as jaundice, spider angiomata, caput medusae, or palmar erythema. Less common causes include nutritional deficiency and light chain (AL) amyloidosis, which could explain both the neuropathy and rash.

The constellation of fever and petechial rash can represent a life‐threatening systemic process. Infectious agents that require immediate consideration with fever and petechiae include Neisseria meningitidis (meningococcemia), Rickettsia rickettsii (Rocky Mountain spotted fever), Staphylococcus, and Streptococcus. However, his normal blood pressure, dependent distribution of rash, and neuropathy make a severe bacterial infection less likely. Thrombotic thrombocytopenic purpura is possible and should prompt assessment of platelets, peripheral blood smear, and lactate dehydrogenase. Among vasculitides, the polyneuropathy, fever, and dependent distribution of petechial rash prioritize a small‐to‐medium vessel vasculitis, where the pathophysiology involves inflammation of dermal vessels and vasa nervorum (blood supply of nerves). Examples include HCV‐related cryoglobulinemic vasculitis, polyarteritis nodosa (PAN), and antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis. However, ANCA‐associated vasculitis is less likely without upper or lower respiratory symptoms. Henoch‐Schonlein purpura may explain the rash but is more common in children and is not associated with neuropathy.

Posterior knee ecchymosis, in absence of trauma, raises suspicion for a ruptured Baker's cyst. However, the bilateral involvement and lack of calf manifestations makes this unlikely. The location raises concern for hemarthrosis, so a more likely explanation would be coagulopathy (eg, an acquired factor inhibitor) or a collagen defect. In developed countries, a commonly overlooked category of diseasenutritional deficiencywarrants serious consideration in alcoholics. Vitamin C deficiency (scurvy) may cause a petechial rash and ecchymosis from perifollicular hemorrhage and impaired collagen synthesis, respectively. Scurvy can masquerade as small vessel vasculitis because of its associated petechial rash. The neuropathy might be explained by concomitant thiamine or cobalamin deficiency. It is important to obtain a thorough dietary history and assess vibration and proprioception, which may be impaired from pathology of the dorsal column in cobalamin deficiency. The low‐grade fever may be a red herring, but if it becomes significant would be difficult to explain with nutritional deficiency.

In summary, a judicious evaluation for infection is mandatory, but the leading diagnoses are a small‐to‐medium vessel vasculitis (PAN or HCV‐related cryoglobulinemia), deficiency of multiple vitamins, and AL amyloidosis.

Initial labs showed white blood cell count 7800/L, hematocrit 39.2%, and platelet count of 251,000/L. Serum chemistry demonstrated a sodium of 131 mEq/L, potassium 4.7 mEq/L, chloride 93 mEq/L, bicarbonate 23 mEq/L, blood urea nitrogen 8 mg/dL, and creatinine 0.8 mg/dL. His aminotransferases, albumin, alkaline phosphatase, and coagulation studies were within normal limits. Urinalysis was remarkable for 2+ urobilinogen, 1+ ketones, and a bland sediment. Urine toxicology screen was negative.

His white blood cell count is normal, so with a heart rate of 93 beats/minute, he barely meets a single criterion of systemic inflammatory response syndrome (SIRS). The lack of SIRS and normal platelet, albumin, white blood cell, and red blood cell counts significantly reduces the likelihood of an infectious or inflammatory process. Without any clinical or biochemical evidence of HCV infection, HCV‐associated cryoglobulinemia is less likely. A normal creatinine might overestimate renal function in setting of decreased protein intake and muscle mass; nevertheless, the bland urine sediment further lowers probability of PAN and ANCA‐associated vasculitides. The normal platelet count and coagulation studies suggest either a qualitative platelet defect (eg, acquired von Willebrand disease) or impaired vessel integrity (eg, collagen defect) to explain the petechial rash. The urine ketones likely represent alcohol and/or starvation‐related ketosis. These data reduce the probability of infection and vasculitis, and prioritize vitamin deficiency and AL amyloidosis. Antibiotic therapy is not appropriate, given the absence of SIRS and subacute course. His presentation likely prompted a wide variety of tests, but most relevant would be a dietary history, cobalamin and vitamin C levels, serum free light chains, and skin biopsy. Biopsy of the rash would allow assessment for vasculitis and AL amyloidosis. The former is marked by inflammatory infiltrate of vessels, and the latter by perivascular invasion with amyloid fibrils. If the dietary history was consistent with ascorbic acid deficiency (scurvy), in addition to thiamine, he should be empirically treated with vitamin C. Patients with scurvy demonstrate rapid clinical improvement with treatment.

C‐reactive protein (CRP) was 47.9 mg/L and erythrocyte sedimentation rate (ESR) was 44 mm/hr. Human immunodeficiency antibody screen was negative. Anti‐nuclear antibodies and anti‐nuclear cytoplasmic antibody panel were negative. Computed tomography angiogram (CTA) of the lower extremities demonstrated severe stenosis of the left superficial femoral artery and severe stenosis of the right posterior tibial artery. Ankle‐brachial indices were 0.83 on the right side and 0.72 on the left, indicating mild to moderate arterial disease.

ESR and CRP are nonspecific markers of inflammation. Their elevation does not prioritize malignancy, autoimmunity, or infection. ANCA might be negative in commonly ANCA‐associated vasculitides such as eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, and granulomatosis with polyangiitis. However, the lack of respiratory and renal involvement in addition to the negative ANCA panel make such diagnoses unlikely. CTA of the patient's legs showed significant peripheral artery disease (PAD). This is unlikely to be the cause of his presentation; PAD should not cause petechiae, and his pain is disproportionate to the severity of the vascular disease reported. The additional information leaves the differential unchanged.

A dermatologist was consulted. She described and photographed a perifollicular distribution of the lower extremity petechiae with associated perifollicular hyperkeratosis and retained curled hairs (Figure 2).

Figure 2

The described rash is specific for scurvy. His homelessness and alcohol intake likely made him vulnerable to ascorbic acid deficiency from lack of access to fruits and vegetables. Measurement of vitamin C level is unnecessary as the pretest probability for scurvy is very high. More relevant than a vitamin C level or skin biopsy is empiric treatment with ascorbic acid; as mentioned, patients with scurvy respond rapidly to vitamin C therapy. Given the neuropathy, he should be assessed for concomitant thiamine and/or cobalamin deficiency. His peripheral arterial disease is unlikely to be related.

His ascorbic acid level was 0.0 mg/dL (reference range, 0.22.0 mg/dL). Further history was obtained, and the patient reported exclusively eating frozen hamburgers and burritos for almost 1 year. He believed he had not had a fruit or vegetable in over 10 years. He was started on 1000 mg daily of ascorbic acid. By hospital day 2, his rash had mostly resolved and he was able to stand with some support. The patient was seen by his primary care physician 3 weeks after diagnosis, with his exercise tolerance nearly back to baseline. His rash had entirely resolved.

DISCUSSION

Unlike other mammals, humans do not have the ability to convert glucose to vitamin C and thus require an exogenous source, such as fruits and vegetables. The oft‐cited observation of scurvy in sailors during long journeys in the 18th century is a classic example of clinical disease due to vitamin C deficiency.[1] Once replete, body stores of vitamin C are usually sufficient to last over 6 months of deprivation. In some patients, symptoms of deficiency may appear within 3 months.[2] The patient in this report likely suffered years of vitamin C deficiency, resulting in the significant manifestations of scurvy reported here.

Vitamin C is a water‐soluble vitamin necessary for the biosynthesis of collagen, L‐carnitine, and neurotransmitters.[3] With deficiency, the resulting impairment in the formation of collagen affects blood vessel integrity and results in perivascular edema and erythrocyte extravasation. Clinically, this leads to hemorrhagic manifestations (eg, periosteal hemorrhage and perifollicular petechiae) and poor wound healing. Corkscrew hairs result because of vitamin C's role in disulfide bonding during hair formation. Woody edema and dyspnea are thought to be a consequence of leaky capillaries.[4]

Scurvy is still a significant cause of morbidity in at‐risk populations in the United States. Several populations have been identified as high risk for vitamin C deficiency, including the elderly, persons who live alone, alcoholics, smokers, individuals of low socioeconomic status, patients on hemodialysis, and those with psychiatric disease.[5] Specifically, the high oxidative stress associated with smoking, the history of alcohol abuse, and homelessness put this patient at an especially high risk.[6] Those with oxidative stressors have been postulated to require up to 125 mg/d of vitamin C compared to 60 to 90 mg/d of those without the same risks.[7] In a national health and nutrition survey in the United States in 2004, the prevalence of vitamin C deficiency as defined by a serum level <0.2 mg/dL was noted in 7.1% of those surveyed.[8] This study also noted a significantly higher prevalence of deficiency in smokers and individuals with low socioeconomic status.

Scurvy is a clinical diagnosis based on clinical features and dietary history. Severe manifestations of scurvy may happen quickly after the initial presentation, making early diagnosis especially important.[2] These include anemia, bone pain, ocular hemorrhage, cerebral hemorrhage, and hemopericardium.[2, 4] If needed, laboratory diagnosis can be made by demonstrating a serum ascorbic acid level <0.2 mg/dL. However, the level may be normal if the patient has had recent intake of vitamin C. In that scenario, the leukocyte vitamin C concentration may be a more accurate measure of the body stores as leukocyte levels change more slowly.[4] Biopsy of skin lesions is not necessary for the diagnosis and typically show a dilated hair follicle with keratin plugging and perifollicular hemorrhage.[9] Given the lack of adverse effects, treatment with vitamin C supplementation should begin immediately, even with low suspicion of scurvy, and response can serve as further clinical evidence and render laboratory testing unnecessary.

In this patient, the diagnosis was challenging for several reasons. The presentation was concerning for vasculitis given the dependent petechiae and elevated inflammatory markers. However, in scurvy, the petechiae are perifollicular and associated with hyperkeratosis, as opposed to the palpable purpura often described in vasculitis. Further, marked elevations in ESR and CRP have also been reported in scurvy.[10] The initial concern for vasculitis and clinician discomfort with a diagnosis based solely on a rash delayed the diagnosis. The complaint of polyneuropathy also seemed inconsistent with scurvy. Very rarely, scurvy may cause a neuropathy by hemorrhage into the nerve sheath, as seen in a case of bilateral femoral neuropathy.[11] Most likely, this patient had an underlying vitamin B deficiency explaining his polyneuropathy. Unfortunately, the patient was lost to follow‐up after his postdischarge visit with his primary physician and was not tested for other concomitant vitamin deficiencies.

Scurvy is very responsive to even small doses of vitamin C supplementation. For rapid recovery, doses ranging from 100 mg 3 times daily to 1000 mg daily of oral vitamin C are recommended for at least 1 month. Resolution of symptoms will begin within 24 hours, and complete recovery should occur by 3 months.[4] Scurvy is a classic example of how nutritional deficiencies can have a myriad of presentations and may mimic other systemic diseases. Clinicians who recall these manifestations and carefully assess patients for nutritional risks may be able to quickly identify the missing element (or elements) in a patient's diet, and initiate treatment that is often rapidly effective.

KEY TEACHING POINTS

1. Vitamin C deficiency initially presents with classic dermatological findings of perifollicular petechiae with associated hyperkeratosis and corkscrew hairs.
2. Scurvy is a clinical diagnosis based on history and presentation. Vitamin C serum level may not accurately reflect body stores, and a leukocyte vitamin C level may be obtained. The diagnosis may also be confirmed with observed response to vitamin C supplementation.
3. Scurvy should be suspected in high‐risk populations, especially the marginally housed, the elderly, alcoholics, and smokers.
4. Clinicians should screen patients with scurvy for other nutritional deficiencies including thiamine, folate, B12, and vitamin D levels.

Disclosures: Nothing to report.

A 57‐year‐old man presented to an emergency department with 1 month of progressive, bilateral lower extremity pain and weakness.

The first step in evaluating weakness is to determine whether it is objective (ie, decreased muscle strength due to pathology along the neuromuscular axis) or subjective. The sensation of weakness without loss of muscle strength may result from a debilitating chronic disease (eg, congestive heart failure, anemia, or chronic obstructive pulmonary disease). In patients with true lower extremity weakness it is prudent to assess for a myelopathy with a focused history and exam that includes assessment of bowel or bladder impairment and anal reflex. The presence of pain along with weakness might suggest disease of the muscle itself. A myopathy may arise from an infectious (eg, influenza), inflammatory (eg, polymyositis), endocrine (eg, hypothyroidism), or drug‐related (eg, statin) process.

The patient described 1 month of generalized weakness and pain in his lower extremities, which had worsened progressively to the point where ambulation was difficult. He was able to rise from a seated position using his arms for assistance, but had difficulty balancing in a standing position without assistance. The pain also involved both of his knees and increased with weight bearing. He also complained of bilateral lower extremity numbness and paresthesias, which had been migrating proximally from his toes over several months. He denied any recent trauma to his legs or back.

These symmetrical, distal sensory deficits favor a peripheral neuropathy over a myopathy, with neuropathic pain and arthralgia causing his impaired ability to ambulate or remain standing. In polyneuropathy, the type of nerve involvement (sensory vs motor) and pathology (axonal vs demyelinating) helps prioritize the differential. In developed countries, the most common causes of polyneuropathy are diabetes mellitus and alcohol. However, the tempo of his disease broadens the possibilities to include acute inflammatory demyelinating polyneuropathy, paraneoplastic syndrome (eg, monoclonal gammopathy), an autoimmune process (eg, rheumatoid arthritis, vasculitis), and heavy metal toxicity such as lead poisoning.

He had no history of chronic medical illness or hospitalizations and took no medications. His social history was notable for a history of alcohol abuse. For the past several years, he had only been drinking 1 to 2 beers daily due to cost, but had a history of more significant alcohol abuse in the distant past. He smoked 1 pack of tobacco per day, and denied illicit drug use. He denied any sexual activity or recent travel. He lived in a van, and had been homeless for over 10 years.

His socioeconomic status adds a layer of complexity to the case. Human immunodeficiency virus and hepatitis C virus (HCV) are more prevalent in the homeless and are associated with polyneuropathy. His lack of funds may drive him to drink illegally distilled alcohol, which can cause polyneuropathy through lead or arsenic toxicity. Excessive smoking could be linked to a peripheral neuropathy through a paraneoplastic syndrome (eg, small cell lung cancer).

Alcohol causes polyneuropathy through toxic effects on nerves and may be playing a role in his polyneuropathy, but the rapid pace and severity suggests an additional process. Alcoholism can be associated with deficiency of various B vitamins, such as thiamine, pyridoxine, and cobalamin, which can cause polyneuropathy. In alcoholics who are hospitalized, thiamine should be administered prior to glucose to decrease risk of Wernicke encephalopathy.

His temperature was 38.0C, heart rate 93 beats/min, blood pressure 121/60 mm Hg, respiratory rate 14/min, with an oxygen saturation of 97% on ambient air. He appeared cachectic and disheveled. He had moist mucous membranes, poor dentition with missing teeth, and no mucosal bleeding or oropharyngeal erythema. His cardiac exam revealed no murmurs, rubs, or gallops. His lungs were clear. His abdominal exam was benign, without masses or tenderness. His skin exam (Figure 1) was notable for nonpalpable petechiae on his anterior shins and thighs up to his buttocks. His extremity exam was significant for diffuse tenderness to light palpation on both lower extremities, a large indurated tender ecchymosis 15 15 cm behind the right knee, and another ecchymosis 6 8 cm behind the left knee. His dorsalis pedis and anterior tibialis pulses were appreciated by Doppler but not by palpation. He had decreased sensation to light touch of his bilateral feet to his ankles. Strength exam was challenging to assess secondary to posterior leg pain, but he demonstrated 4/5 strength of his hip flexors, quadriceps, and plantar flexors of the foot. His upper extremity strength and sensory exam were normal. Examination of the cranial nerves was normal. He had 2+ patellar and Achilles reflexes. Gait could not be adequately assessed.

Figure 1

Petechiae manifest as a nonblanchable rash caused by extravasated red blood cells. Common etiologies include quantitative or qualitative platelet defects, disseminated intravascular coagulopathy, trauma, and vasculitis. Cirrhosis from alcohol leading to thrombocytopenia and petechial rash is unlikely given no other stigmata of liver disease such as jaundice, spider angiomata, caput medusae, or palmar erythema. Less common causes include nutritional deficiency and light chain (AL) amyloidosis, which could explain both the neuropathy and rash.

The constellation of fever and petechial rash can represent a life‐threatening systemic process. Infectious agents that require immediate consideration with fever and petechiae include Neisseria meningitidis (meningococcemia), Rickettsia rickettsii (Rocky Mountain spotted fever), Staphylococcus, and Streptococcus. However, his normal blood pressure, dependent distribution of rash, and neuropathy make a severe bacterial infection less likely. Thrombotic thrombocytopenic purpura is possible and should prompt assessment of platelets, peripheral blood smear, and lactate dehydrogenase. Among vasculitides, the polyneuropathy, fever, and dependent distribution of petechial rash prioritize a small‐to‐medium vessel vasculitis, where the pathophysiology involves inflammation of dermal vessels and vasa nervorum (blood supply of nerves). Examples include HCV‐related cryoglobulinemic vasculitis, polyarteritis nodosa (PAN), and antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis. However, ANCA‐associated vasculitis is less likely without upper or lower respiratory symptoms. Henoch‐Schonlein purpura may explain the rash but is more common in children and is not associated with neuropathy.

Posterior knee ecchymosis, in absence of trauma, raises suspicion for a ruptured Baker's cyst. However, the bilateral involvement and lack of calf manifestations makes this unlikely. The location raises concern for hemarthrosis, so a more likely explanation would be coagulopathy (eg, an acquired factor inhibitor) or a collagen defect. In developed countries, a commonly overlooked category of diseasenutritional deficiencywarrants serious consideration in alcoholics. Vitamin C deficiency (scurvy) may cause a petechial rash and ecchymosis from perifollicular hemorrhage and impaired collagen synthesis, respectively. Scurvy can masquerade as small vessel vasculitis because of its associated petechial rash. The neuropathy might be explained by concomitant thiamine or cobalamin deficiency. It is important to obtain a thorough dietary history and assess vibration and proprioception, which may be impaired from pathology of the dorsal column in cobalamin deficiency. The low‐grade fever may be a red herring, but if it becomes significant would be difficult to explain with nutritional deficiency.

In summary, a judicious evaluation for infection is mandatory, but the leading diagnoses are a small‐to‐medium vessel vasculitis (PAN or HCV‐related cryoglobulinemia), deficiency of multiple vitamins, and AL amyloidosis.

Initial labs showed white blood cell count 7800/L, hematocrit 39.2%, and platelet count of 251,000/L. Serum chemistry demonstrated a sodium of 131 mEq/L, potassium 4.7 mEq/L, chloride 93 mEq/L, bicarbonate 23 mEq/L, blood urea nitrogen 8 mg/dL, and creatinine 0.8 mg/dL. His aminotransferases, albumin, alkaline phosphatase, and coagulation studies were within normal limits. Urinalysis was remarkable for 2+ urobilinogen, 1+ ketones, and a bland sediment. Urine toxicology screen was negative.

His white blood cell count is normal, so with a heart rate of 93 beats/minute, he barely meets a single criterion of systemic inflammatory response syndrome (SIRS). The lack of SIRS and normal platelet, albumin, white blood cell, and red blood cell counts significantly reduces the likelihood of an infectious or inflammatory process. Without any clinical or biochemical evidence of HCV infection, HCV‐associated cryoglobulinemia is less likely. A normal creatinine might overestimate renal function in setting of decreased protein intake and muscle mass; nevertheless, the bland urine sediment further lowers probability of PAN and ANCA‐associated vasculitides. The normal platelet count and coagulation studies suggest either a qualitative platelet defect (eg, acquired von Willebrand disease) or impaired vessel integrity (eg, collagen defect) to explain the petechial rash. The urine ketones likely represent alcohol and/or starvation‐related ketosis. These data reduce the probability of infection and vasculitis, and prioritize vitamin deficiency and AL amyloidosis. Antibiotic therapy is not appropriate, given the absence of SIRS and subacute course. His presentation likely prompted a wide variety of tests, but most relevant would be a dietary history, cobalamin and vitamin C levels, serum free light chains, and skin biopsy. Biopsy of the rash would allow assessment for vasculitis and AL amyloidosis. The former is marked by inflammatory infiltrate of vessels, and the latter by perivascular invasion with amyloid fibrils. If the dietary history was consistent with ascorbic acid deficiency (scurvy), in addition to thiamine, he should be empirically treated with vitamin C. Patients with scurvy demonstrate rapid clinical improvement with treatment.

C‐reactive protein (CRP) was 47.9 mg/L and erythrocyte sedimentation rate (ESR) was 44 mm/hr. Human immunodeficiency antibody screen was negative. Anti‐nuclear antibodies and anti‐nuclear cytoplasmic antibody panel were negative. Computed tomography angiogram (CTA) of the lower extremities demonstrated severe stenosis of the left superficial femoral artery and severe stenosis of the right posterior tibial artery. Ankle‐brachial indices were 0.83 on the right side and 0.72 on the left, indicating mild to moderate arterial disease.

ESR and CRP are nonspecific markers of inflammation. Their elevation does not prioritize malignancy, autoimmunity, or infection. ANCA might be negative in commonly ANCA‐associated vasculitides such as eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, and granulomatosis with polyangiitis. However, the lack of respiratory and renal involvement in addition to the negative ANCA panel make such diagnoses unlikely. CTA of the patient's legs showed significant peripheral artery disease (PAD). This is unlikely to be the cause of his presentation; PAD should not cause petechiae, and his pain is disproportionate to the severity of the vascular disease reported. The additional information leaves the differential unchanged.

A dermatologist was consulted. She described and photographed a perifollicular distribution of the lower extremity petechiae with associated perifollicular hyperkeratosis and retained curled hairs (Figure 2).

Figure 2

The described rash is specific for scurvy. His homelessness and alcohol intake likely made him vulnerable to ascorbic acid deficiency from lack of access to fruits and vegetables. Measurement of vitamin C level is unnecessary as the pretest probability for scurvy is very high. More relevant than a vitamin C level or skin biopsy is empiric treatment with ascorbic acid; as mentioned, patients with scurvy respond rapidly to vitamin C therapy. Given the neuropathy, he should be assessed for concomitant thiamine and/or cobalamin deficiency. His peripheral arterial disease is unlikely to be related.

His ascorbic acid level was 0.0 mg/dL (reference range, 0.22.0 mg/dL). Further history was obtained, and the patient reported exclusively eating frozen hamburgers and burritos for almost 1 year. He believed he had not had a fruit or vegetable in over 10 years. He was started on 1000 mg daily of ascorbic acid. By hospital day 2, his rash had mostly resolved and he was able to stand with some support. The patient was seen by his primary care physician 3 weeks after diagnosis, with his exercise tolerance nearly back to baseline. His rash had entirely resolved.

DISCUSSION

Unlike other mammals, humans do not have the ability to convert glucose to vitamin C and thus require an exogenous source, such as fruits and vegetables. The oft‐cited observation of scurvy in sailors during long journeys in the 18th century is a classic example of clinical disease due to vitamin C deficiency.[1] Once replete, body stores of vitamin C are usually sufficient to last over 6 months of deprivation. In some patients, symptoms of deficiency may appear within 3 months.[2] The patient in this report likely suffered years of vitamin C deficiency, resulting in the significant manifestations of scurvy reported here.

Vitamin C is a water‐soluble vitamin necessary for the biosynthesis of collagen, L‐carnitine, and neurotransmitters.[3] With deficiency, the resulting impairment in the formation of collagen affects blood vessel integrity and results in perivascular edema and erythrocyte extravasation. Clinically, this leads to hemorrhagic manifestations (eg, periosteal hemorrhage and perifollicular petechiae) and poor wound healing. Corkscrew hairs result because of vitamin C's role in disulfide bonding during hair formation. Woody edema and dyspnea are thought to be a consequence of leaky capillaries.[4]

Scurvy is still a significant cause of morbidity in at‐risk populations in the United States. Several populations have been identified as high risk for vitamin C deficiency, including the elderly, persons who live alone, alcoholics, smokers, individuals of low socioeconomic status, patients on hemodialysis, and those with psychiatric disease.[5] Specifically, the high oxidative stress associated with smoking, the history of alcohol abuse, and homelessness put this patient at an especially high risk.[6] Those with oxidative stressors have been postulated to require up to 125 mg/d of vitamin C compared to 60 to 90 mg/d of those without the same risks.[7] In a national health and nutrition survey in the United States in 2004, the prevalence of vitamin C deficiency as defined by a serum level <0.2 mg/dL was noted in 7.1% of those surveyed.[8] This study also noted a significantly higher prevalence of deficiency in smokers and individuals with low socioeconomic status.

Scurvy is a clinical diagnosis based on clinical features and dietary history. Severe manifestations of scurvy may happen quickly after the initial presentation, making early diagnosis especially important.[2] These include anemia, bone pain, ocular hemorrhage, cerebral hemorrhage, and hemopericardium.[2, 4] If needed, laboratory diagnosis can be made by demonstrating a serum ascorbic acid level <0.2 mg/dL. However, the level may be normal if the patient has had recent intake of vitamin C. In that scenario, the leukocyte vitamin C concentration may be a more accurate measure of the body stores as leukocyte levels change more slowly.[4] Biopsy of skin lesions is not necessary for the diagnosis and typically show a dilated hair follicle with keratin plugging and perifollicular hemorrhage.[9] Given the lack of adverse effects, treatment with vitamin C supplementation should begin immediately, even with low suspicion of scurvy, and response can serve as further clinical evidence and render laboratory testing unnecessary.

In this patient, the diagnosis was challenging for several reasons. The presentation was concerning for vasculitis given the dependent petechiae and elevated inflammatory markers. However, in scurvy, the petechiae are perifollicular and associated with hyperkeratosis, as opposed to the palpable purpura often described in vasculitis. Further, marked elevations in ESR and CRP have also been reported in scurvy.[10] The initial concern for vasculitis and clinician discomfort with a diagnosis based solely on a rash delayed the diagnosis. The complaint of polyneuropathy also seemed inconsistent with scurvy. Very rarely, scurvy may cause a neuropathy by hemorrhage into the nerve sheath, as seen in a case of bilateral femoral neuropathy.[11] Most likely, this patient had an underlying vitamin B deficiency explaining his polyneuropathy. Unfortunately, the patient was lost to follow‐up after his postdischarge visit with his primary physician and was not tested for other concomitant vitamin deficiencies.

Scurvy is very responsive to even small doses of vitamin C supplementation. For rapid recovery, doses ranging from 100 mg 3 times daily to 1000 mg daily of oral vitamin C are recommended for at least 1 month. Resolution of symptoms will begin within 24 hours, and complete recovery should occur by 3 months.[4] Scurvy is a classic example of how nutritional deficiencies can have a myriad of presentations and may mimic other systemic diseases. Clinicians who recall these manifestations and carefully assess patients for nutritional risks may be able to quickly identify the missing element (or elements) in a patient's diet, and initiate treatment that is often rapidly effective.

KEY TEACHING POINTS

1. Vitamin C deficiency initially presents with classic dermatological findings of perifollicular petechiae with associated hyperkeratosis and corkscrew hairs.
2. Scurvy is a clinical diagnosis based on history and presentation. Vitamin C serum level may not accurately reflect body stores, and a leukocyte vitamin C level may be obtained. The diagnosis may also be confirmed with observed response to vitamin C supplementation.
3. Scurvy should be suspected in high‐risk populations, especially the marginally housed, the elderly, alcoholics, and smokers.
4. Clinicians should screen patients with scurvy for other nutritional deficiencies including thiamine, folate, B12, and vitamin D levels.

Disclosures: Nothing to report.

A 57‐year‐old man presented to an emergency department with 1 month of progressive, bilateral lower extremity pain and weakness.

The first step in evaluating weakness is to determine whether it is objective (ie, decreased muscle strength due to pathology along the neuromuscular axis) or subjective. The sensation of weakness without loss of muscle strength may result from a debilitating chronic disease (eg, congestive heart failure, anemia, or chronic obstructive pulmonary disease). In patients with true lower extremity weakness it is prudent to assess for a myelopathy with a focused history and exam that includes assessment of bowel or bladder impairment and anal reflex. The presence of pain along with weakness might suggest disease of the muscle itself. A myopathy may arise from an infectious (eg, influenza), inflammatory (eg, polymyositis), endocrine (eg, hypothyroidism), or drug‐related (eg, statin) process.

The patient described 1 month of generalized weakness and pain in his lower extremities, which had worsened progressively to the point where ambulation was difficult. He was able to rise from a seated position using his arms for assistance, but had difficulty balancing in a standing position without assistance. The pain also involved both of his knees and increased with weight bearing. He also complained of bilateral lower extremity numbness and paresthesias, which had been migrating proximally from his toes over several months. He denied any recent trauma to his legs or back.

These symmetrical, distal sensory deficits favor a peripheral neuropathy over a myopathy, with neuropathic pain and arthralgia causing his impaired ability to ambulate or remain standing. In polyneuropathy, the type of nerve involvement (sensory vs motor) and pathology (axonal vs demyelinating) helps prioritize the differential. In developed countries, the most common causes of polyneuropathy are diabetes mellitus and alcohol. However, the tempo of his disease broadens the possibilities to include acute inflammatory demyelinating polyneuropathy, paraneoplastic syndrome (eg, monoclonal gammopathy), an autoimmune process (eg, rheumatoid arthritis, vasculitis), and heavy metal toxicity such as lead poisoning.

He had no history of chronic medical illness or hospitalizations and took no medications. His social history was notable for a history of alcohol abuse. For the past several years, he had only been drinking 1 to 2 beers daily due to cost, but had a history of more significant alcohol abuse in the distant past. He smoked 1 pack of tobacco per day, and denied illicit drug use. He denied any sexual activity or recent travel. He lived in a van, and had been homeless for over 10 years.

His socioeconomic status adds a layer of complexity to the case. Human immunodeficiency virus and hepatitis C virus (HCV) are more prevalent in the homeless and are associated with polyneuropathy. His lack of funds may drive him to drink illegally distilled alcohol, which can cause polyneuropathy through lead or arsenic toxicity. Excessive smoking could be linked to a peripheral neuropathy through a paraneoplastic syndrome (eg, small cell lung cancer).

Alcohol causes polyneuropathy through toxic effects on nerves and may be playing a role in his polyneuropathy, but the rapid pace and severity suggests an additional process. Alcoholism can be associated with deficiency of various B vitamins, such as thiamine, pyridoxine, and cobalamin, which can cause polyneuropathy. In alcoholics who are hospitalized, thiamine should be administered prior to glucose to decrease risk of Wernicke encephalopathy.

His temperature was 38.0C, heart rate 93 beats/min, blood pressure 121/60 mm Hg, respiratory rate 14/min, with an oxygen saturation of 97% on ambient air. He appeared cachectic and disheveled. He had moist mucous membranes, poor dentition with missing teeth, and no mucosal bleeding or oropharyngeal erythema. His cardiac exam revealed no murmurs, rubs, or gallops. His lungs were clear. His abdominal exam was benign, without masses or tenderness. His skin exam (Figure 1) was notable for nonpalpable petechiae on his anterior shins and thighs up to his buttocks. His extremity exam was significant for diffuse tenderness to light palpation on both lower extremities, a large indurated tender ecchymosis 15 15 cm behind the right knee, and another ecchymosis 6 8 cm behind the left knee. His dorsalis pedis and anterior tibialis pulses were appreciated by Doppler but not by palpation. He had decreased sensation to light touch of his bilateral feet to his ankles. Strength exam was challenging to assess secondary to posterior leg pain, but he demonstrated 4/5 strength of his hip flexors, quadriceps, and plantar flexors of the foot. His upper extremity strength and sensory exam were normal. Examination of the cranial nerves was normal. He had 2+ patellar and Achilles reflexes. Gait could not be adequately assessed.

Figure 1

Petechiae manifest as a nonblanchable rash caused by extravasated red blood cells. Common etiologies include quantitative or qualitative platelet defects, disseminated intravascular coagulopathy, trauma, and vasculitis. Cirrhosis from alcohol leading to thrombocytopenia and petechial rash is unlikely given no other stigmata of liver disease such as jaundice, spider angiomata, caput medusae, or palmar erythema. Less common causes include nutritional deficiency and light chain (AL) amyloidosis, which could explain both the neuropathy and rash.

The constellation of fever and petechial rash can represent a life‐threatening systemic process. Infectious agents that require immediate consideration with fever and petechiae include Neisseria meningitidis (meningococcemia), Rickettsia rickettsii (Rocky Mountain spotted fever), Staphylococcus, and Streptococcus. However, his normal blood pressure, dependent distribution of rash, and neuropathy make a severe bacterial infection less likely. Thrombotic thrombocytopenic purpura is possible and should prompt assessment of platelets, peripheral blood smear, and lactate dehydrogenase. Among vasculitides, the polyneuropathy, fever, and dependent distribution of petechial rash prioritize a small‐to‐medium vessel vasculitis, where the pathophysiology involves inflammation of dermal vessels and vasa nervorum (blood supply of nerves). Examples include HCV‐related cryoglobulinemic vasculitis, polyarteritis nodosa (PAN), and antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis. However, ANCA‐associated vasculitis is less likely without upper or lower respiratory symptoms. Henoch‐Schonlein purpura may explain the rash but is more common in children and is not associated with neuropathy.

Posterior knee ecchymosis, in absence of trauma, raises suspicion for a ruptured Baker's cyst. However, the bilateral involvement and lack of calf manifestations makes this unlikely. The location raises concern for hemarthrosis, so a more likely explanation would be coagulopathy (eg, an acquired factor inhibitor) or a collagen defect. In developed countries, a commonly overlooked category of diseasenutritional deficiencywarrants serious consideration in alcoholics. Vitamin C deficiency (scurvy) may cause a petechial rash and ecchymosis from perifollicular hemorrhage and impaired collagen synthesis, respectively. Scurvy can masquerade as small vessel vasculitis because of its associated petechial rash. The neuropathy might be explained by concomitant thiamine or cobalamin deficiency. It is important to obtain a thorough dietary history and assess vibration and proprioception, which may be impaired from pathology of the dorsal column in cobalamin deficiency. The low‐grade fever may be a red herring, but if it becomes significant would be difficult to explain with nutritional deficiency.

In summary, a judicious evaluation for infection is mandatory, but the leading diagnoses are a small‐to‐medium vessel vasculitis (PAN or HCV‐related cryoglobulinemia), deficiency of multiple vitamins, and AL amyloidosis.

Initial labs showed white blood cell count 7800/L, hematocrit 39.2%, and platelet count of 251,000/L. Serum chemistry demonstrated a sodium of 131 mEq/L, potassium 4.7 mEq/L, chloride 93 mEq/L, bicarbonate 23 mEq/L, blood urea nitrogen 8 mg/dL, and creatinine 0.8 mg/dL. His aminotransferases, albumin, alkaline phosphatase, and coagulation studies were within normal limits. Urinalysis was remarkable for 2+ urobilinogen, 1+ ketones, and a bland sediment. Urine toxicology screen was negative.

His white blood cell count is normal, so with a heart rate of 93 beats/minute, he barely meets a single criterion of systemic inflammatory response syndrome (SIRS). The lack of SIRS and normal platelet, albumin, white blood cell, and red blood cell counts significantly reduces the likelihood of an infectious or inflammatory process. Without any clinical or biochemical evidence of HCV infection, HCV‐associated cryoglobulinemia is less likely. A normal creatinine might overestimate renal function in setting of decreased protein intake and muscle mass; nevertheless, the bland urine sediment further lowers probability of PAN and ANCA‐associated vasculitides. The normal platelet count and coagulation studies suggest either a qualitative platelet defect (eg, acquired von Willebrand disease) or impaired vessel integrity (eg, collagen defect) to explain the petechial rash. The urine ketones likely represent alcohol and/or starvation‐related ketosis. These data reduce the probability of infection and vasculitis, and prioritize vitamin deficiency and AL amyloidosis. Antibiotic therapy is not appropriate, given the absence of SIRS and subacute course. His presentation likely prompted a wide variety of tests, but most relevant would be a dietary history, cobalamin and vitamin C levels, serum free light chains, and skin biopsy. Biopsy of the rash would allow assessment for vasculitis and AL amyloidosis. The former is marked by inflammatory infiltrate of vessels, and the latter by perivascular invasion with amyloid fibrils. If the dietary history was consistent with ascorbic acid deficiency (scurvy), in addition to thiamine, he should be empirically treated with vitamin C. Patients with scurvy demonstrate rapid clinical improvement with treatment.

C‐reactive protein (CRP) was 47.9 mg/L and erythrocyte sedimentation rate (ESR) was 44 mm/hr. Human immunodeficiency antibody screen was negative. Anti‐nuclear antibodies and anti‐nuclear cytoplasmic antibody panel were negative. Computed tomography angiogram (CTA) of the lower extremities demonstrated severe stenosis of the left superficial femoral artery and severe stenosis of the right posterior tibial artery. Ankle‐brachial indices were 0.83 on the right side and 0.72 on the left, indicating mild to moderate arterial disease.

ESR and CRP are nonspecific markers of inflammation. Their elevation does not prioritize malignancy, autoimmunity, or infection. ANCA might be negative in commonly ANCA‐associated vasculitides such as eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, and granulomatosis with polyangiitis. However, the lack of respiratory and renal involvement in addition to the negative ANCA panel make such diagnoses unlikely. CTA of the patient's legs showed significant peripheral artery disease (PAD). This is unlikely to be the cause of his presentation; PAD should not cause petechiae, and his pain is disproportionate to the severity of the vascular disease reported. The additional information leaves the differential unchanged.

A dermatologist was consulted. She described and photographed a perifollicular distribution of the lower extremity petechiae with associated perifollicular hyperkeratosis and retained curled hairs (Figure 2).

Figure 2

The described rash is specific for scurvy. His homelessness and alcohol intake likely made him vulnerable to ascorbic acid deficiency from lack of access to fruits and vegetables. Measurement of vitamin C level is unnecessary as the pretest probability for scurvy is very high. More relevant than a vitamin C level or skin biopsy is empiric treatment with ascorbic acid; as mentioned, patients with scurvy respond rapidly to vitamin C therapy. Given the neuropathy, he should be assessed for concomitant thiamine and/or cobalamin deficiency. His peripheral arterial disease is unlikely to be related.

His ascorbic acid level was 0.0 mg/dL (reference range, 0.22.0 mg/dL). Further history was obtained, and the patient reported exclusively eating frozen hamburgers and burritos for almost 1 year. He believed he had not had a fruit or vegetable in over 10 years. He was started on 1000 mg daily of ascorbic acid. By hospital day 2, his rash had mostly resolved and he was able to stand with some support. The patient was seen by his primary care physician 3 weeks after diagnosis, with his exercise tolerance nearly back to baseline. His rash had entirely resolved.

DISCUSSION

Unlike other mammals, humans do not have the ability to convert glucose to vitamin C and thus require an exogenous source, such as fruits and vegetables. The oft‐cited observation of scurvy in sailors during long journeys in the 18th century is a classic example of clinical disease due to vitamin C deficiency.[1] Once replete, body stores of vitamin C are usually sufficient to last over 6 months of deprivation. In some patients, symptoms of deficiency may appear within 3 months.[2] The patient in this report likely suffered years of vitamin C deficiency, resulting in the significant manifestations of scurvy reported here.

Vitamin C is a water‐soluble vitamin necessary for the biosynthesis of collagen, L‐carnitine, and neurotransmitters.[3] With deficiency, the resulting impairment in the formation of collagen affects blood vessel integrity and results in perivascular edema and erythrocyte extravasation. Clinically, this leads to hemorrhagic manifestations (eg, periosteal hemorrhage and perifollicular petechiae) and poor wound healing. Corkscrew hairs result because of vitamin C's role in disulfide bonding during hair formation. Woody edema and dyspnea are thought to be a consequence of leaky capillaries.[4]

Scurvy is still a significant cause of morbidity in at‐risk populations in the United States. Several populations have been identified as high risk for vitamin C deficiency, including the elderly, persons who live alone, alcoholics, smokers, individuals of low socioeconomic status, patients on hemodialysis, and those with psychiatric disease.[5] Specifically, the high oxidative stress associated with smoking, the history of alcohol abuse, and homelessness put this patient at an especially high risk.[6] Those with oxidative stressors have been postulated to require up to 125 mg/d of vitamin C compared to 60 to 90 mg/d of those without the same risks.[7] In a national health and nutrition survey in the United States in 2004, the prevalence of vitamin C deficiency as defined by a serum level <0.2 mg/dL was noted in 7.1% of those surveyed.[8] This study also noted a significantly higher prevalence of deficiency in smokers and individuals with low socioeconomic status.

Scurvy is a clinical diagnosis based on clinical features and dietary history. Severe manifestations of scurvy may happen quickly after the initial presentation, making early diagnosis especially important.[2] These include anemia, bone pain, ocular hemorrhage, cerebral hemorrhage, and hemopericardium.[2, 4] If needed, laboratory diagnosis can be made by demonstrating a serum ascorbic acid level <0.2 mg/dL. However, the level may be normal if the patient has had recent intake of vitamin C. In that scenario, the leukocyte vitamin C concentration may be a more accurate measure of the body stores as leukocyte levels change more slowly.[4] Biopsy of skin lesions is not necessary for the diagnosis and typically show a dilated hair follicle with keratin plugging and perifollicular hemorrhage.[9] Given the lack of adverse effects, treatment with vitamin C supplementation should begin immediately, even with low suspicion of scurvy, and response can serve as further clinical evidence and render laboratory testing unnecessary.

In this patient, the diagnosis was challenging for several reasons. The presentation was concerning for vasculitis given the dependent petechiae and elevated inflammatory markers. However, in scurvy, the petechiae are perifollicular and associated with hyperkeratosis, as opposed to the palpable purpura often described in vasculitis. Further, marked elevations in ESR and CRP have also been reported in scurvy.[10] The initial concern for vasculitis and clinician discomfort with a diagnosis based solely on a rash delayed the diagnosis. The complaint of polyneuropathy also seemed inconsistent with scurvy. Very rarely, scurvy may cause a neuropathy by hemorrhage into the nerve sheath, as seen in a case of bilateral femoral neuropathy.[11] Most likely, this patient had an underlying vitamin B deficiency explaining his polyneuropathy. Unfortunately, the patient was lost to follow‐up after his postdischarge visit with his primary physician and was not tested for other concomitant vitamin deficiencies.

Scurvy is very responsive to even small doses of vitamin C supplementation. For rapid recovery, doses ranging from 100 mg 3 times daily to 1000 mg daily of oral vitamin C are recommended for at least 1 month. Resolution of symptoms will begin within 24 hours, and complete recovery should occur by 3 months.[4] Scurvy is a classic example of how nutritional deficiencies can have a myriad of presentations and may mimic other systemic diseases. Clinicians who recall these manifestations and carefully assess patients for nutritional risks may be able to quickly identify the missing element (or elements) in a patient's diet, and initiate treatment that is often rapidly effective.

KEY TEACHING POINTS

1. Vitamin C deficiency initially presents with classic dermatological findings of perifollicular petechiae with associated hyperkeratosis and corkscrew hairs.
2. Scurvy is a clinical diagnosis based on history and presentation. Vitamin C serum level may not accurately reflect body stores, and a leukocyte vitamin C level may be obtained. The diagnosis may also be confirmed with observed response to vitamin C supplementation.
3. Scurvy should be suspected in high‐risk populations, especially the marginally housed, the elderly, alcoholics, and smokers.
4. Clinicians should screen patients with scurvy for other nutritional deficiencies including thiamine, folate, B12, and vitamin D levels.

Disclosures: 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

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