Clinical Care Conundrums

A 73‐year‐old man was admitted with 6 days of fevers, with rigors and diaphoresis, and associated frontal headache.

Fever in an elderly man is a nonspecific finding, occurring most commonly with infections but also with certain malignancies, rheumatologic disorders, and drug exposures. The complaint of rigors with diaphoresis makes an infection most likely. The acuity of his illness makes infections with more chronic presentations such as tuberculosis or actinomycosis less likely. The presence of frontal headache might suggest a sinus or brain source, but headache also occurs in generalized infections such as pneumonia, bacteremia from any cause, malaria, rickettsial infections, viral illnesses, and others. Additional history should include detailed inquiry into travel, vocational, and avocational exposures.

Since onset, the fevers had been accompanied by malaise, myalgias, decreased oral intake, nausea, and nonbloody, nonbilious vomiting and nonbloody loose stools. On the day of admission, the patient developed the inability to rise from a seated position without the use of his arms.

The patient's difficulty standing implies the development of lower extremity weakness and infections associated with neurological syndromes. His leg weakness may be related to early Guillain‐Barre syndrome, which is associated most commonly with Campylobacter jejuni, but also other bacteria and viruses such as Haemophilus influenza, Mycoplasma pneumonia, Influenza virus, Cytomegalovirus and hepatitis E. Other viral infections associated with pure motor deficits include echovirus, coxsackie virus, enterovirus, and West Nile virus (WNV). The paralytic syndrome associated with enteroviruses is more common in children, whereas the neuroinvasive variant of WNV more often affects the elderly and can be associated with encephalitis as well as a flaccid paralysis. Although acute paralytic shellfish poisoning could account for both his weakness and his acute gastrointestinal syndrome, this diagnosis is unlikely because the symptoms often have a prominent sensory component, and there is usually the history of recent ingestion of the suspect bivalves. Like all adults presenting for medical care, he should be screened for human immunodeficiency virus (HIV) infection; if testing is positive, the differential diagnosis for his current illness broadens significantly. Finally, he may have a spinal cord disorder or infection such as an epidural abscess, or transverse myelitis, which would present with lower extremity weakness and fever. It would be helpful to know the time of year of his illness, exposure to mosquito bites, his neurological exam findings, and results of blood and stool cultures. If the patient had signs of meningitis or encephalitis, cerebral spinal fluid analysis would be helpful. If his neurological exam was suggestive of cord involvement, it would be helpful to know the results of magnetic resonance imaging of the spinal cord.

His past medical history was remarkable for nonobstructive coronary artery disease, paroxysmal atrial fibrillation, hypothyroidism, and prostate cancer (T2N0M0, Gleason 3+4) treated with radical prostatectomy and pelvic lymph node dissection 6 years previously. One month prior to this presentation, the patient developed a small right knee effusion, and x‐ray evaluation at that time showed mild degenerative joint disease. His medications included aspirin 325 mg daily, metoprolol succinate 100 mg daily, levothyroxine 25 g daily, and simvastatin 20 mg nightly. The patient was a lawyer, and lived in the Pacific Northwest. He had never smoked or used illicit drugs, and drank 2 glasses of red wine nightly. His travel history was remarkable for a visit to Uganda 1 year prior to admission; Zurich, Switzerland 6 months prior to admission; and Cape Cod, Massachusetts during the summer season 5 months prior to admission. His exposures included keeping chickens on his property, tending a garden, and ingestion of raw oysters 1 month prior to the onset of symptoms.

The patient's past medical history includes relatively common problems for a 73‐year‐old man and does not substantially influence the differential diagnosis of his current illness. His travel history to Uganda a year previously may be relevant, because malaria (Plasmodium vivax) could present with fever and weakness. Less commonly, African trypanosomiasis (Trypanosoma brucei gambiense) can, in the late phase, present with fever and malaise, but also typically includes symptoms of encephalitis, including depressed mental status, confusion, ataxia, and possibly personality changes. His travel to Zurich should not impose any particular infection risk, unless he was hiking in the mountains around Zurich, where he could have contracted tick‐borne encephalitis; however, his travel more than 6 months prior to presentation makes this unlikely. Lyme disease due to Borrelia burgdorferi is also a potential exposure in the Swiss mountains, and can present with fever in the acute phase, as well as arthritis with chronic disease, but should not cause fever, rigor, diaphoresis, and headache many months later. Summering in Cape Cod puts him at risk for babesiosis, but an incubation period of 5 months is too long. Keeping chickens places him at risk for Salmonella exposure and typhoid fever. Ingesting raw oysters carries a risk for shellfish poisoning and Vibrio infections, but the incubation period (1 month) again seems too long to cause his current symptoms.

On exam, his temperature was 39.4C, heart rate 87 beats/min, blood pressure 129/70 mm Hg, respiratory rate 18/min, with an oxygen saturation of 94% on room air. He was ill appearing. He had injected sclera bilaterally, with moist mucous membranes, no oropharyngeal lesions, and no cervical lymphadenopathy. His cardiac exam revealed no murmurs, rub, or diastolic gallops. His lungs were clear without rales or wheezes. His abdominal exam was benign, without masses or tenderness. He had no musculoskeletal tenderness, lower extremity edema, erythema, or effusion in his lower extremity joints. His neurological exam was notable for difficulty rising from a seated position. He also had a shortened stride length in his gait and a slow, deliberate 180 turn. There was no resting tremor. Romberg's sign was negative, and the remainder of neurological exam was normal.

Notable physical findings are an ill‐appearing man with injected sclera and a high fever but normal blood pressure and heart rate. He also demonstrates proximal lower extremity weakness manifested by difficulty rising from a chair and a slow gait with short strides and deliberate (possibly on‐block) turning. His neurological exam is most consistent with Parkinsonian symptoms that have been described in patients with severe influenza A, which would explain all of his other symptoms as well. Pulse‐temperature dissociation is classically described with typhoid fever but usually occurs later in the disease course, and could be masked by the patient's metoprolol. Typhoid fever can also be associated with neurological symptoms including meningitis and movement disorders.

White blood cell count was 6060/L, with 36% bands, hematocrit 35.5%, and platelet count of 134,000/L. Sodium was 133 mmol/L, potassium 3.3 mmol/L, chloride 97 mmol/L, bicarbonate 30 mmol/L, blood urea nitrogen 19 mg/dL, and creatinine 1.2 mg/dL. Alanine aminotransferase was 79 IU/L (normal, 1541), aspartate aminotransferase 82 IU/L (normal, 1260), total bilirubin 1.8 mg/dL (normal, 0.31.2), direct bilirubin 0.6 mg/dL (normal, 0.00.3), total protein 6.6 mg/dL (normal, 6.48.2), albumin 2.6 mg/dL (normal, 3.54.7), and alkaline phosphatase 356 IU/L (normal, 56119). Creatinine kinase was 137 IU/L (normal, 49397). Erythrocyte sedimentation rate 44 mm/hr (normal, 020). Urinalysis with microscopic examination was notable for moderate blood, negative leukocyte esterase, negative nitrites, protein 100 mg/dL (normal 030 mg/dL), 5 white blood cells (normal, 05), 9 red blood cells (normal, 05), and 3 granular casts. Gamma glutamyl transferase (GGT) was 459 IU/L (normal, 1298). Ferritin was 552 ng/mL (normal, 50200), and haptoglobin 185 mg/dL (normal, 30200). Prostate specific antigen was <0.02 ng/mL (<6.5). Chest x‐ray revealed right perihilar and bibasilar atelectasis without effusions or other consolidation. Computed tomography of the head, abdomen, and pelvis was normal. Ultrasonography of the liver was revealing for mild gallbladder edema without evidence of cholecystitis and normal Doppler indices of the hepatic vessels. Magnetic resonance imaging of the complete spine (cervical, thoracic, and lumbar) was performed and was unremarkable.

The patient has a remarkable bandemia, suggesting a bacterial infection, as well as a slight reduction in hematocrit and platelet count. Additionally, his labs revealed a mild transaminitis, but with significantly elevated alkaline phosphatase and GGT, and microscopic hematuria. His ferritin is significantly elevated, which may simply represent an acute phase reactant. Infections associated with hepatitis, cytopenias, and hematuria include sepsis with disseminated intravascular coagulation, previously mentioned malaria, leptospirosis, dengue, ehrlichiosis, and rickettsial diseases, but he has no special risks for these infections, and other aspects of his illness (Parkinsonian features, bandemia) do not fit. His lung findings with hematuria might suggest a pulmonary/renal syndrome, but, once again, other features of his illness are not typical of these syndromes. Salmonella (typhoid fever) or influenza, now complicated by an early bacterial pneumonia, are viable possibilities.

Through hospital day 2, the patient continued to have fevers over 39C about twice per day. Antibiotic therapy was not started because, other than fevers, the patient did not meet additional criteria for systemic inflammatory response syndrome (SIRS). Initial blood and urine cultures were without growth. Lumbar puncture was planned given ongoing headache symptoms.

The patient's ongoing clinical course is notable for a nontoxic (non‐SIRS) appearance but continued high‐grade fever with blood and urine cultures that are sterile. This argues against a common bacteremia with sepsis, and for either relapsing malaria (P vivax), influenza with a Parkinsonian‐like illness, typhoid fever, leptospirosis, dengue, or a rickettsial infection. Mycoplasma pneumonia is also possible given the atypical chest x‐ray appearance, slightly low hematocrit with elevated bilirubin, and neurological symptoms that may represent ataxia.

Blood cultures, repeated 5 times, each drawn while the patient was febrile, were all negative. Parasite thick and thin smears, repeated 4 times, were also negative. Stool ova and parasite exam was negative, and stool cultures were negative. Antibody and antigen analysis for hepatitis A, B, and C were negative for infection. HIV antibody screen was negative, and rapid plasma reagin for syphilis was nonreactive. Parvovirus B‐19 immunoglobulin (Ig)G was reactive, but IgM was nonreactive. Cytomegalovirus, Epstein‐Barr virus, and respiratory virus panel polymerase chain reaction testing was negative. Lyme antibody enzyme‐linked immunosorbent assay was 0.32 Lyme index units (normal, 0.01.2), leptospira antibody was <1:50 (normal, <1:50), mycoplasma pneumonia IgG was 0.04 U/L (normal, <0.09), and Q fever IgG was <1:16 (normal, <1:16). West Nile and St. Louis encephalitis IgG and IgM from serum specimens were nonreactive. Hantavirus IgM and lymphocytic choriomeningitis IgM from the serum were also negative.

On the evening of hospital day 2, the patient's daughter noticed an odd smell emanating from the patient's car. Further inspection of the car by the patient's family revealed a mouse nest located in the trunk of the car, and suspected mouse urine was noted on the floorboards of the vehicle. The hospital care team was informed.

The subsequent negative laboratory tests listed are helpful in likely excluding many of the diagnoses suggested such as malaria, Babesia, common bacteremias, viral hepatitis, HIV, and WNV. Furthermore, the new history of mouse exposure brings to the forefront rodent‐associated infections, specifically exposure to mouse urine, a vehicle for leptospirosis. The patient's hepatitis, anemia, thrombocytopenia, scleral injection, along with the rest of his symptoms in the context of exposure to mouse urine makes leptospirosis the likely diagnosis. A negative Leptospira antibody early in his illness does not rule out the disease, and a convalescent titer should be obtained to confirm the diagnosis.

Leptospirosis was suspected, and the patient was started on doxycycline. The patient improved after initiation of antibiotics, and was discharged on hospital day 5 with a 14‐day course of antibiotic treatment. At his follow‐up appointment 2 weeks after the onset of his illness, the patient denied further fevers, headache, nausea, and his weakness was improving. Repeat, convalescent Leptospiria antibody testing during this visit resulted positive at 1:400, confirming the diagnosis.

COMMENTARY

This case describes an elderly man who presented with a fever of unknown origin (FUO), and was eventually diagnosed with leptospirosis. FUO presents slightly differently in elderly patients, as elderly patients are less likely to mount a high fever, and when they do, the etiology is more likely to indicate a serious bacterial or viral infection. Additionally, an etiology for FUO in the elderly is found in over 70% of presenting cases, compared to 51% in patients under the age of 65 years.[1] A detailed, comprehensive social, travel, and exposure history and physical examination remains the cornerstone of elucidating the diagnosis for FUO. The exposure to mouse urine in this case was an unusual and a helpful piece of the history to further focus the differential diagnosis.

Leptospirosis is an emerging bacterial zoonosis, and causes both endemic and epidemic severe multisystem disease. The Leptospira spirochete is maintained in nature through a chronic renal infection in mammalian reservoir hosts, such as mice,[2, 4] and is transmitted through direct or aerosolized contact with infected urine or tissue. After a mean incubation period of 10 days, a variety of clinical manifestations may be seen. In this case, the patient's clinical presentation revealed many classic symptoms of leptospirosis, including fevers, rigors, headache, lower extremity myalgias, nausea, vomiting, and diarrhea; however, these symptoms are nonspecific. The presence of a conjunctival suffusion in leptospirosis infection had a specificity of 98% in a high‐incidence cohort of febrile patients in Sri Lanka,[3] and was an important diagnostic clue in this case. Leptospirosis is a self‐limited illness in most patients, with an initial septicemic, febrile phase followed by an immune phase. A more severe presentation may be seen in the immune phase of the illness, which includes renal and hepatic dysfunction (known as Weil's disease), as well as cardiac, pulmonary, and central nervous system abnormalities. With a 14% case fatality rate, the risk of death has been shown to be higher in patients over 40 years old, with altered mental status and multiorgan failure.[4]

The early diagnosis of leptospirosis relies heavily on physical exam findings and epidemiologic history. In this case, the patient's laboratory abnormalities, including immature granulocytes, thrombocytopenia, hyponatremia, hypokalemia, mild hepatitis, and pyuria with granular casts are all reported with leptospirosis infection²; however, independently, these laboratory findings are nonspecific. Patients may not have a detectable antibody levels in the acute phase of the disease. In this case, given the strong clinical suspicion based on the findings of conjunctival suffusion and exposure to mouse urine history, the lack of a more plausible alternate diagnosis, and known delay in antibody positivity, the patient was treated empirically with doxycycline for presumed leptospirosis.[5] Forthcoming novel diagnostic strategies such as next‐generation DNA sequencing techniques may provide real‐time diagnosis of this zoonotic infection, thus decreasing the window period between empirical antimicrobial coverage and diagnostic confirmation.[6]

Leptospirosis is prevalent in tropical climates and has been associated with impoverished communities.[7] Urban slums, with poor sanitation and high rodent density, are an ideal environment for leptospirosis. The reported risk of infection in a Brazilian slum was as high as 3% per year.[8] Additionally, rodent sightings, as well as the presence of chickens, were risk factors for leptospirosis transmission in urban slums.[9] Correspondingly in this case, we hypothesize that the patient's interest in urban farming, specifically the chickens he kept, likely attracted the mice infected with leptospirosis. Urban chicken farming is becoming increasingly popular in the United States,[10] and may be a developing risk factor for human leptospirosis infection. Leptospirosis is one of many emerging zoonoses, such as avian influenza, tick‐borne illness, and ebola, resulting from changing human ecology. Thus, when considering infectious etiologies, clinicians should ask patients about vocational and avocational exposures, including new trends such as urban farming, which may expose them to previously underappreciated illnesses.

TEACHING POINTS

1. Elderly patients with a FUO are more likely to be diagnosed with an underlying serious bacterial or viral infection when compared to a younger cohort of FUO patients.
2. The diagnosis of leptospirosis may initially be based on clinical suspicion in patients with classic features and exposures, noting the high specificity of conjunctival suffusion, and initial titers may be nondiagnostic; therefore, empiric treatment should be considered when clinical suspicion is high.
3. Increased interest in urban chicken farming in the United States, with associated higher rodent density, may represent a newly recognized risk factor for human leptospirosis infection.

Disclosures

The authors report no conflicts of interest.

A 73‐year‐old man was admitted with 6 days of fevers, with rigors and diaphoresis, and associated frontal headache.

Fever in an elderly man is a nonspecific finding, occurring most commonly with infections but also with certain malignancies, rheumatologic disorders, and drug exposures. The complaint of rigors with diaphoresis makes an infection most likely. The acuity of his illness makes infections with more chronic presentations such as tuberculosis or actinomycosis less likely. The presence of frontal headache might suggest a sinus or brain source, but headache also occurs in generalized infections such as pneumonia, bacteremia from any cause, malaria, rickettsial infections, viral illnesses, and others. Additional history should include detailed inquiry into travel, vocational, and avocational exposures.

Since onset, the fevers had been accompanied by malaise, myalgias, decreased oral intake, nausea, and nonbloody, nonbilious vomiting and nonbloody loose stools. On the day of admission, the patient developed the inability to rise from a seated position without the use of his arms.

The patient's difficulty standing implies the development of lower extremity weakness and infections associated with neurological syndromes. His leg weakness may be related to early Guillain‐Barre syndrome, which is associated most commonly with Campylobacter jejuni, but also other bacteria and viruses such as Haemophilus influenza, Mycoplasma pneumonia, Influenza virus, Cytomegalovirus and hepatitis E. Other viral infections associated with pure motor deficits include echovirus, coxsackie virus, enterovirus, and West Nile virus (WNV). The paralytic syndrome associated with enteroviruses is more common in children, whereas the neuroinvasive variant of WNV more often affects the elderly and can be associated with encephalitis as well as a flaccid paralysis. Although acute paralytic shellfish poisoning could account for both his weakness and his acute gastrointestinal syndrome, this diagnosis is unlikely because the symptoms often have a prominent sensory component, and there is usually the history of recent ingestion of the suspect bivalves. Like all adults presenting for medical care, he should be screened for human immunodeficiency virus (HIV) infection; if testing is positive, the differential diagnosis for his current illness broadens significantly. Finally, he may have a spinal cord disorder or infection such as an epidural abscess, or transverse myelitis, which would present with lower extremity weakness and fever. It would be helpful to know the time of year of his illness, exposure to mosquito bites, his neurological exam findings, and results of blood and stool cultures. If the patient had signs of meningitis or encephalitis, cerebral spinal fluid analysis would be helpful. If his neurological exam was suggestive of cord involvement, it would be helpful to know the results of magnetic resonance imaging of the spinal cord.

His past medical history was remarkable for nonobstructive coronary artery disease, paroxysmal atrial fibrillation, hypothyroidism, and prostate cancer (T2N0M0, Gleason 3+4) treated with radical prostatectomy and pelvic lymph node dissection 6 years previously. One month prior to this presentation, the patient developed a small right knee effusion, and x‐ray evaluation at that time showed mild degenerative joint disease. His medications included aspirin 325 mg daily, metoprolol succinate 100 mg daily, levothyroxine 25 g daily, and simvastatin 20 mg nightly. The patient was a lawyer, and lived in the Pacific Northwest. He had never smoked or used illicit drugs, and drank 2 glasses of red wine nightly. His travel history was remarkable for a visit to Uganda 1 year prior to admission; Zurich, Switzerland 6 months prior to admission; and Cape Cod, Massachusetts during the summer season 5 months prior to admission. His exposures included keeping chickens on his property, tending a garden, and ingestion of raw oysters 1 month prior to the onset of symptoms.

The patient's past medical history includes relatively common problems for a 73‐year‐old man and does not substantially influence the differential diagnosis of his current illness. His travel history to Uganda a year previously may be relevant, because malaria (Plasmodium vivax) could present with fever and weakness. Less commonly, African trypanosomiasis (Trypanosoma brucei gambiense) can, in the late phase, present with fever and malaise, but also typically includes symptoms of encephalitis, including depressed mental status, confusion, ataxia, and possibly personality changes. His travel to Zurich should not impose any particular infection risk, unless he was hiking in the mountains around Zurich, where he could have contracted tick‐borne encephalitis; however, his travel more than 6 months prior to presentation makes this unlikely. Lyme disease due to Borrelia burgdorferi is also a potential exposure in the Swiss mountains, and can present with fever in the acute phase, as well as arthritis with chronic disease, but should not cause fever, rigor, diaphoresis, and headache many months later. Summering in Cape Cod puts him at risk for babesiosis, but an incubation period of 5 months is too long. Keeping chickens places him at risk for Salmonella exposure and typhoid fever. Ingesting raw oysters carries a risk for shellfish poisoning and Vibrio infections, but the incubation period (1 month) again seems too long to cause his current symptoms.

On exam, his temperature was 39.4C, heart rate 87 beats/min, blood pressure 129/70 mm Hg, respiratory rate 18/min, with an oxygen saturation of 94% on room air. He was ill appearing. He had injected sclera bilaterally, with moist mucous membranes, no oropharyngeal lesions, and no cervical lymphadenopathy. His cardiac exam revealed no murmurs, rub, or diastolic gallops. His lungs were clear without rales or wheezes. His abdominal exam was benign, without masses or tenderness. He had no musculoskeletal tenderness, lower extremity edema, erythema, or effusion in his lower extremity joints. His neurological exam was notable for difficulty rising from a seated position. He also had a shortened stride length in his gait and a slow, deliberate 180 turn. There was no resting tremor. Romberg's sign was negative, and the remainder of neurological exam was normal.

Notable physical findings are an ill‐appearing man with injected sclera and a high fever but normal blood pressure and heart rate. He also demonstrates proximal lower extremity weakness manifested by difficulty rising from a chair and a slow gait with short strides and deliberate (possibly on‐block) turning. His neurological exam is most consistent with Parkinsonian symptoms that have been described in patients with severe influenza A, which would explain all of his other symptoms as well. Pulse‐temperature dissociation is classically described with typhoid fever but usually occurs later in the disease course, and could be masked by the patient's metoprolol. Typhoid fever can also be associated with neurological symptoms including meningitis and movement disorders.

White blood cell count was 6060/L, with 36% bands, hematocrit 35.5%, and platelet count of 134,000/L. Sodium was 133 mmol/L, potassium 3.3 mmol/L, chloride 97 mmol/L, bicarbonate 30 mmol/L, blood urea nitrogen 19 mg/dL, and creatinine 1.2 mg/dL. Alanine aminotransferase was 79 IU/L (normal, 1541), aspartate aminotransferase 82 IU/L (normal, 1260), total bilirubin 1.8 mg/dL (normal, 0.31.2), direct bilirubin 0.6 mg/dL (normal, 0.00.3), total protein 6.6 mg/dL (normal, 6.48.2), albumin 2.6 mg/dL (normal, 3.54.7), and alkaline phosphatase 356 IU/L (normal, 56119). Creatinine kinase was 137 IU/L (normal, 49397). Erythrocyte sedimentation rate 44 mm/hr (normal, 020). Urinalysis with microscopic examination was notable for moderate blood, negative leukocyte esterase, negative nitrites, protein 100 mg/dL (normal 030 mg/dL), 5 white blood cells (normal, 05), 9 red blood cells (normal, 05), and 3 granular casts. Gamma glutamyl transferase (GGT) was 459 IU/L (normal, 1298). Ferritin was 552 ng/mL (normal, 50200), and haptoglobin 185 mg/dL (normal, 30200). Prostate specific antigen was <0.02 ng/mL (<6.5). Chest x‐ray revealed right perihilar and bibasilar atelectasis without effusions or other consolidation. Computed tomography of the head, abdomen, and pelvis was normal. Ultrasonography of the liver was revealing for mild gallbladder edema without evidence of cholecystitis and normal Doppler indices of the hepatic vessels. Magnetic resonance imaging of the complete spine (cervical, thoracic, and lumbar) was performed and was unremarkable.

The patient has a remarkable bandemia, suggesting a bacterial infection, as well as a slight reduction in hematocrit and platelet count. Additionally, his labs revealed a mild transaminitis, but with significantly elevated alkaline phosphatase and GGT, and microscopic hematuria. His ferritin is significantly elevated, which may simply represent an acute phase reactant. Infections associated with hepatitis, cytopenias, and hematuria include sepsis with disseminated intravascular coagulation, previously mentioned malaria, leptospirosis, dengue, ehrlichiosis, and rickettsial diseases, but he has no special risks for these infections, and other aspects of his illness (Parkinsonian features, bandemia) do not fit. His lung findings with hematuria might suggest a pulmonary/renal syndrome, but, once again, other features of his illness are not typical of these syndromes. Salmonella (typhoid fever) or influenza, now complicated by an early bacterial pneumonia, are viable possibilities.

Through hospital day 2, the patient continued to have fevers over 39C about twice per day. Antibiotic therapy was not started because, other than fevers, the patient did not meet additional criteria for systemic inflammatory response syndrome (SIRS). Initial blood and urine cultures were without growth. Lumbar puncture was planned given ongoing headache symptoms.

The patient's ongoing clinical course is notable for a nontoxic (non‐SIRS) appearance but continued high‐grade fever with blood and urine cultures that are sterile. This argues against a common bacteremia with sepsis, and for either relapsing malaria (P vivax), influenza with a Parkinsonian‐like illness, typhoid fever, leptospirosis, dengue, or a rickettsial infection. Mycoplasma pneumonia is also possible given the atypical chest x‐ray appearance, slightly low hematocrit with elevated bilirubin, and neurological symptoms that may represent ataxia.

Blood cultures, repeated 5 times, each drawn while the patient was febrile, were all negative. Parasite thick and thin smears, repeated 4 times, were also negative. Stool ova and parasite exam was negative, and stool cultures were negative. Antibody and antigen analysis for hepatitis A, B, and C were negative for infection. HIV antibody screen was negative, and rapid plasma reagin for syphilis was nonreactive. Parvovirus B‐19 immunoglobulin (Ig)G was reactive, but IgM was nonreactive. Cytomegalovirus, Epstein‐Barr virus, and respiratory virus panel polymerase chain reaction testing was negative. Lyme antibody enzyme‐linked immunosorbent assay was 0.32 Lyme index units (normal, 0.01.2), leptospira antibody was <1:50 (normal, <1:50), mycoplasma pneumonia IgG was 0.04 U/L (normal, <0.09), and Q fever IgG was <1:16 (normal, <1:16). West Nile and St. Louis encephalitis IgG and IgM from serum specimens were nonreactive. Hantavirus IgM and lymphocytic choriomeningitis IgM from the serum were also negative.

On the evening of hospital day 2, the patient's daughter noticed an odd smell emanating from the patient's car. Further inspection of the car by the patient's family revealed a mouse nest located in the trunk of the car, and suspected mouse urine was noted on the floorboards of the vehicle. The hospital care team was informed.

The subsequent negative laboratory tests listed are helpful in likely excluding many of the diagnoses suggested such as malaria, Babesia, common bacteremias, viral hepatitis, HIV, and WNV. Furthermore, the new history of mouse exposure brings to the forefront rodent‐associated infections, specifically exposure to mouse urine, a vehicle for leptospirosis. The patient's hepatitis, anemia, thrombocytopenia, scleral injection, along with the rest of his symptoms in the context of exposure to mouse urine makes leptospirosis the likely diagnosis. A negative Leptospira antibody early in his illness does not rule out the disease, and a convalescent titer should be obtained to confirm the diagnosis.

Leptospirosis was suspected, and the patient was started on doxycycline. The patient improved after initiation of antibiotics, and was discharged on hospital day 5 with a 14‐day course of antibiotic treatment. At his follow‐up appointment 2 weeks after the onset of his illness, the patient denied further fevers, headache, nausea, and his weakness was improving. Repeat, convalescent Leptospiria antibody testing during this visit resulted positive at 1:400, confirming the diagnosis.

COMMENTARY

This case describes an elderly man who presented with a fever of unknown origin (FUO), and was eventually diagnosed with leptospirosis. FUO presents slightly differently in elderly patients, as elderly patients are less likely to mount a high fever, and when they do, the etiology is more likely to indicate a serious bacterial or viral infection. Additionally, an etiology for FUO in the elderly is found in over 70% of presenting cases, compared to 51% in patients under the age of 65 years.[1] A detailed, comprehensive social, travel, and exposure history and physical examination remains the cornerstone of elucidating the diagnosis for FUO. The exposure to mouse urine in this case was an unusual and a helpful piece of the history to further focus the differential diagnosis.

Leptospirosis is an emerging bacterial zoonosis, and causes both endemic and epidemic severe multisystem disease. The Leptospira spirochete is maintained in nature through a chronic renal infection in mammalian reservoir hosts, such as mice,[2, 4] and is transmitted through direct or aerosolized contact with infected urine or tissue. After a mean incubation period of 10 days, a variety of clinical manifestations may be seen. In this case, the patient's clinical presentation revealed many classic symptoms of leptospirosis, including fevers, rigors, headache, lower extremity myalgias, nausea, vomiting, and diarrhea; however, these symptoms are nonspecific. The presence of a conjunctival suffusion in leptospirosis infection had a specificity of 98% in a high‐incidence cohort of febrile patients in Sri Lanka,[3] and was an important diagnostic clue in this case. Leptospirosis is a self‐limited illness in most patients, with an initial septicemic, febrile phase followed by an immune phase. A more severe presentation may be seen in the immune phase of the illness, which includes renal and hepatic dysfunction (known as Weil's disease), as well as cardiac, pulmonary, and central nervous system abnormalities. With a 14% case fatality rate, the risk of death has been shown to be higher in patients over 40 years old, with altered mental status and multiorgan failure.[4]

The early diagnosis of leptospirosis relies heavily on physical exam findings and epidemiologic history. In this case, the patient's laboratory abnormalities, including immature granulocytes, thrombocytopenia, hyponatremia, hypokalemia, mild hepatitis, and pyuria with granular casts are all reported with leptospirosis infection²; however, independently, these laboratory findings are nonspecific. Patients may not have a detectable antibody levels in the acute phase of the disease. In this case, given the strong clinical suspicion based on the findings of conjunctival suffusion and exposure to mouse urine history, the lack of a more plausible alternate diagnosis, and known delay in antibody positivity, the patient was treated empirically with doxycycline for presumed leptospirosis.[5] Forthcoming novel diagnostic strategies such as next‐generation DNA sequencing techniques may provide real‐time diagnosis of this zoonotic infection, thus decreasing the window period between empirical antimicrobial coverage and diagnostic confirmation.[6]

Leptospirosis is prevalent in tropical climates and has been associated with impoverished communities.[7] Urban slums, with poor sanitation and high rodent density, are an ideal environment for leptospirosis. The reported risk of infection in a Brazilian slum was as high as 3% per year.[8] Additionally, rodent sightings, as well as the presence of chickens, were risk factors for leptospirosis transmission in urban slums.[9] Correspondingly in this case, we hypothesize that the patient's interest in urban farming, specifically the chickens he kept, likely attracted the mice infected with leptospirosis. Urban chicken farming is becoming increasingly popular in the United States,[10] and may be a developing risk factor for human leptospirosis infection. Leptospirosis is one of many emerging zoonoses, such as avian influenza, tick‐borne illness, and ebola, resulting from changing human ecology. Thus, when considering infectious etiologies, clinicians should ask patients about vocational and avocational exposures, including new trends such as urban farming, which may expose them to previously underappreciated illnesses.

TEACHING POINTS

1. Elderly patients with a FUO are more likely to be diagnosed with an underlying serious bacterial or viral infection when compared to a younger cohort of FUO patients.
2. The diagnosis of leptospirosis may initially be based on clinical suspicion in patients with classic features and exposures, noting the high specificity of conjunctival suffusion, and initial titers may be nondiagnostic; therefore, empiric treatment should be considered when clinical suspicion is high.
3. Increased interest in urban chicken farming in the United States, with associated higher rodent density, may represent a newly recognized risk factor for human leptospirosis infection.

Disclosures

The authors report no conflicts of interest.

A 73‐year‐old man was admitted with 6 days of fevers, with rigors and diaphoresis, and associated frontal headache.

Fever in an elderly man is a nonspecific finding, occurring most commonly with infections but also with certain malignancies, rheumatologic disorders, and drug exposures. The complaint of rigors with diaphoresis makes an infection most likely. The acuity of his illness makes infections with more chronic presentations such as tuberculosis or actinomycosis less likely. The presence of frontal headache might suggest a sinus or brain source, but headache also occurs in generalized infections such as pneumonia, bacteremia from any cause, malaria, rickettsial infections, viral illnesses, and others. Additional history should include detailed inquiry into travel, vocational, and avocational exposures.

Since onset, the fevers had been accompanied by malaise, myalgias, decreased oral intake, nausea, and nonbloody, nonbilious vomiting and nonbloody loose stools. On the day of admission, the patient developed the inability to rise from a seated position without the use of his arms.

The patient's difficulty standing implies the development of lower extremity weakness and infections associated with neurological syndromes. His leg weakness may be related to early Guillain‐Barre syndrome, which is associated most commonly with Campylobacter jejuni, but also other bacteria and viruses such as Haemophilus influenza, Mycoplasma pneumonia, Influenza virus, Cytomegalovirus and hepatitis E. Other viral infections associated with pure motor deficits include echovirus, coxsackie virus, enterovirus, and West Nile virus (WNV). The paralytic syndrome associated with enteroviruses is more common in children, whereas the neuroinvasive variant of WNV more often affects the elderly and can be associated with encephalitis as well as a flaccid paralysis. Although acute paralytic shellfish poisoning could account for both his weakness and his acute gastrointestinal syndrome, this diagnosis is unlikely because the symptoms often have a prominent sensory component, and there is usually the history of recent ingestion of the suspect bivalves. Like all adults presenting for medical care, he should be screened for human immunodeficiency virus (HIV) infection; if testing is positive, the differential diagnosis for his current illness broadens significantly. Finally, he may have a spinal cord disorder or infection such as an epidural abscess, or transverse myelitis, which would present with lower extremity weakness and fever. It would be helpful to know the time of year of his illness, exposure to mosquito bites, his neurological exam findings, and results of blood and stool cultures. If the patient had signs of meningitis or encephalitis, cerebral spinal fluid analysis would be helpful. If his neurological exam was suggestive of cord involvement, it would be helpful to know the results of magnetic resonance imaging of the spinal cord.

His past medical history was remarkable for nonobstructive coronary artery disease, paroxysmal atrial fibrillation, hypothyroidism, and prostate cancer (T2N0M0, Gleason 3+4) treated with radical prostatectomy and pelvic lymph node dissection 6 years previously. One month prior to this presentation, the patient developed a small right knee effusion, and x‐ray evaluation at that time showed mild degenerative joint disease. His medications included aspirin 325 mg daily, metoprolol succinate 100 mg daily, levothyroxine 25 g daily, and simvastatin 20 mg nightly. The patient was a lawyer, and lived in the Pacific Northwest. He had never smoked or used illicit drugs, and drank 2 glasses of red wine nightly. His travel history was remarkable for a visit to Uganda 1 year prior to admission; Zurich, Switzerland 6 months prior to admission; and Cape Cod, Massachusetts during the summer season 5 months prior to admission. His exposures included keeping chickens on his property, tending a garden, and ingestion of raw oysters 1 month prior to the onset of symptoms.

The patient's past medical history includes relatively common problems for a 73‐year‐old man and does not substantially influence the differential diagnosis of his current illness. His travel history to Uganda a year previously may be relevant, because malaria (Plasmodium vivax) could present with fever and weakness. Less commonly, African trypanosomiasis (Trypanosoma brucei gambiense) can, in the late phase, present with fever and malaise, but also typically includes symptoms of encephalitis, including depressed mental status, confusion, ataxia, and possibly personality changes. His travel to Zurich should not impose any particular infection risk, unless he was hiking in the mountains around Zurich, where he could have contracted tick‐borne encephalitis; however, his travel more than 6 months prior to presentation makes this unlikely. Lyme disease due to Borrelia burgdorferi is also a potential exposure in the Swiss mountains, and can present with fever in the acute phase, as well as arthritis with chronic disease, but should not cause fever, rigor, diaphoresis, and headache many months later. Summering in Cape Cod puts him at risk for babesiosis, but an incubation period of 5 months is too long. Keeping chickens places him at risk for Salmonella exposure and typhoid fever. Ingesting raw oysters carries a risk for shellfish poisoning and Vibrio infections, but the incubation period (1 month) again seems too long to cause his current symptoms.

On exam, his temperature was 39.4C, heart rate 87 beats/min, blood pressure 129/70 mm Hg, respiratory rate 18/min, with an oxygen saturation of 94% on room air. He was ill appearing. He had injected sclera bilaterally, with moist mucous membranes, no oropharyngeal lesions, and no cervical lymphadenopathy. His cardiac exam revealed no murmurs, rub, or diastolic gallops. His lungs were clear without rales or wheezes. His abdominal exam was benign, without masses or tenderness. He had no musculoskeletal tenderness, lower extremity edema, erythema, or effusion in his lower extremity joints. His neurological exam was notable for difficulty rising from a seated position. He also had a shortened stride length in his gait and a slow, deliberate 180 turn. There was no resting tremor. Romberg's sign was negative, and the remainder of neurological exam was normal.

Notable physical findings are an ill‐appearing man with injected sclera and a high fever but normal blood pressure and heart rate. He also demonstrates proximal lower extremity weakness manifested by difficulty rising from a chair and a slow gait with short strides and deliberate (possibly on‐block) turning. His neurological exam is most consistent with Parkinsonian symptoms that have been described in patients with severe influenza A, which would explain all of his other symptoms as well. Pulse‐temperature dissociation is classically described with typhoid fever but usually occurs later in the disease course, and could be masked by the patient's metoprolol. Typhoid fever can also be associated with neurological symptoms including meningitis and movement disorders.

White blood cell count was 6060/L, with 36% bands, hematocrit 35.5%, and platelet count of 134,000/L. Sodium was 133 mmol/L, potassium 3.3 mmol/L, chloride 97 mmol/L, bicarbonate 30 mmol/L, blood urea nitrogen 19 mg/dL, and creatinine 1.2 mg/dL. Alanine aminotransferase was 79 IU/L (normal, 1541), aspartate aminotransferase 82 IU/L (normal, 1260), total bilirubin 1.8 mg/dL (normal, 0.31.2), direct bilirubin 0.6 mg/dL (normal, 0.00.3), total protein 6.6 mg/dL (normal, 6.48.2), albumin 2.6 mg/dL (normal, 3.54.7), and alkaline phosphatase 356 IU/L (normal, 56119). Creatinine kinase was 137 IU/L (normal, 49397). Erythrocyte sedimentation rate 44 mm/hr (normal, 020). Urinalysis with microscopic examination was notable for moderate blood, negative leukocyte esterase, negative nitrites, protein 100 mg/dL (normal 030 mg/dL), 5 white blood cells (normal, 05), 9 red blood cells (normal, 05), and 3 granular casts. Gamma glutamyl transferase (GGT) was 459 IU/L (normal, 1298). Ferritin was 552 ng/mL (normal, 50200), and haptoglobin 185 mg/dL (normal, 30200). Prostate specific antigen was <0.02 ng/mL (<6.5). Chest x‐ray revealed right perihilar and bibasilar atelectasis without effusions or other consolidation. Computed tomography of the head, abdomen, and pelvis was normal. Ultrasonography of the liver was revealing for mild gallbladder edema without evidence of cholecystitis and normal Doppler indices of the hepatic vessels. Magnetic resonance imaging of the complete spine (cervical, thoracic, and lumbar) was performed and was unremarkable.

The patient has a remarkable bandemia, suggesting a bacterial infection, as well as a slight reduction in hematocrit and platelet count. Additionally, his labs revealed a mild transaminitis, but with significantly elevated alkaline phosphatase and GGT, and microscopic hematuria. His ferritin is significantly elevated, which may simply represent an acute phase reactant. Infections associated with hepatitis, cytopenias, and hematuria include sepsis with disseminated intravascular coagulation, previously mentioned malaria, leptospirosis, dengue, ehrlichiosis, and rickettsial diseases, but he has no special risks for these infections, and other aspects of his illness (Parkinsonian features, bandemia) do not fit. His lung findings with hematuria might suggest a pulmonary/renal syndrome, but, once again, other features of his illness are not typical of these syndromes. Salmonella (typhoid fever) or influenza, now complicated by an early bacterial pneumonia, are viable possibilities.

Through hospital day 2, the patient continued to have fevers over 39C about twice per day. Antibiotic therapy was not started because, other than fevers, the patient did not meet additional criteria for systemic inflammatory response syndrome (SIRS). Initial blood and urine cultures were without growth. Lumbar puncture was planned given ongoing headache symptoms.

The patient's ongoing clinical course is notable for a nontoxic (non‐SIRS) appearance but continued high‐grade fever with blood and urine cultures that are sterile. This argues against a common bacteremia with sepsis, and for either relapsing malaria (P vivax), influenza with a Parkinsonian‐like illness, typhoid fever, leptospirosis, dengue, or a rickettsial infection. Mycoplasma pneumonia is also possible given the atypical chest x‐ray appearance, slightly low hematocrit with elevated bilirubin, and neurological symptoms that may represent ataxia.

Blood cultures, repeated 5 times, each drawn while the patient was febrile, were all negative. Parasite thick and thin smears, repeated 4 times, were also negative. Stool ova and parasite exam was negative, and stool cultures were negative. Antibody and antigen analysis for hepatitis A, B, and C were negative for infection. HIV antibody screen was negative, and rapid plasma reagin for syphilis was nonreactive. Parvovirus B‐19 immunoglobulin (Ig)G was reactive, but IgM was nonreactive. Cytomegalovirus, Epstein‐Barr virus, and respiratory virus panel polymerase chain reaction testing was negative. Lyme antibody enzyme‐linked immunosorbent assay was 0.32 Lyme index units (normal, 0.01.2), leptospira antibody was <1:50 (normal, <1:50), mycoplasma pneumonia IgG was 0.04 U/L (normal, <0.09), and Q fever IgG was <1:16 (normal, <1:16). West Nile and St. Louis encephalitis IgG and IgM from serum specimens were nonreactive. Hantavirus IgM and lymphocytic choriomeningitis IgM from the serum were also negative.

On the evening of hospital day 2, the patient's daughter noticed an odd smell emanating from the patient's car. Further inspection of the car by the patient's family revealed a mouse nest located in the trunk of the car, and suspected mouse urine was noted on the floorboards of the vehicle. The hospital care team was informed.

The subsequent negative laboratory tests listed are helpful in likely excluding many of the diagnoses suggested such as malaria, Babesia, common bacteremias, viral hepatitis, HIV, and WNV. Furthermore, the new history of mouse exposure brings to the forefront rodent‐associated infections, specifically exposure to mouse urine, a vehicle for leptospirosis. The patient's hepatitis, anemia, thrombocytopenia, scleral injection, along with the rest of his symptoms in the context of exposure to mouse urine makes leptospirosis the likely diagnosis. A negative Leptospira antibody early in his illness does not rule out the disease, and a convalescent titer should be obtained to confirm the diagnosis.

Leptospirosis was suspected, and the patient was started on doxycycline. The patient improved after initiation of antibiotics, and was discharged on hospital day 5 with a 14‐day course of antibiotic treatment. At his follow‐up appointment 2 weeks after the onset of his illness, the patient denied further fevers, headache, nausea, and his weakness was improving. Repeat, convalescent Leptospiria antibody testing during this visit resulted positive at 1:400, confirming the diagnosis.

COMMENTARY

This case describes an elderly man who presented with a fever of unknown origin (FUO), and was eventually diagnosed with leptospirosis. FUO presents slightly differently in elderly patients, as elderly patients are less likely to mount a high fever, and when they do, the etiology is more likely to indicate a serious bacterial or viral infection. Additionally, an etiology for FUO in the elderly is found in over 70% of presenting cases, compared to 51% in patients under the age of 65 years.[1] A detailed, comprehensive social, travel, and exposure history and physical examination remains the cornerstone of elucidating the diagnosis for FUO. The exposure to mouse urine in this case was an unusual and a helpful piece of the history to further focus the differential diagnosis.

Leptospirosis is an emerging bacterial zoonosis, and causes both endemic and epidemic severe multisystem disease. The Leptospira spirochete is maintained in nature through a chronic renal infection in mammalian reservoir hosts, such as mice,[2, 4] and is transmitted through direct or aerosolized contact with infected urine or tissue. After a mean incubation period of 10 days, a variety of clinical manifestations may be seen. In this case, the patient's clinical presentation revealed many classic symptoms of leptospirosis, including fevers, rigors, headache, lower extremity myalgias, nausea, vomiting, and diarrhea; however, these symptoms are nonspecific. The presence of a conjunctival suffusion in leptospirosis infection had a specificity of 98% in a high‐incidence cohort of febrile patients in Sri Lanka,[3] and was an important diagnostic clue in this case. Leptospirosis is a self‐limited illness in most patients, with an initial septicemic, febrile phase followed by an immune phase. A more severe presentation may be seen in the immune phase of the illness, which includes renal and hepatic dysfunction (known as Weil's disease), as well as cardiac, pulmonary, and central nervous system abnormalities. With a 14% case fatality rate, the risk of death has been shown to be higher in patients over 40 years old, with altered mental status and multiorgan failure.[4]

The early diagnosis of leptospirosis relies heavily on physical exam findings and epidemiologic history. In this case, the patient's laboratory abnormalities, including immature granulocytes, thrombocytopenia, hyponatremia, hypokalemia, mild hepatitis, and pyuria with granular casts are all reported with leptospirosis infection²; however, independently, these laboratory findings are nonspecific. Patients may not have a detectable antibody levels in the acute phase of the disease. In this case, given the strong clinical suspicion based on the findings of conjunctival suffusion and exposure to mouse urine history, the lack of a more plausible alternate diagnosis, and known delay in antibody positivity, the patient was treated empirically with doxycycline for presumed leptospirosis.[5] Forthcoming novel diagnostic strategies such as next‐generation DNA sequencing techniques may provide real‐time diagnosis of this zoonotic infection, thus decreasing the window period between empirical antimicrobial coverage and diagnostic confirmation.[6]

Leptospirosis is prevalent in tropical climates and has been associated with impoverished communities.[7] Urban slums, with poor sanitation and high rodent density, are an ideal environment for leptospirosis. The reported risk of infection in a Brazilian slum was as high as 3% per year.[8] Additionally, rodent sightings, as well as the presence of chickens, were risk factors for leptospirosis transmission in urban slums.[9] Correspondingly in this case, we hypothesize that the patient's interest in urban farming, specifically the chickens he kept, likely attracted the mice infected with leptospirosis. Urban chicken farming is becoming increasingly popular in the United States,[10] and may be a developing risk factor for human leptospirosis infection. Leptospirosis is one of many emerging zoonoses, such as avian influenza, tick‐borne illness, and ebola, resulting from changing human ecology. Thus, when considering infectious etiologies, clinicians should ask patients about vocational and avocational exposures, including new trends such as urban farming, which may expose them to previously underappreciated illnesses.

TEACHING POINTS

1. Elderly patients with a FUO are more likely to be diagnosed with an underlying serious bacterial or viral infection when compared to a younger cohort of FUO patients.
2. The diagnosis of leptospirosis may initially be based on clinical suspicion in patients with classic features and exposures, noting the high specificity of conjunctival suffusion, and initial titers may be nondiagnostic; therefore, empiric treatment should be considered when clinical suspicion is high.
3. Increased interest in urban chicken farming in the United States, with associated higher rodent density, may represent a newly recognized risk factor for human leptospirosis infection.

Disclosures

The authors report no conflicts of interest.

A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.

The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.

The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.

Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.

Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.

On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.

The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.

Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm³. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).

The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.

Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.

The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.

Figure 1

A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.

The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.

Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.

As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.

The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.

The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).

Figure 2

Figure 3

The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.

The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.

COMMENTARY

The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.

Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]

In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]

The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]

The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]

Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.

KEY POINTS

1. Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
2. CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
3. Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.

Disclosure

Nothing to report.

A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.

The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.

The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.

Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.

Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.

On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.

The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.

Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm³. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).

The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.

Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.

The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.

Figure 1

A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.

The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.

Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.

As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.

The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.

The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).

Figure 2

Figure 3

The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.

The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.

COMMENTARY

The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.

Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]

In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]

The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]

The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]

Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.

KEY POINTS

1. Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
2. CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
3. Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.

Disclosure

Nothing to report.

A 60‐year‐old woman presented to a community hospital's emergency department with 4 days of right‐sided abdominal pain and multiple episodes of black stools. She reported nausea without vomiting. She denied light‐headedness, chest pain, or shortness of breath. She also denied difficulty in swallowing, weight loss, jaundice, or other bleeding.

The first priority when assessing a patient with gastrointestinal (GI) bleeding is to ensure hemodynamic stability. Next, it is important to carefully characterize the stools to help narrow the differential diagnosis. As blood is a cathartic, frequent, loose, and black stools suggest vigorous bleeding. It is essential to establish that the stools are actually black, as some patients will mistake dark brown stools for melena. Using a visual aid like a black pen or shoes as a point of reference can help the patient differentiate between dark stool and melena. It is also important to obtain a thorough medication history because iron supplements or bismuth‐containing remedies can turn stool black. The use of any antiplatelet agents or anticoagulants should also be noted. The right‐sided abdominal pain should be characterized by establishing the frequency, severity, and association with eating, movement, and position. For this patient's presentation, increased pain with eating would rapidly heighten concern for mesenteric ischemia.

The patient reported having 1 to 2 semiformed, tarry, black bowel movements per day. The night prior to admission she had passed some bright red blood along with the melena. The abdominal pain had increased gradually over 4 days, was dull, constant, did not radiate, and there were no evident aggravating or relieving factors. She rated the pain as 4 out of 10 in intensity, worst in her right upper quadrant.

Her past medical history was notable for recurrent deep venous thromboses and pulmonary emboli that had occurred even while on oral anticoagulation. Inferior vena cava (IVC) filters had twice been placed many years prior; anticoagulation had been subsequently discontinued. Additionally, she was known to have chronic superior vena cava (SVC) occlusion, presumably related to hypercoagulability. Previous evaluation had identified only hyperhomocysteinemia as a risk factor for recurrent thromboses. Other medical problems included hemorrhoids, gastroesophageal reflux disease, and asthma. Her only surgical history was an abdominal hysterectomy and bilateral oophorectomy many years ago for nonmalignant disease. Home medications were omeprazole, ranitidine, albuterol, and fluticasone‐salmeterol. She denied using nonsteroidal anti‐inflammatory drugs, aspirin, or any dietary supplements. She denied smoking, alcohol, or recreational drug use.

Because melena is confirmed, an upper GI tract bleeding source is most likely. The more recent appearance of bright red blood is concerning for acceleration of bleeding, or may point to a distal small bowel or right colonic source. Given the history of thromboembolic disease and likely underlying hypercoagulability, vascular occlusion is a leading possibility. Thus, mesenteric arterial insufficiency or mesenteric venous thrombosis should be considered, even though the patient does not report the characteristic postprandial exacerbation of pain. Ischemic colitis due to arterial insufficiency typically presents with severe, acute pain, with or without hematochezia. This syndrome is typically manifested in vascular watershed areas such as the splenic flexure, but can also affect the right colon. Mesenteric venous thrombosis is a rare condition that most often occurs in patients with hypercoagulability. Patients present with variable degrees of abdominal pain and often with GI bleeding. Finally, portal venous thrombosis may be seen alongside thromboses of other mesenteric veins or may occur independently. Portal hypertension due to portal vein thrombosis can result in esophageal and/or gastric varices. Although variceal bleeding classically presents with dramatic hematemesis, the absence of hematemesis does not rule out a variceal bleed in this patient.

On physical examination, the patient had a temperature of 37.1C with a pulse of 90 beats per minute and blood pressure of 161/97 mm Hg. Orthostatics were not performed. No blood was seen on nasal and oropharyngeal exam. Respiratory and cardiovascular exams were normal. On abdominal exam, there was tenderness to palpation of the right upper quadrant without rebound or guarding. The spleen and the liver were not palpable. There was a lower midline incisional scar. Rectal exam revealed nonbleeding hemorrhoids and heme‐positive stool without gross blood. Bilateral lower extremities had trace pitting edema, hyperpigmentation, and superficial venous varicosities. On skin exam, there were distended subcutaneous veins radiating outward from around the umbilicus as well as prominent subcutaneous venous collaterals over the chest and lateral abdomen.

The collateral veins over the chest and lateral abdomen are consistent with central venous obstruction from the patient's known SVC thrombus. However, the presence of paraumbilical venous collaterals (caput medusa) is highly suggestive of portal hypertension. This evidence, in addition to the known central venous occlusion and history of thromboembolic disease, raises the suspicion for mesenteric thrombosis as a cause of her bleeding and pain. The first diagnostic procedure should be an esophagogastroduodenoscopy (EGD) to identify and potentially treat the source of bleeding, whether it is portal hypertension related (portal gastropathy, variceal bleed) or from a more common cause (peptic ulcer disease, stress gastritis). If the EGD is not diagnostic, the next step should be to obtain computed tomography (CT) of the abdomen and pelvis with intravenous (IV) and oral contrast. In many patients with GI bleed, a colonoscopy would typically be performed as the next diagnostic study after EGD. However, in this patient, a CT scan is likely to be of higher yield because it could help assess the mesenteric and portal vessels for patency and characterize the appearance of the small intestine and colon. Depending on the findings of the CT, additional dedicated vascular diagnostics might be needed.

Hemoglobin was 8.5 g/dL (12.4 g/dL 6 weeks prior) with a normal mean corpuscular volume and red cell distribution. The white cell count was normal, and the platelet count was 142,000/mm³. The blood urea nitrogen was 27 mg/dL, with a creatinine of 1.1 mg/dL. Routine chemistries, liver enzymes, bilirubin, and coagulation parameters were normal. Ferritin was 15 ng/mL (normal: 15200 ng/mL).

The patient was admitted to the intensive care unit. An EGD revealed a hiatal hernia and grade II nonbleeding esophageal varices with normal=appearing stomach and duodenum. The varices did not have stigmata of a recent bleed and were not ligated. The patient continued to bleed and received 2 U of packed red blood cells (RBCs), as her hemoglobin had decreased to 7.3 g/dL. On hospital day 3, a colonoscopy was done that showed blood clots in the ascending colon but was otherwise normal. The patient had ongoing abdominal pain, melena, and hematochezia, and continued to require blood transfusions every other day.

Esophageal varices were confirmed on EGD. However, no high‐risk stigmata were seen. Findings that suggest either recent bleeding or are risk factors for subsequent bleeding include large size of the varices, nipple sign referring to a protruding vessel from an underlying varix, or red wale sign, referring to a longitudinal red streak on a varix. The lack of evidence for an esophageal, gastric, or duodenal bleeding source correlates with lack of clinical signs of upper GI tract hemorrhage such as hematemesis or coffee ground emesis. Because the colonoscopy also did not identify a bleeding source, the bleeding remains unexplained. The absence of significant abnormalities in liver function or liver inflammation labs suggests that the patient does not have advanced cirrhosis and supports the suspicion of a vascular cause of the portal hypertension. At this point, it would be most useful to obtain a CT scan of the abdomen and pelvis.

The patient continued to bleed, requiring a total of 7 U of packed RBCs over 7 days. On hospital day 4, a repeat EGD showed nonbleeding varices with a red wale sign that were banded. Despite this, the hemoglobin continued to drop. A technetium‐tagged RBC study showed a small area of subumbilical activity, which appeared to indicate transverse colonic or small bowel bleeding (Figure 1). A subsequent mesenteric angiogram failed to show active bleeding.

Figure 1

A red wale sign confers a higher risk of bleeding from esophageal varices. However, this finding can be subjective, and the endoscopist must individualize the decision for banding based on the size and appearance of the varices. It was reasonable to proceed with banding this time because the varices were large, had a red wale sign, and there was otherwise unexplained ongoing bleeding. Because her hemoglobin continued to drop after the banding and a tagged RBC study best localized the bleeding to the small intestine or transverse colon, it is unlikely that the varices are the primary source of bleeding. It is not surprising that the mesenteric angiogram did not show a source of bleeding, because this study requires active bleeding at a sufficient rate to radiographically identify the source.

The leading diagnosis remains an as yet uncharacterized small bowel bleeding source related to mesenteric thrombotic disease. Cross‐sectional imaging with IV contrast to identify significant vascular occlusion should be the next diagnostic step. Capsule endoscopy would be a more expensive and time‐consuming option, and although this could reveal the source of bleeding, it might not characterize the underlying vascular nature of the problem.

Due to persistent abdominal pain, a CT without intravenous contrast was done on hospital day 10. This showed extensive collateral vessels along the chest and abdominal wall with a distended azygos vein. The study was otherwise unrevealing. Her bloody stools cleared, so she was discharged with a plan for capsule endoscopy and outpatient follow‐up with her gastroenterologist. On the day of discharge (hospital day 11), hemoglobin was 7.5 g/dL and she received an eighth unit of packed RBCs. Overt bleeding was absent.

As an outpatient, intermittent hematochezia and melena recurred. The capsule endoscopy showed active bleeding approximately 45 minutes after the capsule exited the stomach. The lesion was not precisely located or characterized, but was believed to be in the distal small bowel.

The capsule finding supports the growing body of evidence implicating a small bowel source of bleeding. Furthermore, the ongoing but slow rate of blood loss makes a venous bleed more likely than an arterial bleed. A CT scan was performed prior to capsule study, but this was done without intravenous contrast. The brief description of the CT findings emphasizes the subcutaneous venous changes; a contraindication to IV contrast is not mentioned. Certainly IV contrast would have been very helpful to characterize the mesenteric arterial and venous vasculature. If there is no contraindication, a repeat CT scan with IV contrast should be performed. If there is a contraindication to IV contrast, it would be beneficial to revisit the noncontrast study with the specific purpose of searching for clues suggesting mesenteric or portal thrombosis. If the source still remains unclear, the next steps should be to perform push enteroscopy to assess the small intestine from the luminal side and magnetic resonance angiogram with venous phase imaging (or CT venogram if there is no contraindication to contrast) to evaluate the venous circulation.

The patient was readmitted 9 days after discharge with persistent melena and hematochezia. Her hemoglobin was 7.2 g/dL. Given the lack of a diagnosis, the patient was transferred to a tertiary care hospital, where a second colonoscopy and mesenteric angiogram were negative for bleeding. Small bowel enteroscopy showed no source of bleeding up to 60 cm past the pylorus. A third colonoscopy was performed due to recurrent bleeding; this showed a large amount of dark blood and clots throughout the entire colon including the cecum (Figure 2). After copious irrigation, the underlying mucosa was seen to be normal. At this point, a CT angiogram with both venous and arterial phases was done due to the high suspicion for a distal jejunal bleeding source. The CT angiogram showed numerous venous collaterals encasing a loop of midsmall bowel demonstrating progressive submucosal venous enhancement. In addition, a venous collateral ran down the right side of the sternum to the infraumbilical area and drained through the encasing collaterals into the portal venous system (Figure 3). The CT scan also revealed IVC obstruction below the distal IVC filter and an enlarged portal vein measuring 18 mm (normal <12 mm).

Figure 2

Figure 3

The CT angiogram provides much‐needed clarity. The continued bleeding is likely due to ectopic varices in the small bowel. The venous phase of the CT angiogram shows thrombosis of key venous structures and evidence of a dilated portal vein (indicating portal hypertension) leading to ectopic varices in the abdominal wall and jejunum. Given the prior studies that suggest a small bowel source of bleeding, jejunal varices are the most likely cause of recurrent GI bleeding in this patient.

The patient underwent exploratory laparotomy. Loops of small bowel were found to be adherent to the hysterectomy scar. There were many venous collaterals from the abdominal wall to these loops of bowel, dilating the veins both in intestinal walls and those in the adjacent mesentery. After clamping these veins, the small bowel was detached from the abdominal wall. On unclamping, the collaterals bled with a high venous pressure. Because these systemic‐portal shunts were responsible for the bleeding, the collaterals were sutured, stopping the bleeding. Thus, partial small bowel resection was not necessary. Postoperatively, her bleeding resolved completely and she maintained normal hemoglobin at 1‐year follow‐up.

COMMENTARY

The axiom common ailments are encountered most frequently underpins the classical stepwise approach to GI bleeding. First, a focused history helps localize the source of bleeding to the upper or lower GI tract. Next, endoscopy is performed to identify and treat the cause of bleeding. Finally, advanced tests such as angiography and capsule endoscopy are performed if needed. For this patient, following the usual algorithm failed to make the diagnosis or stop the bleeding. Despite historical and examination features suggesting that her case fell outside of the common patterns of GI bleeding, this patient underwent 3 upper endoscopies, 3 colonoscopies, a capsule endoscopy, a technetium‐tagged RBC study, 2 mesenteric angiograms, and a noncontrast CT scan before the study that was ultimately diagnostic was performed. The clinicians caring for this patient struggled to incorporate the atypical features of her history and presentation and failed to take an earlier detour from the usual algorithm. Instead, the same studies that had not previously led to the diagnosis were repeated multiple times.

Ectopic varices are enlarged portosystemic venous collaterals located anywhere outside the gastroesophageal region.[1] They occur in the setting of portal hypertension, surgical procedures involving abdominal viscera and vasculature, and venous occlusion. Ectopic varices account for 4% to 5% of all variceal bleeding episodes.[1] The most common sites include the anorectal junction (44%), duodenum (17%33%), jejunum/emleum (5%17%), colon (3.5%14%), and sites of previous abdominal surgery.[2, 3] Ectopic varices can cause either luminal or extraluminal (i.e., peritoneal) bleeding.[3] Luminal bleeding, seen in this case, is caused by venous protrusion into the submucosa. Ectopic varices present as a slow venous ooze, which explains this patient's ongoing requirement for recurrent blood transfusions.[4]

In this patient, submucosal ectopic varices developed as a result of a combination of known risk factors: portal hypertension in the setting of chronic venous occlusion from her hypercoagulability and a history of abdominal surgery (hysterectomy). [5] The apposition of her abdominal wall structures (drained by the systemic veins) to the bowel (drained by the portal veins) resulted in adhesion formation, detour of venous flow, collateralization, and submucosal varix formation.[1, 2, 6]

The key diagnostic study for this patient was a CT angiogram, with both arterial and venous phases. The prior 2 mesenteric angiograms had been limited to the arterial phase, which had missed identifying the venous abnormalities altogether. This highlights an important lesson from this case: contrast‐enhanced CT may have a higher yield in diagnosing ectopic varices compared to repeated endoscopiesespecially when captured in the late venous phaseand should strongly be considered for unexplained bleeding in patients with stigmata of liver disease or portal hypertension.[7, 8] Another clue for ectopic varices in a bleeding patient are nonbleeding esophageal or gastric varices, as was the case in this patient.[9]

The initial management of ectopic varices is similar to bleeding secondary to esophageal varices.[1] Definitive treatment includes endoscopic embolization or ligation, interventional radiological procedures such as portosystemic shunting or percutaneous embolization, and exploratory laparotomy to either resect the segment of bowel that is the source of bleeding or to decompress the collaterals surgically.[9] Although endoscopic ligation has been shown to have a lower rebleeding rate and mortality compared to endoscopic injection sclerotherapy in patients with esophageal varices, the data are too sparse in jejunal varices to recommend 1 treatment over another. Both have been used successfully either alone or in combination with each other, and can be useful alternatives for patients who are unable to undergo laparotomy.[9]

Diagnostic errors due to cognitive biases can be avoided by following diagnostic algorithms. However, over‐reliance on algorithms can result in vertical line failure, a form of cognitive bias in which the clinician subconsciously adheres to an inflexible diagnostic approach.[10] To overcome this bias, clinicians need to think laterally and consider alternative diagnoses when algorithms do not lead to expected outcomes. This case highlights the challenges of knowing when to break free of conventional approaches and the rewards of taking a well‐chosen detour that leads to the diagnosis.

KEY POINTS

1. Recurrent, occult gastrointestinal bleeding should raise concern for a small bowel source, and clinicians may need to take a detour away from the usual workup to arrive at a diagnosis.
2. CT angiography of the abdomen and pelvis may miss venous sources of bleeding, unless a venous phase is specifically requested.
3. Ectopic varices can occur in patients with portal hypertension who have had a history of abdominal surgery; these patients can develop venous collaterals for decompression into the systemic circulation through the abdominal wall.

Disclosure

Nothing to report.

A 51‐year‐old man presented to the emergency department after 1 day of progressive dyspnea and increasing confusion.

Acute dyspnea most commonly stems from a cardiac or pulmonary disorder such as heart failure, acute coronary syndrome, pneumonia, pulmonary embolism, or exacerbations of asthma or chronic obstructive pulmonary disease. Less frequent cardiopulmonary considerations include pericardial or pleural effusion, pneumothorax, aspiration, and upper airway obstruction. Dyspnea might also be the initial manifestation of profound anemia or metabolic acidosis.

The presence of confusion suggests either a severe presentation of any of the aforementioned possibilities (with confusion resulting from hypoxia, hypercapnia, or hypotension); a multiorgan illness such as sepsis, malignancy, thromboembolic disease, vasculitis, thyroid dysfunction, or toxic ingestion; or a metabolic derangement related to the underlying cause of dyspnea (for example, hypercalcemia or hyponatremia associated with lung cancer).

Twelve hours prior to presentation, he started to have visual hallucinations. He denied fever, chills, cough, chest discomfort, palpitations, weight gain, headache, neck pain, or weakness.

Visual hallucinations could result from a toxic‐metabolic encephalopathy, such as drug overdose or withdrawal, liver or kidney failure, or hypoxia. A structural brain abnormality may also manifest with visual hallucination. Acute onset at age 51 and the absence of auditory hallucinations argue against a neurodegenerative illness and a primary psychiatric disturbance, respectively.

Episodic hallucinations would support the possibility of seizures, monocular hallucinations would point to a retinal or ocular problem, and a description of yellow‐green hue would suggest a side effect of digoxin.

His past medical history was remarkable for diet‐controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, and chronic low back pain. His medications included metoprolol tartrate 25 mg twice daily, omeprazole 40 mg daily, baclofen 15 mg twice daily, oxycodone 30 mg 3 times daily, and hydrocodone 10 mg/acetaminophen 325 mg, 2 tablets 3 times daily as needed for back pain. He was a smoker with a 30 pack‐year history. He had a history of alcohol and cocaine use, but denied any recent substance use. He had no known history of obstructive pulmonary disease.

The patient takes 3 medications well known to cause confusion and hallucinations (oxycodone, hydrocodone, and baclofen), especially when they accumulate due to excessive ingestion or impaired clearance. Although these medications may suppress ventilatory drive, dyspnea would not be a common presenting complaint. He has risk factors for ischemic heart disease and cardiomyopathy, and his smoking history raises the possibility of malignancy.

On exam, the patient's temperature was 94.4C, heart rate 128 beats per minute, respiration rate 28 breaths per minute, blood pressure 155/63 mm Hg, and oxygen saturation 100% while breathing ambient air. The patient was cachectic and appeared in moderate respiratory distress. His pupils were equal and reactive to light, and extraocular movements were intact. He did not have scleral icterus, or cervical or clavicular lymphadenopathy. His oropharynx was negative for erythema, edema, or exudate. His cardiovascular exam revealed a regular tachycardia without rubs or diastolic gallops. There was a 2/6 systolic murmur heard best at left sternal border, without radiation. He did not have jugular venous distention. His pulmonary exam was notable for tachypnea but with normal vesicular breath sounds throughout. He did not have stridor, wheezing, rhonchi, or rales. His abdomen had normal bowel tones and was soft without tenderness, distention, or organomegaly. His extremities were warm, revealed normal pulses, and no edema was present. His joints were cool to palpation, without effusion. On neurologic exam, he was oriented to person and place and able to answer yes/no questions, but unable to provide detailed history. His speech was fluent. His motor exam was without focal deficits. His skin was without any notable lesions.

The constellation of findings does not point to a specific toxidrome. The finding of warm extremities in a hypothermic patient suggests heat loss due to inappropriate peripheral vasodilation. In the absence of vasodilators or features of aortic insufficiency, sepsis becomes a leading consideration. Infection could result in hypothermia and altered sensorium, and accompanying lactic acidosis could trigger tachypnea.

Shortly after admission, he became more somnolent and developed progressive respiratory distress, requiring intubation. Arterial blood gas revealed a pH of 6.93, PaCO₂<20 mm Hg, PaO₂ 127 mm Hg, and HCO₃<5 mEq/L. Other laboratory results included a lactate of 4.1 mmol/L, blood urea nitrogen 49 mg/dL, creatinine 2.3 mg/dL (0.8 at 1 month prior), sodium level of 143 mmol/L, chloride of 106 mmol/L, and bicarbonate level of <5 mg/dL. His aspartate aminotransferase was 34 IU/L, alanine transaminase was 28 IU/L, total bilirubin was 0.6 mg/dL, International Normalized Ratio was 1.3. A complete blood count revealed a white blood cell count of 23,000/L, hemoglobin of 10.6 g/dL, and platelet count of 454,000/L. A urinalysis was unremarkable. Cultures of blood, urine, and sputum were collected. Head computed tomography was negative.

This patient has a combined anion gap and nongap metabolic acidosis, as well as respiratory alkalosis. Although his acute kidney failure could produce these 2 types of metabolic acidosis, the modest elevation of the serum creatinine is not commensurate with such profound acidosis. Similarly, sepsis without hypotension or more striking elevation in lactate levels would not account for the entirety of the acidosis. Severe diabetic ketoacidosis can result in profound metabolic acidosis, and marked hyperglycemia or hyperosmolarity could result in somnolence; however, his diabetes has been controlled without medication and there is no obvious precipitant for an episode of ketoacidosis.

Remaining causes of anion gap acidosis include ingestion of methanol, ethylene glycol, ethanol, or salicylates. A careful history of ingestions and medications from witnesses including any prehospital personnel might suggest a source of intoxication. Absent this information, the hypothermia favors an ingestion of an alcohol over salicylates, and the lack of urine crystals and the presence of prominent visual hallucinations would point more toward methanol poisoning than ethylene glycol. A serum osmolarity measurement would allow determination of the osmolar gap, which would be elevated in the setting of methanol or ethylene glycol poisoning. If he were this ill from ethanol, I would have expected to see evidence of hepatotoxicity.

I would administer sodium bicarbonate to reverse the acidosis and to promote renal clearance of salicylates, methanol, ethylene glycol, and their metabolites. Orogastric decontamination with activated charcoal should be considered. If the osmolar gap is elevated, I would also administer intravenous fomepizole to attempt to reverse methanol or ethylene glycol poisoning. I would not delay treatment while waiting for these serum levels to return.

Initial serologic toxicology performed in the emergency department revealed negative ethanol, salicylates, and ketones. His osmolar gap was 13 mOsm/kg. His acetaminophen level was 69 g/mL (normal <120 g/mL). A creatinine phosphokinase was 84 IU/L and myoglobin was 93 ng/mL. His subsequent serum toxicology screen was negative for methanol, ethylene glycol, isopropranol, and hippuric acid. Urine toxicology was positive for opiates, but negative for amphetamine, benzodiazepine, cannabinoid, and cocaine.

Serum and urine ketone assays typically involve the nitroprusside reaction and detect acetoacetate, but not ‐hydroxybutyrate, and can lead to negative test results early in diabetic or alcoholic ketoacidosis. However, the normal ethanol level argues against alcoholic ketoacidosis. Rare causes of elevated anion gap acidosis include toluene toxicity, acetaminophen poisoning, and ingestion of other alcohols. Toluene is metabolized to hippuric acid, and acetaminophen toxicity and associated glutathione depletion can lead to 5‐oxoproline accumulation, producing an anion gap. Patients who abuse alcohol are at risk for acetaminophen toxicity even at doses considered normal. However, this degree of encephalopathy would be unusual for acetaminophen toxicity unless liver failure had developed or unless there was another ingestion that might alter sensorium. Furthermore, the elevated osmolar gap is not a feature of acetaminophen poisoning. I would monitor liver enzyme tests and consider a serum ammonia level, but would not attribute the entire picture to acetaminophen.

The combination of elevated anion gap with an elevated osmolar gap narrows the diagnostic possibilities. Ingestion of several alcohols (ethanol, methanol, ethylene glycol, diethylene glycol) or toluene could produce these abnormalities. Of note, the osmolar gap is typically most markedly elevated early in methanol and ethylene glycol ingestions, and then as the parent compound is metabolized, the osmolar gap closes and the accumulation of metabolites produces the anion gap. Hallucinations are more common with methanol and toluene, and renal failure is more typical of ethylene glycol or toluene. The lack of oxalate crystalluria does not exclude ethylene glycol poisoning. Unfortunately, urine testing for oxalate crystals or fluorescein examination are neither sensitive nor specific enough to diagnosis ethylene glycol toxicity reliably. In most hospitals, assays used for serum testing for alcohols are insensitive, and require confirmation with gas chromatography performed at a specialty lab.

Additional history might reveal the likely culprit or culprits. Inhalant abuse including huffing would point to toluene or organic acid exposure. Solvent ingestion (eg, antifreeze, brake fluid) would suggest methanol or ethylene glycol. Absent this history, I remain suspicious for poisoning with methanol or ethylene glycol and would consider empiric treatment after urgent consultation with a medical toxicologist. A careful ophthalmologic exam might demonstrate characteristic features of methanol poisoning. Serum samples should be sent to a regional lab for analysis for alcohols and organic acids.

He was admitted to the intensive care unit, and empiric antibiotics started. He was empirically started on N‐acetylcysteine and sodium bicarbonate drips. However, his acidemia persisted and he required hemodialysis, which was initiated 12 hours after initial presentation. His acidemia and mental status quickly improved after hemodialysis. He was extubated on hospital day 2 and no longer required hemodialysis.

The differential diagnosis at this point consists of 3 main possibilities: ingestion of methanol, ethylene glycol, or inhalant abuse such as from toluene. The normal hippuric acid level points away from toluene, whereas serum levels can be misleading in the alcohol poisonings. Other discriminating features to consider include exposure history and unique clinical aspects. In this patient, an exposure history is lacking, but 4 clinical features stand out: visual hallucinations, acute kidney injury, mild lactic acidosis, and rapid improvement with hemodialysis. Both ethylene glycol and methanol toxicity may produce a mild lactic acidosis by increasing hepatic metabolism of pyruvate to lactate, and both are rapidly cleared by dialysis. Although it is tempting to place methanol at the top of the list of possibilities due to the report of visual hallucinations, the subjective visual complaints without objective exam corollaries (loss of visual acuity, abnormal pupillary reflexes, or optic disc hyperemia) are nonspecific and might be provoked by alcohol or an inhalant. Furthermore, the acute renal failure is much more typical of ethylene glycol, and thus I would consider ethylene glycol as being the more likely of the ingestions. Coingestion of multiple alcohols is a possibility, but it would be statistically less likely. Confirmation of ethylene glycol poisoning would consist of further insight into his exposures and measurement of levels using gas chromatography.

A urine sample from his emergency department presentation was sent to an outside lab for organic acid levels. Based on high clinical suspicion for 5‐oxoprolinemia (pyroglutamic acidemia) the patient was counseled to avoid any acetaminophen. His primary care provider was informed of this and acetaminophen was added as an adverse drug reaction. The patient left against medical advice soon after extubation. Following discharge, his 5‐oxoproline (pyroglutamic acid) level returned markedly elevated at greater than 10,000 mmol/mol creatinine (200 times the upper limit of normal).

Elevations in 5‐oxoproline levels in this patient most likely stem from glutathione depletion related to chronic acetaminophen use. Alcohol use and malnutrition may have heightened this patient's susceptibility. Despite the common occurrence of acetaminophen use in alcohol abusers or the malnourished, the rarity of severe 5‐oxoproline toxicity suggests unknown factors may be present in predisposed individuals, or under‐recognition. Although acetaminophen‐induced hepatotoxicity may occur along with 5‐oxoprolinemia, this does not always occur.

Several features led me away from this syndrome. First, its rarity lowered my pretest probability. Second, the lack of exposure history and details about the serum assays, specifically whether the measurements were confirmed by gas chromatography, reduced my confidence in eliminating more common ingestions. Third, several aspects proved to be less useful discriminating features: the mild elevation in osmolar gap, renal failure, and hallucinations, which in retrospect proved to be nonspecific.

The patient admitted that he had a longstanding use of acetaminophen in addition to using his girlfriend's acetaminophen‐hydrocodone. He had significant weight loss of over 50 pounds over the previous year, which he attributed to poor appetite. On further chart review, he had been admitted 3 times with a similar clinical presentation and recovered quickly with intensive and supportive care, with no etiology found at those times. He had 2 subsequent hospital admissions for altered mental status and respiratory failure, and his final hospitalization resulted in cardiac arrest and death.

DISCUSSION

5‐Oxoprolinemia is a rare, but potentially lethal cause of severe anion gap metabolic acidosis.[1, 2] The mechanism is thought to be impairment of glutathione metabolism, in the context of other predisposing factors. This can be a congenital error of metabolism, or can be acquired and exacerbated by acetaminophen use. Ingestion of acetaminophen leads to glutathione depletion, which in turn may precipitate accumulation of pyroglutamic acid and subsequent anion gap metabolic acidosis (Figure 1). Additional risk factors that may predispose patients to this condition include malnutrition, renal insufficiency, concurrent infection, and female gender.[1, 2, 3]

Figure 1

The diagnosis of 5‐oxoprolinemia is made via urine or serum organic acid analysis, testing routinely performed in pediatric populations when screening for congenital metabolic disorders. The pathophysiology suggests that obtaining a urine sample early in presentation, when acidosis is greatest, would lead to the highest 5‐oxoproline levels and best chance for diagnosis. Case patients have had normal levels prior to and in convalescent phases after the acute episode.[4] Given the long turnaround time for lab testing, presumptive diagnosis and treatment may be necessary.

Treatment of 5‐oxoprolinemia is primarily supportive, aimed at the metabolic acidosis. Fluid resuscitation and bicarbonate therapy are reasonable temporizing measures. Hemodialysis can clear 5‐oxoproline and may be indicated in severe acidosis.[5] Furthermore, the proposed pathophysiology suggests that administration of N‐acetylcysteine (NAC) may help to address the underlying process, but there are no trials to support a specific dosing regimen. However, given the fulminant presentation and common competing concern for acetaminophen toxicity, it is reasonable to initiate NAC aimed at treatment for possible acetaminophen overdose. Prevention of recurrence includes avoidance of acetaminophen, and counseling the patient to avoid acetaminophen in prescription combination medications and over‐the‐counter preparations.

Recent regulatory changes regarding acetaminophen/opioid combinations may reduce the incidence of 5‐oxoprolinemia. The US Food and Drug Administration has taken action to reduce adverse effects from acetaminophen exposure by limiting the amount of acetaminophen in opioid combination pills from 500 mg to a maximum of 325 mg per pill. This is aimed at preventing hepatotoxicity from ingestion of higher‐than‐recommended doses. However, clinicians should remember that 5‐oxoprolinemia can result from ingestion of acetaminophen at therapeutic levels.

Given its rare incidence, low clinical suspicion, and transient nature of confirmatory testing, it is likely this remains an underdiagnosed syndrome. In the case discussed, subsequent chart review demonstrated 5 previous admissions in multiple hospitals for severe transient anion gap acidosis. The likelihood that 5‐oxoprolinemia was missed in each of these cases supports a lack of awareness of this syndrome. In this patient, the discussant appropriately identified the possibility of 5‐oxoproline toxicity, but felt ethylene glycol ingestion was more likely. As this case underscores, a cornerstone in the management of suspected ingestions is empiric treatment for the most likely etiologies. Here, treatment for acetaminophen overdose and for methanol or ethylene glycol were warranted, and fortunately also addressed the rarer possibility of 5‐oxoproline toxicity.

The mnemonic MUDPILES is commonly used to identify possible causes of life‐threatening anion gap metabolic acidosis, as such heuristics have benefits in rapidly generating a differential diagnosis to guide initial evaluation. Given the fact that the traditional letter P (paraldehyde) in MUDPILES is no longer clinically utilized, some authors have suggested replacing this with pyroglutamic acid (a synonym of 5‐oxoproline). Such a change may help providers who have ruled out other causes of a high anion gap metabolic acidosis, facilitating diagnosis of this life‐threatening syndrome. In any case, clinicians must be mindful that simple memory aids may mislead clinicians, and a complete differential diagnosis may require more than a mnemonic.

TEACHING POINTS

1. Acetaminophen use, even at therapeutic levels, can lead to 5‐oxoprolinemia, a potentially lethal anion gap metabolic acidosis.
2. 5‐oxoprolinemia is likely related to glutathione depletion, worsened by acetaminophen, malnutrition, renal insufficiency, female gender, and infection. This implies theoretical benefit from administration of NAC for glutathione repletion.
3. Mnemonics can be useful, but have limitations by way of oversimplification. This case suggests that changing the letter P in MUDPILES from paraldehyde to pyroglutamic acid could reduce underdiagnosis.

Disclosure: Nothing to report.

A 51‐year‐old man presented to the emergency department after 1 day of progressive dyspnea and increasing confusion.

Acute dyspnea most commonly stems from a cardiac or pulmonary disorder such as heart failure, acute coronary syndrome, pneumonia, pulmonary embolism, or exacerbations of asthma or chronic obstructive pulmonary disease. Less frequent cardiopulmonary considerations include pericardial or pleural effusion, pneumothorax, aspiration, and upper airway obstruction. Dyspnea might also be the initial manifestation of profound anemia or metabolic acidosis.

The presence of confusion suggests either a severe presentation of any of the aforementioned possibilities (with confusion resulting from hypoxia, hypercapnia, or hypotension); a multiorgan illness such as sepsis, malignancy, thromboembolic disease, vasculitis, thyroid dysfunction, or toxic ingestion; or a metabolic derangement related to the underlying cause of dyspnea (for example, hypercalcemia or hyponatremia associated with lung cancer).

Twelve hours prior to presentation, he started to have visual hallucinations. He denied fever, chills, cough, chest discomfort, palpitations, weight gain, headache, neck pain, or weakness.

Visual hallucinations could result from a toxic‐metabolic encephalopathy, such as drug overdose or withdrawal, liver or kidney failure, or hypoxia. A structural brain abnormality may also manifest with visual hallucination. Acute onset at age 51 and the absence of auditory hallucinations argue against a neurodegenerative illness and a primary psychiatric disturbance, respectively.

Episodic hallucinations would support the possibility of seizures, monocular hallucinations would point to a retinal or ocular problem, and a description of yellow‐green hue would suggest a side effect of digoxin.

His past medical history was remarkable for diet‐controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, and chronic low back pain. His medications included metoprolol tartrate 25 mg twice daily, omeprazole 40 mg daily, baclofen 15 mg twice daily, oxycodone 30 mg 3 times daily, and hydrocodone 10 mg/acetaminophen 325 mg, 2 tablets 3 times daily as needed for back pain. He was a smoker with a 30 pack‐year history. He had a history of alcohol and cocaine use, but denied any recent substance use. He had no known history of obstructive pulmonary disease.

The patient takes 3 medications well known to cause confusion and hallucinations (oxycodone, hydrocodone, and baclofen), especially when they accumulate due to excessive ingestion or impaired clearance. Although these medications may suppress ventilatory drive, dyspnea would not be a common presenting complaint. He has risk factors for ischemic heart disease and cardiomyopathy, and his smoking history raises the possibility of malignancy.

On exam, the patient's temperature was 94.4C, heart rate 128 beats per minute, respiration rate 28 breaths per minute, blood pressure 155/63 mm Hg, and oxygen saturation 100% while breathing ambient air. The patient was cachectic and appeared in moderate respiratory distress. His pupils were equal and reactive to light, and extraocular movements were intact. He did not have scleral icterus, or cervical or clavicular lymphadenopathy. His oropharynx was negative for erythema, edema, or exudate. His cardiovascular exam revealed a regular tachycardia without rubs or diastolic gallops. There was a 2/6 systolic murmur heard best at left sternal border, without radiation. He did not have jugular venous distention. His pulmonary exam was notable for tachypnea but with normal vesicular breath sounds throughout. He did not have stridor, wheezing, rhonchi, or rales. His abdomen had normal bowel tones and was soft without tenderness, distention, or organomegaly. His extremities were warm, revealed normal pulses, and no edema was present. His joints were cool to palpation, without effusion. On neurologic exam, he was oriented to person and place and able to answer yes/no questions, but unable to provide detailed history. His speech was fluent. His motor exam was without focal deficits. His skin was without any notable lesions.

The constellation of findings does not point to a specific toxidrome. The finding of warm extremities in a hypothermic patient suggests heat loss due to inappropriate peripheral vasodilation. In the absence of vasodilators or features of aortic insufficiency, sepsis becomes a leading consideration. Infection could result in hypothermia and altered sensorium, and accompanying lactic acidosis could trigger tachypnea.

Shortly after admission, he became more somnolent and developed progressive respiratory distress, requiring intubation. Arterial blood gas revealed a pH of 6.93, PaCO₂<20 mm Hg, PaO₂ 127 mm Hg, and HCO₃<5 mEq/L. Other laboratory results included a lactate of 4.1 mmol/L, blood urea nitrogen 49 mg/dL, creatinine 2.3 mg/dL (0.8 at 1 month prior), sodium level of 143 mmol/L, chloride of 106 mmol/L, and bicarbonate level of <5 mg/dL. His aspartate aminotransferase was 34 IU/L, alanine transaminase was 28 IU/L, total bilirubin was 0.6 mg/dL, International Normalized Ratio was 1.3. A complete blood count revealed a white blood cell count of 23,000/L, hemoglobin of 10.6 g/dL, and platelet count of 454,000/L. A urinalysis was unremarkable. Cultures of blood, urine, and sputum were collected. Head computed tomography was negative.

This patient has a combined anion gap and nongap metabolic acidosis, as well as respiratory alkalosis. Although his acute kidney failure could produce these 2 types of metabolic acidosis, the modest elevation of the serum creatinine is not commensurate with such profound acidosis. Similarly, sepsis without hypotension or more striking elevation in lactate levels would not account for the entirety of the acidosis. Severe diabetic ketoacidosis can result in profound metabolic acidosis, and marked hyperglycemia or hyperosmolarity could result in somnolence; however, his diabetes has been controlled without medication and there is no obvious precipitant for an episode of ketoacidosis.

Remaining causes of anion gap acidosis include ingestion of methanol, ethylene glycol, ethanol, or salicylates. A careful history of ingestions and medications from witnesses including any prehospital personnel might suggest a source of intoxication. Absent this information, the hypothermia favors an ingestion of an alcohol over salicylates, and the lack of urine crystals and the presence of prominent visual hallucinations would point more toward methanol poisoning than ethylene glycol. A serum osmolarity measurement would allow determination of the osmolar gap, which would be elevated in the setting of methanol or ethylene glycol poisoning. If he were this ill from ethanol, I would have expected to see evidence of hepatotoxicity.

I would administer sodium bicarbonate to reverse the acidosis and to promote renal clearance of salicylates, methanol, ethylene glycol, and their metabolites. Orogastric decontamination with activated charcoal should be considered. If the osmolar gap is elevated, I would also administer intravenous fomepizole to attempt to reverse methanol or ethylene glycol poisoning. I would not delay treatment while waiting for these serum levels to return.

Initial serologic toxicology performed in the emergency department revealed negative ethanol, salicylates, and ketones. His osmolar gap was 13 mOsm/kg. His acetaminophen level was 69 g/mL (normal <120 g/mL). A creatinine phosphokinase was 84 IU/L and myoglobin was 93 ng/mL. His subsequent serum toxicology screen was negative for methanol, ethylene glycol, isopropranol, and hippuric acid. Urine toxicology was positive for opiates, but negative for amphetamine, benzodiazepine, cannabinoid, and cocaine.

Serum and urine ketone assays typically involve the nitroprusside reaction and detect acetoacetate, but not ‐hydroxybutyrate, and can lead to negative test results early in diabetic or alcoholic ketoacidosis. However, the normal ethanol level argues against alcoholic ketoacidosis. Rare causes of elevated anion gap acidosis include toluene toxicity, acetaminophen poisoning, and ingestion of other alcohols. Toluene is metabolized to hippuric acid, and acetaminophen toxicity and associated glutathione depletion can lead to 5‐oxoproline accumulation, producing an anion gap. Patients who abuse alcohol are at risk for acetaminophen toxicity even at doses considered normal. However, this degree of encephalopathy would be unusual for acetaminophen toxicity unless liver failure had developed or unless there was another ingestion that might alter sensorium. Furthermore, the elevated osmolar gap is not a feature of acetaminophen poisoning. I would monitor liver enzyme tests and consider a serum ammonia level, but would not attribute the entire picture to acetaminophen.

The combination of elevated anion gap with an elevated osmolar gap narrows the diagnostic possibilities. Ingestion of several alcohols (ethanol, methanol, ethylene glycol, diethylene glycol) or toluene could produce these abnormalities. Of note, the osmolar gap is typically most markedly elevated early in methanol and ethylene glycol ingestions, and then as the parent compound is metabolized, the osmolar gap closes and the accumulation of metabolites produces the anion gap. Hallucinations are more common with methanol and toluene, and renal failure is more typical of ethylene glycol or toluene. The lack of oxalate crystalluria does not exclude ethylene glycol poisoning. Unfortunately, urine testing for oxalate crystals or fluorescein examination are neither sensitive nor specific enough to diagnosis ethylene glycol toxicity reliably. In most hospitals, assays used for serum testing for alcohols are insensitive, and require confirmation with gas chromatography performed at a specialty lab.

Additional history might reveal the likely culprit or culprits. Inhalant abuse including huffing would point to toluene or organic acid exposure. Solvent ingestion (eg, antifreeze, brake fluid) would suggest methanol or ethylene glycol. Absent this history, I remain suspicious for poisoning with methanol or ethylene glycol and would consider empiric treatment after urgent consultation with a medical toxicologist. A careful ophthalmologic exam might demonstrate characteristic features of methanol poisoning. Serum samples should be sent to a regional lab for analysis for alcohols and organic acids.

He was admitted to the intensive care unit, and empiric antibiotics started. He was empirically started on N‐acetylcysteine and sodium bicarbonate drips. However, his acidemia persisted and he required hemodialysis, which was initiated 12 hours after initial presentation. His acidemia and mental status quickly improved after hemodialysis. He was extubated on hospital day 2 and no longer required hemodialysis.

The differential diagnosis at this point consists of 3 main possibilities: ingestion of methanol, ethylene glycol, or inhalant abuse such as from toluene. The normal hippuric acid level points away from toluene, whereas serum levels can be misleading in the alcohol poisonings. Other discriminating features to consider include exposure history and unique clinical aspects. In this patient, an exposure history is lacking, but 4 clinical features stand out: visual hallucinations, acute kidney injury, mild lactic acidosis, and rapid improvement with hemodialysis. Both ethylene glycol and methanol toxicity may produce a mild lactic acidosis by increasing hepatic metabolism of pyruvate to lactate, and both are rapidly cleared by dialysis. Although it is tempting to place methanol at the top of the list of possibilities due to the report of visual hallucinations, the subjective visual complaints without objective exam corollaries (loss of visual acuity, abnormal pupillary reflexes, or optic disc hyperemia) are nonspecific and might be provoked by alcohol or an inhalant. Furthermore, the acute renal failure is much more typical of ethylene glycol, and thus I would consider ethylene glycol as being the more likely of the ingestions. Coingestion of multiple alcohols is a possibility, but it would be statistically less likely. Confirmation of ethylene glycol poisoning would consist of further insight into his exposures and measurement of levels using gas chromatography.

A urine sample from his emergency department presentation was sent to an outside lab for organic acid levels. Based on high clinical suspicion for 5‐oxoprolinemia (pyroglutamic acidemia) the patient was counseled to avoid any acetaminophen. His primary care provider was informed of this and acetaminophen was added as an adverse drug reaction. The patient left against medical advice soon after extubation. Following discharge, his 5‐oxoproline (pyroglutamic acid) level returned markedly elevated at greater than 10,000 mmol/mol creatinine (200 times the upper limit of normal).

Elevations in 5‐oxoproline levels in this patient most likely stem from glutathione depletion related to chronic acetaminophen use. Alcohol use and malnutrition may have heightened this patient's susceptibility. Despite the common occurrence of acetaminophen use in alcohol abusers or the malnourished, the rarity of severe 5‐oxoproline toxicity suggests unknown factors may be present in predisposed individuals, or under‐recognition. Although acetaminophen‐induced hepatotoxicity may occur along with 5‐oxoprolinemia, this does not always occur.

Several features led me away from this syndrome. First, its rarity lowered my pretest probability. Second, the lack of exposure history and details about the serum assays, specifically whether the measurements were confirmed by gas chromatography, reduced my confidence in eliminating more common ingestions. Third, several aspects proved to be less useful discriminating features: the mild elevation in osmolar gap, renal failure, and hallucinations, which in retrospect proved to be nonspecific.

The patient admitted that he had a longstanding use of acetaminophen in addition to using his girlfriend's acetaminophen‐hydrocodone. He had significant weight loss of over 50 pounds over the previous year, which he attributed to poor appetite. On further chart review, he had been admitted 3 times with a similar clinical presentation and recovered quickly with intensive and supportive care, with no etiology found at those times. He had 2 subsequent hospital admissions for altered mental status and respiratory failure, and his final hospitalization resulted in cardiac arrest and death.

DISCUSSION

5‐Oxoprolinemia is a rare, but potentially lethal cause of severe anion gap metabolic acidosis.[1, 2] The mechanism is thought to be impairment of glutathione metabolism, in the context of other predisposing factors. This can be a congenital error of metabolism, or can be acquired and exacerbated by acetaminophen use. Ingestion of acetaminophen leads to glutathione depletion, which in turn may precipitate accumulation of pyroglutamic acid and subsequent anion gap metabolic acidosis (Figure 1). Additional risk factors that may predispose patients to this condition include malnutrition, renal insufficiency, concurrent infection, and female gender.[1, 2, 3]

Figure 1

The diagnosis of 5‐oxoprolinemia is made via urine or serum organic acid analysis, testing routinely performed in pediatric populations when screening for congenital metabolic disorders. The pathophysiology suggests that obtaining a urine sample early in presentation, when acidosis is greatest, would lead to the highest 5‐oxoproline levels and best chance for diagnosis. Case patients have had normal levels prior to and in convalescent phases after the acute episode.[4] Given the long turnaround time for lab testing, presumptive diagnosis and treatment may be necessary.

Treatment of 5‐oxoprolinemia is primarily supportive, aimed at the metabolic acidosis. Fluid resuscitation and bicarbonate therapy are reasonable temporizing measures. Hemodialysis can clear 5‐oxoproline and may be indicated in severe acidosis.[5] Furthermore, the proposed pathophysiology suggests that administration of N‐acetylcysteine (NAC) may help to address the underlying process, but there are no trials to support a specific dosing regimen. However, given the fulminant presentation and common competing concern for acetaminophen toxicity, it is reasonable to initiate NAC aimed at treatment for possible acetaminophen overdose. Prevention of recurrence includes avoidance of acetaminophen, and counseling the patient to avoid acetaminophen in prescription combination medications and over‐the‐counter preparations.

Recent regulatory changes regarding acetaminophen/opioid combinations may reduce the incidence of 5‐oxoprolinemia. The US Food and Drug Administration has taken action to reduce adverse effects from acetaminophen exposure by limiting the amount of acetaminophen in opioid combination pills from 500 mg to a maximum of 325 mg per pill. This is aimed at preventing hepatotoxicity from ingestion of higher‐than‐recommended doses. However, clinicians should remember that 5‐oxoprolinemia can result from ingestion of acetaminophen at therapeutic levels.

Given its rare incidence, low clinical suspicion, and transient nature of confirmatory testing, it is likely this remains an underdiagnosed syndrome. In the case discussed, subsequent chart review demonstrated 5 previous admissions in multiple hospitals for severe transient anion gap acidosis. The likelihood that 5‐oxoprolinemia was missed in each of these cases supports a lack of awareness of this syndrome. In this patient, the discussant appropriately identified the possibility of 5‐oxoproline toxicity, but felt ethylene glycol ingestion was more likely. As this case underscores, a cornerstone in the management of suspected ingestions is empiric treatment for the most likely etiologies. Here, treatment for acetaminophen overdose and for methanol or ethylene glycol were warranted, and fortunately also addressed the rarer possibility of 5‐oxoproline toxicity.

The mnemonic MUDPILES is commonly used to identify possible causes of life‐threatening anion gap metabolic acidosis, as such heuristics have benefits in rapidly generating a differential diagnosis to guide initial evaluation. Given the fact that the traditional letter P (paraldehyde) in MUDPILES is no longer clinically utilized, some authors have suggested replacing this with pyroglutamic acid (a synonym of 5‐oxoproline). Such a change may help providers who have ruled out other causes of a high anion gap metabolic acidosis, facilitating diagnosis of this life‐threatening syndrome. In any case, clinicians must be mindful that simple memory aids may mislead clinicians, and a complete differential diagnosis may require more than a mnemonic.

TEACHING POINTS

1. Acetaminophen use, even at therapeutic levels, can lead to 5‐oxoprolinemia, a potentially lethal anion gap metabolic acidosis.
2. 5‐oxoprolinemia is likely related to glutathione depletion, worsened by acetaminophen, malnutrition, renal insufficiency, female gender, and infection. This implies theoretical benefit from administration of NAC for glutathione repletion.
3. Mnemonics can be useful, but have limitations by way of oversimplification. This case suggests that changing the letter P in MUDPILES from paraldehyde to pyroglutamic acid could reduce underdiagnosis.

Disclosure: Nothing to report.

A 51‐year‐old man presented to the emergency department after 1 day of progressive dyspnea and increasing confusion.

Acute dyspnea most commonly stems from a cardiac or pulmonary disorder such as heart failure, acute coronary syndrome, pneumonia, pulmonary embolism, or exacerbations of asthma or chronic obstructive pulmonary disease. Less frequent cardiopulmonary considerations include pericardial or pleural effusion, pneumothorax, aspiration, and upper airway obstruction. Dyspnea might also be the initial manifestation of profound anemia or metabolic acidosis.

The presence of confusion suggests either a severe presentation of any of the aforementioned possibilities (with confusion resulting from hypoxia, hypercapnia, or hypotension); a multiorgan illness such as sepsis, malignancy, thromboembolic disease, vasculitis, thyroid dysfunction, or toxic ingestion; or a metabolic derangement related to the underlying cause of dyspnea (for example, hypercalcemia or hyponatremia associated with lung cancer).

Twelve hours prior to presentation, he started to have visual hallucinations. He denied fever, chills, cough, chest discomfort, palpitations, weight gain, headache, neck pain, or weakness.

Visual hallucinations could result from a toxic‐metabolic encephalopathy, such as drug overdose or withdrawal, liver or kidney failure, or hypoxia. A structural brain abnormality may also manifest with visual hallucination. Acute onset at age 51 and the absence of auditory hallucinations argue against a neurodegenerative illness and a primary psychiatric disturbance, respectively.

Episodic hallucinations would support the possibility of seizures, monocular hallucinations would point to a retinal or ocular problem, and a description of yellow‐green hue would suggest a side effect of digoxin.

His past medical history was remarkable for diet‐controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, and chronic low back pain. His medications included metoprolol tartrate 25 mg twice daily, omeprazole 40 mg daily, baclofen 15 mg twice daily, oxycodone 30 mg 3 times daily, and hydrocodone 10 mg/acetaminophen 325 mg, 2 tablets 3 times daily as needed for back pain. He was a smoker with a 30 pack‐year history. He had a history of alcohol and cocaine use, but denied any recent substance use. He had no known history of obstructive pulmonary disease.

The patient takes 3 medications well known to cause confusion and hallucinations (oxycodone, hydrocodone, and baclofen), especially when they accumulate due to excessive ingestion or impaired clearance. Although these medications may suppress ventilatory drive, dyspnea would not be a common presenting complaint. He has risk factors for ischemic heart disease and cardiomyopathy, and his smoking history raises the possibility of malignancy.

On exam, the patient's temperature was 94.4C, heart rate 128 beats per minute, respiration rate 28 breaths per minute, blood pressure 155/63 mm Hg, and oxygen saturation 100% while breathing ambient air. The patient was cachectic and appeared in moderate respiratory distress. His pupils were equal and reactive to light, and extraocular movements were intact. He did not have scleral icterus, or cervical or clavicular lymphadenopathy. His oropharynx was negative for erythema, edema, or exudate. His cardiovascular exam revealed a regular tachycardia without rubs or diastolic gallops. There was a 2/6 systolic murmur heard best at left sternal border, without radiation. He did not have jugular venous distention. His pulmonary exam was notable for tachypnea but with normal vesicular breath sounds throughout. He did not have stridor, wheezing, rhonchi, or rales. His abdomen had normal bowel tones and was soft without tenderness, distention, or organomegaly. His extremities were warm, revealed normal pulses, and no edema was present. His joints were cool to palpation, without effusion. On neurologic exam, he was oriented to person and place and able to answer yes/no questions, but unable to provide detailed history. His speech was fluent. His motor exam was without focal deficits. His skin was without any notable lesions.

The constellation of findings does not point to a specific toxidrome. The finding of warm extremities in a hypothermic patient suggests heat loss due to inappropriate peripheral vasodilation. In the absence of vasodilators or features of aortic insufficiency, sepsis becomes a leading consideration. Infection could result in hypothermia and altered sensorium, and accompanying lactic acidosis could trigger tachypnea.

Shortly after admission, he became more somnolent and developed progressive respiratory distress, requiring intubation. Arterial blood gas revealed a pH of 6.93, PaCO₂<20 mm Hg, PaO₂ 127 mm Hg, and HCO₃<5 mEq/L. Other laboratory results included a lactate of 4.1 mmol/L, blood urea nitrogen 49 mg/dL, creatinine 2.3 mg/dL (0.8 at 1 month prior), sodium level of 143 mmol/L, chloride of 106 mmol/L, and bicarbonate level of <5 mg/dL. His aspartate aminotransferase was 34 IU/L, alanine transaminase was 28 IU/L, total bilirubin was 0.6 mg/dL, International Normalized Ratio was 1.3. A complete blood count revealed a white blood cell count of 23,000/L, hemoglobin of 10.6 g/dL, and platelet count of 454,000/L. A urinalysis was unremarkable. Cultures of blood, urine, and sputum were collected. Head computed tomography was negative.

This patient has a combined anion gap and nongap metabolic acidosis, as well as respiratory alkalosis. Although his acute kidney failure could produce these 2 types of metabolic acidosis, the modest elevation of the serum creatinine is not commensurate with such profound acidosis. Similarly, sepsis without hypotension or more striking elevation in lactate levels would not account for the entirety of the acidosis. Severe diabetic ketoacidosis can result in profound metabolic acidosis, and marked hyperglycemia or hyperosmolarity could result in somnolence; however, his diabetes has been controlled without medication and there is no obvious precipitant for an episode of ketoacidosis.

Remaining causes of anion gap acidosis include ingestion of methanol, ethylene glycol, ethanol, or salicylates. A careful history of ingestions and medications from witnesses including any prehospital personnel might suggest a source of intoxication. Absent this information, the hypothermia favors an ingestion of an alcohol over salicylates, and the lack of urine crystals and the presence of prominent visual hallucinations would point more toward methanol poisoning than ethylene glycol. A serum osmolarity measurement would allow determination of the osmolar gap, which would be elevated in the setting of methanol or ethylene glycol poisoning. If he were this ill from ethanol, I would have expected to see evidence of hepatotoxicity.

I would administer sodium bicarbonate to reverse the acidosis and to promote renal clearance of salicylates, methanol, ethylene glycol, and their metabolites. Orogastric decontamination with activated charcoal should be considered. If the osmolar gap is elevated, I would also administer intravenous fomepizole to attempt to reverse methanol or ethylene glycol poisoning. I would not delay treatment while waiting for these serum levels to return.

Initial serologic toxicology performed in the emergency department revealed negative ethanol, salicylates, and ketones. His osmolar gap was 13 mOsm/kg. His acetaminophen level was 69 g/mL (normal <120 g/mL). A creatinine phosphokinase was 84 IU/L and myoglobin was 93 ng/mL. His subsequent serum toxicology screen was negative for methanol, ethylene glycol, isopropranol, and hippuric acid. Urine toxicology was positive for opiates, but negative for amphetamine, benzodiazepine, cannabinoid, and cocaine.

Serum and urine ketone assays typically involve the nitroprusside reaction and detect acetoacetate, but not ‐hydroxybutyrate, and can lead to negative test results early in diabetic or alcoholic ketoacidosis. However, the normal ethanol level argues against alcoholic ketoacidosis. Rare causes of elevated anion gap acidosis include toluene toxicity, acetaminophen poisoning, and ingestion of other alcohols. Toluene is metabolized to hippuric acid, and acetaminophen toxicity and associated glutathione depletion can lead to 5‐oxoproline accumulation, producing an anion gap. Patients who abuse alcohol are at risk for acetaminophen toxicity even at doses considered normal. However, this degree of encephalopathy would be unusual for acetaminophen toxicity unless liver failure had developed or unless there was another ingestion that might alter sensorium. Furthermore, the elevated osmolar gap is not a feature of acetaminophen poisoning. I would monitor liver enzyme tests and consider a serum ammonia level, but would not attribute the entire picture to acetaminophen.

The combination of elevated anion gap with an elevated osmolar gap narrows the diagnostic possibilities. Ingestion of several alcohols (ethanol, methanol, ethylene glycol, diethylene glycol) or toluene could produce these abnormalities. Of note, the osmolar gap is typically most markedly elevated early in methanol and ethylene glycol ingestions, and then as the parent compound is metabolized, the osmolar gap closes and the accumulation of metabolites produces the anion gap. Hallucinations are more common with methanol and toluene, and renal failure is more typical of ethylene glycol or toluene. The lack of oxalate crystalluria does not exclude ethylene glycol poisoning. Unfortunately, urine testing for oxalate crystals or fluorescein examination are neither sensitive nor specific enough to diagnosis ethylene glycol toxicity reliably. In most hospitals, assays used for serum testing for alcohols are insensitive, and require confirmation with gas chromatography performed at a specialty lab.

Additional history might reveal the likely culprit or culprits. Inhalant abuse including huffing would point to toluene or organic acid exposure. Solvent ingestion (eg, antifreeze, brake fluid) would suggest methanol or ethylene glycol. Absent this history, I remain suspicious for poisoning with methanol or ethylene glycol and would consider empiric treatment after urgent consultation with a medical toxicologist. A careful ophthalmologic exam might demonstrate characteristic features of methanol poisoning. Serum samples should be sent to a regional lab for analysis for alcohols and organic acids.

He was admitted to the intensive care unit, and empiric antibiotics started. He was empirically started on N‐acetylcysteine and sodium bicarbonate drips. However, his acidemia persisted and he required hemodialysis, which was initiated 12 hours after initial presentation. His acidemia and mental status quickly improved after hemodialysis. He was extubated on hospital day 2 and no longer required hemodialysis.

The differential diagnosis at this point consists of 3 main possibilities: ingestion of methanol, ethylene glycol, or inhalant abuse such as from toluene. The normal hippuric acid level points away from toluene, whereas serum levels can be misleading in the alcohol poisonings. Other discriminating features to consider include exposure history and unique clinical aspects. In this patient, an exposure history is lacking, but 4 clinical features stand out: visual hallucinations, acute kidney injury, mild lactic acidosis, and rapid improvement with hemodialysis. Both ethylene glycol and methanol toxicity may produce a mild lactic acidosis by increasing hepatic metabolism of pyruvate to lactate, and both are rapidly cleared by dialysis. Although it is tempting to place methanol at the top of the list of possibilities due to the report of visual hallucinations, the subjective visual complaints without objective exam corollaries (loss of visual acuity, abnormal pupillary reflexes, or optic disc hyperemia) are nonspecific and might be provoked by alcohol or an inhalant. Furthermore, the acute renal failure is much more typical of ethylene glycol, and thus I would consider ethylene glycol as being the more likely of the ingestions. Coingestion of multiple alcohols is a possibility, but it would be statistically less likely. Confirmation of ethylene glycol poisoning would consist of further insight into his exposures and measurement of levels using gas chromatography.

A urine sample from his emergency department presentation was sent to an outside lab for organic acid levels. Based on high clinical suspicion for 5‐oxoprolinemia (pyroglutamic acidemia) the patient was counseled to avoid any acetaminophen. His primary care provider was informed of this and acetaminophen was added as an adverse drug reaction. The patient left against medical advice soon after extubation. Following discharge, his 5‐oxoproline (pyroglutamic acid) level returned markedly elevated at greater than 10,000 mmol/mol creatinine (200 times the upper limit of normal).

Elevations in 5‐oxoproline levels in this patient most likely stem from glutathione depletion related to chronic acetaminophen use. Alcohol use and malnutrition may have heightened this patient's susceptibility. Despite the common occurrence of acetaminophen use in alcohol abusers or the malnourished, the rarity of severe 5‐oxoproline toxicity suggests unknown factors may be present in predisposed individuals, or under‐recognition. Although acetaminophen‐induced hepatotoxicity may occur along with 5‐oxoprolinemia, this does not always occur.

Several features led me away from this syndrome. First, its rarity lowered my pretest probability. Second, the lack of exposure history and details about the serum assays, specifically whether the measurements were confirmed by gas chromatography, reduced my confidence in eliminating more common ingestions. Third, several aspects proved to be less useful discriminating features: the mild elevation in osmolar gap, renal failure, and hallucinations, which in retrospect proved to be nonspecific.

The patient admitted that he had a longstanding use of acetaminophen in addition to using his girlfriend's acetaminophen‐hydrocodone. He had significant weight loss of over 50 pounds over the previous year, which he attributed to poor appetite. On further chart review, he had been admitted 3 times with a similar clinical presentation and recovered quickly with intensive and supportive care, with no etiology found at those times. He had 2 subsequent hospital admissions for altered mental status and respiratory failure, and his final hospitalization resulted in cardiac arrest and death.

DISCUSSION

5‐Oxoprolinemia is a rare, but potentially lethal cause of severe anion gap metabolic acidosis.[1, 2] The mechanism is thought to be impairment of glutathione metabolism, in the context of other predisposing factors. This can be a congenital error of metabolism, or can be acquired and exacerbated by acetaminophen use. Ingestion of acetaminophen leads to glutathione depletion, which in turn may precipitate accumulation of pyroglutamic acid and subsequent anion gap metabolic acidosis (Figure 1). Additional risk factors that may predispose patients to this condition include malnutrition, renal insufficiency, concurrent infection, and female gender.[1, 2, 3]

Figure 1

The diagnosis of 5‐oxoprolinemia is made via urine or serum organic acid analysis, testing routinely performed in pediatric populations when screening for congenital metabolic disorders. The pathophysiology suggests that obtaining a urine sample early in presentation, when acidosis is greatest, would lead to the highest 5‐oxoproline levels and best chance for diagnosis. Case patients have had normal levels prior to and in convalescent phases after the acute episode.[4] Given the long turnaround time for lab testing, presumptive diagnosis and treatment may be necessary.

Treatment of 5‐oxoprolinemia is primarily supportive, aimed at the metabolic acidosis. Fluid resuscitation and bicarbonate therapy are reasonable temporizing measures. Hemodialysis can clear 5‐oxoproline and may be indicated in severe acidosis.[5] Furthermore, the proposed pathophysiology suggests that administration of N‐acetylcysteine (NAC) may help to address the underlying process, but there are no trials to support a specific dosing regimen. However, given the fulminant presentation and common competing concern for acetaminophen toxicity, it is reasonable to initiate NAC aimed at treatment for possible acetaminophen overdose. Prevention of recurrence includes avoidance of acetaminophen, and counseling the patient to avoid acetaminophen in prescription combination medications and over‐the‐counter preparations.

Recent regulatory changes regarding acetaminophen/opioid combinations may reduce the incidence of 5‐oxoprolinemia. The US Food and Drug Administration has taken action to reduce adverse effects from acetaminophen exposure by limiting the amount of acetaminophen in opioid combination pills from 500 mg to a maximum of 325 mg per pill. This is aimed at preventing hepatotoxicity from ingestion of higher‐than‐recommended doses. However, clinicians should remember that 5‐oxoprolinemia can result from ingestion of acetaminophen at therapeutic levels.

Given its rare incidence, low clinical suspicion, and transient nature of confirmatory testing, it is likely this remains an underdiagnosed syndrome. In the case discussed, subsequent chart review demonstrated 5 previous admissions in multiple hospitals for severe transient anion gap acidosis. The likelihood that 5‐oxoprolinemia was missed in each of these cases supports a lack of awareness of this syndrome. In this patient, the discussant appropriately identified the possibility of 5‐oxoproline toxicity, but felt ethylene glycol ingestion was more likely. As this case underscores, a cornerstone in the management of suspected ingestions is empiric treatment for the most likely etiologies. Here, treatment for acetaminophen overdose and for methanol or ethylene glycol were warranted, and fortunately also addressed the rarer possibility of 5‐oxoproline toxicity.

The mnemonic MUDPILES is commonly used to identify possible causes of life‐threatening anion gap metabolic acidosis, as such heuristics have benefits in rapidly generating a differential diagnosis to guide initial evaluation. Given the fact that the traditional letter P (paraldehyde) in MUDPILES is no longer clinically utilized, some authors have suggested replacing this with pyroglutamic acid (a synonym of 5‐oxoproline). Such a change may help providers who have ruled out other causes of a high anion gap metabolic acidosis, facilitating diagnosis of this life‐threatening syndrome. In any case, clinicians must be mindful that simple memory aids may mislead clinicians, and a complete differential diagnosis may require more than a mnemonic.

TEACHING POINTS

1. Acetaminophen use, even at therapeutic levels, can lead to 5‐oxoprolinemia, a potentially lethal anion gap metabolic acidosis.
2. 5‐oxoprolinemia is likely related to glutathione depletion, worsened by acetaminophen, malnutrition, renal insufficiency, female gender, and infection. This implies theoretical benefit from administration of NAC for glutathione repletion.
3. Mnemonics can be useful, but have limitations by way of oversimplification. This case suggests that changing the letter P in MUDPILES from paraldehyde to pyroglutamic acid could reduce underdiagnosis.

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

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