Lawrence M. Tierney, MD

Fever is a nonspecific phenomenon that can result from many inciting causes such as infection, inflammation, malignancy, thromboembolic disease, drugs, and endocrine disease. In hospitalized patients, one of the most important clinical considerations is bacteremia. Although vital signs compose 3 of the 4 current criteria for the diagnosis of Systemic Inflammatory Response Syndrome (SIRS),1, 2 they contribute little to the diagnosis of the cause, which can be inflammation or infection. Unfortunately, the physician's clinical diagnosis of bacteremia lacks both sensitivity and specificity.35 Blood culture acquisition is a simple and basic diagnostic procedure routinely used in clinical practice that yields essential information for the evaluation of various infectious diseases.6 Positive blood cultures can demonstrate not only an infectious cause of disease but also the microbiological response to antibiotic therapy.7 However, studies have reported that 35% to 50% of positive blood cultures are falsely positive owing to contamination.711 False‐positive cultures may lead to the use of inappropriate or unnecessary antibiotics, additional testing and consultation, and prolonged hospitalizations that increase patient care costs.9, 12

Nursing staff caring for patients are generally able to assess oral intake, general clinical state, and care requirements. Moreover, the nursing staff are often able to identify problems with patients before physicians.13 In Japan, nurse‐assessed food consumption of every meal is standardized, and is frequently regarded as an indicator of the patient's clinical status, akin to a vital sign. In this context, we hypothesized that quantitative variations in food consumption could accurately distinguish those patients with or without bacteremia.

MATERIALS AND METHODS

RESULTS

During the study period, 851 patients aged 16 to 99 years (66.8 16.6), were eligible for inclusion (Figure 1). Baseline characteristics of the subjects are given in Table 1. The mean body temperature ( standard deviation [SD]) was 38.1 1.1C, and the mean CRP level was 8.7 8.1 mg/dL. The results show that the patients had at least 2 SIRS criteria with elevations in temperature and heart rate. Of the 851 patients entered into the study, only 122 (14.3%) had positive blood cultures. Of these, 75 patients (8.8%) were considered to have true‐positive blood culture. In this study, blood cultures were taken at the time of onset of fever, whether that was a new inpatient admission, or during the course of an admission to the hospital. On average, blood cultures were drawn 12 days after admission (SD, 5.6 days). Despite the variation in onset of fever, the inverse relationship of blood culture positivity to decreased food consumption held true (data not shown). Gram‐positive and Gram‐negative organisms were obtained in near equal amounts. The main pathogens recovered from the true‐positive blood cultures were Gram‐positive cocci (26 patients [34.7% in true‐positive blood cultures]), and Gram‐negative bacilli (46 patients [61.3%]), as shown in Table 1. The underlying clinical diagnosis included 28 urinary tract infections; 9 catheter‐associated infections; 5 cases each of pneumonia and abscess; 3 cases of phlebitis; 2 cases of meningitis and osteomyelitis; 1 case each of infective endocarditis, decubitus ulcer, and pelvic infection; and 17 cases of infection with an unknown focus.

Figure 1

Low, moderate, and high food consumption groups consisted of 344 patients (40.4%), 152 patients (17.9%), and 354 patients (41.7%), respectively (Table 1). Of these, 63 patients, 6 patients, and 6 patients had bacteremia in the low, moderate, and high food consumption group, respectively. In order to distinguish those patients who had decreased food consumption compared to almost normal food consumption, low and moderate food consumption groups were combined and compared to the high food consumption group. Comparison of the combined low and moderate food consumption group versus the high food consumption group revealed a sensitivity of 92.0% and a negative predictive value of 98.3% for excluding true bacteremia. Conversely, the specificity (45.1%) and the positive predictive value (13.9%) were poor.

In the univariate analysis, the following variables were not statistically significantly associated with true bacteremia: age, heart rate, and leukocyte counts. Significant univariate predictors of bacteremia and their associated cut‐off points were body temperature of 36 or 38C (odds ratio [OR], 2.5; 95% CI, 1.54.4), CRP 10.0 mg/dL (OR, 2.0; 95% CI, 1.23.2), and food consumption (OR, 8.5; 95% CI, 3.818.6) (Table 2). There was no evidence of colinearity. In the final stepwise logistic regression (Table 3), the significant predictors of bacteremia were body temperature of 36 or 38C (OR, 2.4; 95% CI, 1.44.2; P = 0.002), C‐reactive protein of 10.0 mg/dL (OR, 1.9; 95% CI, 1.23.0; P = 0.011), and food consumption (OR, 7.5; 95% CI, 3.416.6; P < 0.001). We identified only 6 patients with bacteremia in the high food consumption group. Three of the patients had been previously treated with antibiotics for conditions including infective endocarditis, osteomyelitis, and myelodysplasic syndrome.

On further analysis, we excluded patients who had received antibiotics before blood culture acquisition. There were 661 patients in this subanalysis. Low, moderate, and high food consumption groups consisted of 282 patients (41.4%), 118 patients (17.3%), and 261 patients (38.3%), respectively. Of these, 50 patients (17.7%), 5 patients (4.2%), and 4 patients (1.5%) had bacteremia in the low, moderate, and high food consumption groups, respectively. The sensitivity and negative predictive values were 93.2% and 98.5%, respectively. In the stepwise logistic regression, significant predictors of bacteremia were body temperature of 36 or 38C (OR, 3.0; 95% CI, 1.55.6; P = 0.001), CRP 10.0 mg/dL (OR, 2.1; 95% CI, 1.23.7; P = 0.006), and food consumption (OR, 9.3; 95% CI, 3.326.1; P < 0.001).

DISCUSSION

We found that in a group of 851 Japanese patients who were suspected with bacterial infection, the estimated food consumption was negatively associated, both significantly and independently, with the subsequent isolation of microorganisms from their blood cultures. If validated in other studies, this simple rule of thumb can provide the clinician with reasonable confidence that a febrile patient has a low probability of being bacteremic, as long as the appetite remains normal. Both the sensitivity and the negative predictive value were extremely high at 92.3% and 98.3%, respectively, suggesting that adequate oral intake is a strong marker against the presence of bacteremia. In this study, it was the strongest predictor of bacteremia in multivariate analysis. After including only antibiotic‐naive patients, the sensitivity and the negative predictive values were 93.2% and 98.5%, respectively. Administration of antibiotics may lead to improved appetite in febrile patients despite bacteremia in the presence of fever, and therefore, inquiring about recent or current antimicrobial usage should be a requirement when considering oral intake as an indicator of bacteremia.

Our study has limitations. Since we did not make treatment decisions based on oral intake, we cannot conclude that it is safe to withhold antibiotic treatment on the basis of food intake alone. Additionally, this study would need to be repeated across many different age groups and racial groups to ensure applicability to the general population. It is also unknown whether this rule would be applicable to patients with underlying immunosuppression. Finally, although inter‐rater reliability was high in our center, nurses in other settings may not be as diligent in their assessment of food consumption. The high inter‐assessor reliability in our setting, however, suggests that objective assessment of food intake can be performed reliably in settings in which accurate documentation of food consumption is expected.

In summary, we found that normal food intake was strongly and negatively associated with bacteremia in febrile patients. This observation, if validated in other settings, may serve as a simple aid to assist in the clinical diagnosis of bacteremia or for recruitment of patients with a high likelihood of bacteremia into clinical trials.

Fever is a nonspecific phenomenon that can result from many inciting causes such as infection, inflammation, malignancy, thromboembolic disease, drugs, and endocrine disease. In hospitalized patients, one of the most important clinical considerations is bacteremia. Although vital signs compose 3 of the 4 current criteria for the diagnosis of Systemic Inflammatory Response Syndrome (SIRS),1, 2 they contribute little to the diagnosis of the cause, which can be inflammation or infection. Unfortunately, the physician's clinical diagnosis of bacteremia lacks both sensitivity and specificity.35 Blood culture acquisition is a simple and basic diagnostic procedure routinely used in clinical practice that yields essential information for the evaluation of various infectious diseases.6 Positive blood cultures can demonstrate not only an infectious cause of disease but also the microbiological response to antibiotic therapy.7 However, studies have reported that 35% to 50% of positive blood cultures are falsely positive owing to contamination.711 False‐positive cultures may lead to the use of inappropriate or unnecessary antibiotics, additional testing and consultation, and prolonged hospitalizations that increase patient care costs.9, 12

Nursing staff caring for patients are generally able to assess oral intake, general clinical state, and care requirements. Moreover, the nursing staff are often able to identify problems with patients before physicians.13 In Japan, nurse‐assessed food consumption of every meal is standardized, and is frequently regarded as an indicator of the patient's clinical status, akin to a vital sign. In this context, we hypothesized that quantitative variations in food consumption could accurately distinguish those patients with or without bacteremia.

MATERIALS AND METHODS

RESULTS

During the study period, 851 patients aged 16 to 99 years (66.8 16.6), were eligible for inclusion (Figure 1). Baseline characteristics of the subjects are given in Table 1. The mean body temperature ( standard deviation [SD]) was 38.1 1.1C, and the mean CRP level was 8.7 8.1 mg/dL. The results show that the patients had at least 2 SIRS criteria with elevations in temperature and heart rate. Of the 851 patients entered into the study, only 122 (14.3%) had positive blood cultures. Of these, 75 patients (8.8%) were considered to have true‐positive blood culture. In this study, blood cultures were taken at the time of onset of fever, whether that was a new inpatient admission, or during the course of an admission to the hospital. On average, blood cultures were drawn 12 days after admission (SD, 5.6 days). Despite the variation in onset of fever, the inverse relationship of blood culture positivity to decreased food consumption held true (data not shown). Gram‐positive and Gram‐negative organisms were obtained in near equal amounts. The main pathogens recovered from the true‐positive blood cultures were Gram‐positive cocci (26 patients [34.7% in true‐positive blood cultures]), and Gram‐negative bacilli (46 patients [61.3%]), as shown in Table 1. The underlying clinical diagnosis included 28 urinary tract infections; 9 catheter‐associated infections; 5 cases each of pneumonia and abscess; 3 cases of phlebitis; 2 cases of meningitis and osteomyelitis; 1 case each of infective endocarditis, decubitus ulcer, and pelvic infection; and 17 cases of infection with an unknown focus.

Figure 1

Low, moderate, and high food consumption groups consisted of 344 patients (40.4%), 152 patients (17.9%), and 354 patients (41.7%), respectively (Table 1). Of these, 63 patients, 6 patients, and 6 patients had bacteremia in the low, moderate, and high food consumption group, respectively. In order to distinguish those patients who had decreased food consumption compared to almost normal food consumption, low and moderate food consumption groups were combined and compared to the high food consumption group. Comparison of the combined low and moderate food consumption group versus the high food consumption group revealed a sensitivity of 92.0% and a negative predictive value of 98.3% for excluding true bacteremia. Conversely, the specificity (45.1%) and the positive predictive value (13.9%) were poor.

In the univariate analysis, the following variables were not statistically significantly associated with true bacteremia: age, heart rate, and leukocyte counts. Significant univariate predictors of bacteremia and their associated cut‐off points were body temperature of 36 or 38C (odds ratio [OR], 2.5; 95% CI, 1.54.4), CRP 10.0 mg/dL (OR, 2.0; 95% CI, 1.23.2), and food consumption (OR, 8.5; 95% CI, 3.818.6) (Table 2). There was no evidence of colinearity. In the final stepwise logistic regression (Table 3), the significant predictors of bacteremia were body temperature of 36 or 38C (OR, 2.4; 95% CI, 1.44.2; P = 0.002), C‐reactive protein of 10.0 mg/dL (OR, 1.9; 95% CI, 1.23.0; P = 0.011), and food consumption (OR, 7.5; 95% CI, 3.416.6; P < 0.001). We identified only 6 patients with bacteremia in the high food consumption group. Three of the patients had been previously treated with antibiotics for conditions including infective endocarditis, osteomyelitis, and myelodysplasic syndrome.

On further analysis, we excluded patients who had received antibiotics before blood culture acquisition. There were 661 patients in this subanalysis. Low, moderate, and high food consumption groups consisted of 282 patients (41.4%), 118 patients (17.3%), and 261 patients (38.3%), respectively. Of these, 50 patients (17.7%), 5 patients (4.2%), and 4 patients (1.5%) had bacteremia in the low, moderate, and high food consumption groups, respectively. The sensitivity and negative predictive values were 93.2% and 98.5%, respectively. In the stepwise logistic regression, significant predictors of bacteremia were body temperature of 36 or 38C (OR, 3.0; 95% CI, 1.55.6; P = 0.001), CRP 10.0 mg/dL (OR, 2.1; 95% CI, 1.23.7; P = 0.006), and food consumption (OR, 9.3; 95% CI, 3.326.1; P < 0.001).

DISCUSSION

We found that in a group of 851 Japanese patients who were suspected with bacterial infection, the estimated food consumption was negatively associated, both significantly and independently, with the subsequent isolation of microorganisms from their blood cultures. If validated in other studies, this simple rule of thumb can provide the clinician with reasonable confidence that a febrile patient has a low probability of being bacteremic, as long as the appetite remains normal. Both the sensitivity and the negative predictive value were extremely high at 92.3% and 98.3%, respectively, suggesting that adequate oral intake is a strong marker against the presence of bacteremia. In this study, it was the strongest predictor of bacteremia in multivariate analysis. After including only antibiotic‐naive patients, the sensitivity and the negative predictive values were 93.2% and 98.5%, respectively. Administration of antibiotics may lead to improved appetite in febrile patients despite bacteremia in the presence of fever, and therefore, inquiring about recent or current antimicrobial usage should be a requirement when considering oral intake as an indicator of bacteremia.

Our study has limitations. Since we did not make treatment decisions based on oral intake, we cannot conclude that it is safe to withhold antibiotic treatment on the basis of food intake alone. Additionally, this study would need to be repeated across many different age groups and racial groups to ensure applicability to the general population. It is also unknown whether this rule would be applicable to patients with underlying immunosuppression. Finally, although inter‐rater reliability was high in our center, nurses in other settings may not be as diligent in their assessment of food consumption. The high inter‐assessor reliability in our setting, however, suggests that objective assessment of food intake can be performed reliably in settings in which accurate documentation of food consumption is expected.

In summary, we found that normal food intake was strongly and negatively associated with bacteremia in febrile patients. This observation, if validated in other settings, may serve as a simple aid to assist in the clinical diagnosis of bacteremia or for recruitment of patients with a high likelihood of bacteremia into clinical trials.

Fever is a nonspecific phenomenon that can result from many inciting causes such as infection, inflammation, malignancy, thromboembolic disease, drugs, and endocrine disease. In hospitalized patients, one of the most important clinical considerations is bacteremia. Although vital signs compose 3 of the 4 current criteria for the diagnosis of Systemic Inflammatory Response Syndrome (SIRS),1, 2 they contribute little to the diagnosis of the cause, which can be inflammation or infection. Unfortunately, the physician's clinical diagnosis of bacteremia lacks both sensitivity and specificity.35 Blood culture acquisition is a simple and basic diagnostic procedure routinely used in clinical practice that yields essential information for the evaluation of various infectious diseases.6 Positive blood cultures can demonstrate not only an infectious cause of disease but also the microbiological response to antibiotic therapy.7 However, studies have reported that 35% to 50% of positive blood cultures are falsely positive owing to contamination.711 False‐positive cultures may lead to the use of inappropriate or unnecessary antibiotics, additional testing and consultation, and prolonged hospitalizations that increase patient care costs.9, 12

Nursing staff caring for patients are generally able to assess oral intake, general clinical state, and care requirements. Moreover, the nursing staff are often able to identify problems with patients before physicians.13 In Japan, nurse‐assessed food consumption of every meal is standardized, and is frequently regarded as an indicator of the patient's clinical status, akin to a vital sign. In this context, we hypothesized that quantitative variations in food consumption could accurately distinguish those patients with or without bacteremia.

MATERIALS AND METHODS

RESULTS

During the study period, 851 patients aged 16 to 99 years (66.8 16.6), were eligible for inclusion (Figure 1). Baseline characteristics of the subjects are given in Table 1. The mean body temperature ( standard deviation [SD]) was 38.1 1.1C, and the mean CRP level was 8.7 8.1 mg/dL. The results show that the patients had at least 2 SIRS criteria with elevations in temperature and heart rate. Of the 851 patients entered into the study, only 122 (14.3%) had positive blood cultures. Of these, 75 patients (8.8%) were considered to have true‐positive blood culture. In this study, blood cultures were taken at the time of onset of fever, whether that was a new inpatient admission, or during the course of an admission to the hospital. On average, blood cultures were drawn 12 days after admission (SD, 5.6 days). Despite the variation in onset of fever, the inverse relationship of blood culture positivity to decreased food consumption held true (data not shown). Gram‐positive and Gram‐negative organisms were obtained in near equal amounts. The main pathogens recovered from the true‐positive blood cultures were Gram‐positive cocci (26 patients [34.7% in true‐positive blood cultures]), and Gram‐negative bacilli (46 patients [61.3%]), as shown in Table 1. The underlying clinical diagnosis included 28 urinary tract infections; 9 catheter‐associated infections; 5 cases each of pneumonia and abscess; 3 cases of phlebitis; 2 cases of meningitis and osteomyelitis; 1 case each of infective endocarditis, decubitus ulcer, and pelvic infection; and 17 cases of infection with an unknown focus.

Figure 1

Low, moderate, and high food consumption groups consisted of 344 patients (40.4%), 152 patients (17.9%), and 354 patients (41.7%), respectively (Table 1). Of these, 63 patients, 6 patients, and 6 patients had bacteremia in the low, moderate, and high food consumption group, respectively. In order to distinguish those patients who had decreased food consumption compared to almost normal food consumption, low and moderate food consumption groups were combined and compared to the high food consumption group. Comparison of the combined low and moderate food consumption group versus the high food consumption group revealed a sensitivity of 92.0% and a negative predictive value of 98.3% for excluding true bacteremia. Conversely, the specificity (45.1%) and the positive predictive value (13.9%) were poor.

In the univariate analysis, the following variables were not statistically significantly associated with true bacteremia: age, heart rate, and leukocyte counts. Significant univariate predictors of bacteremia and their associated cut‐off points were body temperature of 36 or 38C (odds ratio [OR], 2.5; 95% CI, 1.54.4), CRP 10.0 mg/dL (OR, 2.0; 95% CI, 1.23.2), and food consumption (OR, 8.5; 95% CI, 3.818.6) (Table 2). There was no evidence of colinearity. In the final stepwise logistic regression (Table 3), the significant predictors of bacteremia were body temperature of 36 or 38C (OR, 2.4; 95% CI, 1.44.2; P = 0.002), C‐reactive protein of 10.0 mg/dL (OR, 1.9; 95% CI, 1.23.0; P = 0.011), and food consumption (OR, 7.5; 95% CI, 3.416.6; P < 0.001). We identified only 6 patients with bacteremia in the high food consumption group. Three of the patients had been previously treated with antibiotics for conditions including infective endocarditis, osteomyelitis, and myelodysplasic syndrome.

On further analysis, we excluded patients who had received antibiotics before blood culture acquisition. There were 661 patients in this subanalysis. Low, moderate, and high food consumption groups consisted of 282 patients (41.4%), 118 patients (17.3%), and 261 patients (38.3%), respectively. Of these, 50 patients (17.7%), 5 patients (4.2%), and 4 patients (1.5%) had bacteremia in the low, moderate, and high food consumption groups, respectively. The sensitivity and negative predictive values were 93.2% and 98.5%, respectively. In the stepwise logistic regression, significant predictors of bacteremia were body temperature of 36 or 38C (OR, 3.0; 95% CI, 1.55.6; P = 0.001), CRP 10.0 mg/dL (OR, 2.1; 95% CI, 1.23.7; P = 0.006), and food consumption (OR, 9.3; 95% CI, 3.326.1; P < 0.001).

DISCUSSION

We found that in a group of 851 Japanese patients who were suspected with bacterial infection, the estimated food consumption was negatively associated, both significantly and independently, with the subsequent isolation of microorganisms from their blood cultures. If validated in other studies, this simple rule of thumb can provide the clinician with reasonable confidence that a febrile patient has a low probability of being bacteremic, as long as the appetite remains normal. Both the sensitivity and the negative predictive value were extremely high at 92.3% and 98.3%, respectively, suggesting that adequate oral intake is a strong marker against the presence of bacteremia. In this study, it was the strongest predictor of bacteremia in multivariate analysis. After including only antibiotic‐naive patients, the sensitivity and the negative predictive values were 93.2% and 98.5%, respectively. Administration of antibiotics may lead to improved appetite in febrile patients despite bacteremia in the presence of fever, and therefore, inquiring about recent or current antimicrobial usage should be a requirement when considering oral intake as an indicator of bacteremia.

Our study has limitations. Since we did not make treatment decisions based on oral intake, we cannot conclude that it is safe to withhold antibiotic treatment on the basis of food intake alone. Additionally, this study would need to be repeated across many different age groups and racial groups to ensure applicability to the general population. It is also unknown whether this rule would be applicable to patients with underlying immunosuppression. Finally, although inter‐rater reliability was high in our center, nurses in other settings may not be as diligent in their assessment of food consumption. The high inter‐assessor reliability in our setting, however, suggests that objective assessment of food intake can be performed reliably in settings in which accurate documentation of food consumption is expected.

In summary, we found that normal food intake was strongly and negatively associated with bacteremia in febrile patients. This observation, if validated in other settings, may serve as a simple aid to assist in the clinical diagnosis of bacteremia or for recruitment of patients with a high likelihood of bacteremia into clinical trials.

A 19‐year‐old Japanese man was admitted to a hospital near Kyoto, Japan, because of fever and rash. Two weeks prior to admission, he developed mild headache and low‐grade fever; a rapid test for influenza was negative. His symptoms transiently improved with acetaminophen, but 8 days prior to admission, he developed fever to 38.5C and a pruritic maculopapular rash over his back that spread to his limbs. Six days prior to admission, a chest radiograph was clear; clarithromycin was prescribed for presumed upper respiratory infection. He visited the emergency department the day before admission because of continued fever of greater than 39C, fatigue, and headache. Because there was no jolt accentuation of the headache (ie, worsening with rapid horizontal rotation), or neck pain with extreme neck flexion, he was discharged on acetaminophen. He returned the next day with worsening fatigue and was admitted. He denied chills, rigor, weight loss, photosensitivity, sore throat, neck pain, cough, dyspnea, chest pain, nausea, vomiting, diarrhea, abdominal pain, back pain, and arthralgia.

Fever and diffuse rash are often due to infection, although drugs, autoimmune processes, and cancer must be considered. The presence of headache does not focus the differential diagnosis substantially, because many of the candidate diagnoses can be accompanied by meningitis or encephalitis, or even more frequently, nonspecific headaches. In one small study, jolt‐induced aggravation of headache was shown to be a sensitive indicator of cerebrospinal fluid pleocytosis. The absence of neck stiffness and the 2‐week duration makes bacterial meningitis unlikely, but a more indolent form of aseptic meningitis may need to be evaluated with a lumbar puncture.

The 2‐week illness without rapid deterioration makes some serious causes of fever and rash, such as toxic shock syndrome, disseminated meningococcal infection, or toxic epidermal necrolysis unlikely. A viral exanthema is possible, although the 2‐week duration is longer than usual. Given his youth, however, his immunization history should be queried, and acute infection with human immunodeficiency virus (HIV) should be considered. A more indolent infection, such as subacute bacterial endocarditis, disseminated gonococcal infection, or syphilis is plausible. Among autoimmune etiologies, systemic lupus erythematosus (SLE) and Behcet's disease (which is prevalent in Japan) can involve the central nervous system and cause fever. A careful inquiry directed at prescribed, complementary, and illicit drugs is required.

The patient's past medical history was notable only for mumps at the age of 10. His medications included acetaminophen, clarithromycin, and an herbal medicine, which he had been taking for the prior several days. He reported no tobacco or illicit drug use and rarely drank alcohol. He had never been sexually active. He worked in a factory and reported occasional contact with silver. He lived with his parents; there was no family history of tuberculosis or connective tissue diseases. His father was from Kyushu (the southernmost major island in Japan) and had chronic hepatitis C. The patient denied recent animal exposure or recent travel. His childhood vaccinations were said to be up to date.

Mumps at age 10 might signal general lack of immunization, in which case childhood viral exanthema‐like measles (characterized by fever, headache, and diffuse rash) would warrant consideration. The listed medications had been started after the onset of illness and therefore are unlikely to be causal. Silver causes at least 2 skin conditionscontact dermatitis and argyriabut not the systemic illness seen here. Human T lymphotropic virus‐1 (HTLV‐1) is endemic in southern Japan, but only a minority of infected humans are afflicted with associated adult T cell leukemia/lymphoma or myelopathy. Leukemia and lymphoma are the most likely cancers to cause fever, rash, and central nervous system involvement (with T cell disorders demonstrating a particular tropism for the skin). Overall, however, the differential has not changed substantially.

On physical examination, the patient was mildly overweight and appeared acutely ill. His blood pressure was 136/78 mm Hg, pulse rate was 76 and regular, temperature was 39.2C and respiratory rate was 20 with an oxygen saturation of 98% on room air. A diffuse but nonconfluent erythematous maculopapular rash was present over his chest wall, back, medial aspects of both thighs, and around the knees. There was no jolt‐induced headache. His eyes, nose, oral cavity, and throat were all clear. The neck was supple. There were palpable lymph nodes, each about 1 cm in size, which were firm and moderately tender, in his left neck and left axilla. Lungs and heart were normal. The abdomen was soft, nontender, with normal bowel sounds and no hepatosplenomegaly. His genitalia were normal. Rectal examination revealed no masses or tenderness and a scant amount of brown stool that was negative for occult blood. Neurologic examination was unremarkable.

The multifocal lymphadenopathy does not help distinguish among the categories of disease under consideration. The diffuse maculopapular rash is similarly nonspecific, occurring more frequently with infection and drug reaction than malignancy and autoimmunity. Acute HIV, Epstein‐Barr virus (EBV), syphilis, SLE, drug exposure, or a hematologic malignancy would all be suitable explanations for fever, headache, diffuse rash, and disseminated lymphadenopathy in a previously healthy young man.

Laboratory data obtained on admission was notable for a white blood cell (WBC) count of 2100/L with 72% neutrophils, 19% lymphocytes, and 9% monocytes. Hemoglobin was 13.5 mg/dL with a mean corpuscular volume of 85 fL. Platelet count was 136,000/L. Erythrocyte sedimentation rate was 26 mm/hour. Serum chemistries revealed a sodium level of 135 mEq/L, potassium level of 3.6 mEq/L, chloride level of 100 mEq/L, blood urea nitrogen of 9.8 mg/dL, creatinine level of 1.0 mg/dL, glucose level of 101 mg/dL, calcium level of 8.8 mg/dL, albumin of 4.6 mg/dL, total protein of 8.4 mg/dL, aspartate aminotransferase of 42 IU/L (normal < 35 IU/L), alanine aminotransferase of 27 IU/L, total bilirubin of 0.5 mg/dL, and lactate dehydrogenase (LDH) level of 463 IU/L (normal < 260 IU/L). Chest radiography and electrocardiogram were normal.

A mild elevation in LDH is nonspecific, but without hemolysis or infarction of the kidney, lung, or muscle, it suggests a lymphoproliferative process. Leukopenia with thrombocytopenia can be seen in a number of disorders, most commonly infections including viruses (e.g., EBV, HIV, dengue), malaria, Rocky Mountain spotted fever, or ehrlichiosis/anaplasmosis. Confirmation of his lack of travel could help prioritize those considerations. An invasive bone marrow disorder cannot be excluded, although the near‐normal hemoglobin argues against it. Autoimmune cytopenias are seen in SLE. Given his age, lymphadenopathy, LDH elevation, and absence of infectious exposures, lymphoma rises to the top of the list.

Noninvasive measures should include examination of the peripheral smear, HIV testing (including HIV RNA for acute infection), EBV serologies, and tests for syphilis and SLE. Lumbar puncture (for evaluation of aseptic meningitis) and lymph node biopsy would be informative. Skin biopsy may be helpful to evaluate for aggressive T cell lymphoproliferative disorder, but this can await the results of initial testing.

The patient was given intravenous fluids and acetaminophen as needed. Blood cultures, urine culture, cytomegalovirus and EBV serologies, hepatitis B surface antigen, hepatitis C virus antibody, HIV antibody, antinuclear antibody, complement and ferritin levels, and quantiferon‐TB were ordered. The urine was normal and a urinary antigen test for Legionella was negative. Contrast‐enhanced computed tomography scan of the chest and abdomen was normal except for mild splenomegaly and an enlarged left axillary lymph node.

The ferritin may have been ordered to help evaluate for Still's disease, which is characterized by sustained fever, lymphadenopathy, and transient rash; however, the characteristic leukocytosis and arthralgias are absent. The computed tomography findings are most notable for the absence of generalized lymphadenopathy or significant hepatosplenomegaly that is seen in lymphoma, leukemia, and lymphotropic processes such as acute EBV infection. The localization of disease to the skin (where the predominant lymphocytes are of T cell origin) with relatively modest lymphadenopathy suggests a T cell lymphoma, perhaps of an indolent variety. Vertical transmission of HTLV‐1 decades ago would make adult T cell leukemia or lymphoma a major consideration.

On the third hospital day, WBC count was 1800/L with 67% neutrophils, 22% lymphocytes, and 1% atypical lymphocytes; LDH rose to 623 IU/L. He had continued fatigue and high fever while the rash gradually faded with oral antihistamines and steroid ointment. On hospital day 4, bone marrow biopsy and skin biopsy of his left thigh were performed.

The further decline in WBC and rise in LDH are modest and therefore do not significantly modify the differential diagnosis. Likewise, 1% atypical lymphocytosis is too low to pinpoint an etiology. Because unremitting fevers start to extend into their third week without a clear source of infection, the probability of malignancy and autoimmunity rise. Improvement with oral antihistamines and topical steroids frequently suggests an underlying allergic process, but the remainder of the clinical picture is not in keeping with atopy or allergy. Cutaneous lymphomas (eg, mycosis fungoides) can have waxing and waning skin manifestations, and can be temporarily or definitively treated by topical steroids. The persistence of his fatigue is of concern given the absence of anemia, cardiopulmonary involvement, or motor weakness.

Bone marrow biopsy showed normocellular marrow with no abnormal cells and some activated macrophages with hemophagocytic activity. Skin biopsy failed to show specific pathology.

His left cervical lymph nodes gradually enlarged. Ultrasound of the neck showed multiple enlarged lymph nodes (left side dominant) with dimension of 17 mm 9 mm 31 mm. Blood and urine cultures returned negative, as did HIV antibody. cytomegalovirus and EBV serologies were consistent with previous infection and the ferritin level was 578 ng/mL (normal, 39‐340 ng/mL). Toxoplasma serology and HTLV‐1 antibody were ordered.

The absence of malignant cells on bone marrow biopsy does not exclude lymphoma, but makes a myelophthisic cause of the cytopenias less likely. The macrophage hemophagocytosis reflects immune activation, which in turn is usually caused by the same viral infections, autoimmune conditions, and lymphoproliferative disorders which constitute the current differential diagnosis.

Bone marrow and skin biopsies are both subject to sampling error, and detection of cutaneous T cell lymphoma is notoriously difficult. However, taken together, the absence of cancer on 2 specimens reduces that possibility.

Sustained unilateral cervical lymphadenopathy with fever in a young Japanese man without any histologic evidence of lymphoma points to Kikuchi's disease, ie, lymphadenitis of unknown etiology associated with varying degrees of systemic manifestations. Fever is a frequent feature, we believe, but diffuse sustained rash, cytopenias, and headache are less common or are seen in severe forms of the disease. The diagnosis of Kikuchi's requires the diligent exclusion of SLE and lymphoma. Examination of the peripheral smear and a lymph node biopsy are required.

Of note, there is also a localized form of Castleman's disease, a nonmalignant lymphoproliferative disorder, that similarly is characterized by focal lymphadenopathy. In distinction to Kikuchi's, however, localized Castleman's is largely asymptomatic and responds marvelously to excision.

On hospital day 9, an excisional biopsy of his left anterior cervical lymph nodes was performed, which revealed paracortical foci with necrosis and a histiocytic cellular infiltrate consistent with subacute necrotizing lymphadenitis (Kikuchi‐Fujimoto disease). Antinuclear antibody, Toxoplasma, and HTLV‐1 antibodies returned negative.

There is no treatment for Kikuchi's. It is usually self‐limited, but steroids are sometimes given for symptomatic control.

His condition began to improve after hospital day 9 without specific treatment, including his WBC count and LDH level. He was discharged home on hospital day 15. In the outpatient clinic 1 and 3 months later, he was well and active without recurrences of any symptoms or laboratory abnormalities. His WBC count was 6600/L and LDH was 268 IU/L.

Commentary

Kikuchi‐Fujimoto disease (KFD), also called Kikuchi's disease, is a benign histiocytic necrotizing lymphadenitis described by both Kikuchi and Fujimoto in 1972.1, 2 It is rare in the United States, but seems more common in Asia, especially Japan, where at least 143 cases have been reported since 1972. The etiology has not been determined, but a viral causeincluding EBV, and human herpesvirus 6 and 8has been suggested.3 An autoimmune etiology is also implicated because of infrequent association with SLE. In general, young women are most likely to be affected. In a review of 244 cases by Kucukardali and colleagues, 77% of patients were female and the mean age was 25; 70% were younger than 30 years of age.4

The common presentation is low‐grade fever with unilateral cervical lymphadenopathy.4 Although generalized lymphadenopathy can occur, it is rare. Other common clinical manifestations include malaise, joint pain, rash, arthritis, and hepatosplenomegaly. No specific laboratory tests for diagnosis are available, but leukopenia (seen in 43% of patients), increased erythrocyte sedimentation rate (40%), and anemia (23%) may be observed.4 In this case, atypical lymphocytes were seen, and are reported in one‐third of patients.5 KFD is generally diagnosed by lymph node biopsy, which typically shows irregular paracortical areas of coagulation necrosis that can distort the nodal architecture, while different types of histiocytes are observed at the margin of necrotic areas.

Other diseases in the differential diagnosisseveral of which were considered by the discussantinclude lymphoma, tuberculosis, SLE, and even metastatic adenocarcinoma. KFD is self‐limited; symptoms typically resolve within 1 to 4 months. Patients with severe manifestations have been treated with anti‐inflammatory drugs and glucocorticosteroids. A recurrence rate of 3% to 4% has been reported.6

The clinicians taking care of this patient initially focused on ruling out those infections occasionally resulting in prolonged fever in a previously healthy young man, such as viruses from the herpes family, HIV, viral hepatitis, tuberculosis, syphilis, infective endocarditis, and intra‐abdominal abscess. Physical examination, specifically lymphadenopathy and mild splenomegaly, made Herpesviridae infections, tuberculosis, syphilis, and lymphoma difficult to exclude. Once the initial evaluation ruled out common infections, attention focused on malignancy and histiocytic necrotizing lymphadenitis, given his ethnicity and geographic location.

The discussant was similarly concerned about infection, malignancy, and noninfectious inflammatory diseases, such as SLE, as possible causes. As evidence of these treatable diseases failed to accumulate, the discussant, an American physician with teaching and clinical experience in Japan, considered endemic diseases such as Behcet's, HTLV‐1, and KFD because they fit the unfolding pattern. Given our global society, clinicians will increasingly benefit from becoming familiar with the less common diseases that afflict the various populations around the world.

A 19‐year‐old Japanese man was admitted to a hospital near Kyoto, Japan, because of fever and rash. Two weeks prior to admission, he developed mild headache and low‐grade fever; a rapid test for influenza was negative. His symptoms transiently improved with acetaminophen, but 8 days prior to admission, he developed fever to 38.5C and a pruritic maculopapular rash over his back that spread to his limbs. Six days prior to admission, a chest radiograph was clear; clarithromycin was prescribed for presumed upper respiratory infection. He visited the emergency department the day before admission because of continued fever of greater than 39C, fatigue, and headache. Because there was no jolt accentuation of the headache (ie, worsening with rapid horizontal rotation), or neck pain with extreme neck flexion, he was discharged on acetaminophen. He returned the next day with worsening fatigue and was admitted. He denied chills, rigor, weight loss, photosensitivity, sore throat, neck pain, cough, dyspnea, chest pain, nausea, vomiting, diarrhea, abdominal pain, back pain, and arthralgia.

Fever and diffuse rash are often due to infection, although drugs, autoimmune processes, and cancer must be considered. The presence of headache does not focus the differential diagnosis substantially, because many of the candidate diagnoses can be accompanied by meningitis or encephalitis, or even more frequently, nonspecific headaches. In one small study, jolt‐induced aggravation of headache was shown to be a sensitive indicator of cerebrospinal fluid pleocytosis. The absence of neck stiffness and the 2‐week duration makes bacterial meningitis unlikely, but a more indolent form of aseptic meningitis may need to be evaluated with a lumbar puncture.

The 2‐week illness without rapid deterioration makes some serious causes of fever and rash, such as toxic shock syndrome, disseminated meningococcal infection, or toxic epidermal necrolysis unlikely. A viral exanthema is possible, although the 2‐week duration is longer than usual. Given his youth, however, his immunization history should be queried, and acute infection with human immunodeficiency virus (HIV) should be considered. A more indolent infection, such as subacute bacterial endocarditis, disseminated gonococcal infection, or syphilis is plausible. Among autoimmune etiologies, systemic lupus erythematosus (SLE) and Behcet's disease (which is prevalent in Japan) can involve the central nervous system and cause fever. A careful inquiry directed at prescribed, complementary, and illicit drugs is required.

The patient's past medical history was notable only for mumps at the age of 10. His medications included acetaminophen, clarithromycin, and an herbal medicine, which he had been taking for the prior several days. He reported no tobacco or illicit drug use and rarely drank alcohol. He had never been sexually active. He worked in a factory and reported occasional contact with silver. He lived with his parents; there was no family history of tuberculosis or connective tissue diseases. His father was from Kyushu (the southernmost major island in Japan) and had chronic hepatitis C. The patient denied recent animal exposure or recent travel. His childhood vaccinations were said to be up to date.

Mumps at age 10 might signal general lack of immunization, in which case childhood viral exanthema‐like measles (characterized by fever, headache, and diffuse rash) would warrant consideration. The listed medications had been started after the onset of illness and therefore are unlikely to be causal. Silver causes at least 2 skin conditionscontact dermatitis and argyriabut not the systemic illness seen here. Human T lymphotropic virus‐1 (HTLV‐1) is endemic in southern Japan, but only a minority of infected humans are afflicted with associated adult T cell leukemia/lymphoma or myelopathy. Leukemia and lymphoma are the most likely cancers to cause fever, rash, and central nervous system involvement (with T cell disorders demonstrating a particular tropism for the skin). Overall, however, the differential has not changed substantially.

On physical examination, the patient was mildly overweight and appeared acutely ill. His blood pressure was 136/78 mm Hg, pulse rate was 76 and regular, temperature was 39.2C and respiratory rate was 20 with an oxygen saturation of 98% on room air. A diffuse but nonconfluent erythematous maculopapular rash was present over his chest wall, back, medial aspects of both thighs, and around the knees. There was no jolt‐induced headache. His eyes, nose, oral cavity, and throat were all clear. The neck was supple. There were palpable lymph nodes, each about 1 cm in size, which were firm and moderately tender, in his left neck and left axilla. Lungs and heart were normal. The abdomen was soft, nontender, with normal bowel sounds and no hepatosplenomegaly. His genitalia were normal. Rectal examination revealed no masses or tenderness and a scant amount of brown stool that was negative for occult blood. Neurologic examination was unremarkable.

The multifocal lymphadenopathy does not help distinguish among the categories of disease under consideration. The diffuse maculopapular rash is similarly nonspecific, occurring more frequently with infection and drug reaction than malignancy and autoimmunity. Acute HIV, Epstein‐Barr virus (EBV), syphilis, SLE, drug exposure, or a hematologic malignancy would all be suitable explanations for fever, headache, diffuse rash, and disseminated lymphadenopathy in a previously healthy young man.

Laboratory data obtained on admission was notable for a white blood cell (WBC) count of 2100/L with 72% neutrophils, 19% lymphocytes, and 9% monocytes. Hemoglobin was 13.5 mg/dL with a mean corpuscular volume of 85 fL. Platelet count was 136,000/L. Erythrocyte sedimentation rate was 26 mm/hour. Serum chemistries revealed a sodium level of 135 mEq/L, potassium level of 3.6 mEq/L, chloride level of 100 mEq/L, blood urea nitrogen of 9.8 mg/dL, creatinine level of 1.0 mg/dL, glucose level of 101 mg/dL, calcium level of 8.8 mg/dL, albumin of 4.6 mg/dL, total protein of 8.4 mg/dL, aspartate aminotransferase of 42 IU/L (normal < 35 IU/L), alanine aminotransferase of 27 IU/L, total bilirubin of 0.5 mg/dL, and lactate dehydrogenase (LDH) level of 463 IU/L (normal < 260 IU/L). Chest radiography and electrocardiogram were normal.

A mild elevation in LDH is nonspecific, but without hemolysis or infarction of the kidney, lung, or muscle, it suggests a lymphoproliferative process. Leukopenia with thrombocytopenia can be seen in a number of disorders, most commonly infections including viruses (e.g., EBV, HIV, dengue), malaria, Rocky Mountain spotted fever, or ehrlichiosis/anaplasmosis. Confirmation of his lack of travel could help prioritize those considerations. An invasive bone marrow disorder cannot be excluded, although the near‐normal hemoglobin argues against it. Autoimmune cytopenias are seen in SLE. Given his age, lymphadenopathy, LDH elevation, and absence of infectious exposures, lymphoma rises to the top of the list.

Noninvasive measures should include examination of the peripheral smear, HIV testing (including HIV RNA for acute infection), EBV serologies, and tests for syphilis and SLE. Lumbar puncture (for evaluation of aseptic meningitis) and lymph node biopsy would be informative. Skin biopsy may be helpful to evaluate for aggressive T cell lymphoproliferative disorder, but this can await the results of initial testing.

The patient was given intravenous fluids and acetaminophen as needed. Blood cultures, urine culture, cytomegalovirus and EBV serologies, hepatitis B surface antigen, hepatitis C virus antibody, HIV antibody, antinuclear antibody, complement and ferritin levels, and quantiferon‐TB were ordered. The urine was normal and a urinary antigen test for Legionella was negative. Contrast‐enhanced computed tomography scan of the chest and abdomen was normal except for mild splenomegaly and an enlarged left axillary lymph node.

The ferritin may have been ordered to help evaluate for Still's disease, which is characterized by sustained fever, lymphadenopathy, and transient rash; however, the characteristic leukocytosis and arthralgias are absent. The computed tomography findings are most notable for the absence of generalized lymphadenopathy or significant hepatosplenomegaly that is seen in lymphoma, leukemia, and lymphotropic processes such as acute EBV infection. The localization of disease to the skin (where the predominant lymphocytes are of T cell origin) with relatively modest lymphadenopathy suggests a T cell lymphoma, perhaps of an indolent variety. Vertical transmission of HTLV‐1 decades ago would make adult T cell leukemia or lymphoma a major consideration.

On the third hospital day, WBC count was 1800/L with 67% neutrophils, 22% lymphocytes, and 1% atypical lymphocytes; LDH rose to 623 IU/L. He had continued fatigue and high fever while the rash gradually faded with oral antihistamines and steroid ointment. On hospital day 4, bone marrow biopsy and skin biopsy of his left thigh were performed.

The further decline in WBC and rise in LDH are modest and therefore do not significantly modify the differential diagnosis. Likewise, 1% atypical lymphocytosis is too low to pinpoint an etiology. Because unremitting fevers start to extend into their third week without a clear source of infection, the probability of malignancy and autoimmunity rise. Improvement with oral antihistamines and topical steroids frequently suggests an underlying allergic process, but the remainder of the clinical picture is not in keeping with atopy or allergy. Cutaneous lymphomas (eg, mycosis fungoides) can have waxing and waning skin manifestations, and can be temporarily or definitively treated by topical steroids. The persistence of his fatigue is of concern given the absence of anemia, cardiopulmonary involvement, or motor weakness.

Bone marrow biopsy showed normocellular marrow with no abnormal cells and some activated macrophages with hemophagocytic activity. Skin biopsy failed to show specific pathology.

His left cervical lymph nodes gradually enlarged. Ultrasound of the neck showed multiple enlarged lymph nodes (left side dominant) with dimension of 17 mm 9 mm 31 mm. Blood and urine cultures returned negative, as did HIV antibody. cytomegalovirus and EBV serologies were consistent with previous infection and the ferritin level was 578 ng/mL (normal, 39‐340 ng/mL). Toxoplasma serology and HTLV‐1 antibody were ordered.

The absence of malignant cells on bone marrow biopsy does not exclude lymphoma, but makes a myelophthisic cause of the cytopenias less likely. The macrophage hemophagocytosis reflects immune activation, which in turn is usually caused by the same viral infections, autoimmune conditions, and lymphoproliferative disorders which constitute the current differential diagnosis.

Bone marrow and skin biopsies are both subject to sampling error, and detection of cutaneous T cell lymphoma is notoriously difficult. However, taken together, the absence of cancer on 2 specimens reduces that possibility.

Sustained unilateral cervical lymphadenopathy with fever in a young Japanese man without any histologic evidence of lymphoma points to Kikuchi's disease, ie, lymphadenitis of unknown etiology associated with varying degrees of systemic manifestations. Fever is a frequent feature, we believe, but diffuse sustained rash, cytopenias, and headache are less common or are seen in severe forms of the disease. The diagnosis of Kikuchi's requires the diligent exclusion of SLE and lymphoma. Examination of the peripheral smear and a lymph node biopsy are required.

Of note, there is also a localized form of Castleman's disease, a nonmalignant lymphoproliferative disorder, that similarly is characterized by focal lymphadenopathy. In distinction to Kikuchi's, however, localized Castleman's is largely asymptomatic and responds marvelously to excision.

On hospital day 9, an excisional biopsy of his left anterior cervical lymph nodes was performed, which revealed paracortical foci with necrosis and a histiocytic cellular infiltrate consistent with subacute necrotizing lymphadenitis (Kikuchi‐Fujimoto disease). Antinuclear antibody, Toxoplasma, and HTLV‐1 antibodies returned negative.

There is no treatment for Kikuchi's. It is usually self‐limited, but steroids are sometimes given for symptomatic control.

His condition began to improve after hospital day 9 without specific treatment, including his WBC count and LDH level. He was discharged home on hospital day 15. In the outpatient clinic 1 and 3 months later, he was well and active without recurrences of any symptoms or laboratory abnormalities. His WBC count was 6600/L and LDH was 268 IU/L.

Commentary

Kikuchi‐Fujimoto disease (KFD), also called Kikuchi's disease, is a benign histiocytic necrotizing lymphadenitis described by both Kikuchi and Fujimoto in 1972.1, 2 It is rare in the United States, but seems more common in Asia, especially Japan, where at least 143 cases have been reported since 1972. The etiology has not been determined, but a viral causeincluding EBV, and human herpesvirus 6 and 8has been suggested.3 An autoimmune etiology is also implicated because of infrequent association with SLE. In general, young women are most likely to be affected. In a review of 244 cases by Kucukardali and colleagues, 77% of patients were female and the mean age was 25; 70% were younger than 30 years of age.4

The common presentation is low‐grade fever with unilateral cervical lymphadenopathy.4 Although generalized lymphadenopathy can occur, it is rare. Other common clinical manifestations include malaise, joint pain, rash, arthritis, and hepatosplenomegaly. No specific laboratory tests for diagnosis are available, but leukopenia (seen in 43% of patients), increased erythrocyte sedimentation rate (40%), and anemia (23%) may be observed.4 In this case, atypical lymphocytes were seen, and are reported in one‐third of patients.5 KFD is generally diagnosed by lymph node biopsy, which typically shows irregular paracortical areas of coagulation necrosis that can distort the nodal architecture, while different types of histiocytes are observed at the margin of necrotic areas.

Other diseases in the differential diagnosisseveral of which were considered by the discussantinclude lymphoma, tuberculosis, SLE, and even metastatic adenocarcinoma. KFD is self‐limited; symptoms typically resolve within 1 to 4 months. Patients with severe manifestations have been treated with anti‐inflammatory drugs and glucocorticosteroids. A recurrence rate of 3% to 4% has been reported.6

The clinicians taking care of this patient initially focused on ruling out those infections occasionally resulting in prolonged fever in a previously healthy young man, such as viruses from the herpes family, HIV, viral hepatitis, tuberculosis, syphilis, infective endocarditis, and intra‐abdominal abscess. Physical examination, specifically lymphadenopathy and mild splenomegaly, made Herpesviridae infections, tuberculosis, syphilis, and lymphoma difficult to exclude. Once the initial evaluation ruled out common infections, attention focused on malignancy and histiocytic necrotizing lymphadenitis, given his ethnicity and geographic location.

The discussant was similarly concerned about infection, malignancy, and noninfectious inflammatory diseases, such as SLE, as possible causes. As evidence of these treatable diseases failed to accumulate, the discussant, an American physician with teaching and clinical experience in Japan, considered endemic diseases such as Behcet's, HTLV‐1, and KFD because they fit the unfolding pattern. Given our global society, clinicians will increasingly benefit from becoming familiar with the less common diseases that afflict the various populations around the world.

A 19‐year‐old Japanese man was admitted to a hospital near Kyoto, Japan, because of fever and rash. Two weeks prior to admission, he developed mild headache and low‐grade fever; a rapid test for influenza was negative. His symptoms transiently improved with acetaminophen, but 8 days prior to admission, he developed fever to 38.5C and a pruritic maculopapular rash over his back that spread to his limbs. Six days prior to admission, a chest radiograph was clear; clarithromycin was prescribed for presumed upper respiratory infection. He visited the emergency department the day before admission because of continued fever of greater than 39C, fatigue, and headache. Because there was no jolt accentuation of the headache (ie, worsening with rapid horizontal rotation), or neck pain with extreme neck flexion, he was discharged on acetaminophen. He returned the next day with worsening fatigue and was admitted. He denied chills, rigor, weight loss, photosensitivity, sore throat, neck pain, cough, dyspnea, chest pain, nausea, vomiting, diarrhea, abdominal pain, back pain, and arthralgia.

Fever and diffuse rash are often due to infection, although drugs, autoimmune processes, and cancer must be considered. The presence of headache does not focus the differential diagnosis substantially, because many of the candidate diagnoses can be accompanied by meningitis or encephalitis, or even more frequently, nonspecific headaches. In one small study, jolt‐induced aggravation of headache was shown to be a sensitive indicator of cerebrospinal fluid pleocytosis. The absence of neck stiffness and the 2‐week duration makes bacterial meningitis unlikely, but a more indolent form of aseptic meningitis may need to be evaluated with a lumbar puncture.

The 2‐week illness without rapid deterioration makes some serious causes of fever and rash, such as toxic shock syndrome, disseminated meningococcal infection, or toxic epidermal necrolysis unlikely. A viral exanthema is possible, although the 2‐week duration is longer than usual. Given his youth, however, his immunization history should be queried, and acute infection with human immunodeficiency virus (HIV) should be considered. A more indolent infection, such as subacute bacterial endocarditis, disseminated gonococcal infection, or syphilis is plausible. Among autoimmune etiologies, systemic lupus erythematosus (SLE) and Behcet's disease (which is prevalent in Japan) can involve the central nervous system and cause fever. A careful inquiry directed at prescribed, complementary, and illicit drugs is required.

The patient's past medical history was notable only for mumps at the age of 10. His medications included acetaminophen, clarithromycin, and an herbal medicine, which he had been taking for the prior several days. He reported no tobacco or illicit drug use and rarely drank alcohol. He had never been sexually active. He worked in a factory and reported occasional contact with silver. He lived with his parents; there was no family history of tuberculosis or connective tissue diseases. His father was from Kyushu (the southernmost major island in Japan) and had chronic hepatitis C. The patient denied recent animal exposure or recent travel. His childhood vaccinations were said to be up to date.

Mumps at age 10 might signal general lack of immunization, in which case childhood viral exanthema‐like measles (characterized by fever, headache, and diffuse rash) would warrant consideration. The listed medications had been started after the onset of illness and therefore are unlikely to be causal. Silver causes at least 2 skin conditionscontact dermatitis and argyriabut not the systemic illness seen here. Human T lymphotropic virus‐1 (HTLV‐1) is endemic in southern Japan, but only a minority of infected humans are afflicted with associated adult T cell leukemia/lymphoma or myelopathy. Leukemia and lymphoma are the most likely cancers to cause fever, rash, and central nervous system involvement (with T cell disorders demonstrating a particular tropism for the skin). Overall, however, the differential has not changed substantially.

On physical examination, the patient was mildly overweight and appeared acutely ill. His blood pressure was 136/78 mm Hg, pulse rate was 76 and regular, temperature was 39.2C and respiratory rate was 20 with an oxygen saturation of 98% on room air. A diffuse but nonconfluent erythematous maculopapular rash was present over his chest wall, back, medial aspects of both thighs, and around the knees. There was no jolt‐induced headache. His eyes, nose, oral cavity, and throat were all clear. The neck was supple. There were palpable lymph nodes, each about 1 cm in size, which were firm and moderately tender, in his left neck and left axilla. Lungs and heart were normal. The abdomen was soft, nontender, with normal bowel sounds and no hepatosplenomegaly. His genitalia were normal. Rectal examination revealed no masses or tenderness and a scant amount of brown stool that was negative for occult blood. Neurologic examination was unremarkable.

The multifocal lymphadenopathy does not help distinguish among the categories of disease under consideration. The diffuse maculopapular rash is similarly nonspecific, occurring more frequently with infection and drug reaction than malignancy and autoimmunity. Acute HIV, Epstein‐Barr virus (EBV), syphilis, SLE, drug exposure, or a hematologic malignancy would all be suitable explanations for fever, headache, diffuse rash, and disseminated lymphadenopathy in a previously healthy young man.

Laboratory data obtained on admission was notable for a white blood cell (WBC) count of 2100/L with 72% neutrophils, 19% lymphocytes, and 9% monocytes. Hemoglobin was 13.5 mg/dL with a mean corpuscular volume of 85 fL. Platelet count was 136,000/L. Erythrocyte sedimentation rate was 26 mm/hour. Serum chemistries revealed a sodium level of 135 mEq/L, potassium level of 3.6 mEq/L, chloride level of 100 mEq/L, blood urea nitrogen of 9.8 mg/dL, creatinine level of 1.0 mg/dL, glucose level of 101 mg/dL, calcium level of 8.8 mg/dL, albumin of 4.6 mg/dL, total protein of 8.4 mg/dL, aspartate aminotransferase of 42 IU/L (normal < 35 IU/L), alanine aminotransferase of 27 IU/L, total bilirubin of 0.5 mg/dL, and lactate dehydrogenase (LDH) level of 463 IU/L (normal < 260 IU/L). Chest radiography and electrocardiogram were normal.

A mild elevation in LDH is nonspecific, but without hemolysis or infarction of the kidney, lung, or muscle, it suggests a lymphoproliferative process. Leukopenia with thrombocytopenia can be seen in a number of disorders, most commonly infections including viruses (e.g., EBV, HIV, dengue), malaria, Rocky Mountain spotted fever, or ehrlichiosis/anaplasmosis. Confirmation of his lack of travel could help prioritize those considerations. An invasive bone marrow disorder cannot be excluded, although the near‐normal hemoglobin argues against it. Autoimmune cytopenias are seen in SLE. Given his age, lymphadenopathy, LDH elevation, and absence of infectious exposures, lymphoma rises to the top of the list.

Noninvasive measures should include examination of the peripheral smear, HIV testing (including HIV RNA for acute infection), EBV serologies, and tests for syphilis and SLE. Lumbar puncture (for evaluation of aseptic meningitis) and lymph node biopsy would be informative. Skin biopsy may be helpful to evaluate for aggressive T cell lymphoproliferative disorder, but this can await the results of initial testing.

The patient was given intravenous fluids and acetaminophen as needed. Blood cultures, urine culture, cytomegalovirus and EBV serologies, hepatitis B surface antigen, hepatitis C virus antibody, HIV antibody, antinuclear antibody, complement and ferritin levels, and quantiferon‐TB were ordered. The urine was normal and a urinary antigen test for Legionella was negative. Contrast‐enhanced computed tomography scan of the chest and abdomen was normal except for mild splenomegaly and an enlarged left axillary lymph node.

The ferritin may have been ordered to help evaluate for Still's disease, which is characterized by sustained fever, lymphadenopathy, and transient rash; however, the characteristic leukocytosis and arthralgias are absent. The computed tomography findings are most notable for the absence of generalized lymphadenopathy or significant hepatosplenomegaly that is seen in lymphoma, leukemia, and lymphotropic processes such as acute EBV infection. The localization of disease to the skin (where the predominant lymphocytes are of T cell origin) with relatively modest lymphadenopathy suggests a T cell lymphoma, perhaps of an indolent variety. Vertical transmission of HTLV‐1 decades ago would make adult T cell leukemia or lymphoma a major consideration.

On the third hospital day, WBC count was 1800/L with 67% neutrophils, 22% lymphocytes, and 1% atypical lymphocytes; LDH rose to 623 IU/L. He had continued fatigue and high fever while the rash gradually faded with oral antihistamines and steroid ointment. On hospital day 4, bone marrow biopsy and skin biopsy of his left thigh were performed.

The further decline in WBC and rise in LDH are modest and therefore do not significantly modify the differential diagnosis. Likewise, 1% atypical lymphocytosis is too low to pinpoint an etiology. Because unremitting fevers start to extend into their third week without a clear source of infection, the probability of malignancy and autoimmunity rise. Improvement with oral antihistamines and topical steroids frequently suggests an underlying allergic process, but the remainder of the clinical picture is not in keeping with atopy or allergy. Cutaneous lymphomas (eg, mycosis fungoides) can have waxing and waning skin manifestations, and can be temporarily or definitively treated by topical steroids. The persistence of his fatigue is of concern given the absence of anemia, cardiopulmonary involvement, or motor weakness.

Bone marrow biopsy showed normocellular marrow with no abnormal cells and some activated macrophages with hemophagocytic activity. Skin biopsy failed to show specific pathology.

His left cervical lymph nodes gradually enlarged. Ultrasound of the neck showed multiple enlarged lymph nodes (left side dominant) with dimension of 17 mm 9 mm 31 mm. Blood and urine cultures returned negative, as did HIV antibody. cytomegalovirus and EBV serologies were consistent with previous infection and the ferritin level was 578 ng/mL (normal, 39‐340 ng/mL). Toxoplasma serology and HTLV‐1 antibody were ordered.

The absence of malignant cells on bone marrow biopsy does not exclude lymphoma, but makes a myelophthisic cause of the cytopenias less likely. The macrophage hemophagocytosis reflects immune activation, which in turn is usually caused by the same viral infections, autoimmune conditions, and lymphoproliferative disorders which constitute the current differential diagnosis.

Bone marrow and skin biopsies are both subject to sampling error, and detection of cutaneous T cell lymphoma is notoriously difficult. However, taken together, the absence of cancer on 2 specimens reduces that possibility.

Sustained unilateral cervical lymphadenopathy with fever in a young Japanese man without any histologic evidence of lymphoma points to Kikuchi's disease, ie, lymphadenitis of unknown etiology associated with varying degrees of systemic manifestations. Fever is a frequent feature, we believe, but diffuse sustained rash, cytopenias, and headache are less common or are seen in severe forms of the disease. The diagnosis of Kikuchi's requires the diligent exclusion of SLE and lymphoma. Examination of the peripheral smear and a lymph node biopsy are required.

Of note, there is also a localized form of Castleman's disease, a nonmalignant lymphoproliferative disorder, that similarly is characterized by focal lymphadenopathy. In distinction to Kikuchi's, however, localized Castleman's is largely asymptomatic and responds marvelously to excision.

On hospital day 9, an excisional biopsy of his left anterior cervical lymph nodes was performed, which revealed paracortical foci with necrosis and a histiocytic cellular infiltrate consistent with subacute necrotizing lymphadenitis (Kikuchi‐Fujimoto disease). Antinuclear antibody, Toxoplasma, and HTLV‐1 antibodies returned negative.

There is no treatment for Kikuchi's. It is usually self‐limited, but steroids are sometimes given for symptomatic control.

His condition began to improve after hospital day 9 without specific treatment, including his WBC count and LDH level. He was discharged home on hospital day 15. In the outpatient clinic 1 and 3 months later, he was well and active without recurrences of any symptoms or laboratory abnormalities. His WBC count was 6600/L and LDH was 268 IU/L.

Commentary

Kikuchi‐Fujimoto disease (KFD), also called Kikuchi's disease, is a benign histiocytic necrotizing lymphadenitis described by both Kikuchi and Fujimoto in 1972.1, 2 It is rare in the United States, but seems more common in Asia, especially Japan, where at least 143 cases have been reported since 1972. The etiology has not been determined, but a viral causeincluding EBV, and human herpesvirus 6 and 8has been suggested.3 An autoimmune etiology is also implicated because of infrequent association with SLE. In general, young women are most likely to be affected. In a review of 244 cases by Kucukardali and colleagues, 77% of patients were female and the mean age was 25; 70% were younger than 30 years of age.4

The common presentation is low‐grade fever with unilateral cervical lymphadenopathy.4 Although generalized lymphadenopathy can occur, it is rare. Other common clinical manifestations include malaise, joint pain, rash, arthritis, and hepatosplenomegaly. No specific laboratory tests for diagnosis are available, but leukopenia (seen in 43% of patients), increased erythrocyte sedimentation rate (40%), and anemia (23%) may be observed.4 In this case, atypical lymphocytes were seen, and are reported in one‐third of patients.5 KFD is generally diagnosed by lymph node biopsy, which typically shows irregular paracortical areas of coagulation necrosis that can distort the nodal architecture, while different types of histiocytes are observed at the margin of necrotic areas.

Other diseases in the differential diagnosisseveral of which were considered by the discussantinclude lymphoma, tuberculosis, SLE, and even metastatic adenocarcinoma. KFD is self‐limited; symptoms typically resolve within 1 to 4 months. Patients with severe manifestations have been treated with anti‐inflammatory drugs and glucocorticosteroids. A recurrence rate of 3% to 4% has been reported.6

The clinicians taking care of this patient initially focused on ruling out those infections occasionally resulting in prolonged fever in a previously healthy young man, such as viruses from the herpes family, HIV, viral hepatitis, tuberculosis, syphilis, infective endocarditis, and intra‐abdominal abscess. Physical examination, specifically lymphadenopathy and mild splenomegaly, made Herpesviridae infections, tuberculosis, syphilis, and lymphoma difficult to exclude. Once the initial evaluation ruled out common infections, attention focused on malignancy and histiocytic necrotizing lymphadenitis, given his ethnicity and geographic location.

The discussant was similarly concerned about infection, malignancy, and noninfectious inflammatory diseases, such as SLE, as possible causes. As evidence of these treatable diseases failed to accumulate, the discussant, an American physician with teaching and clinical experience in Japan, considered endemic diseases such as Behcet's, HTLV‐1, and KFD because they fit the unfolding pattern. Given our global society, clinicians will increasingly benefit from becoming familiar with the less common diseases that afflict the various populations around the world.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A 36 year‐old male physician was admitted to a Baltimore hospital in April 1907 with weight loss, weakness, arthralgias, and abdominal distension that had progressed over 5 years.

In 1907, major causes of unexplained weight loss included tuberculosis, hyperthyroidism, cancer, and diabetes. Arthralgias and weakness are not specific. The insidious progression over 5 years narrows the infectious possibilities; tuberculosis and syphilis are important considerations. Since surgical removal was the main treatment for malignancy in 1907, a history of prior surgery might point to a previously diagnosed malignancy that is now progressing.

Five years earlier, while visiting Turkey as a medical missionary, he first noted the onset of arthralgias that lasted 6 to 8 hours and occurred 3 to 4 times per week. Over time, these attacks lasted up to 24 hours and became associated with warmth, swelling, and tenderness of both small and large joints. He gradually lost weight and strength. One year prior to arrival in the hospital, he developed a cough productive of yellow sputum. Seven months prior, he returned from Turkey to Atlanta and noticed an increase in his cough, along with fevers of 100 Fahrenheit and night sweats.

The primacy of the arthralgias in this illness lead me to consider primary rheumatic diseases, and multisystem diseases (including infections) with a predominant skeletal component. In 1907, tests for lupus and the rheumatoid factor were not available. Neither skeletal remains nor works of art provide evidence that rheumatoid arthritis existed until the 19th century, whereas ankylosing spondylitis, gout, and rickets were present by then.

As a medical missionary, he might have acquired a disease endemic to the areas he visited, or the travel history may be a red herring. Familial Mediterranean fever, though prevalent in Turkey and a cause of arthralgias accompanied by recurrent attacks of abdominal pain and fever, is not an acquired disease. Behcet's disease, also known as Silk Trader's Route disease, is found in descendents of the countries that comprised the ancient Silk Route from Japan to the Middle East and may cause arthritis along with oral ulcers, genital lesions, pathergy or uveitis. I would inquire about his ancestry and fevers before dismissing these possibilities.

Although 5 years would be unusually long for tuberculosis to go unrecognized, a physician in the first half of the 20th century would place tuberculosis near the top of possible diagnoses. In 1930, a time when the population of the United States was considerably less, there were over 300,000 cases of tuberculosis. Physicians, and in particular pathologists since autopsies were more commonly performed, often died from tuberculosis since streptomycin, the first antituberculous medication, did not arrive until 1944. At the turn of the 20th century, the ability to detect tubercle bacilli was quite good. Thus, I would include tuberculous peritonitis as a cause of the progressive abdominal symptoms in this physician. In approximately one‐third of patients with tuberculous peritonitis there is evidence of pulmonary disease, and I would try to culture tuberculosis in samples of sputum, a test then so common it probably rivaled our frequent complete blood counts in popularity.

Six months prior, examinations of sputum were negative for tubercle bacilli. Four months prior to arrival, the patient moved to New Mexico. His cough improved but he continued to lose weight and had diarrhea consisting of 3 to 4 loose or semiformed bowel movements per day. Three months prior to admission, he noted an increase in abdominal girth along with right lower quadrant fullness. One month prior, he noted painful swelling and warmth in both ankles as well as dyspnea with exertion.

The increased abdominal girth in the context of chronic illness might be due to ascites, adenopathy, visceromegaly, or mass lesions such as a neoplasm or abscess. If ascites is the cause, one would need to consider primary hepatic disorders, as well as extrahepatic diseases that could progress over years. Infection with hepatitis A virus does not cause chronic liver disease. Hepatitis B, in those days, was referred to as serum hepatitis, and a serum marker for the B virusthe Australia antigenwas not identified until 1967. Cardiac causes of ascites include congestive heart failure and constrictive pericarditis, the latter an important consideration because it is potentially curable. Also, constrictive pericarditis can present as an indolent weight‐losing disease because of chronic visceral congestion. Other considerations include nephrotic syndrome, infection, and neoplasm, including mesothelioma.

Abdominal distention might also be seen with a smoldering abscess. In addition to an appendiceal process, the travel and right lower quadrant localization reminds us to consider ameboma. This patient surely was in an area where amebiasis was endemic, and amebomaa chronic inflammatory form of infection with E. histolytica not associated with diarrhea or liver cystsmay mimic cecal carcinoma. Exertional dyspnea suggests at least the possibility of cardiac disease. Despite the negative sputum cultures, tuberculosis remains high on the list as a cause of constrictive pericarditis or peritonitis, either of which may occur in the absence of active pulmonary disease.

Past medical history included measles and whooping cough as a child, mild pleurisy at age 14, mild influenza 7 years previously. The patient had a tonsillectomy as a child and had a portion of his inferior turbinate bone removed in an attempt to relieve a nasal condition.

On physical exam, the patient was thin and the skin over his face and hands was deep brown. His temperature was 101.5 Fahrenheit, the heart rate was 100, and the respiratory rate was 24. Small lymph nodes were palpable in the axillary and epitrochlear areas. His thorax moved asymmetrically, with less movement on the left apex and slight dullness to percussion in that area. The pulmonic component of the second heart sound was mildly accentuated. The abdomen displayed fullness and tympany, most pronounced in the right lower quadrant without hepatosplenomegaly. The left ankle was swollen, and the overlying skin was tense, shiny, and hot. On both lower legs, areas of discoloration and slight induration were observed, felt to be consistent with faded erythema nodosum.

Though pleurisy has numerous causes, its presence raises the specter of tuberculosis again. The nasal condition triggers thoughts of Wegener's granulomatosis or lethal midline granuloma, both unlikely diagnoses here. The pulmonary exam suggests an apical process, such as tuberculosis, and the accentuated pulmonic heart sound implies pulmonary hypertension, which could be due to a number of chronic pulmonary diseases. The epitrochlear nodes are of interest since lymphoma and Hodgkin's disease rarely involve this area; syphilis and human immunodeficiency virus (HIV) are a few of the chronic diseases that may involve this lymph node region. More helpful is the absence of hepatosplenomegaly, since many indolent malignancies and infections would be expected to enlarge these organs by this point.

Monoarticular arthritis is often due to infection, and less likely due to rheumatoid disease. When rheumatoid arthritis flares, the entire skeleton flares, not single joints. Given the indolence and this single joint involvement, tuberculosis again comes to mind.

I would next want to obtain a plain chest radiograph, looking for evidence of tuberculosis. As with any test, one should ask how this will change management. In 1907, antituberculous medications were not available, so therapy was directed at lowering oxygen tension in the primary site of infection; for example, pulmonary disease was addressed via pneumothorax. If the chest radiograph provides little hint of tuberculosis, then consideration must be given to exploratory surgery of the abdomen given the focal abnormality in the right lower quadrant.

A peripheral blood smear revealed a hypochromic microcytic anemia. The total red blood cell count was 4.468 million/mm³ (normal range for men is 4.52‐5.90 million/mm³), white blood cell count was 8180/mm³, including 80% granulocytes and 9% eosinophils. On gross inspection, the stool was clay‐colored, and stool microscopy demonstrated large numbers of neutral fat droplets, but no ova, parasites, or tubercle bacilli. Urinalysis revealed no albumin or casts, and the bones were normal on ankle radiographs. Another sample of sputum revealed no tubercle bacilli, and intradermal placement of tuberculin provoked no reaction.

His negative tuberculin skin reaction is unusual for that era, because of the prevalence of tuberculosis. Most likely, he is anergic because of his severe underlying illness, and the absent reaction is thus not all that helpful a clue. Multiple negative sputum examinations lower the possibility of pulmonary, but not extrapulmonary, tuberculosis. The absence of bony destruction on ankle radiographs lowers my suspicion for tuberculous arthritis.

The excess stool fat implies steatogenic diarrhea from malabsorption, and 2 categories here are pancreatic and luminal diseases. Of these 2, pancreatic etiologies produce more severe malabsorption. We do not hear mention of jaundice, however, and I cannot see how to link the pancreas to the arthritis. A chronic infection which may produce malabsorption and eosinophilia is strongyloidiasis, endemic in the southeastern United States. However, this patient did not manifest the most common finding of chronic strongyloidiasis, namely asthma. Adrenal insufficiency, as might result from disseminated tuberculosis, is associated with increased skin pigmentation, diarrhea, and eosinophilia. However, the diarrhea of adrenal insufficiency is not malabsorptive, and serum electrolytes and cortisol tests were not available then to confirm this diagnosis antemortem.

In an attempt to identify a unifying cause of chronic arthritis, malabsorption, and increased skin pigmentation, I must consider Whipple's disease first and foremost. Physicians then were strapped and observation was often the default mode of the day. Given the abdominal findings, an exploratory laparotomy would be warranted if his condition deteriorated.

Despite forced oral feedings, the patient continued to lose weight, from his normal of 175 pounds to a nadir of 145 pounds. Because of worsening abdominal distention, the patient underwent exploratory abdominal surgery on the twenty‐first hospital day. Intraoperatively, no ascites was seen, but his mesenteric lymph nodes were hard and markedly enlarged. The abdomen was closed without further intervention. Two days after the surgery, the patient abruptly developed dyspnea. His respirations were 40 per minute, heart rate was 120, and he had minimal rales at the lung bases without findings of consolidation. He died 2 hours later, on the twenty‐third hospital day, and an autopsy was performed.

The final event may have been a pulmonary embolism. As for the adenopathy, lymphoma and tuberculosis are possible. Heavy chain disease, an unusual lymphoproliferative disorder found in persons from the old Silk Trader's Route from the Middle East to the Orient, is a remote prospect. However, 5 years is just too indolent for most cancers and would be very unusual for tuberculosis. I think the findings support Whipple's disease, and I wonder if this was the first reported case.

On postmortem examination, the abdominal adenopathy was striking. The small intestine contained enlarged villi with thickened submucosa, and the mesenteric nodes were enlarged with fat deposits and abnormal foamy cells. Within these foamy cells, microscopy revealed numerous rod‐shaped organisms. All studies were negative for tuberculosis, and although the pathologist, Dr. George Hoyt Whipple, suspected an infectious etiology, he offered the name intestinal lipodystrophy to emphasize the striking small intestinal changes he witnessed at autopsy, and which are the hallmarks of the disease that now bears his name. Whipple also shared the 1934 Nobel Prize in Physiology or Medicine with Minot and Murphy for their discovery that a nutritional substance in liver, now known as vitamin B12, was beneficial in treating pernicious anemia.

COMMENTARY

This is the index case of Whipple's disease, summarized from the original 1907 description.1 George Hoyt Whipple, then a pathologist at Johns Hopkins, highlights the value of keen observation and a well‐done case report in describing a new disease entity. One of the roles of case reports is to detail the features of an unknown disease. In this capacity, Whipple's summary is exemplary. His achievement was having the openness of mind to realize he was witnessing something novel, and to take the first step on the road to discovery. Although Whipple suspected he was staring at a unique disease, he could not pinpoint the culprit bacteria and he had trouble squaring the extraintestinal findings with the marked intestinal anomalies. It was left to decades of input from others to confirm the association of arthralgias, eosinophilia, skin hyperpigmentation, and cardiac valve abnormalities with intestinal malabsorption, and to culture the infectious agent.

In his discussion, Whipple recognized he was confronted with a novel clinical entity. Prior to surgery, pulmonary and mesenteric tuberculosis were suspected, based on the fevers, weight loss, cough, fat malabsorption, and lymphadenopathy. However, he felt the left apical exam was more representative of retraction from prior disease than active infection. He was also bothered by the negative skin reaction and sputum tests. At surgery, the pronounced adenopathy suggested sarcoma or Hodgkin's disease but postmortem examination eliminated these possibilities. At autopsy, the abdominal findings were most striking. The small intestine demonstrated enlarged villi with thickened submucosa and markedly enlarged mesenteric lymph glands containing large fat deposits and distinctly abnormal foamy cells. These foamy macrophages contained great numbers of rod‐shaped organisms resembling the tubercle bacillus. However, all tests were negative for tuberculosis, and the lungs contained no active disease. Though he suspected an infectious etiology, Whipple offered the name intestinal lipodystrophy to emphasize the striking small intestinal pathology.

Although Whipple had surmised a novel infectious agent in 1907, it took almost a century to isolate the causative microbe. Granules within foamy macrophages of the small intestine were detected on periodic acid‐Schiff (PAS) staining in 1949.2 Similar PAS‐positive granules were soon discovered in other tissues and fluid, providing a plausible explanation for the systemic features of the disease.3 Electron microscopy confirmed the presence of infectious bacilli in 1961,4 ushering in the era of antimicrobial treatment for this disease. More recently, using polymerase chain reaction (PCR), a unique bacterial 16S ribosomal RNA gene was isolated in patients with Whipple's disease.5, 6 Phylogenetically classified with the actinobacteria, Tropheryma whipplei (fom the Greek trophe, nourishment, and eryma, barrier) was ultimately subcultured in 2000,7 and immunodetection testing became possible. Using this technique, the archived pathology specimens from the 1907 index case demonstrated numerous intracellular bacteria in the lamina propria, closing the loop started by Whipple nearly a century earlier.8

Whipple's index case report described most of the manifestations of the disease we are familiar with today. As in the original description, arthralgias are the most common initial symptom and may precede diagnosis by a mean of 8 years. Other cardinal features include weight loss, abdominal pain and steatorrhea due to small intestinal involvement. Table 1 summarizes the important signs and symptoms of Whipple's disease.9, 10 One notable manifestation missing in Whipple's report is central nervous system involvement. Central nervous system (CNS) disease ranges from cognitive deficits to encephalitis and focal defects, and may occur years after treatment and without concomitant intestinal symptoms.

A remaining mystery is why this pathogen results only rarely in clinical disease. Caucasians comprise the majority of infected patients, and men are affected 8 times more often than women. An overrepresentation of HLA‐B27 suggests a genetic predisposition, though its role in pathogenesis is unclear. T. whipplei has been identified by PCR methods in asymptomatic individuals, implying additional abnormalities must be present in susceptible hosts for symptoms to occur following colonization.11 The exact immune defects are speculative, and immunodeficiency states (such as HIV) have not been consistently identified in patients with Whipple's disease.

The cornerstone of diagnosing Whipple's disease is upper endoscopy with duodenal biopsy. Flattening of the villi and markedly increased PAS‐positive staining of lamina propria macrophages are strongly suggestive of the diagnosis. PAS‐positive staining is not unique to T. whipplei, however. In patients with profound immunodeficiency, Mycobacterium avium intracellulare may stain positive with PAS. Since Whipple's disease is only rarely associated with HIV, a negative HIV test would favor a diagnosis of Whipple's disease. Electron microscopy may distinguish T. whipplei from its mimickers by morphology. For extraintestinal disease, PCR testing on samples from infected tissue has been found to be a reliable diagnostic aid.9

Given the rarity of the disease, controlled clinical trials addressing optimal treatment are lacking. Current recommendations include initial therapy for 14 days with an agent that crosses the blood‐brain barrier (eg, ceftriaxone) to reduce the incidence of CNS disease. This is then followed by a year or more of oral antimicrobial therapy with trimethoprim‐sulfamethoxazole or a tetracycline.9 While most patients respond within 2 to 3 weeks, relapse may occur in as many as one‐third of patients.

Historical case reports reinforce the case‐based learning paradigm. As the discussant remarks, observation was all too often the only recourse for physicians a century ago. In recounting the 7‐year progression of disease in 1 individual, Whipple provides a unique window into the natural evolution of the key features of this systemic disease. Viewed through the prism of Whipple's eyes, we can recall the striking lymphoid hyperplasia and unusual organisms in the small intestine, cementing our understanding of the pathogenesis of this disorder. Revisiting past cases allows us to learn of and learn from the past.

A 47‐year‐old woman was brought to the emergency department by her family because of 1 week of abdominal pain. The pain had begun in the epigastrium but had spread across the abdomen. She described it as constant and 10 of 10 in intensity but could not identify aggravating or alleviating factors. She also complained of nausea and vomiting, beginning 4 days prior to presentation, occurring 25 times per day. She noted poor oral intake and mild diarrhea. She denied melena or hematochezia. She reported no recent fever, dysuria, chills, or night sweats; however, she reported upper respiratory symptoms 2 weeks prior to presentation. On the day of presentation, her family felt she was becoming increasingly lethargic.

Epigastric pain in a middle‐aged woman suggests several possible diagnoses. Conditions such as acute cholecystitis begin abruptly, whereas small bowel obstruction, appendicitis, and diverticulitis start gradually. Nausea and vomiting are common concomitants of abdominal pain and are nonspecific. The absence of fever and chills is reassuring. Of greatest concern is the mental status. Initially, I think of enterohemorrhagic E. coli syndromes with associated glomerulonephritis. With a more systemic metabolic abnormality such as this, the rapid development of the disease tends to exaggerate symptoms.

The patient had a history of nephrolithiasis and underwent total abdominal hysterectomy and bilateral salpingo‐oopherectomy secondary to uterine fibroids in the past. She took occasional acetaminophen, smoked two cigarettes per day, and rarely consumed alcohol. Temperature was 38.5C, heart rate was 160 beats/minute, respiratory rate was 28/minute, and blood pressure was 92/52 mm Hg; oxygen saturation was 100% breathing 2 L of oxygen by nasal cannula. She was a moderately obese African American woman in moderate distress, lying in bed moaning. Mucous membranes were dry. There was no lymphadenopathy or thyromegaly. Heart rate was regular without appreciable murmur, rub, or gallop. Lungs were clear. Abdomen was soft and nondistended, with diffuse tenderness to palpation; bowel sounds were present; there was no rebound or guarding. She had normal rectal tone with brown, guaiac‐negative stool. There was no costovertebral angle tenderness. She was oriented to person, place, and time but lethargic; deep tendon reflexes were 3+ bilaterally, and no focal signs were elicited.

Renal stones certainly produce abdominal pain, and the rare patient undergoes laparotomy for this reason. The hysterectomy tells us that small bowel obstruction could be a reason for her symptoms, although abnormal mental status would not be expected without additional problems such as infection. The tachycardia seems out of proportion to her temperature. Hyperpnea and absent respiratory symptoms, along with hypotension and tachycardia, suggest a sepsis syndrome. Her physical exam confirms dehydration. Examination of the abdomen makes me speculate about whether she has a nonsurgical cause of acute abdomen. The lethargy remains unexplained. Sepsis syndrome, possibly from a perinephric abscess, is my leading diagnosis.

White blood cell count was 15.9/mm³ with 78% neutrophils, a hemoglobin of 14.3 g/dL with a MCV of 76 and a platelet count of 320/mm³. Sodium was 159 mmol/L, chloride 128 mmol/L, bicarbonate 19 mmol/L, blood urea nitrogen 120 mmol/L, creatinine 3.1 mg/dL, calcium 11.7 mg/dL, albumin 3.3 g/dL, serum aspartate aminotransferase 65 U/L, serum alanine aminotransferase 72 U/L, total bilirubin 0.7 mg/dL, amylase 137 U/L (normal 30100), and lipase 92 IU/dL (normal 424). Urine obtained from a Foley catheter revealed negative nitrite and leukocyte esterase, 5075 red blood cells, and 1025 white blood cells per high‐powered field.

The elevated serum sodium is likely contributing to her abnormal mental status. It is unusual for a previously healthy and conscious woman to become this hypernatremic because persons with a normal mental status will defend their sodium balance strenuously, assuming regulatory mechanisms are intact. Generally, this level of hypernatremia indicates 2 things. One, a patient was not allowed, or did not seek access to, free water. The other is the presence of diabetes insipidus. It is unlikely she became this dehydrated from the initial gastrointestinal episode as described. The low MCV suggests she may be a thalassemia carrier, as microcytosis with iron deficiency typically does not occur until the patient is anemic, although she may be when rehydrated. Serum calcium, while elevated, also will likely return to the normal range with hydration. The metabolic abnormalities strongly suggest a problem in the central nervous system. The hematuria in the urinalysis continues to raise the possibility of nephrolithiasis as a cause of abdominal pain, though it does not fit well with the rest of the patient's clinical picture. The hematuria and pyuria both could still indicate a urinary tract infection such as pyelonephritis or perinephric abscess causing a sepsis syndrome.

An acute abdominal series and chest radiograph revealed a paucity of gas in the abdomen but no free air under the diaphragm or active cardiopulmonary disease. Abdominal ultrasound showed cholelithiasis without biliary dilation. There was no evidence of hydronephrosis, hydroureter, or perinephric abscess. A noncontrast abdominal‐pelvic computed tomography (CT) scan demonstrated no peripancreatic stranding or fluid collection and no nephrolithiasis or fluid collection suggestive of abscess. The admission electrocardiogram, read as sinus tachycardia with a rate of 160, is displayed in Figure 1.

Figure 1

I have long believed that unexplained sinus tachycardia is one of the most ominous rhythms in clinical medicine; it is expected after vigorous exercise, among other situations, but not in the condition in which this woman finds herself. The nature of the tracing does not indicate the likelihood of a supraventricular arrhythmia, particularly atrial flutter, which should be considered given the rate. The absence of free air under the diaphragm on chest radiography is reassuring. Though the pancreatic enzymes are mildly elevated, they are usually far more striking in gallstone pancreatitis. Hypercalcemia may result in abdominal pain by several mechanisms. I remain concerned about her central nervous system.

The patient was admitted to the intensive care unit (ICU), where she received intravenous antibiotics and aggressive rehydration. The following morning, she continued to complain of abdominal pain. Her systolic blood pressure was 115 mmHg, and her heart rate ranged between 140 and 150 beats/minute. The remainder of her physical exam was unchanged. Repeat laboratory tests revealed a white blood cell count of 14.7/mm³, a blood urea nitrogen of 66 mg/dL, a creatinine of 1.3 mg.dL, amylase of 67 IU/L, and lipase of 70 IU/dL. A contrast‐enhanced abdominal‐pelvic CT scan did not reveal intra‐abdominal pathology. Blood and urine cultures obtained at admission were negative for any growth.

The patient was appropriately admitted to the ICU. When caring for a critically ill patient, establishing a diagnosis is less important initially than addressing treatable conditions with dispatch. The negative CT scans rule out previously entertained diagnoses like nephrolithiasis and perinephric abscess. It is possible that the initially positive urinalysis was a result of urinary catheter placement trauma. Given the course to date, I believe this patient likely has a nonsurgical cause of abdominal pain. I am considering entities such as lead intoxication, hypercalcemia, a tear of the rectus abdominus caused by vomiting, systemic vasculitis, or a hypercoagulable state leading to intra‐abdominal venous thrombosis.

By hospital day 3 her sodium decreased to 149 mmol/L and her creatinine was 1.0 mg/dL. Abdominal pain persisted, unchanged from admission. Her systolic blood pressure had stabilized at 120 mmHg, but the heart rate remained near 150 beats/minute. Her abdomen remained soft and nondistended on exam but diffusely tender to palpation. Her amylase and lipase continued to decrease, and her repeat electrocardiogram demonstrated tachycardia with a rate of 144.

We are gratified to see that her serum sodium has waned but not with the persistence of the tachycardia. It must be assumed that this patient has an infectious disease that we are not clever enough to diagnose at this time. I am also considering an autoimmune process, such as systemic lupus erythematosus. It is difficult to envision a neoplastic disorder causing these problems. The differential remains broad, however, because we have not ruled out metabolic or endocrine causes. It is difficult to imagine she could have Addison's diseasea common cause of severe abdominal pain, tachycardia, and hypotensiongiven her serum sodium level. Hyperthyroidism has been known to produce mild hypercalcemia and abdominal complaints and is an intriguing possibility. The striking elevation of her serum sodium makes me consider the possibility of a problem in the posterior pituitary gland such as sarcoidosis. I cannot explain how sarcoidosis would cause her abdominal pain, unless the hypercalcemia were related. The tachycardia remains of concern, especially if she is otherwise improving. Thus, I would likely administer a small dose of adenosine to ascertain that this is not a different supraventricular tachycardia. In sinus tachycardia, the rate is usually attendant to the clinical picture and thus begs explanation given her clinical improvement.

After receiving 6 mg of intravenous adenosine, the patient's heart rate declined; atrial flutter waves were observed.

This case nicely demonstrates a key teaching point: a fast regular heart rate of about 150, irrespective of the electrocardiogram, suggests atrial flutter. Who gets atrial flutter? Patients with chronic lung disease, myocardial ischemia (albeit rarely), alcohol‐induced cardiomyopathy, and infiltrative cardiac disorders do. Additionally, we also have to consider thyroid dysfunction.

If forced to come up with a single unifying diagnosis at this point, I would have to say this patient most likely has sarcoidosis because this entity would account for modest hypercalcemia, the myocardial conduction disturbance, and hypernatremia because of diabetes insipidus; furthermore, it would fit the patient's demographic profile. However, I am also concerned about hyperthyroidism and would not proceed until thyroid function studies were obtained.

Thyroid studies revealed thyroid stimulating hormone of less than 0.01 mU/L (normal range, 0.305.50), free thyroxine (T4) of 5.81 ng.dL (normal range, 0.731.79), free triiodothyronine (T3) of 15.7 pg/mL (normal range, 2.85.3), and total triiodothyronine (T3) of 218 ng/dL (normal range, 95170). The patient was diagnosed with thyroid crisis and was started on propranolol, propylthiouracil, hydrocortisone, and a saturated solution of potassium iodine. Thyroid stimulating immunoglobulins were obtained and found to be markedly elevated (3.4 TSI index; normal < 1.3), suggestive of Grave's disease. Over the next several days, the patient's abdominal pain and tachycardia resolved. Her mental status returned to normal. A workup for her microcytic anemia revealed beta thalassemia trait. The patient was discharged home on hospital day 9 and has done well as an outpatient.

COMMENTARY

As Sir Zachary Cope stated in his classic text Cope's Early Diagnosis of the Acute Abdomen, [I]t is only by thorough history taking and physical examination that one can propound a diagnosis.1 When first presented with a patient whose chief complaint is abdominal pain, physicians tend to focus on the disorders of both the hollow and solid organs of the abdomen as potential sources of the pain. The differential diagnosis traditionally includes disorders such as cholecystitis, peptic ulcer disease, pancreatitis, small bowel obstruction, bowel ischemia or perforation, splenic abscess and infarct, nephrolithiasis, diverticulitis, and appendicitis, all of which were initially considered by the clinicians involved in this case. But as our discussant pointed out, in this case the differential needed to be broadened to include less common disorders, particularly given the patient's altered mental status, numerous electrolyte abnormalities, and lethargy and the lack of explanation provided by the physical examination and sophisticated imaging studies.

Specifically, a myriad of systemic diseases and metabolic derangements can cause abdominal complaints and mimic surgical abdominal disease, including hypercalcemia, acute intermittent porphyria, diabetic ketoacidosis, lead intoxication, familial Mediterranean fever, vasculopathies, adrenal insufficiency, and hyperthyroidism. Unfortunately, the frequency with which abdominal pain occurs in many of these less common disease processes and the pathophysiology that underlies its occurrence are not well defined. For example, abdominal pain is well described as a typical manifestation of both diabetic ketoacidosis and lead poisoning, but the pathophysiology behind its occurrence is poorly understood in both. Further, as a manifestation of thyrotoxicosis and as one of the diagnostic criteria for thyroid storm, the reported prevalence of abdominal pain in this condition is variable, ranging from rare to 20%47%.24 Also, although other gastrointestinal manifestations of hyperthyroidism (such as nausea, vomiting, and hyperdefecation) are thought to be the result of the effect of excess thyroid hormone on gastrointestinal motility, it is unclear whether this similar mechanism is responsible for the perception of abdominal pain.4

An important clue to the underlying diagnosis in this case was the patient's marked tachycardia. Classically, a persistent heart rate of 150 should raise suspicion of atrial flutter with a 2:1 conduction block, as was eventually discovered in this case. Adenosine, in addition to other vagal maneuvers such as carotid massage or Valsalva that also block atrioventricular (AV) node conduction, has been recognized as a safe and effective means of establishing a diagnosis in tachyarrhythmias.5 In AV nodal‐dependent tachycardias, such as AV node reentrant tachycardia or AV reentrant tachycardia, adenosine will often terminate the tachyarrhythmia by blocking the anterograde limb of the reentrant circuit. In AV nodeindependent tachyarrhythmias, such as atrial flutter or atrial fibrillation, adenosine will not terminate the rhythm. However, in the case of flutter, blocking the AV node will usually transiently unmask the underlying P waves, thereby facilitating the diagnosis.5, 6

In this patient, the discovery of atrial flutter was the main clue that thyrotoxicosis may provide the unifying diagnosis. Thyroid hormone has a direct positive cardiac chronotropic effect, resulting in the increased resting heart characteristic of thyrotoxicosis. Specifically, this hormone increases sinoatrial‐node firing, shortens the refractory period of conduction tissue within the heart, and decreases the electrical threshold for atrial excitation. In addition to predisposing to sinus tachycardia (the most common rhythm associated with this disorder), thyrotoxicosis is also associated with atrial tachycardias such as atrial flutter and, more classically, atrial fibrillation.7, 8 Though no studies have specifically evaluated the incidence of atrial flutter in thyrotoxicosis, atrial fibrillation has been found in 9%22% of these patients.7

Finally, several of the patient's electrolyte derangements could explain some of her clinical findings and are clues to the underlying diagnosis. She initially presented with a mild hypercalcemia that persisted even after hydration. Potential explanations include her severe dehydration or her underlying thyrotoxicosis because hypercalcemia is present in up to 20% of patients with hyperthyroidism.9, 10 However, the presence of significant hypercalcemia in the setting of thyrotoxicosis may actually make the diagnosis of thyrotoxicosis more difficult, masking the hypermetabolic signs and symptoms of the hyperthyroid state.11 Interestingly, coexistent primary hyperparathyroidism does occur in a few of these patients, but it likely was not an underlying cause in our patient given that her calcium normalized after receipt of propylthiouracil therapy.12

The patient's marked hypernatremia is more difficult to explain. She may have developed nephrogenic diabetes insipidus secondary to hypercalcemia, explained by a renal concentrating defect that can become evident once the calcium is persistently above 11 mg/dL.13 Combined with her altered mental status, which likely limited her ability to access free water, this may be enough to explain her marked hypernatremia. Her rapid improvement with rehydration is also consistent with this explanation, mediated through the improvement of her serum free calcium.

This case highlights the importance of using all the clinical clues provided by the history, physical exam, and laboratory and imaging studies when generating an initial differential diagnosis, as well as the importance of being willing to appropriately broaden and narrow the list of possibilities as a case evolves. When this patient was initially evaluated by physicians in the emergency department, they believed her symptoms were most consistent with generalized peritonitis that was likely secondary to an infectious or inflammatory intra‐abdominal process such as pancreatitis (especially in light of her mildly elevated lipase and amylase), appendicitis, or diverticulitis. When the medical team in the intensive care unit assumed care of this patient, members of the team failed to recognize several of the early clues, including the patient's markedly abnormal mental status, electrolyte derangements, and persistent tachycardia despite aggressive rehydration, which suggested the possibility of alternative, and less common, etiologies of her abdominal pain. Instead, they continued to aggressively pursue the possibility of the initial differential diagnosis, even repeating some of the previously negative studies from the emergency department. This case illustrates the importance of constantly reevaluating the available information from physical examination and laboratory and imaging studies and not falling victim to intellectual blind spots created by suggested diagnoses by other care providers. Fortunately for this patient, her thyroid crisis was diagnosed, albeit with some delay, before any long‐term complications occurred.

A 47‐year‐old woman was brought to the emergency department by her family because of 1 week of abdominal pain. The pain had begun in the epigastrium but had spread across the abdomen. She described it as constant and 10 of 10 in intensity but could not identify aggravating or alleviating factors. She also complained of nausea and vomiting, beginning 4 days prior to presentation, occurring 25 times per day. She noted poor oral intake and mild diarrhea. She denied melena or hematochezia. She reported no recent fever, dysuria, chills, or night sweats; however, she reported upper respiratory symptoms 2 weeks prior to presentation. On the day of presentation, her family felt she was becoming increasingly lethargic.

Epigastric pain in a middle‐aged woman suggests several possible diagnoses. Conditions such as acute cholecystitis begin abruptly, whereas small bowel obstruction, appendicitis, and diverticulitis start gradually. Nausea and vomiting are common concomitants of abdominal pain and are nonspecific. The absence of fever and chills is reassuring. Of greatest concern is the mental status. Initially, I think of enterohemorrhagic E. coli syndromes with associated glomerulonephritis. With a more systemic metabolic abnormality such as this, the rapid development of the disease tends to exaggerate symptoms.

The patient had a history of nephrolithiasis and underwent total abdominal hysterectomy and bilateral salpingo‐oopherectomy secondary to uterine fibroids in the past. She took occasional acetaminophen, smoked two cigarettes per day, and rarely consumed alcohol. Temperature was 38.5C, heart rate was 160 beats/minute, respiratory rate was 28/minute, and blood pressure was 92/52 mm Hg; oxygen saturation was 100% breathing 2 L of oxygen by nasal cannula. She was a moderately obese African American woman in moderate distress, lying in bed moaning. Mucous membranes were dry. There was no lymphadenopathy or thyromegaly. Heart rate was regular without appreciable murmur, rub, or gallop. Lungs were clear. Abdomen was soft and nondistended, with diffuse tenderness to palpation; bowel sounds were present; there was no rebound or guarding. She had normal rectal tone with brown, guaiac‐negative stool. There was no costovertebral angle tenderness. She was oriented to person, place, and time but lethargic; deep tendon reflexes were 3+ bilaterally, and no focal signs were elicited.

Renal stones certainly produce abdominal pain, and the rare patient undergoes laparotomy for this reason. The hysterectomy tells us that small bowel obstruction could be a reason for her symptoms, although abnormal mental status would not be expected without additional problems such as infection. The tachycardia seems out of proportion to her temperature. Hyperpnea and absent respiratory symptoms, along with hypotension and tachycardia, suggest a sepsis syndrome. Her physical exam confirms dehydration. Examination of the abdomen makes me speculate about whether she has a nonsurgical cause of acute abdomen. The lethargy remains unexplained. Sepsis syndrome, possibly from a perinephric abscess, is my leading diagnosis.

White blood cell count was 15.9/mm³ with 78% neutrophils, a hemoglobin of 14.3 g/dL with a MCV of 76 and a platelet count of 320/mm³. Sodium was 159 mmol/L, chloride 128 mmol/L, bicarbonate 19 mmol/L, blood urea nitrogen 120 mmol/L, creatinine 3.1 mg/dL, calcium 11.7 mg/dL, albumin 3.3 g/dL, serum aspartate aminotransferase 65 U/L, serum alanine aminotransferase 72 U/L, total bilirubin 0.7 mg/dL, amylase 137 U/L (normal 30100), and lipase 92 IU/dL (normal 424). Urine obtained from a Foley catheter revealed negative nitrite and leukocyte esterase, 5075 red blood cells, and 1025 white blood cells per high‐powered field.

The elevated serum sodium is likely contributing to her abnormal mental status. It is unusual for a previously healthy and conscious woman to become this hypernatremic because persons with a normal mental status will defend their sodium balance strenuously, assuming regulatory mechanisms are intact. Generally, this level of hypernatremia indicates 2 things. One, a patient was not allowed, or did not seek access to, free water. The other is the presence of diabetes insipidus. It is unlikely she became this dehydrated from the initial gastrointestinal episode as described. The low MCV suggests she may be a thalassemia carrier, as microcytosis with iron deficiency typically does not occur until the patient is anemic, although she may be when rehydrated. Serum calcium, while elevated, also will likely return to the normal range with hydration. The metabolic abnormalities strongly suggest a problem in the central nervous system. The hematuria in the urinalysis continues to raise the possibility of nephrolithiasis as a cause of abdominal pain, though it does not fit well with the rest of the patient's clinical picture. The hematuria and pyuria both could still indicate a urinary tract infection such as pyelonephritis or perinephric abscess causing a sepsis syndrome.

An acute abdominal series and chest radiograph revealed a paucity of gas in the abdomen but no free air under the diaphragm or active cardiopulmonary disease. Abdominal ultrasound showed cholelithiasis without biliary dilation. There was no evidence of hydronephrosis, hydroureter, or perinephric abscess. A noncontrast abdominal‐pelvic computed tomography (CT) scan demonstrated no peripancreatic stranding or fluid collection and no nephrolithiasis or fluid collection suggestive of abscess. The admission electrocardiogram, read as sinus tachycardia with a rate of 160, is displayed in Figure 1.

Figure 1

I have long believed that unexplained sinus tachycardia is one of the most ominous rhythms in clinical medicine; it is expected after vigorous exercise, among other situations, but not in the condition in which this woman finds herself. The nature of the tracing does not indicate the likelihood of a supraventricular arrhythmia, particularly atrial flutter, which should be considered given the rate. The absence of free air under the diaphragm on chest radiography is reassuring. Though the pancreatic enzymes are mildly elevated, they are usually far more striking in gallstone pancreatitis. Hypercalcemia may result in abdominal pain by several mechanisms. I remain concerned about her central nervous system.

The patient was admitted to the intensive care unit (ICU), where she received intravenous antibiotics and aggressive rehydration. The following morning, she continued to complain of abdominal pain. Her systolic blood pressure was 115 mmHg, and her heart rate ranged between 140 and 150 beats/minute. The remainder of her physical exam was unchanged. Repeat laboratory tests revealed a white blood cell count of 14.7/mm³, a blood urea nitrogen of 66 mg/dL, a creatinine of 1.3 mg.dL, amylase of 67 IU/L, and lipase of 70 IU/dL. A contrast‐enhanced abdominal‐pelvic CT scan did not reveal intra‐abdominal pathology. Blood and urine cultures obtained at admission were negative for any growth.

The patient was appropriately admitted to the ICU. When caring for a critically ill patient, establishing a diagnosis is less important initially than addressing treatable conditions with dispatch. The negative CT scans rule out previously entertained diagnoses like nephrolithiasis and perinephric abscess. It is possible that the initially positive urinalysis was a result of urinary catheter placement trauma. Given the course to date, I believe this patient likely has a nonsurgical cause of abdominal pain. I am considering entities such as lead intoxication, hypercalcemia, a tear of the rectus abdominus caused by vomiting, systemic vasculitis, or a hypercoagulable state leading to intra‐abdominal venous thrombosis.

By hospital day 3 her sodium decreased to 149 mmol/L and her creatinine was 1.0 mg/dL. Abdominal pain persisted, unchanged from admission. Her systolic blood pressure had stabilized at 120 mmHg, but the heart rate remained near 150 beats/minute. Her abdomen remained soft and nondistended on exam but diffusely tender to palpation. Her amylase and lipase continued to decrease, and her repeat electrocardiogram demonstrated tachycardia with a rate of 144.

We are gratified to see that her serum sodium has waned but not with the persistence of the tachycardia. It must be assumed that this patient has an infectious disease that we are not clever enough to diagnose at this time. I am also considering an autoimmune process, such as systemic lupus erythematosus. It is difficult to envision a neoplastic disorder causing these problems. The differential remains broad, however, because we have not ruled out metabolic or endocrine causes. It is difficult to imagine she could have Addison's diseasea common cause of severe abdominal pain, tachycardia, and hypotensiongiven her serum sodium level. Hyperthyroidism has been known to produce mild hypercalcemia and abdominal complaints and is an intriguing possibility. The striking elevation of her serum sodium makes me consider the possibility of a problem in the posterior pituitary gland such as sarcoidosis. I cannot explain how sarcoidosis would cause her abdominal pain, unless the hypercalcemia were related. The tachycardia remains of concern, especially if she is otherwise improving. Thus, I would likely administer a small dose of adenosine to ascertain that this is not a different supraventricular tachycardia. In sinus tachycardia, the rate is usually attendant to the clinical picture and thus begs explanation given her clinical improvement.

After receiving 6 mg of intravenous adenosine, the patient's heart rate declined; atrial flutter waves were observed.

This case nicely demonstrates a key teaching point: a fast regular heart rate of about 150, irrespective of the electrocardiogram, suggests atrial flutter. Who gets atrial flutter? Patients with chronic lung disease, myocardial ischemia (albeit rarely), alcohol‐induced cardiomyopathy, and infiltrative cardiac disorders do. Additionally, we also have to consider thyroid dysfunction.

If forced to come up with a single unifying diagnosis at this point, I would have to say this patient most likely has sarcoidosis because this entity would account for modest hypercalcemia, the myocardial conduction disturbance, and hypernatremia because of diabetes insipidus; furthermore, it would fit the patient's demographic profile. However, I am also concerned about hyperthyroidism and would not proceed until thyroid function studies were obtained.

Thyroid studies revealed thyroid stimulating hormone of less than 0.01 mU/L (normal range, 0.305.50), free thyroxine (T4) of 5.81 ng.dL (normal range, 0.731.79), free triiodothyronine (T3) of 15.7 pg/mL (normal range, 2.85.3), and total triiodothyronine (T3) of 218 ng/dL (normal range, 95170). The patient was diagnosed with thyroid crisis and was started on propranolol, propylthiouracil, hydrocortisone, and a saturated solution of potassium iodine. Thyroid stimulating immunoglobulins were obtained and found to be markedly elevated (3.4 TSI index; normal < 1.3), suggestive of Grave's disease. Over the next several days, the patient's abdominal pain and tachycardia resolved. Her mental status returned to normal. A workup for her microcytic anemia revealed beta thalassemia trait. The patient was discharged home on hospital day 9 and has done well as an outpatient.

COMMENTARY

As Sir Zachary Cope stated in his classic text Cope's Early Diagnosis of the Acute Abdomen, [I]t is only by thorough history taking and physical examination that one can propound a diagnosis.1 When first presented with a patient whose chief complaint is abdominal pain, physicians tend to focus on the disorders of both the hollow and solid organs of the abdomen as potential sources of the pain. The differential diagnosis traditionally includes disorders such as cholecystitis, peptic ulcer disease, pancreatitis, small bowel obstruction, bowel ischemia or perforation, splenic abscess and infarct, nephrolithiasis, diverticulitis, and appendicitis, all of which were initially considered by the clinicians involved in this case. But as our discussant pointed out, in this case the differential needed to be broadened to include less common disorders, particularly given the patient's altered mental status, numerous electrolyte abnormalities, and lethargy and the lack of explanation provided by the physical examination and sophisticated imaging studies.

Specifically, a myriad of systemic diseases and metabolic derangements can cause abdominal complaints and mimic surgical abdominal disease, including hypercalcemia, acute intermittent porphyria, diabetic ketoacidosis, lead intoxication, familial Mediterranean fever, vasculopathies, adrenal insufficiency, and hyperthyroidism. Unfortunately, the frequency with which abdominal pain occurs in many of these less common disease processes and the pathophysiology that underlies its occurrence are not well defined. For example, abdominal pain is well described as a typical manifestation of both diabetic ketoacidosis and lead poisoning, but the pathophysiology behind its occurrence is poorly understood in both. Further, as a manifestation of thyrotoxicosis and as one of the diagnostic criteria for thyroid storm, the reported prevalence of abdominal pain in this condition is variable, ranging from rare to 20%47%.24 Also, although other gastrointestinal manifestations of hyperthyroidism (such as nausea, vomiting, and hyperdefecation) are thought to be the result of the effect of excess thyroid hormone on gastrointestinal motility, it is unclear whether this similar mechanism is responsible for the perception of abdominal pain.4

An important clue to the underlying diagnosis in this case was the patient's marked tachycardia. Classically, a persistent heart rate of 150 should raise suspicion of atrial flutter with a 2:1 conduction block, as was eventually discovered in this case. Adenosine, in addition to other vagal maneuvers such as carotid massage or Valsalva that also block atrioventricular (AV) node conduction, has been recognized as a safe and effective means of establishing a diagnosis in tachyarrhythmias.5 In AV nodal‐dependent tachycardias, such as AV node reentrant tachycardia or AV reentrant tachycardia, adenosine will often terminate the tachyarrhythmia by blocking the anterograde limb of the reentrant circuit. In AV nodeindependent tachyarrhythmias, such as atrial flutter or atrial fibrillation, adenosine will not terminate the rhythm. However, in the case of flutter, blocking the AV node will usually transiently unmask the underlying P waves, thereby facilitating the diagnosis.5, 6

In this patient, the discovery of atrial flutter was the main clue that thyrotoxicosis may provide the unifying diagnosis. Thyroid hormone has a direct positive cardiac chronotropic effect, resulting in the increased resting heart characteristic of thyrotoxicosis. Specifically, this hormone increases sinoatrial‐node firing, shortens the refractory period of conduction tissue within the heart, and decreases the electrical threshold for atrial excitation. In addition to predisposing to sinus tachycardia (the most common rhythm associated with this disorder), thyrotoxicosis is also associated with atrial tachycardias such as atrial flutter and, more classically, atrial fibrillation.7, 8 Though no studies have specifically evaluated the incidence of atrial flutter in thyrotoxicosis, atrial fibrillation has been found in 9%22% of these patients.7

Finally, several of the patient's electrolyte derangements could explain some of her clinical findings and are clues to the underlying diagnosis. She initially presented with a mild hypercalcemia that persisted even after hydration. Potential explanations include her severe dehydration or her underlying thyrotoxicosis because hypercalcemia is present in up to 20% of patients with hyperthyroidism.9, 10 However, the presence of significant hypercalcemia in the setting of thyrotoxicosis may actually make the diagnosis of thyrotoxicosis more difficult, masking the hypermetabolic signs and symptoms of the hyperthyroid state.11 Interestingly, coexistent primary hyperparathyroidism does occur in a few of these patients, but it likely was not an underlying cause in our patient given that her calcium normalized after receipt of propylthiouracil therapy.12

The patient's marked hypernatremia is more difficult to explain. She may have developed nephrogenic diabetes insipidus secondary to hypercalcemia, explained by a renal concentrating defect that can become evident once the calcium is persistently above 11 mg/dL.13 Combined with her altered mental status, which likely limited her ability to access free water, this may be enough to explain her marked hypernatremia. Her rapid improvement with rehydration is also consistent with this explanation, mediated through the improvement of her serum free calcium.

This case highlights the importance of using all the clinical clues provided by the history, physical exam, and laboratory and imaging studies when generating an initial differential diagnosis, as well as the importance of being willing to appropriately broaden and narrow the list of possibilities as a case evolves. When this patient was initially evaluated by physicians in the emergency department, they believed her symptoms were most consistent with generalized peritonitis that was likely secondary to an infectious or inflammatory intra‐abdominal process such as pancreatitis (especially in light of her mildly elevated lipase and amylase), appendicitis, or diverticulitis. When the medical team in the intensive care unit assumed care of this patient, members of the team failed to recognize several of the early clues, including the patient's markedly abnormal mental status, electrolyte derangements, and persistent tachycardia despite aggressive rehydration, which suggested the possibility of alternative, and less common, etiologies of her abdominal pain. Instead, they continued to aggressively pursue the possibility of the initial differential diagnosis, even repeating some of the previously negative studies from the emergency department. This case illustrates the importance of constantly reevaluating the available information from physical examination and laboratory and imaging studies and not falling victim to intellectual blind spots created by suggested diagnoses by other care providers. Fortunately for this patient, her thyroid crisis was diagnosed, albeit with some delay, before any long‐term complications occurred.

A 47‐year‐old woman was brought to the emergency department by her family because of 1 week of abdominal pain. The pain had begun in the epigastrium but had spread across the abdomen. She described it as constant and 10 of 10 in intensity but could not identify aggravating or alleviating factors. She also complained of nausea and vomiting, beginning 4 days prior to presentation, occurring 25 times per day. She noted poor oral intake and mild diarrhea. She denied melena or hematochezia. She reported no recent fever, dysuria, chills, or night sweats; however, she reported upper respiratory symptoms 2 weeks prior to presentation. On the day of presentation, her family felt she was becoming increasingly lethargic.

Epigastric pain in a middle‐aged woman suggests several possible diagnoses. Conditions such as acute cholecystitis begin abruptly, whereas small bowel obstruction, appendicitis, and diverticulitis start gradually. Nausea and vomiting are common concomitants of abdominal pain and are nonspecific. The absence of fever and chills is reassuring. Of greatest concern is the mental status. Initially, I think of enterohemorrhagic E. coli syndromes with associated glomerulonephritis. With a more systemic metabolic abnormality such as this, the rapid development of the disease tends to exaggerate symptoms.

The patient had a history of nephrolithiasis and underwent total abdominal hysterectomy and bilateral salpingo‐oopherectomy secondary to uterine fibroids in the past. She took occasional acetaminophen, smoked two cigarettes per day, and rarely consumed alcohol. Temperature was 38.5C, heart rate was 160 beats/minute, respiratory rate was 28/minute, and blood pressure was 92/52 mm Hg; oxygen saturation was 100% breathing 2 L of oxygen by nasal cannula. She was a moderately obese African American woman in moderate distress, lying in bed moaning. Mucous membranes were dry. There was no lymphadenopathy or thyromegaly. Heart rate was regular without appreciable murmur, rub, or gallop. Lungs were clear. Abdomen was soft and nondistended, with diffuse tenderness to palpation; bowel sounds were present; there was no rebound or guarding. She had normal rectal tone with brown, guaiac‐negative stool. There was no costovertebral angle tenderness. She was oriented to person, place, and time but lethargic; deep tendon reflexes were 3+ bilaterally, and no focal signs were elicited.

Renal stones certainly produce abdominal pain, and the rare patient undergoes laparotomy for this reason. The hysterectomy tells us that small bowel obstruction could be a reason for her symptoms, although abnormal mental status would not be expected without additional problems such as infection. The tachycardia seems out of proportion to her temperature. Hyperpnea and absent respiratory symptoms, along with hypotension and tachycardia, suggest a sepsis syndrome. Her physical exam confirms dehydration. Examination of the abdomen makes me speculate about whether she has a nonsurgical cause of acute abdomen. The lethargy remains unexplained. Sepsis syndrome, possibly from a perinephric abscess, is my leading diagnosis.

White blood cell count was 15.9/mm³ with 78% neutrophils, a hemoglobin of 14.3 g/dL with a MCV of 76 and a platelet count of 320/mm³. Sodium was 159 mmol/L, chloride 128 mmol/L, bicarbonate 19 mmol/L, blood urea nitrogen 120 mmol/L, creatinine 3.1 mg/dL, calcium 11.7 mg/dL, albumin 3.3 g/dL, serum aspartate aminotransferase 65 U/L, serum alanine aminotransferase 72 U/L, total bilirubin 0.7 mg/dL, amylase 137 U/L (normal 30100), and lipase 92 IU/dL (normal 424). Urine obtained from a Foley catheter revealed negative nitrite and leukocyte esterase, 5075 red blood cells, and 1025 white blood cells per high‐powered field.

The elevated serum sodium is likely contributing to her abnormal mental status. It is unusual for a previously healthy and conscious woman to become this hypernatremic because persons with a normal mental status will defend their sodium balance strenuously, assuming regulatory mechanisms are intact. Generally, this level of hypernatremia indicates 2 things. One, a patient was not allowed, or did not seek access to, free water. The other is the presence of diabetes insipidus. It is unlikely she became this dehydrated from the initial gastrointestinal episode as described. The low MCV suggests she may be a thalassemia carrier, as microcytosis with iron deficiency typically does not occur until the patient is anemic, although she may be when rehydrated. Serum calcium, while elevated, also will likely return to the normal range with hydration. The metabolic abnormalities strongly suggest a problem in the central nervous system. The hematuria in the urinalysis continues to raise the possibility of nephrolithiasis as a cause of abdominal pain, though it does not fit well with the rest of the patient's clinical picture. The hematuria and pyuria both could still indicate a urinary tract infection such as pyelonephritis or perinephric abscess causing a sepsis syndrome.

An acute abdominal series and chest radiograph revealed a paucity of gas in the abdomen but no free air under the diaphragm or active cardiopulmonary disease. Abdominal ultrasound showed cholelithiasis without biliary dilation. There was no evidence of hydronephrosis, hydroureter, or perinephric abscess. A noncontrast abdominal‐pelvic computed tomography (CT) scan demonstrated no peripancreatic stranding or fluid collection and no nephrolithiasis or fluid collection suggestive of abscess. The admission electrocardiogram, read as sinus tachycardia with a rate of 160, is displayed in Figure 1.

Figure 1

I have long believed that unexplained sinus tachycardia is one of the most ominous rhythms in clinical medicine; it is expected after vigorous exercise, among other situations, but not in the condition in which this woman finds herself. The nature of the tracing does not indicate the likelihood of a supraventricular arrhythmia, particularly atrial flutter, which should be considered given the rate. The absence of free air under the diaphragm on chest radiography is reassuring. Though the pancreatic enzymes are mildly elevated, they are usually far more striking in gallstone pancreatitis. Hypercalcemia may result in abdominal pain by several mechanisms. I remain concerned about her central nervous system.

The patient was admitted to the intensive care unit (ICU), where she received intravenous antibiotics and aggressive rehydration. The following morning, she continued to complain of abdominal pain. Her systolic blood pressure was 115 mmHg, and her heart rate ranged between 140 and 150 beats/minute. The remainder of her physical exam was unchanged. Repeat laboratory tests revealed a white blood cell count of 14.7/mm³, a blood urea nitrogen of 66 mg/dL, a creatinine of 1.3 mg.dL, amylase of 67 IU/L, and lipase of 70 IU/dL. A contrast‐enhanced abdominal‐pelvic CT scan did not reveal intra‐abdominal pathology. Blood and urine cultures obtained at admission were negative for any growth.

The patient was appropriately admitted to the ICU. When caring for a critically ill patient, establishing a diagnosis is less important initially than addressing treatable conditions with dispatch. The negative CT scans rule out previously entertained diagnoses like nephrolithiasis and perinephric abscess. It is possible that the initially positive urinalysis was a result of urinary catheter placement trauma. Given the course to date, I believe this patient likely has a nonsurgical cause of abdominal pain. I am considering entities such as lead intoxication, hypercalcemia, a tear of the rectus abdominus caused by vomiting, systemic vasculitis, or a hypercoagulable state leading to intra‐abdominal venous thrombosis.

By hospital day 3 her sodium decreased to 149 mmol/L and her creatinine was 1.0 mg/dL. Abdominal pain persisted, unchanged from admission. Her systolic blood pressure had stabilized at 120 mmHg, but the heart rate remained near 150 beats/minute. Her abdomen remained soft and nondistended on exam but diffusely tender to palpation. Her amylase and lipase continued to decrease, and her repeat electrocardiogram demonstrated tachycardia with a rate of 144.

We are gratified to see that her serum sodium has waned but not with the persistence of the tachycardia. It must be assumed that this patient has an infectious disease that we are not clever enough to diagnose at this time. I am also considering an autoimmune process, such as systemic lupus erythematosus. It is difficult to envision a neoplastic disorder causing these problems. The differential remains broad, however, because we have not ruled out metabolic or endocrine causes. It is difficult to imagine she could have Addison's diseasea common cause of severe abdominal pain, tachycardia, and hypotensiongiven her serum sodium level. Hyperthyroidism has been known to produce mild hypercalcemia and abdominal complaints and is an intriguing possibility. The striking elevation of her serum sodium makes me consider the possibility of a problem in the posterior pituitary gland such as sarcoidosis. I cannot explain how sarcoidosis would cause her abdominal pain, unless the hypercalcemia were related. The tachycardia remains of concern, especially if she is otherwise improving. Thus, I would likely administer a small dose of adenosine to ascertain that this is not a different supraventricular tachycardia. In sinus tachycardia, the rate is usually attendant to the clinical picture and thus begs explanation given her clinical improvement.

After receiving 6 mg of intravenous adenosine, the patient's heart rate declined; atrial flutter waves were observed.

This case nicely demonstrates a key teaching point: a fast regular heart rate of about 150, irrespective of the electrocardiogram, suggests atrial flutter. Who gets atrial flutter? Patients with chronic lung disease, myocardial ischemia (albeit rarely), alcohol‐induced cardiomyopathy, and infiltrative cardiac disorders do. Additionally, we also have to consider thyroid dysfunction.

If forced to come up with a single unifying diagnosis at this point, I would have to say this patient most likely has sarcoidosis because this entity would account for modest hypercalcemia, the myocardial conduction disturbance, and hypernatremia because of diabetes insipidus; furthermore, it would fit the patient's demographic profile. However, I am also concerned about hyperthyroidism and would not proceed until thyroid function studies were obtained.

Thyroid studies revealed thyroid stimulating hormone of less than 0.01 mU/L (normal range, 0.305.50), free thyroxine (T4) of 5.81 ng.dL (normal range, 0.731.79), free triiodothyronine (T3) of 15.7 pg/mL (normal range, 2.85.3), and total triiodothyronine (T3) of 218 ng/dL (normal range, 95170). The patient was diagnosed with thyroid crisis and was started on propranolol, propylthiouracil, hydrocortisone, and a saturated solution of potassium iodine. Thyroid stimulating immunoglobulins were obtained and found to be markedly elevated (3.4 TSI index; normal < 1.3), suggestive of Grave's disease. Over the next several days, the patient's abdominal pain and tachycardia resolved. Her mental status returned to normal. A workup for her microcytic anemia revealed beta thalassemia trait. The patient was discharged home on hospital day 9 and has done well as an outpatient.

COMMENTARY

As Sir Zachary Cope stated in his classic text Cope's Early Diagnosis of the Acute Abdomen, [I]t is only by thorough history taking and physical examination that one can propound a diagnosis.1 When first presented with a patient whose chief complaint is abdominal pain, physicians tend to focus on the disorders of both the hollow and solid organs of the abdomen as potential sources of the pain. The differential diagnosis traditionally includes disorders such as cholecystitis, peptic ulcer disease, pancreatitis, small bowel obstruction, bowel ischemia or perforation, splenic abscess and infarct, nephrolithiasis, diverticulitis, and appendicitis, all of which were initially considered by the clinicians involved in this case. But as our discussant pointed out, in this case the differential needed to be broadened to include less common disorders, particularly given the patient's altered mental status, numerous electrolyte abnormalities, and lethargy and the lack of explanation provided by the physical examination and sophisticated imaging studies.

Specifically, a myriad of systemic diseases and metabolic derangements can cause abdominal complaints and mimic surgical abdominal disease, including hypercalcemia, acute intermittent porphyria, diabetic ketoacidosis, lead intoxication, familial Mediterranean fever, vasculopathies, adrenal insufficiency, and hyperthyroidism. Unfortunately, the frequency with which abdominal pain occurs in many of these less common disease processes and the pathophysiology that underlies its occurrence are not well defined. For example, abdominal pain is well described as a typical manifestation of both diabetic ketoacidosis and lead poisoning, but the pathophysiology behind its occurrence is poorly understood in both. Further, as a manifestation of thyrotoxicosis and as one of the diagnostic criteria for thyroid storm, the reported prevalence of abdominal pain in this condition is variable, ranging from rare to 20%47%.24 Also, although other gastrointestinal manifestations of hyperthyroidism (such as nausea, vomiting, and hyperdefecation) are thought to be the result of the effect of excess thyroid hormone on gastrointestinal motility, it is unclear whether this similar mechanism is responsible for the perception of abdominal pain.4

An important clue to the underlying diagnosis in this case was the patient's marked tachycardia. Classically, a persistent heart rate of 150 should raise suspicion of atrial flutter with a 2:1 conduction block, as was eventually discovered in this case. Adenosine, in addition to other vagal maneuvers such as carotid massage or Valsalva that also block atrioventricular (AV) node conduction, has been recognized as a safe and effective means of establishing a diagnosis in tachyarrhythmias.5 In AV nodal‐dependent tachycardias, such as AV node reentrant tachycardia or AV reentrant tachycardia, adenosine will often terminate the tachyarrhythmia by blocking the anterograde limb of the reentrant circuit. In AV nodeindependent tachyarrhythmias, such as atrial flutter or atrial fibrillation, adenosine will not terminate the rhythm. However, in the case of flutter, blocking the AV node will usually transiently unmask the underlying P waves, thereby facilitating the diagnosis.5, 6

In this patient, the discovery of atrial flutter was the main clue that thyrotoxicosis may provide the unifying diagnosis. Thyroid hormone has a direct positive cardiac chronotropic effect, resulting in the increased resting heart characteristic of thyrotoxicosis. Specifically, this hormone increases sinoatrial‐node firing, shortens the refractory period of conduction tissue within the heart, and decreases the electrical threshold for atrial excitation. In addition to predisposing to sinus tachycardia (the most common rhythm associated with this disorder), thyrotoxicosis is also associated with atrial tachycardias such as atrial flutter and, more classically, atrial fibrillation.7, 8 Though no studies have specifically evaluated the incidence of atrial flutter in thyrotoxicosis, atrial fibrillation has been found in 9%22% of these patients.7

Finally, several of the patient's electrolyte derangements could explain some of her clinical findings and are clues to the underlying diagnosis. She initially presented with a mild hypercalcemia that persisted even after hydration. Potential explanations include her severe dehydration or her underlying thyrotoxicosis because hypercalcemia is present in up to 20% of patients with hyperthyroidism.9, 10 However, the presence of significant hypercalcemia in the setting of thyrotoxicosis may actually make the diagnosis of thyrotoxicosis more difficult, masking the hypermetabolic signs and symptoms of the hyperthyroid state.11 Interestingly, coexistent primary hyperparathyroidism does occur in a few of these patients, but it likely was not an underlying cause in our patient given that her calcium normalized after receipt of propylthiouracil therapy.12

The patient's marked hypernatremia is more difficult to explain. She may have developed nephrogenic diabetes insipidus secondary to hypercalcemia, explained by a renal concentrating defect that can become evident once the calcium is persistently above 11 mg/dL.13 Combined with her altered mental status, which likely limited her ability to access free water, this may be enough to explain her marked hypernatremia. Her rapid improvement with rehydration is also consistent with this explanation, mediated through the improvement of her serum free calcium.

This case highlights the importance of using all the clinical clues provided by the history, physical exam, and laboratory and imaging studies when generating an initial differential diagnosis, as well as the importance of being willing to appropriately broaden and narrow the list of possibilities as a case evolves. When this patient was initially evaluated by physicians in the emergency department, they believed her symptoms were most consistent with generalized peritonitis that was likely secondary to an infectious or inflammatory intra‐abdominal process such as pancreatitis (especially in light of her mildly elevated lipase and amylase), appendicitis, or diverticulitis. When the medical team in the intensive care unit assumed care of this patient, members of the team failed to recognize several of the early clues, including the patient's markedly abnormal mental status, electrolyte derangements, and persistent tachycardia despite aggressive rehydration, which suggested the possibility of alternative, and less common, etiologies of her abdominal pain. Instead, they continued to aggressively pursue the possibility of the initial differential diagnosis, even repeating some of the previously negative studies from the emergency department. This case illustrates the importance of constantly reevaluating the available information from physical examination and laboratory and imaging studies and not falling victim to intellectual blind spots created by suggested diagnoses by other care providers. Fortunately for this patient, her thyroid crisis was diagnosed, albeit with some delay, before any long‐term complications occurred.