The n e w e ng l a n d j o u r na l of m e dic i n e Case Records of the Massachusetts General Hospital Founded by Richard C. Cabot Eric S. Rosenberg, M.D., Editor Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D., Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors Kathy M. Tran, M.D., Case Records Editorial Fellow Emily K. McDonald, Tara Corpuz, Production Editors Case 3-2020: A 44-Year-Old Man with Weight Loss, Diarrhea, and Abdominal Pain Robert C. Lowe, M.D., Jacqueline N. Chu, M.D., Theodore T. Pierce, M.D., Ana A. Weil, M.D., and John A. Branda, M.D. Pr e sen tat ion of C a se Dr. Jacqueline N. Chu: A 44-year-old man was evaluated at this hospital because of diarrhea, weight loss, and abdominal pain. Approximately 6 months before admission, the patient began to have early satiety, nausea approximately 30 minutes after eating small amounts of food, and intermittent anorexia. He began to consume primarily liquids for breakfast and lunch and would skip dinner; during the next 5 months, he lost 9 kg. One month before admission, the patient was admitted to another hospital because of fever, malaise, neck pain, photophobia, retro-orbital pain, and headache. The temperature was 38.5°C, the heart rate 118 beats per minute, and the blood pressure 94/72 mm Hg. The white-cell count was 28,600 per microliter (reference range, 4500 to 10,800); other laboratory test results are shown in Table 1. Blood samples were obtained for culture. Computed tomography (CT) of the head, performed after the administration of intravenous contrast material, was reportedly normal. Empirical vancomycin, ceftriaxone, acyclovir, and dexamethasone were administered intravenously. A lumbar puncture (opening pressure not recorded) revealed cloudy cerebrospinal fluid (CSF) with 4 red cells per microliter and 1306 white cells per microliter, of which 83% were neutrophils (reference value, <25%), 12% were monocytes, and 5% were lymphocytes. Gram’s staining of the CSF revealed no organisms; the CSF protein level was 98 mg per deciliter (reference range, 15 to 45) and the glucose level was 68 mg per deciliter (3.8 mmol per liter; reference range, 35 to 65 mg per deciliter [1.9 to 3.6 mmol per liter]). On the third day at the other hospital, dysuria, nausea, and episodes of hemoptysis and diarrhea developed. CT of the chest and abdomen was performed after the administration of intravenous contrast material; the results were reportedly unremarkable. On the fifth hospital day, after CSF culture revealed no growth and polymerase-chain-reaction (PCR) testing for herpes simplex virus types 1 and 2 was negative, antimicrobial and glucocorticoid therapies were discontinued and the patient was discharged home. The vitamin B12 level and results of serum protein n engl j med 382;4 nejm.org From the Department of Medicine, Bos­ ton Medical Center (R.C.L.), the Depart­ ment of Medicine, Boston University School of Medicine (R.C.L.), the Depart­ ments of Medicine (J.N.C., A.A.W.), Radi­ ology (T.T.P.), and Pathology (J.A.B.), Massachusetts General Hospital, and the Departments of Medicine (J.N.C., A.A.W.), Radiology (T.T.P.), and Pathol­ ogy (J.A.B.), Harvard Medical School — all in Boston. N Engl J Med 2020;382:365-74. DOI: 10.1056/NEJMcpc1913473 Copyright © 2020 Massachusetts Medical Society. January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 365 The n e w e ng l a n d j o u r na l of m e dic i n e Table 1. Laboratory Data.* Reference Range, Other Hospital 1 Mo before Current Admission, on Admission, Other Hospital Hemoglobin (g/dl) 14.0–18.0 12.3 12.4 13.5–17.5 Hematocrit (%) 42.0–52.0 37.4 37.8 41.0–53.0 40.6 4500–10,800 28,600 10,300 4500–11,000 11,170 Neutrophils 40.0–80.0 63.9 35.9 40–70 53.4 Bands 0.0–10.0 16.8 0.7 0–0.9 0.5 7.0–36.0 5.0 43.3 22–44 29.5 0 0.8 0 0 Monocytes 4.0–8.0 9.2 9.7 4–11 12.4 Eosinophils 1.0–6.0 0.8 9.8 0–8 5.0 0–1 0.5 0.6 0–1 0.4 Variable White-cell count (per μl) 3 Wk before Current Admission, Day before Discharge, Reference Range, Other Hospital This Hospital† On Admission, This Hospital 13.2 Differential count (%) Immature granulocytes Lymphocytes Atypical lymphocytes Basophils 0.0–2.0 3.4 Platelet count (per μl) Metamyelocytes 150,000–450,000 258,000 415,000 150,000–400,000 395,000 Sodium (mmol/liter) 135–145 133 126 135–145 131 Potassium (mmol/liter) 3.3–4.5 4.0 4.6 3.4–5.0 4.3 Chloride (mmol/liter) 98–109 100 92 100–108 98 Carbon dioxide (mmol/liter) 24–32 22 23 23–32 23 Urea nitrogen (mg/dl) 0 6–19 14 11 8–25 11 Creatinine (mg/dl) 0.4–1.2 1.0 0.8 0.60–1.50 0.62 Glucose (mg/dl) 70–100 126 101 70–110 96 Calcium (mg/dl) 8.5–10.5 8.1 8.0 8.5–10.5 8.1 Total protein (g/dl) 6.0–8.5 5.3 5.4 6.0–8.3 5.2 Albumin (g/dl) 3.3–5.2 2.4 2.4 3.3–5.0 2.2 Alanine aminotransferase (U/liter) 0–40 32 17 10–55 38 Aspartate aminotransferase (U/liter) 0–37 19 12 10–40 30 40–129 62 53 45–115 68 Alkaline phosphatase (U/liter) Total bilirubin (mg/dl) 0.2–1.2 0.3 0.2 0.0–1.0 0.2 Serum osmolality (mOsm/kg) 285–295 272 263 280–290 268 Lactate (mmol/liter) 0.5–1.9 1.9 0.5–2.2 1.2 Iron (μg/dl) 45–160 37 30–160 36 Total iron-binding capacity (μg/dl) 228–428 205 230–404 105 Ferritin (ng/ml) 20–250 82 10–200 130 Erythrocyte sedimentation rate (mm/hr) 0–13 7 C-reactive protein (mg/liter) <8 59.2 Fecal calprotectin (μg/g) <50 1038.8 *To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for lactate to milligrams per deciliter, divide by 0.1110. To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. †Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. 366 n engl j med 382;4 nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital electrophoresis were normal; other laboratory test results obtained the day before discharge are shown in Table 1. After the patient’s discharge from the other hospital, new, near-constant epigastric pain developed. Approximately 1 hour after meals, nausea and vomiting occurred, with diffuse abdominal bloating and cramping. In addition, watery diarrhea began to occur twice daily, without hematochezia or melena. One week after discharge, the patient’s primary care physician prescribed omeprazole. The patient lost an additional 14 kg. Approximately 3 weeks later, he presented to the emergency department of this hospital for evaluation. The patient’s medical history was notable for depression, lumbar pain, and vitamin D deficiency. Intermittent diffuse headache persisted in the 3 weeks after discharge from the other hospital, and the patient reported low-grade fever. A review of systems was negative for night sweats, chills, neck pain, photophobia, vision changes, chest pain, dyspnea, cough, coryza, sore throat, oral ulcers, back pain, dysuria, hematuria, rashes, joint or muscle pain, edema, and pruritus. Medications included venlafaxine, cholecalciferol, and omeprazole. The patient took an herbal supplement of unknown type in the week after discharge from the other hospital. He had never used nonsteroidal antiinflammatory drugs. He had no known medication allergies. The patient grew up on an island in the Caribbean and had immigrated to the United States 10 years earlier; he had last returned to the Caribbean 4 months before admission. He had traveled extensively in the northeastern and Mountain West regions of the United States. He was married with one child but had no known sick contacts. He drank one beer per day and had never smoked cigarettes; he occasionally smoked marijuana. There was no family history of gastrointestinal infections, gastrointestinal cancers (his mother had ovarian cancer), pepticulcer disease, pancreatitis, irritable bowel syndrome, inflammatory bowel disease, autoimmune conditions, or malabsorption syndromes. The temperature was 37.2°C, the heart rate 107 beats per minute, the blood pressure 101/57 mm Hg, and the oxygen saturation 99% while the patient was breathing ambient air; the body-mass index (the weight in kilograms divided by the square of the height in meters) was 18.6. Examination was notable for cachexia. The abn engl j med 382;4 domen was soft and nondistended, with no organomegaly. There was mild epigastric tenderness, without rebound or guarding. No rashes, skin ulcerations, or lymphadenopathy were noted. The remainder of the examination was normal. The international normalized ratio and blood levels of magnesium, phosphorus, lipase, vitamin B12, folate, globulin, and IgA were normal, as were the results of a urinalysis; other laboratory test results are shown in Table 1. An electrocardiogram showed right bundle-branch block, with no evidence of ischemia. Dr. Theodore T. Pierce: A CT scan of the abdomen and pelvis (Fig. 1), obtained after the administration of intravenous contrast material, showed diffuse mild distention of the large and small bowel without a transition point to indicate a bowel obstruction. The presence of diffuse mild thickening of the bowel wall, mural enhancement, and prominent mesenteric vessels suggested diffuse inflammation. Additional nonspecific findings included a reduced number of jejunal folds and an increased number of ileal folds (collectively known as jejunoileal fold pattern reversal) as well as mesenteric lymphadenopathy. Dr. Chu: Normal saline was administered intravenously, and sucralfate and dicyclomine were given orally. The patient was admitted to this hospital. Diarrhea and abdominal pain persisted on the second hospital day. Tests for human immunodeficiency virus (HIV) type 1 and type 2 antibodies and antigen, Treponema pallidum antibodies, Clostridium difficile antigen, and tissue transglutaminase IgA were negative. Blood testing for Helicobacter pylori IgG was positive; however, a stool test for H. pylori antigen was negative. Additional diagnostic tests were performed. Differ en t i a l Di agnosis Dr. Robert C. Lowe: This 44-year-old man presents with a subacute gastrointestinal illness that is characterized by epigastric pain, vomiting, diarrhea, and progressive weight loss during a 6-month period, with an intercurrent episode of neutrocytic, culture-negative meningitis. Laboratory findings are notable for marked hypoalbuminemia, elevated levels of inflammatory markers, an elevated fecal calprotectin level, and a fluctuating absolute eosinophil count that approaches the threshold for eosinophilia (1500 cells nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 367 The n e w e ng l a n d j o u r na l A B C D of m e dic i n e Figure 1. CT Scan of the Abdomen and Pelvis. A coronal reformation image (Panel A) shows prominent air­filled and fluid­filled loops of small bowel throughout the abdomen with mural thickening and enhancement (arrows). The jejunum, located in the left upper quadrant, lacks typical mural folds. An axial image of the pelvis (Panel B) shows dilatation of the ileum, thickening of the ileal wall, and prominent mural folds (arrows). An axial image of the transverse colon (Panel C) shows mild thickening of the haustral folds (arrows). An axial image of the midabdomen (Panel D) shows engorged mesenteric vessels (yel­ low dashed line) and a representative enlarged mesenteric lymph node (blue dashed line). This constellation of findings is compatible with diffuse enterocolonic inflammation. per microliter) but does not reach it. CT shows only marked hyperemia of the small bowel and evidence of mesenteric lymphadenopathy. This case raises several diagnostic possibilities, including cancer, autoimmune disease, and infection. likely, given the diffuse nature of the intestinal abnormality seen on CT imaging; nevertheless, we need to consider the possibility of lymphoma. The gastrointestinal tract is the most common extranodal site of lymphoma. In the United States, up to 75% of cases of gastrointestinal Cancer lymphoma involve the stomach, whereas less Although cancer must be included in the differ- than 10% involve the small bowel. However, in ential diagnosis, a malignant process seems un- the Middle East and the Mediterranean, primary 368 n engl j med 382;4 nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital small-bowel lymphoma accounts for most cases. This patient has evidence of H. pylori infection, which may contribute to lymphoma involving the mucosa-associated lymphoid tissue of the stomach. The Mediterranean variety of small-bowel lymphoma, known as immunoproliferative small intestinal disease, may be manifested by abdominal pain, diarrhea, malabsorption, and weight loss. The other small-bowel lymphomas include enteropathy-associated T-cell lymphoma (associated with celiac disease), Burkitt’s lymphoma, and B-cell lymphomas other than immunoproliferative small intestinal disease.1 Most often, these tumors are associated with obstruction, perforation, or hemorrhage, and although they can be associated with more subtle mucosal disease, the extent of this patient’s bowel abnormality makes these diagnoses unlikely. Lymphomas may also involve the meninges, but a neutrocytic meningitis that resolves after antibiotic therapy is not a feature of lymphomatous meningitis. several extraintestinal manifestations, but neurologic syndromes have not been described.3 Eosinophilic gastroenteritis is a rare inflammatory disorder of the gastrointestinal tract in which eosinophilic infiltration of the mucosa of the stomach and small bowel leads to abdominal pain, nausea, vomiting, and watery diarrhea, with weight loss occurring in a minority of patients. In some cases, the muscular layers of the gastrointestinal tract are involved, leading to gut dysmotility and obstructive symptoms. Serosal disease manifesting as ascites may also occur. Peripheral eosinophilia occurs in up to 80% of patients with eosinophilic gastroenteritis, and imaging studies may show wall thickening of the gastric antrum and small bowel. The diagnosis of this condition is made by examination of endoscopic biopsy specimens, which show eosinophilic infiltration of the gut wall.4 This patient does not have persistent absolute eosinophilia, which makes this diagnosis unlikely. Infection Autoimmune Disease Celiac disease, which can cause a subacute syndrome of diarrhea and weight loss as well as hypoalbuminemia and evidence of mucosal hyperemia on imaging, is a consideration in this case. This patient had a negative tissue transglutaminase IgA test, but the total IgA level is not reported. When considering celiac disease, it is important to first rule out concomitant IgA deficiency. If the total IgA level is low, a tissue transglutaminase IgG test should be performed. However, in this case, the evidence of mesenteric lymphadenopathy that was seen on CT and the episode of meningitis are not characteristic of celiac disease. Although celiac disease may have neurologic manifestations, including seizures, neuropathy, ataxia, and cognitive slowing, it is not manifested by meningeal symptoms.2 Autoimmune enteropathy is a rare disorder that can lead to subacute diarrhea and weight loss. It is characterized by a lymphocytic immune reaction that causes enterocyte destruction and intestinal villous blunting that can mimic severe celiac disease. The presence of antienterocyte or anti–goblet-cell antibodies is suggestive of this disorder, and intestinal biopsies typically show villous blunting and evidence of lymphocytosis in the intestinal crypts. Autoimmune enteropathy has been associated with n engl j med 382;4 Many HIV-associated infections can cause a prolonged diarrheal syndrome with weight loss, and the presence of diffuse bowel abnormality and mesenteric lymphadenopathy on CT imaging in this patient is consistent with Mycobacterium avium complex infection. However, this patient’s HIV screening test was negative, which rules out opportunistic infections resulting from advanced HIV infection. I would be remiss if I did not raise the possibility of Whipple’s disease in this case. Whipple’s disease may be manifested by a subacute wasting illness. Infection with Tropheryma whipplei leads to infiltration of foamy macrophages into the small bowel, which results in a syndrome of abdominal pain, diarrhea, and malabsorption that is typically accompanied by joint pain. Other extraintestinal features include fever, lymphadenopathy, and central nervous system abnormalities, such as dementia, cerebellar ataxia, and in rare cases, oculomasticatory myorhythmia. Central nervous system involvement may be manifested by mild lymphocytic pleocytosis in the CSF with an elevated total protein level. The diagnosis of Whipple’s disease can be made by periodic acid–Schiff staining of a small-bowel biopsy specimen, which would show foamy macrophages in the lamina propria of the gut. The organism can be identified on electron micros- nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 369 The n e w e ng l a n d j o u r na l copy of biopsy specimens or with PCR testing of biopsy specimens or peripheral blood.5 The absence of joint symptoms and the occurrence of an acute episode of neutrocytic meningitis are atypical for this rare disease, making it an unlikely diagnosis in this case. Tropical sprue should always be considered in patients from the Caribbean who present with a wasting diarrheal illness. This disorder is thought to be due to an uncharacterized intestinal infection that leads to persistent small-bowel mucosal damage. Patients may have severe hypoalbuminemia as well as diffuse bowel-wall edema similar to that seen on this patient’s imaging studies. However, this patient has mesenteric lymphadenopathy, which is not a characteristic of tropical sprue. Patients with tropical sprue typically have megaloblastic anemia, which results from both folate deficiency and vitamin B12 deficiency, and neutrocytic meningitis is not a feature of this disorder. Treatment of tropical sprue includes folate repletion and a prolonged course of tetracycline.6 In a patient who is from a tropical region of the world and has persistent gastrointestinal symptoms, parasitic infestation should also be considered. A common parasitic infection that seems to fit with this patient’s presentation is strongyloidiasis with an associated hyperinfection syndrome. Strongyloides stercoralis is a nematode that is endemic in large parts of the tropics and subtropics. Infection begins with inoculation of the skin with filariform larvae that reside in the soil. The larvae migrate through the skin into the bloodstream, which carries them to the lungs. The organisms then penetrate the alveolar wall and ascend the bronchi and trachea until they reach the pharynx, where they are swallowed and subsequently come to rest in the proximal small bowel. The larvae mature into adult worms that inhabit the mucosa of the gut, where they shed eggs that hatch into rhabditiform larvae that are eventually excreted in the stool. A well-known characteristic of strongyloides is that it can complete its life cycle within the human host. In this autoinfection cycle, the rhabditiform larvae mature into invasive filariform larvae in the small bowel and colon and then burrow through the bowel wall or perianal skin to restart the life cycle within the same host. In this way, the infection can last for de- 370 n engl j med 382;4 of m e dic i n e cades after the patient has left the region where the organism is endemic.7 There are several gastrointestinal manifestations of strongyloidiasis, including epigastric pain, nausea, and vomiting, features that mimic peptic-ulcer disease. Watery diarrhea is a common manifestation that may be accompanied by frank malabsorption of fat and vitamin B12. Malabsorption syndrome can mimic celiac disease or tropical sprue and may manifest as a protein-losing enteropathy, characterized by hypoalbuminemia and peripheral edema. Hyperinfection syndrome is associated with a greatly increased worm burden, which often occurs in the context of immunosuppression or human T-lymphotropic virus type 1 (HTLV-1) infection. The nematode becomes more invasive, penetrating the bowel mucosa and causing watery or bloody stools and severe abdominal pain. The worms often carry bowel flora, typically gramnegative bacteria, through the intestinal wall, leading to episodes of bacteremia or meningitis. Although a bacterial cause can be identified in most cases of meningitis, neutrocytic, culturenegative meningitis has been described in association with strongyloidiasis.8 This patient is from a region in which strongyloides is endemic, and he has a subacute wasting illness with abdominal pain, diarrhea, hypoalbuminemia, and evidence of a diffuse small-bowel abnormality on imaging. He has mild intermittent eosinophilia and had an episode of apparent bacterial meningitis that responded to antibiotic therapy. His transient episodes of hemoptysis are consistent with the pulmonary phase of autoinfection; although the chest CT report does not support this hypothesis, the eosinophilic infiltrates associated with strongyloidiasis (known as the Löffler syndrome) may be transient. All the features of this patient’s presentation are consistent with strongyloidiasis with hyperinfection syndrome. Although the patient is not known to be immunosuppressed, he may have acquired HTLV-1 infection, which would contribute to the hyperinfection cascade. To establish this diagnosis, I would begin his workup with a stool examination for rhabditiform larvae; if the examination is negative, I would perform esophagogastroduodenoscopy as well as a duodenal biopsy to look for mucosal infestation with this parasite. nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital A B C D Figure 2. Upper and Lower Endoscopic Images. Endoscopic views of the stomach (Panel A) and duodenum (Panel B) show diffuse edema and subepithelial hemor­ rhages, and diffuse edema and small erosions are seen in the colon (Panel C). The terminal ileum (Panel D) is nota­ ble for a loss of villi. Dr . Rober t C . L ow e’s Di agnosis Strongyloidiasis with hyperinfection syndrome. Pathol o gic a l Discussion Cl inic a l Impr e ssion a nd End osc opic E va luat ion Dr. Chu: Our differential diagnosis included strongyloidiasis, celiac disease, tropical sprue, giardia infection, Whipple’s disease, inflammatory bowel disease, eosinophilic gastroenteritis, and microscopic colitis. To assess for these conditions, we performed upper and lower endoscopy (Fig. 2). On the upper endoscopy, diffuse edema and subepithelial hemorrhages were noted throughout the stomach (Fig. 2A) and duodenum (Fig. 2B), and diffuse edema and small erosions were present throughout the colon (Fig. 2C). The terminal ileum (Fig. 2D) had a notable loss of n engl j med 382;4 villi. We obtained biopsy specimens throughout the upper and lower gastrointestinal tract. Dr. John A. Branda: Histologic examination of the biopsy specimens of the gastrointestinal mucosa revealed moderately active gastritis, duodenitis, ileitis, and colitis, along with abundant nematodes and ova diagnostic of strongyloidiasis (Fig. 3). A stool examination for ova and parasites was also positive for a moderate amount of S. stercoralis rhabditiform larvae (Fig. 4). Separately, a blood enzyme-linked immunosorbent assay for HTLV-1 and HTLV-2 IgG was reactive, and an immunoassay for HTLV-1 and HTLV-2 showed seroreactivity with a band pattern that met the criteria for HTLV-1 infection. Thus, the final diagnosis was strongyloidiasis with HTLV-1 coinfection. nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 371 The n e w e ng l a n d j o u r na l of m e dic i n e A Figure 4. Stool Preparation. A concentrated wet preparation of stool contained rhabditiform larvae of S. stercoralis. Characteristic features of the larvae include a short buccal canal, a bulbous esophagus, a prominent genital primor­ dium, and a pointed tail. B Figure 3. Biopsy Specimen of the Duodenum. Hematoxylin and eosin staining of a duodenal­biopsy specimen shows dense inflammatory infiltrates involv­ ing the lamina propria, with prominent eosinophils. The crypt epithelium contains Strongyloides stercoralis ova (Panel A, arrows), larvae (Panels A and B, arrow­ heads), and adult worms (Panel B, arrows). The mor­ phologic features and the simultaneous presence of ova, larval nematodes, and adult nematodes in the mu­ cosal tissue are diagnostic of S. stercoralis infection. Discussion of M a nagemen t Dr. Ana A. Weil: S. stercoralis is a nematode that causes strongyloidiasis, which can be asymptomatic or manifested by a range of symptoms, including shock. Mild infections are most likely to be characterized by nonspecific gastrointestinal symptoms or incidentally identified peripheral eosinophilia. Among patients with a high burden of disease, pulmonary, gastrointestinal, and skin symptoms can be present, and infections such as bacteremia and meningitis with enteric organisms can occur owing to translocation of bacteria enabled by migration of the 372 n engl j med 382;4 adult worm or larvae out of the intestinal lumen. For this reason, culture-negative bacterial meningitis in an otherwise healthy adult who has not had intracranial interventions should arouse suspicion for strongyloidiasis. In this case, it is likely that meningitis was a consequence of strongyloidiasis due to transient bacteremia from migrating organisms. Although meningitis can also be caused by bacterial contamination from worm migration across the blood–brain barrier, this situation is rare and typically occurs in patients with disseminated infection in whom the burden of nematodes can be found in many organs. This patient’s presentation is more typical of hyperinfection with severe single-organ intestinal disease than of classic disseminated strongyloidiasis, which usually manifests as multiorgan dysfunction due to widespread tissue infiltration by rhabditiform larvae. The severity of symptoms is closely related to the patient’s cell-mediated immune status. In this case, infection with HTLV-1 is the patient’s most important risk factor, because HTLV-1 increases both the likelihood of strongyloidiasis and the severity of disease.9,10 Studies indicate that peripheral-blood mononuclear cells of patients with HTLV-1 infection produce a higher amount of γ-interferon and a lower amount of polyclonal, parasite-specific IgE than the amounts produced in patients without HTLV-1 infection,11,12 which may result in decreased immunologic control of nejm.org January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. Case Records of the Massachuset ts Gener al Hospital infection among HTLV-1–infected patients. Among patients with hyperinfection, such as this patient, and especially among those with disseminated disease with organ infiltration due to widespread organisms, peripheral eosinophilia is often absent.13 Additional risk factors that increase the likelihood of strongyloidiasis include glucocorticoid use and other forms of immunosuppression that result in decreased cell-mediated immunity. In this patient, the administration of glucocorticoids, although brief, is likely to have contributed to the overall nematode burden and consequent symptoms. Treatment options for strongyloidiasis have not been well studied. As with many neglected tropical diseases, clinical trials are small and are rarely conducted. For uncomplicated infection, the Centers for Disease Control and Prevention recommends a weight-based dose of ivermectin (200 μg per kilogram of body weight), administered once daily for 1 or 2 days.14 Persistent symptoms after ivermectin treatment should arouse suspicion for treatment failure. Although declining serologic titers may be reassuring and indicative of cure, quantitative serologic tests are not widely available.15 For hyperinfection or disseminated disease, treatment with ivermectin at a daily dose of 200 μg per kilogram is recommended, at least until stool examinations are negative and symptoms are resolved; repeat examination of the stool is recommended thereafter to test for relapse.16 Because persons who have compromised cell-mediated immunity, including those with HTLV-1 infection, are at risk for treatment failure, continued monitoring of these patients is recommended.17 A high suspicion of disease is critical for reaching a diagnosis of strongyloidiasis, especially considering the high prevalence of the condition in many areas of the world. For example, among newly arrived refugees to the United States who are found to have asymptomatic peReferences 1. Lightner AL, Shannon E, Gibbons MM, Russell MM. Primary gastrointestinal non-Hodgkin’s lymphoma of the small and large intestines: a systematic review. J Gastrointest Surg 2016;20:827-39. 2. Hadjivassiliou M, Croall ID, Zis P, et al. Neurologic deficits in patients with newly diagnosed celiac disease are frequent and linked with autoimmunity to ripheral eosinophilia, more than half will have a parasitic infection, and strongyloides is a common culprit.18 In general, we suggest testing for strongyloidiasis in persons who have geographic risk factors and present with peripheral eosinophilia or symptoms involving the gastrointestinal or respiratory system or the skin. Hyperinfection or disseminated disease should be included in the differential diagnosis in persons who are from areas in which strongyloides is endemic and who present with unexpected infections involving enteric pathogens, especially in combination with symptoms involving the skin or respiratory or gastrointestinal tract. Suspicion of hyperinfection or disseminated disease would be increased in persons from areas in which HTLV-1 is endemic or in persons in whom immunosuppressive therapy, particularly glucocorticoids, is used. Dr. Chu: Because of the severity of this patient’s presentation, he was treated with ivermectin (200 μg per kilogram per day) for 14 days, followed by tapering doses every 2 weeks for 1 month. He continued to receive monthly treatment with ivermectin thereafter, given that he was infected with HTLV-1 and had a high risk of persistent and recurrent infection. Serial stool evaluation was negative. His gastrointestinal symptoms resolved completely, and he gained back more than 23 kg over the course of several months after he began treatment. Pathol o gic a l Di agnosis Strongyloidiasis with human T-lymphotropic virus type 1 infection. This case was presented at the Medical Case Conference. Dr. Lowe reports receiving fees for serving as a reviewer from GI Reviewers; and Dr. Branda, receiving grant support from Zeus Scientific, bioMérieux, and Immunetics, and consulting fees from T2 Biosystems, DiaSorin, and Roche Diagnostics. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. transglutaminase 6. Clin Gastroenterol Hepatol 2019;17(13):2678-2686.e2. 3. Gentile NM, Murray JA, Pardi DS. Autoimmune enteropathy: a review and update of clinical management. Curr Gastroenterol Rep 2012;14:380-5. 4. Zhang M, Li Y. Eosinophilic gastroenteritis: a state-of-the-art review. J Gastroenterol Hepatol 2017;32:64-72. n engl j med 382;4 nejm.org 5. Marth T, Moos V, Müller C, Biagi F, Schneider T. Tropheryma whipplei infection and Whipple’s disease. Lancet Infect Dis 2016;16(3):e13-e22. 6. Sharma P, Baloda V, Gahlot GP, et al. Clinical, endoscopic, and histological differentiation between celiac disease and tropical sprue: a systematic review. J Gastroenterol Hepatol 2019;34:74-83. January 23, 2020 The New England Journal of Medicine Downloaded from nejm.org on April 4, 2020. For personal use only. No other uses without permission. Copyright © 2020 Massachusetts Medical Society. All rights reserved. 373 Case Records of the Massachuset ts Gener al Hospital Krolewiecki A, Nutman TB. Strongyloidiasis: a neglected tropical disease. Infect Dis Clin North Am 2019;33:135-51. 8. Mukaigawara M, Nakayama I, Gibo K. Strongyloidiasis and culture-negative suppurative meningitis, Japan, 1993-2015. Emerg Infect Dis 2018;24:2378-80. 9. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17: 208-17. 10. Hayashi J, Kishihara Y, Yoshimura E, et al. 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Kobayashi J, Sato Y, Toma H, Takara M, Shiroma Y. Application of enzyme immunoassay for postchemotherapy evaluation of human strongyloidiasis. Diagn Microbiol Infect Dis 1994;18:19-23. 16. Segarra-Newnham M. Manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. Ann Pharmacother 2007;41:1992-2001. 17. Terashima A, Alvarez H, Tello R, Infante R, Freedman DO, Gotuzzo E. Treatment failure in intestinal strongyloidiasis: an indicator of HTLV-I infection. Int J Infect Dis 2002;6:28-30. 18. Seybolt LM, Christiansen D, Barnett ED. Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Clin Infect Dis 2006;42:363-7. Copyright © 2020 Massachusetts Medical Society. journal archive at nejm.org Every article published by the Journal is now available at NEJM.org, beginning with the first article published in January 1812. The entire archive is fully searchable, and browsing of titles and tables of contents is easy and available to all. 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