A Gut Feeling 2008

clinical problem-solving

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;1 www.nejm.org july 3, 2008 75

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with

the reader (regular type). The authors’ commentary follows.

From the Interdepartmental Division of Critical Care Medicine (E.F.) and the De-partment of Medicine (E.F., K.C.K., A.S.D.), the McLaughlin–Rotman Centre for Glob-al Health (K.C.K.), the McLaughlin Centre for Molecular Medicine (K.C.K.), and the Department of Health Policy, Manage-ment, and Evaluation (A.S.D.), University of Toronto; the Ontario Provincial Health Laboratory (K.C.K.) and the Department of Medicine (K.C.K., A.S.D.), Mount Sinai Hospital and University Health Network — all in Toronto; and the Department of Medicine, William Osler Health Centre, Etobicoke, ON, Canada (C.S.). Address reprint requests to Dr. Detsky at Mount Sinai Hospital, 600 University Ave., Suite 427, Toronto, ON M5G 1X5, Canada, or at [email protected].

N Engl J Med 2008;359:75-80.Copyright © 2008 Massachusetts Medical Society.

A 72-year-old man presented with a 3-month history of watery diarrhea. This condi-tion was associated with intermittent fevers, abdominal pain, and weight loss of 15 lb (6.8 kg).

This patient’s symptoms may be due to a number of infectious or noninfectious causes, including persistent intestinal infections, inflammatory enteropathies, and neoplastic disorders. More details regarding the frequency and volume of diarrhea would be helpful. A history of recent travel or evidence of immunosuppression would extend the differential diagnosis to include a broader array of potential causal agents. Since infectious diseases, notably intestinal protozoa, are common causes of chronic diarrhea, appropriate initial investigations would include the ex-amination of stool for ova and parasites (including special stains for cryptospo-ridia and cyclospora), stool culture, and an assay for Clostridium difficile toxin.

The patient was originally from the Philippines and had immigrated to Canada 8 years earlier. Since then, he had visited the Philippines on a regular basis, most recently approximately 9 months before presentation. During the most recent trip, when he had visited both urban and rural areas, he had had no symptoms. His symptoms had begun 6 months after his return to Canada. He had no medical or family history as-sociated with his symptoms and was taking no regular medications.

Although the prolonged time between the patient’s most recent travel to the Philip-pines and the reported onset of his gastrointestinal symptoms makes a travel-associ-ated infection less likely, infectious agents — particularly parasites — must routinely be considered in patients with chronic diarrhea after traveling. These infections range from common ones (e.g., giardiasis, cryptosporidiosis, and amebiasis) to less frequent ones (e.g., isosporiasis, strongyloidiasis, and schistosomiasis) to rare and geographically restricted ones (e.g., Capillaria philippinensis), all of which may present months after exposure. Other important diagnostic considerations include intesti-nal tuberculosis, tropical sprue, and global pathogens that are either common (e.g., human immunodeficiency virus [HIV]) or uncommon (e.g., Tropheryma whippelii), although the patient had no history of extraintestinal manifestations (e.g., arthal-gia, lymphadenopathy, and neurologic and cardiovascular symptoms) to support the diagnosis of Whipple’s disease. Noninfectious causes to consider include in-flammatory bowel disease, adult-onset celiac disease, and neoplastic disorders (e.g., intestinal lymphoma, villous adenoma, and functional neuroendocrine tumors, such as gastrinoma, carcinoid, and vasoactive intestinal polypeptide–secreting tumor).

A Gut FeelingEddy Fan, M.D., Christine Soong, M.D., Kevin C. Kain, M.D.,

and Allan S. Detsky, M.D., Ph.D.

The New England Journal of Medicine Downloaded from nejm.org on May 25, 2013. For personal use only. No other uses without permission.

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n engl j med 359;1 www.nejm.org july 3, 200876

On examination, the patient was afebrile; his blood pressure was 110/60 mm Hg, and his heart rate was 70 beats per minute. There was no palpable lymphadenopathy. The abdominal examination was benign, and the remainder of the physical ex-amination was normal. The white-cell count was 10.7×103 per cubic millimeter (neutrophils, 59%; lymphocytes, 25%; monocytes, 10%; and eosino-phils, 6%). The hemoglobin concentration was 13.7 g per deciliter. The levels of serum electro-lytes, creatinine (1.0 mg per deciliter [88 μmol per liter]), liver enzymes (including alkaline phos-phatase), and bilirubin were within normal limits. A single stool sample was negative for ova and parasites. Abdominal ultrasonography revealed no abnormalities.

Although peripheral eosinophilia may be observed in a number of noninfectious diseases, including allergic, rheumatologic, and neoplastic disorders, it is frequently associated with migrating and tissue-resident helminthic infections. Commonly recognized causes of eosinophilia in immigrants from Asia are hookworm and Strongyloides stercoralis infection. Strongyloidiasis is a potentially fatal infection that may cause persistent diarrhea and malabsorption. Hookworm (e.g., Ancylostoma duodenale) may be associated with diarrhea in cases of massive infection, but anemia would have been expected. Other helminthic infections acquired in the Philippines that may cause eosinophilia and gastrointestinal symptoms include schistosomia-sis (which may cause intermittent diarrhea), trichinellosis (typically associated with early short-term diarrhea), and intestinal trematode infec-tions associated with diarrhea (such as echinos-tomiasis). However, none of these infections would routinely be expected to present with persistent diarrhea and weight loss. Other than strongy-loidiasis, capillariasis is the only other helminth from this geographic region in which chronic di-arrhea, weight loss, and persistent eosinophilia would be the expected presentation. Protozoan parasites are generally not associated with periph-eral eosinophilia, with the exception of isospo-riasis, which may cause chronic diarrhea and weight loss, especially in immunocompromised patients.

Simultaneous infection with multiple agents is common with parasitic infections and may produce a complicated clinical syndrome. Multi-ple fecal samples should be examined, as well as

endoscopic biopsy specimens from the small bowel and content sampling for ova and para-sites. A fecal culture for strongyloides and sero-logic testing for strongyloidiasis and schistoso-miasis should be performed. Serologic testing for other helminths (e.g., trichinellosis, toxocariasis, and filariasis) should be considered if there was a suggestive exposure history (e.g., consumption of poorly cooked pork).

The patient was referred to a gastroenterologist and underwent panendoscopy. Upper endoscopy revealed mild gastritis and normal-appearing small-bowel mucosa. Colonoscopy revealed patchy areas of mild inflammation and bowel-wall edema consistent with resolving infectious colitis. The duodenal biopsy was normal. Specimens from random colonic biopsies were consistent with nonspecific chronic inflammation with marked eosinophilia (Fig. 1). A biopsy of the terminal ileum captured fragments of an adult helminth embedded within the mucosa (Fig. 2A). The pa-thology report stated the fragment had features suggestive of a cestode scolex, but the exact spe-cies could not be determined. Correlation with clinical presentation and stool microscopic and culture results was recommended.

Humans can serve as hosts for several intestinal cestodes (e.g., diphyllobothrium, hymenolepis, and taenia species), but adult forms do not invade the host, and infections are generally asymptom-

Figure 1. Biopsy Specimen of Colonic Mucosa.

The lamina propria is markedly expanded by a mixed infiltrate of inflammatory cells, including abundant eosinophils (hematoxylin and eosin staining). No para-sitic organisms were identified in the multiple colonic-biopsy specimens that were obtained.





atic. However, since persistent diarrhea, weight loss, and eosinophilic colitis would be uncom-mon with the cestodes mentioned above and since polyparasitism is common, evidence of al-ternative parasitic causes, including strongyloidi-asis, should still be sought. The biopsy specimen should be reviewed as soon as possible with a parasitologist to facilitate identification and prompt initiation of specific therapy. If repeat stool samples are negative for ova and parasites, repeat colonoscopy with small-bowel aspirate or biopsy should be performed, and colonic-biopsy specimens should be reviewed for Schistosoma japonicum ova.

Serologic testing for strongyloidiasis was or-dered. Testing for HIV was negative. Three stool samples that were collected on different days were negative for ova and parasites. Abdominal com-puted tomography (CT) with the administration of an intravenous contrast material revealed no important abnormalities. Because of the low like-lihood that infection with a cestode was causing the patient’s symptoms and the lack of confirma-tory stool testing for an active cestode infection, no antimicrobial therapy was initiated pending clinical reassessment. A month later, the patient’s symptoms had improved without any therapy.

Four weeks after the follow-up visit at which the patient reported improvement, his diarrhea worsened (8 to 10 bowel movements per day) with associated episodes of presyncope, for which he was admitted to the hospital. On examination, the patient appeared cachectic. His temperature was 35.6°C, his blood pressure 100/70 mm Hg, his heart rate 110 beats per minute, and his res-piratory rate 21 breaths per minute. His oxygen saturation was 100% while breathing ambient air. His lungs were clear to auscultation. Cardiac examination was normal except for a low jugular venous pressure. The abdominal examination re-vealed hyperactive bowel sounds but was other-wise normal. Bilateral edema was present in the lower limbs. The remainder of the physical exami-nation was normal.

The white-cell count was 13.3×103 per cubic

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Figure 2. Specimens from the Patient Showing the Presence of a Rare Helminth.

In Panel A, a biopsy specimen from the terminal ileum of the patient shows a portion of a helminth attached to the surface epithelium (arrow, hematoxylin and eosin staining). The initial pathology report stated the frag-ment had features suggestive of a cestode scolex, but the exact species could not be determined. The mucosa shows a loss of normal villous architecture, and the lamina propria includes a mixed infiltrate of inflamma-tory cells. In Panel B, in a fecal specimen obtained from the patient after his hospital admission, eggs are visible in the uterus of an adult female Capillaria philippinensis. In Panel C, an egg of C. philippinensis that was obtained from the patient has characteristic flattened bipolar plugs, which along with the striated shell and quadrate shape help to distinguish the eggs of C. philippinensis from those of a more common helminth, Trichuris trichiura (whipworm). The eggs were 36 to 45 μm long and 21 μm wide. (Photographs in Panels B and C are courtesy of Don Martin and Billy Yu, Ontario Provincial Health Laboratory.)





millimeter (neutrophils, 70%; lymphocytes, 21%; monocytes, 6%; and eosinophils, 3%). The hemo-globin concentration was 14.2 g per deciliter, and the platelet count was 418×103 per cubic millimeter. The serum sodium level was 129 mmol per liter; potassium, 3.2 mmol per liter; chloride, 105 mmol per liter; and bicarbonate, 14 mmol per liter. Serum urea was 10.2 mg per deciliter (3.6 mmol per liter), and creatinine was 1.3 mg per deciliter (115 μmol per liter). Aspartate and alanine amino-transferase levels were 53 and 41 IU per liter, re-spectively. Alkaline phosphatase was 65 IU per liter. Serum albumin was less than 1.0 g per deci-liter. Cardiac enzymes were within normal limits. Chest radiography was normal. Three separate stool samples were sent for culture and examina-tion for ova and parasites. The patient was started on intravenous hydration with 2 liters of normal saline, and a single 600-mg dose of oral praziquan-tel was given for a presumed cestode infection.

The patient now fulfills the criteria for sepsis with evidence of hypovolemia and metabolic acidosis. I would undertake a comprehensive clinical and laboratory evaluation to assess for evidence of other organ system involvement (for example, ad-renal insufficiency and coagulopathy). Adequate source control of the infection, presumed to be in the gastrointestinal tract, should be obtained if possible. Rapid volume resuscitation should be continued in keeping with early goal-directed therapy for sepsis. Given his acute deterioration, ongoing monitoring and assessment should be performed in an intensive care unit (ICU).

Although he may have multiple potential sources of infection, the history of chronic diar-rhea, peripheral eosinophilia, and past residence in a region in which strongyloides is endemic suggests possible disseminated strongyloidiasis, which occurs when large numbers of parasite larvae breach the intestinal mucosa and invade multiple organs, causing a life-threatening syn-drome that is frequently complicated by polymi-crobial sepsis or meningitis. Although more common in patients with immunosuppression, disseminated strongyloidiasis occasionally occurs in patients with no apparent underlying medical condition. The preceding negative stool exami-nation does not exclude a parasitic infection, since the sample may have been collected during the prepatent period (i.e., the time between in-fection and the production of detectable ova or

larvae) or because the target organism may have been shed inconsistently or in low numbers, as is frequently the case with strongyloides larvae.

Since disseminated strongyloidiasis can be rapidly fatal, broad-spectrum antibiotics should be started for possibly associated polymicrobial sepsis. Additional stool or endoscopy samples should be urgently examined for strongyloides larvae. Any change in respiratory status or chest radiography should prompt an examination of bronchoscopy and sputum samples for larvae. If evidence of strongyloidiasis is found, ivermectin and albendazole should be started.

Despite aggressive fluid resuscitation with more than 4 liters of crystalloid, the patient continued to have significant hypotension (blood pressure, 70/40 mm Hg) and was transferred to the ICU. Norepinephrine and bicarbonate infusions were initiated for hemodynamic support and worsen-ing non–anion gap metabolic acidosis, respective-ly. Stool cultures were positive for campylobacter, and an assay for C. difficile toxin was also positive. Radiography of the abdomen revealed gas through-out the small and large bowel with no evidence of toxic megacolon or obstruction. Intravenous azithromycin, metronidazole, and oral vancomy-cin were started.

Septic shock has been described with both campy-lobacter and C. difficile infections but is relatively rare. C. difficile is typically associated with previ-ous antibiotic use and nosocomial acquisition, but an increased rate of community-acquired dis-ease has been reported even in patients without previous antibiotic exposure. Although abdomi-nal radiography did not show evidence of severe disease (e.g., perforation or toxic megacolon), CT might reveal subclinical perforations or abscesses. However, these infections do not explain other features of this patient’s presentation (e.g., eosino-philia); they are probably superimposed on the underlying problem rather than being the pri-mary cause. Therefore, broader antimicrobial cov-erage for presumed polymicrobial sepsis should be initiated, along with a continued attempt to identify other potential causes, including strongy-loidiasis.

After the initiation of antibiotics, the patient’s hypotension improved, and he was weaned off norepinephrine. However, he continued to have





5 to 6 liters of diarrhea per day. A random serum cortisol level was 21.4 μg per deciliter (590 nmol per liter); after stimulation with corticotropin, the level rose to 25.4 μg per deciliter (701 nmol per liter) at 30 minutes and 22.4 μg per deciliter (618 nmol per liter) at 60 minutes. At 24 hours, the urinary level of 5-hydroxyindoleacetic acid was normal. The patient underwent upper and lower endoscopy, which revealed evidence of small, nonbleeding pyloric channel ulcers but no colonic pseudomembranes. A random duodenal biopsy revealed a possible helminth ovum in a single gland with no other significant abnormali-ties. Blood and stool cultures were negative.

The elevated random cortisol level rules out frank adrenal insufficiency, but the modest increment after corticotropin stimulation suggests the pos-sibility of relative adrenal insufficiency compli-cating sepsis. Infectious diarrhea may unmask underlying gastrointestinal disease, although small-bowel endoscopy and biopsy have not re-vealed evidence of tropical or celiac sprue, inflam-matory bowel disease, or Whipple’s disease. The history of duodenal ulcers and diarrhea also prompts consideration of noninfectious causes, in-cluding the Zollinger–Ellison syndrome. Though the abdominal CT was normal, gastrinomas may be small and difficult to detect. Other neoplastic disorders (e.g., intestinal lymphomas and carci-noid) are unlikely, owing to the lack of support-ing clinical evidence for these diagnoses.

Although it is unusual for a helminth infec-tion to produce the severe diarrhea observed in this patient, strongyloidiasis and capillariasis are capable of doing so, and both can be associated with ova in the small bowel. Both of these infec-tions may be life-threatening because of their ability to autoinfect their hosts. The ova in the biopsy specimen should be reviewed to identify the species and initiate specific treatment.

During the next 72 hours, the patient continued to have worsening watery diarrhea, producing nearly 10 liters per day. Total parenteral nutrition was administered. He required ongoing aggressive fluid resuscitation and was restarted on norepi-nephrine and vasopressin infusions for hemody-namic support. He developed worsening pulmo-nary edema and was intubated for hypoxemic respiratory failure. Serologic analysis for strongy-loides returned and was negative. Stool sent for

ova and parasites at the time of hospital admission came back positive for nematode C. philippinensis (Fig. 2B and 2C). A 200-mg dose of albendazole was administered orally twice daily. Ten hours later, the patient had an asystolic cardiac arrest and died. A request for an autopsy was declined by the family.

Discussion

An important component of clinical problem solving, as evidenced in this case, is the concept of “context specificity”; successful clinical reason-ing is strongly related to having the appropriate content knowledge.1 This concept challenges the classical model of hypothetico-deductive reason-ing (i.e., generating numerous hypotheses and then eliminating them as new information is ob-tained), since both novice and expert clinicians use this method.2 The difficulty in making the diagnosis in this case was multifactorial but prob-ably due, in large part, to the rarity of intestinal capillariasis in North America. To our knowledge, this case was the first report of human intestinal capillariasis diagnosed in Canada or in the United States. However, appropriate context specificity is probably the explanation for why our discus-sant, whose expertise is in tropical medicine, in-cluded intestinal capillariasis in his initial dif-ferential diagnosis on the basis of a limited amount of data.

Intestinal capillariasis that is caused by C. philippinensis is a relatively recent infection discov-ered in humans, first described in 1963.3 Though the disease is uncommon, reports of C. philippinensis infection are growing and spreading geo-graphically. Cases have been reported in South-east Asia, the Middle East, and southern Europe.4 Humans acquire C. philippinensis mainly through the ingestion of raw freshwater fish. After an asymptomatic phase, abdominal pain, borboryg-mus, and intermittent diarrhea typically develop as the worm burden increases through autoin-fection.5 Over time, the diarrhea may progress to frequent voluminous stools, resulting in sig-nificant dehydration, electrolyte imbalances, and weight loss. Unlike infections with many other intestinal nematodes, C. philippinensis infection will frequently lead to death if left untreated for weeks to months, typically owing to cardiomyo-pathy from irreversible electrolyte losses or sep-





sis from secondary bacterial infection.6 The treat-ment of choice is a 10-day course of albendazole, which is effective against both larval and adult worms. Supportive treatment, with judicious fluid and electrolyte replacement and a high-protein diet, should accompany antihelminthic therapy. Symptomatic improvement typically occurs with-in days to weeks.

The initial clinical presentation of intestinal capillariasis is nonspecific, and diagnosis rests on identifying eggs, larvae, or adult worms in intestinal content or biopsy specimens. These may be difficult to identify, and the inexperi-enced observer may confuse them with other helminths.4 In the present case, the histopatho-logical report from the small-bowel biopsy re-vealed a helminth with features suggestive of a cestode scolex; subsequent review of this speci-men by the discussant revealed features sugges-tive of capillaria. In this case, lack of “context specificity” led to the failure to correctly identify the helminth on initial pathological examination.

Multiple stool samples and intestinal biopsy specimens or aspirates should be examined to make and confirm the diagnosis (Fig. 2B and 2C). However, given the deleterious consequences of delays in treatment, empiric antihelminthic ther-apy should be considered for patients from areas in which helminths are endemic, and capillari-

asis should be suspected if a definitive diagnosis cannot be established in a timely manner.

The delay in diagnosis in the present case highlights the importance of timely review of histopathological specimens and early expert con-sultation when a diagnosis is difficult, particu-larly in cases such as this, in which diagnostic possibilities included imported infections unfa-miliar to the treating physicians. Online search engines, such as Google, may be especially help-ful in diagnosing difficult and rare cases.7,8 We performed a search (at www.google.com on Oc-tober 4, 2007) using the key words “Philippines,” “endemic,” “parasite,” and “chronic diarrhea,” which yielded approximately 24,300 hits, of which the first 2 hits were case reports of intestinal capillariasis. Given the rapidly growing body of medical knowledge, especially in the recognition of rare diseases, Internet search engines are proving to be an invaluable diagnostic tool.

Supported by a Fellowship Award from the Canadian Insti-tutes of Health Research and a Detweiler Traveling Fellowship from the Royal College of Physicians and Surgeons of Canada (to Dr. Fan) and a grant from the Canadian Institutes of Health Research (to Dr. Kain).

No potential conflict of interest relevant to this article was reported.

We thank Mahin Baqi, M.D., and Steven Loken, M.D., both from the William Osler Health Centre, for their assistance in the preparation of the manuscript and of the pathological images in Figures 1 and 2A, respectively.

References

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Elstein AS, Schwartz A. Clinical prob-2. lem solving and diagnostic decision mak-ing: selective review of the cognitive litera-ture. BMJ 2002;324:729-32. [Erratum, BMJ 2006;333:944.]

Chitwood MB, Valasquez C, Salazar 3. NG. Capillaria philippinensis sp. n. (Nematoda:

Trichinellida) from intestine of man in the Philippines. J Parasitol 1968;54:368-71.

Bair MJ, Hwang KP, Wang TE, et al. 4. Clinical features of human intestinal cap-illariasis in Taiwan. World J Gastroenterol 2004;10:2391-3.

Whalen GE, Rosenberg EB, Strickland 5. GT, Gutman RA, Cross JH, Watten RH. Intestinal capillariasis: a new disease in man. Lancet 1969;1:13-6.

Cross JH. Intestinal capillariasis. Clin 6. Microbiol Rev 1992;5:120-9.

Greenwald R. . . . And a diagnostic 7. test was performed. N Engl J Med 2005; 353:2089-90.

Tang H, Ng JHW. Googling for a diag-8. nosis — use of Google as a diagnostic aid: Internet based study. BMJ 2006;333: 1143-5.Copyright © 2008 Massachusetts Medical Society.

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A Gut Feeling 2008

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