A 59-Year-Old Man with Abdominal Pain and Weight Loss. Parnita Harsh Rhymia Raspberry Sean McCarty Christopher Choi

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1 A 59-Year-Old Man with Abdominal Pain and Weight Loss Parnita Harsh Rhymia Raspberry Sean McCarty Christopher Choi

2 Who Is Our Patient Today? 59-Year Old Man Born in Caribbean country, immigrated to U.S. 25 years before admission, only returned back once in the past 10 years (1-month earlier) Spoke only Spanish Divorced, lived alone, had 3 children Unable to work due to a pelvic fracture Did not smoke, no illicit drug use or alcohol consumption Admitted into Mass. Gen. Hospital due to abdominal pain, nausea, vomiting and weight loss

3 9-Months Prior to Mass. Gen. Admission In his usual state of health up until 9-months prior Developed signs of weakness and anorexia Normal blood levels of thyrotropin and Vitamin B12 Healthy stool, normal signs of esophagus and stomach However abnormalities in right colon and transverse colon - erythema, without ulceration Pathological examination of duodenal-biopsy specimen: villous blunting, active inflammation, and intraepithelial lymphocytes Was considered consistent with celiac disease Colonic lamina propria; chronic inflammatory changes, without granulomas *Patient did not recall of being told of a diagnosis of celiac disease at the time*

4 Question 1 Upon initial examination, the patient suffered from inflammation in the duodenum. Which of the following is false regarding inflammation? A. Inflammation is a fundamentally protective response, designed to rid the organism of both the initial cause of cell injury as well as consequences of such injuries. B. Acute inflammation is rapid in onset, and is associated with the presence of lymphocytes and macrophages, proliferation of blood vessels, fibrosis, and tissue destruction. C. Regarding the practice of medicine, the importance of inflammation is that it can sometimes be inappropriately triggered and poorly controlled, therefore causing tissue injury in many disorders. D. Without inflammation, injured tissues might remain permanent festering sores. E. All of the above are true.

5 Question 1 Upon initial examination, the patient suffered from inflammation in the duodenum. Which of the following is false regarding inflammation? A. Inflammation is a fundamentally protective response, designed to rid the organism of both the initial cause of cell injury as well as consequences of such injuries. B. Acute inflammation is rapid in onset, and is associated with the presence of lymphocytes and macrophages, proliferation of blood vessels, fibrosis, and tissue destruction. C. Regarding the practice of medicine, the importance of inflammation is that it can sometimes be inappropriately triggered and poorly controlled, therefore causing tissue injury in many disorders. D. Without inflammation, injured tissues might remain permanent festering sores. E. All of the above are true.

6 Question 2 The patient had inflammation within his small intestine. Which of the following types of leukocytes would be most important in typical inflammatory reactions? A. Natural Killer Cells and Basophils B. Neutrophils and Eosinophils C. Eosinophils and Natural Killer Cells D. Macrophages and Neutrophils E. Basophils and Macrophages

7 Question 2 The patient had inflammation within his small intestine. Which of the following types of leukocytes would be most important in typical inflammatory reactions? A. Natural Killer Cells and Basophils B. Neutrophils and Eosinophils C. Eosinophils and Natural Killer Cells D. Macrophages and Neutrophils E. Basophils and Macrophages

8 Looking at 9-months before admission: -Hematocrit % through White cell count (low, low, high) -Lymphocytes (low) - Platelet count (high) -Iron (low) -Ferritin (low)

9 Prior to Mass. Gen. Admission... 3-Months Prior Episodes of abdominal discomfort anorexia and a 10-kg weight loss 3-Weeks Prior Diffuse, crampy abdominal pain, nausea that worsened after eating, increased frequency of formed stools Goes back to other hospital: Amylase and lipase levels liver function - Normal Helicobacter pylori IgA antibody to endomysial antigen IgA and IgG antibodies to tissue transglutaminase - negative CT of chest and abdomen: Atherosclerotic disease in distal aorta and iliac vessels No bowel-wall thickening or obstruction Diagnosis of celiac disease communicated to patient Gluten-free diet - only ate soup 1-Week Prior Intermittent bilious non-bloody emesis developed Evening before admission: nausea and abdominal pain worsened vomiting recurred stopped eating

10 Question 3 Prior to his admission into Mass. Gen., it is clear that the patient had been suffering from chronic inflammation in his digestive track for months. Which of the following is/are associated with chronic inflammation? A. Infiltration with mononuclear cells B. Tissue destruction C. Attempts at tissue repair D. All of the above E. None of above

11 Question 3 Prior to his admission into Mass. Gen., it s obvious that the patient been suffering from chronic inflammation in his digestive track for months. Which of the following is/are associated with chronic inflammation? A. Infiltration with mononuclear cells B. Tissue destruction C. Attempts at tissue repair D. All of the above E. None of above

12 Admission to Mass. Gen. Hospital Patient reported leg swelling for a 3-week duration chronic constipation recent increase in stool frequency without overt diarrhea Noted that he was confused about the gluten-free diet 14 years earlier - patient sustained multiple fractures in an accident Recovery complicated by nonunion of left iliac wing and persistent intestinal hernia in nonunion region 4 years earlier - neurofibroma of jejunum was resected after patient presented small-bowel obstruction Helminths consistent with Strongyloides stercoralis were noted in restricted bowel Ivermectin (12mg) administered orally, to be repeated 7 days later. Had hypertension and hyperlipidemia Medications: lisinopril atorvastatin acetaminophen docusate sodium No family history of bowel disease

13 1st Examination at Mass. Gen. Hospital Patient was thin: BP - 116/71 mmhg 74 bpm Temperature degrees Celsius Respiratory rate - 16 breaths/min Oxygen saturation 100% while breathing ambient air Coarse inspiratory breath sounds (more on right side) distended tympanic abdomen (without tenderness or hernias) hypoactive bowel sounds blanching erythematous macules (1-2 mm in diameter on torso) 1+ pitting edema on the legs CT of abdomen after administration of contrast material: Mucosal enhancement in duodenum, jejunum and splenic flexure of colon Dilated loops of small bowl up to 6 cm in diameter Dilation of cecum to 8 cm normal appendix colonic-wall thickening at splenic flexure

14 -White cell count (high) -Neutrophil (high) -Lymphocytes (low) -Platelet count (very high) -Iron (low) -Iron binding capacity (low) Sodium (little low) -Chloride (little low) -Albumin (low) -Calcium (low)

15 Question 4 The patient has elevated mucus levels within the gut, implying that the innate immune system has been triggered and is trying to expel a pathogen. Which of the following is not considered to be a part of the innate immune system? A. Epithelial Cells B. Antimicrobial peptides C. Antibodies D. Mast Cells E. Dendritic Cells

16 Question 4 The patient has elevated mucus levels within the gut, implying that the innate immune system has been triggered and is trying to expel a pathogen. Which of the following is not considered to be a part of the innate immune system? A. Epithelial Cells B. Antimicrobial peptides C. Antibodies D. Mast Cells E. Dendritic Cells

17 1st Examination cont. Patient s temperature rose to 37.9 degrees Celsius and vomiting developed Normal saline esomeprazole ondansetron metoclopramide were administered intravenously Nasogastric tube was placed and 700 ml of bilious fluid suctioned - improvement in the patient s symptoms Discharged on the third day Took ciprofloxacin, nutritional supplements, ferrous sulfate, ascorbic acid, and his usual medications

18 Second Trip to Mass. Gen. Hospital Four days after discharge, patient returned to the emergency department due to recurrent abdominal pain Examination was unchanged: Levels of glucose globulin lipase amylase coagulation liver and renal function - normal Urinalysis was positive for nitrites, 3-5 white cells per high-power field, and bacteria Trimethoprim - sulfamethoxazole was administered for presumptive UTI Nine days later: Temp. rose to 38 degrees Celcius anorexia, postprandial nausea, and occasional vomiting recurred Upon examination - appeared chachetic height cm; weight 53.1 kg; BMI 18.9; other vital signs were normal bowel sounds were faint abdomen was diffusely tender rest of examination remained the same Stool positive for occult blood chest radiograph revealed increased linear opacities in lungs CT of abdomen and pelvis after intravenous and oral administration of contrast material was unchanged Blood levels of IgG, IgA, glucose, phosphorus, magnesium serum protein electrophoresis and testing of liver and renal function - normal testing for IgA antibodies to tissue transglutaminase - negative Patient readmitted to hospital; analysis of stool revealed 25% fat (reference value <20%)

19 -Hematocrit% (low) -White-cell count (high) -Neutrophils (high) -Band forms (high) -Lymphocytes (low) -Platelet count (high) -Iron (low) -Iron binding capacity (low) -Sodium (low) -Chloride (low) -Protein total and Albumin (low) -Calcium (low) -25-Hydroxycholecalciferol IgM Prealbumin Thyrotropin -(all low)

20 Question 5 The patient has a high white blood cell count as well as a slightly high level of neutrophils. Phagocytosis is an important function of these types of cells. Which of the following make this process more efficient? A. IgA B. IgD C. IgB D. IgG E. IgE

21 Question 5 The patient has a high white blood cell count as well as a slightly high level of neutrophils. Phagocytosis is an important function of these types of cells. Which of the following make this process more efficient? A. IgA B. IgD C. IgB D. IgG E. IgE

22 Differential Diagnosis - During the first day of admission a CT scan of the abdomen and pelvis was performed - This revealed diffusely dilated loops of fluid- filled small and large bowel with mucosal hyperemia and bowel-wall thickening - Marked atherosclerotic calcification of the abdominal aorta - Distribution of abnormal bowel does not conform to a vascular territory - Chronic non-united left pelvic fracture through which a loop of large bowel had herniated - Laboratory tests showed evidence of malabsorption with folate and iron deficiency, mild anemia, and hypoalbuminemia - Imaging scans and biopsy specimens showed no abdominal tumor - CT scan performed on second day is unchanged from the previous scan

24 Celiac Disease - Known as celiac sprue or gluten-sensitive enteropathy - Adherence to gluten free diet alleviates symptoms - Strongly associated with HLA types and is most common in people of northern European descent - Symptoms range from fatigue and no gastrointestinal symptoms to profuse diarrhea with metabolic disturbances - Dermatologic manifestations include eczema and dermatitis herpetiformis - Serologic testing is important - In this patient serologic testing was negative, his symptoms worsened after being on a gluten free diet, European ancestry is unlikely from his ethnic background, old age for celiac disease

26 Common Variable Immunodeficiency - Patients have reductions of serum levels of IgG, IgA, IgM, or a combination - Poor responses to immunizations and often have recurrent infections including bacterial, fungal, and protozoal infections - 20% of people with disease have gastrointestinal manifestations - Diagnosis usually made before 30 - This patient has normal serum immunoglobulin level, no history of chronic bacterial or other infections, and is beyond the age of 30 so CVID is unlikely

27 Tropical Sprue - Endemic in many tropical regions including the Caribbean - Characterized by chronic diarrhea, malabsorption, and nutritional deficiencies of folate and vitamin B12 - Suspected in anyone who has lived in a region where the disease is endemic for more than a month - Symptoms develop several years after emigration - Tropical sprue mimics celiac disease - Causes are presumed to be infectious and patients typically present voluminous diarrhea - This patient has many of the symptoms of tropical sprue so it will not be ruled out but there are more specific diagnosis to better fit this patient

28 Crohn s Disease - Affects the small bowel in 80% of patients - Symptoms can occur anywhere from the mouth to the anus - Thought to be due to an abnormal immune response to resident gut bacteria in patients with genetic susceptibilities - Can have a spectrum of severity from increased intraepithelial lymphocytes ulceration and inflammation - This patient's symptoms are compatible with Crohn s disease but the epidemiologic factors make it unlikely since the prevalence in the Hispanic population is 1/10 of that in the white population and in the US people who have lived closer to the equator have a lower risk of developing an inflammatory bowel disease

30 Strongyloidiasis - Human parasitic disease caused by the nematode called Strongyloides Stercoralis - S. Stercoralis is endemic in the tropics and subtropics and is often diagnosed in immigrants or people from the military who returned to the US - The organism matures in the small intestine and releases eggs which are typically excreted in the stool - Most cases are asymptomatic or cause only mild symptoms - An acute manifestation is duodenitis which causes abdominal pain, nausea, vomiting, diarrhea, or a combination of these - In this patient, recurring abdominal symptoms, the rash, and the results of gastrointestinal-biopsy specimens are consistent with this disease

31 Question 6 If the patient was infected with parasites, one would expect to see elevated levels of which antibody? A. IgA B. IgD C. IgE D. IgG E. IgM

32 Question 6 If the patient was infected with parasites, one would expect to see elevated levels of which antibody? A. IgA B. IgD C. IgE D. IgG E. IgM

33 Question 7 As shown back in the laboratory data, the patient had an elevated white blood cell count. Which of the following leukocyte populations would normally be diagnostic if the patient was infected with parasites? A. Dendritic Cells B. Eosinophil C. Macrophage D. Neutrophil E. NK Cells

34 Question 7 As shown back in the laboratory data, the patient had an elevated white blood cell count. Which of the following leukocyte populations would be diagnostic if the patient was infected with parasites? A. Dendritic Cells B. Eosinophil C. Macrophage D. Neutrophil E. NK Cells

35 Pathological Discussion Stool specimen examination showed numerous rhabditiform larvae (stool larvae) and some filariform larvae (larvae that travel to intestine) of S. stercoralis after four days in the hospital. Given the severity of the patient s symptoms, upper and lower gastrointestinal endoscopic evaluations were done to observe any damage of strongyloidiasis Marked erythema, edema, and villous blunting (flattening) in the distal duodenum and jejunum. Colonoscopy revealed extensive areas of inflammation characterized by erythema, edema, and deep, serpiginous (wavy) ulcerations throughout the entire colon. Right colon more affected than left with only occasional appearing mucosa. Biopsy specimens were obtained.

36 Pathological Discussion (Con.) Extensive inflammation of the small and large bowel present with a right-sided predominance in the colon + the previous infection history were consistent with enterocolitis caused by strongyloides. The extensive inflammation found during the endoscopy was consistent with hyperinfection (repeated infection by multiple life cycles of parasites), which explains why the patient was malnourished. When the patient needed a benign myxoid neurofibroma removed four years prior to this incident, histologic sections then also revealed larval and adult forms of a parasite that were consistent with S. stercoralis but no evidence of invasion beyond the epithelial compartment.

37 Pathological Discontinuities 9 months before admission, duodenal and colonic biopsies were performed at the other hospital. The duodenal biopsy showed villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis and foci of active inflammation. Report said that the appearances were consistent with celiac disease. HOWEVER THEY WERE WRONG 1. The combination of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis is not specific for CD 2. Active inflammation is not a typical feature of celiac disease, especially since there were signs of chronic damage 3. Serologic tests for CD were negative at the time (but no parasites were seen as well) The duodenum and colon both showed active inflammation with evidence of chronicity (inflammatory bowel disease, like Crohn s disease?)

38 Pathological Discussion (Con.) Low to nil chance of Celiac Disease (because of serologic tests) Crohn s disease is now on the table Strongyloidiasis is not ruled out yet even though parasites are not seen (since the infection can have a patchy distribution and the endoscopy biopsy sample may not have gotten it)

39 Pathological Discussion (Con.) During the patient s second admission to the hospital, biopsy specimens of the duodenum, jejunum and colon were submitted for pathological examination. Duodenum: florid active duodenitis, parasites not seen Jejunum: also active jejunitis with small aphthous ulcers on surface, subtotal villous atrophy, and pseudopyloric metaplasia (which, along with the villous atrophy, suggests chronicity). Strongyloides organisms were seen in crypts eliciting mainly neutrophilic cryptitis.

40 Question 8 During infection, the patient had developed ulcers in the gastrointestinal tract. While this is probably uncomfortable and slightly painful, it poses a much larger threat which is: A. A bacterial infection by opportunistic gram-positive bacteria in the gut B. Mucus leaking into the peripheral tissues C. Over activation of the adaptive immune system D. A and B E. B and C

41 Question 8 During infection, the patient had developed ulcers in the gastrointestinal tract. While this is probably uncomfortable and slightly painful, it poses a much larger threat which is: A. A bacterial infection by opportunistic gram-positive bacteria in the gut B. Mucus leaking into the peripheral tissues C. Over activation of the adaptive immune system D. A and B E. B and C

42 Pathological Discussion (Con.) Colon: Showed variable chronic active inflammation with ulceration and fibrosis. S. stercoralis was identified. Parasite was not confined to epithelial compartment and was seen in lamina propria, muscularis mucosae, and submucosa. Present were granulomas with foreign body type giant cells that contained degenerated parasitic matter These three biopsy reports differ from four years ago both in numbers and invasiveness of the parasite

43 What was our patient diagnosed with? - Diagnosed with Strongyloides stercoralis hyperinfection associated with human T-cell lymphotropic virus type 1 (HTLV-1) - Hyperinfection with S.stercoralis is the accumulation of a large burden of parasites during the autoinfection cycle - Parasites accumulate primarily in the colon which triggers mucosal compromise and sepsis caused by gram negative rods - HTLV-1 is endemic in the Caribbean, South America, southern Japan, south and central Africa, and Middle East. Which resonates with our patient - Stool examination for ova and parasites are detectable in patients with hyperinfection

44 Question 9 Human T-cell lymphotropic Virus Type 1 (HTLV-1), as you can guess from the name, is a virus that infects T cells in the active immune system. Infection and destruction of which of the following T-cells could lead to hyperinfection by parasites? A. T H 1 B. T H 2 C. T H 17 D. All of the above E. None of the Above

45 Question 9 Human T-cell Lymphotropic Virus Type 1 (HTLV-1), as you can guess from the name, is a virus that infects T cells in the active immune system. Infection and destruction of which of the following T-cells could lead to hyperinfection by parasites? A. T H 1 B. T H 2 C. T H 17 D. All of the above E. None of the Above

46 Question 10 During infection, the body has multiple ways of detecting foreign pathogens. Which of the following toll-like receptors (TLRs) would most likely be involved in detecting an intracellular virus? A. TLR 1 B. TLR 6 C. TLR 4 D. TLR 5 E. TLR 3

47 Question 10 During infection, the body has multiple ways of detecting foreign pathogens. Which of the following toll-like receptors (TLRs) would most likely be involved in detecting an intracellular virus? A. TLR 1 B. TLR 6 C. TLR 4 D. TLR 5 E. TLR 3

48 S. stercoralis Typically localized in the small intestine, but involvement of the colon and stomach may occur. Localization in the colon and association with severe inflammation, ulceration, and burrowing beyond the mucosa are uncommon in uncomplicated infection and suggest autoinfection and hyperinfection. Infective filariform larvae of S. stercoralis and the rhabditiform larvae present support strongyloides hyperinfection syndrome. Immunosuppression must have occurred. HTLV-1 testing was positive

49 Recovery After the diagnosis was made, a 2-week course of ivermectin was administered with follow up doses 2 weeks after completion Examination of stool at that time showed negative for S. stercoralis larvae Stool examinations were done daily until parasite could no longer be seen and then periodically after the fact HIV testing was negative Hyponatremia, hypocalcemia, and anemia all improved after antiparasitic therapy and vitamin/iron supplements were given. Patient discharged after 17 days. At the 1-month follow up, a test for anti-strongyloides antibody tested positive. 8 months after, patient reports feeling well and stool was negative for parasites. Anti-strongyloides antibody was negative. T-cell subsets were normal. HTLV-1 infection was asymptomatic.

50 Timeline Symptoms Start (abdominal pain, vomiting, weight loss) -6mo Symptoms worsen, goes to other hospital, begins gluten-free diet 0 Discharged x+4d Temperature rose, vomiting, and nausea come back, readmitted x+26d Follow-up, patient reports feeling well -9mo Recurring -3w abdominal discomfort episodes with weight loss Admitted through emergency, symptoms at their worst, stops eating x Patient returns to ED because of recurring pain x+9d Discharged with appropriate antibiotics 2mo

51 Recap/What can be learned Man in his 50 s from the caribbean contracts a retrovirus that impairs his ability to fight off parasitic infections. This causes his parasitic infection to slowly build for years until hyperinfection occurs and becomes life threatening. Wear sandals in the caribbean to avoid roundworm infections Worms can help you lose weight Misdiagnoses can lead to seriou consequences

Immunological Aspects of Parasitic Diseases in Immunocompromised Individuals. Taniawati Supali. Department of Parasitology

Immunological Aspects of Parasitic Diseases in Immunocompromised Individuals Taniawati Supali Department of Parasitology 1 Defense mechanism in human Th17 (? ) Acute Chronic Th1 Th 2 Intracellular Treg