Hypothermia: Incidental finding or critical illness? Incidental finding or critical illness? ... Signs and symptoms of hypothermia can manifest in ... TB infiltration of his basal

References

Discussion

Hospital Course

Hypothermia: Incidental finding or critical illness?Jennifer Beckman, MD

University of Utah Department of Internal Medicine

Case Presentation

1. Dick DJ, et al. Chronic hypothermia following tuberculosis meningitis. Journal of Neurology, Neurosurgery, and Psychiatry, 1981,44,255-57.

2. Joshi VV, et al. Hypothermia due to transient hypothalamic dysfunction in tuberculosis meningitis with hydrocephalus. British Journal of Neurosurgery. 1992;6(4):385-7

3. McCullough L, et al. Diagnosis and Treatment of Hypothermia. American Family physician. Volume 70, number 12, 2325-32. Dec 14,2004

4. Mallet ML. Pathophysiology of accidental hypothermia. QJ Med 2002: 95: 775-85

This is a case of incidentally found hypothermia in a26 year old male who was transferred from the prisoninfirmary for hematemesis during the month of May.He reports having chills for he at least the last weekwith nausea and vomiting and development ofhematemesis starting within the last 24 hours.Further questioning revealed that he had headaches,worsening lower extremity weakness, and urinaryincontinence in the last several days. His initialtemperature was 36°C but repeat readings wereconsistently around 30. His blood pressure was124/91 with a heart rate of 60, respiratory rate of 15,and oxygen saturation of 98% on room air. His WBCwas 6 with a normal differential. The prison infirmarystated that the patient’s only past medical history waspossible sarcoidosis.

Hypothermia due to environmental exposure is oftenthought about, however, other causes includemetabolic, neurologic, and sepsis.

TB meningitis can cause hypothermia by directinvolvement of the CNS or sepsis. TB can infiltratethe hypothalamus or causes hydrocephalus whichplaces pressure on the hypothalamus, which isresponsible for thermoregulation. Hypothermia dueto sepsis is caused by a failure of vasoconstrictionor by inducing an abnormality in the hypothalamicresponse via a cytokine response.

Signs and symptoms of hypothermia can manifest inalmost every organ system:

A lumbar puncture was performed with a protein levelof 552, glucose of 8, total WBC count of 138 with 13%PMN, 51% lymphocytes. Gram stain and cultureremained negative. MRI imaging showed findingsconsistent with basilar meningitis. Reports obtainedfrom a previous hospitalization had imaging with hilarlymphadenopathy and a pulmonary nodule biopsywith positive AFB organisms suggesting that hissymptoms were from TB meningitis.

ConclusionIn the case of this patient, TB infiltration of his basalganglia and hydrocephalous were the causes of hishypothermia. With treatment of his meningitis hishypothermia and presenting symptoms did improve.

Many of his presenting symptoms can be linked tomanifestations of his hypothermia. His hematemesiswas likely the punctate hemorrhages found withhypothermia. His new on-set urinary incontinence canbe attributed to the cold-induced diuresis.

Bradycardia and repolarizationabnormalities are found in thecardiovascular system.

Manifestations of the nervous systeminclude ataxia, hyporeflexia, anddecreased nerve conduction.

Cold-induced diuresis is caused bythe loss of the ability to reabsorbwater and resistance for ADH.

Ileus or punctate hemorrhages developin the GI system.

Chronic Kidney Disease in an Elderly Patient

General: Cheerful, energetic thin elderly woman, enjoying visiting with familyVital Signs: 127/62, P 60, R 20, T 96.1, Ht 66” weight 125, BMI 20Eyes: wears glasses, mono-ocular vision, 20/200Pulm: normal respiratory mechanics, clearCV: RRR Ext: 2+ bilateral pedal edemaBack: kyphosis, no vertebral tenderness to palpationGeriatric Assessment: mini-cog unable to draw clock due to low vision, 3/3 recall, Oriented x 3

-Chronic glomerulonephritis-Vasculitis-Multiple myeloma-Rheumatoid Arthritis-Wegener Granulomatosis-Infection-Malignancy-Acute Injury

References

EvaluationHistory

Physical

Differential Diagnosis

Conclusions

Referral

90 year old woman with osteoporosis, chronic kidney disease, hypertension with lower extremity edema, mild dyspnea &feeling weak for past few weeks presents to her PCPROS: no weight loss, falls, depression, other resp, CV, GI all negPMHx: chronic back pain, hx of vertebral fxs, macular degenerationpolymyalgia rheumaticaADLS: independent in all IADLS: help with transportation,shopping, finances (decreased vision) Meds: Calcium/Vit D 600 mg/1000 IU bid, Alendronate 70 mg/wk

Lucille Brunker1 C. P. Brunker1,2 1 University of Utah School of Medicine, 2 Intermountain Healthcare, Salt Lake City, UT

Shared Decision Making with patient → Nephrology ReferralPatient’s Goals: maintain high quality of life and function, avoid dialysis2/2011 Serum Immunofixation: IgG monoclonal protein, lambda light chain Immunologic studies: neg except c-ANCA +Radiology: Renal U/S kidneys normal in size and echotexture, no hydronephrosis, lesions, calculus & cortex well-preserved

4/2011 Biopsy: CKD, “onion skinning” Necrotizing glomerulonephritis 25/37, with crescentsH & E example from Stone, John H. - Rheumatology, 1547

The prevalence of chronic kidney disease (CKD) is growing most rapidly in people ages 60 and older .

Following practice guidelines can result in significant cost savings, even in (or perhaps especially in) older adults. In accordance with recommendations, our patient was referred to nephrology where she received biopsy for diagnosis and was treated for Wegener’s Granulomatosiswith prednisone and cyclophosphamide. Her therapy was adjusted to monotherapy with prednisone because of an adverse reaction to the cyclophosphamide. She had dramatic improvement in renal function, almost returning to baseline. Progression of chronic kidney disease to end stage renal disease (ESRD) changes health care costs dramatically. In 2009, the cost for hemodialysis treatment at a clinic per patient was roughly $82,000, much greater expense than the cost to evaluate and treat our patient. In accordance with practice guidelines, early referral to nephrology resulted in improvement of her renal function to almost baseline and approximately $110,000 savings over 2 years and she reports excellent quality of life and maintenance of independence in ADLs.Aasarød K et al. Wegener's granulomatosis: : clinical course in 108 patients with renal involvement. Nephrology Dialysis Transplantation. 2000;15(5):611-618.

Fink et al. Screening for, Monitoring, and Treatment of Chronic Kidney Disease Stages 1 to 3: A Systematic Review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Annals of Internal Medicine. 2012;156(8):570-81.

Hoffman et al. Wegener Granulomatosis: An Analysis of 158 Patients. Ann of Intern Med. 1992

Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 CPG. Ann Intern Med. 2013;158(11):825-830.

Kidney Disease Statistics for the United States. National Kidney and Urologic Diseases Information Clearinghouse. U.S. Department of Health and Human Services. NIH Publication No. 12-3895. 2012.

Matsushita K et al. Chronic Kidney Disease Prognosis Consortium. Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA. 2012;307:1941-51.

Palmer SC, Craig JC, Navaneethan SD, et al. Benefits and harms of statin therapy for

DATE BUN Cr GFR

Other UA, micro

2/2007 22 1.33/2008 19 1.1 Vit D 27 Ca 9.8,

iPTH 561/2010 23 1.4 37 Ca 9.8, T Chol 153

TG 105 HDL 43 LDL 96

1/2011 27 1.5 Vit D 40, Hct 34.3 Prot 200 mg/dl, 19 leuk, 90 RBC

2/2011 35 1.8 28 Phos 4.3(bisphosphonate discontinued)

3/2011 Nephrology

22 2.1 23

4/2011 28 4.4 <10 Alb 2.66/2011 32 1.8 28 Alb 3.77/2012 49 1.93/13 42 1.8

PCP

Improving Global Outcomes 2012 CPG. Ann Intern Med. 2013;158(11)

A Therapeutic Vaccine for Prevention of Metastatic Outgrowth of Breast CancerKimberley Davenport, Atakan Ekiz, Alana Welm, PhD

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah

A Therapeutic Vaccine for Prevention of Metastatic Outgrowth of Breast Cancer

Background Breast cancer is the second biggest cause of mortality in women with cancer – mostly as a result of metastasis. An estimated 40% ofhuman breast tumors over-express a tyrosine kinase called Ron. The Ron-MSP pathway functions as a critical immunosuppressive signal between atumor and the immune system, thereby promoting tumor growth and especially metastasis. Ron is a receptor tyrosine kinase that is expressed oncertain cell types, including some macrophages. When Macrophage Stimulating Protein (MSP) is in the tumor environment, it binds to Ron andinitiates a signal that serves to suppress the immune system as reflected by the number of CD8+ cells activated, the cytotoxicity of these effectorCD8+ cells and other immune cytokines. The exact mechanism by which the Ron-MSP pathway signals is presently unknown. A previous study fromCancer Discovery established that in female mice with transplanted PyMT-MSP tumors, similar tumor growth was seen in wild type mice (WT)compared with mice genetically engineered to not express Ron (Ron knock outs). However, the WT mice saw significantly greater incidence ofmetastasis compared with the Ron knock out mice. This is due to the fact that if the Ron receptor is not expressed, then there is no signaling whenMSP is present in the environment. Therefore, inhibition of Ron translates to significantly lower metastasis. Our hypothesis is that inhibition of Ron(and thereby the Ron-MSP pathway) in conjunction with a therapeutic whole cell tumor vaccine, will produce even lower rates of both primary tumorgrowth and metastasis than inhibition of Ron alone.

Methods A total of 20 FVB mice were used for two cohorts. Because a target antigen for breast cancer has not yet been identified, a whole cell tumorvaccine was used consisting of 1 million irradiated cells per injection. PyMT-MSP breast tumor cells were irradiated with 10,000 rads. Initialvaccination was administered subcutaneously to six female FVB Wild Type (WT) mice and six female FVB Ron knock out mice. Follow up boostershots were subsequently given at day 8 and day 15 to half these mice. For the control cohort: four female FVB WT mice and four female FVB Ronknock out mice were injected with HBSS saline on the day of initial vaccination. One cohort was sacrificed at day 5 and the other on day 18.Peripheral blood cells and splenocytes were harvested, blood cells were stained with antibodies to detect levels of lymphocytes and cytokines thenanalyzed using FACS. Investigators in this study did not use an adjuvant, to remove any confounding effect that an adjuvant could have on inducingthe immune response. Once proof of concept is confirmed using the vaccine, then an endogenous adjuvant, GM-CSF, will be added to the vaccine tomeasure any amplification of the anti-tumor effect.

Results Vaccinated mice (both WT and Ron knock out) demonstrated a roughly three-fold increase in activated CD8+ cells in the spleen vs. thecontrol mice vaccinated with HBSS. The largest increase in vaccinated spleen CD8+ cell markers was in INF gamma. However, peripheral blood didnot yield nearly as great an increase in CD8+ cell activation. When comparing WT to Ron knock outs, both the day 5 cohort and day 18 cohortshowed no significant difference in higher immune markers.

Conclusions Whole cell irradiated tumor vaccination when used in conjunction with inhibition of the Ron-MSP pathway appears to slightly augment theanti-tumor effect at certain time points as measured by CD8+ and CD4+ activation and elevations of anti-tumor cytokines including INF gamma,Granzyme B, IL-2, TNF alpha, CD69, CD62, LAMPI, and CD25. Along with increasing the number of lymphocytes activated, it also slightly increasedeffector cell toxicity. However, neither elevations represented a significant difference.

Fever, Dyspnea, and a Previously Septic KneeEric B. Fox, MD and John C. Christensen, MD

Intermountain Medical Center

Differential Diagnosis and Hospital Course

HIstory

Physical Exam/Diagnostic Studies

Discussion

References1. Solomon, Joshua, and Marvin Schwarz. "Drug-, toxin-, and radiation therapy-induced eosinophilic

pneumonia." Seminars in Respiratory and Critical Care Medicine. Vol. 27. No. 022. Kim, Peter W., et al. "Eosinophilic Pneumonia in Patients Treated with Daptomycin." Drug safety 35.6

(2012): 447-457.3. US Food and Drug Administration. FDA drug safety communication: eosinophilic pneumonia associated

with the use of Cubicin (daptomycin) [online]. Available from URL:http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm220273.htm. [accessed Sept. 16, 2013]

4. Lal, Yasir, and Aristides P. Assimacopoulos. "Two cases of daptomycin-induced eosinophilic pneumonia and chronic pneumonitis." Clinical infectious diseases 50.5 (2010): 737-740.

On exam, temp. 38.3 deg. C, BP 119/61, HR 109, and 92% on 4LPM of O2. He was a morbidly obese, pleasant gentleman who appeared in mild distress secondary to dyspnea, speaking in 3-5 word phrases. His lungs demonstrated mild end-expiratory wheezes and distant breath sounds with mildly increased work of breathing. His left knee demonstrated a healing surgical incision with no fluctuance, erythema, or drainage. He had 2+ pitting edema to the knee in bilateral lower extremities, with the remainder of the exam unremarkable.

Initial labs demonstrated a white count of 13.2 (69% PMNs, 10% lymphocytes, 13% monocytes, 6.5% eosinophils). Serum chemistries were notable for a sodium of 129, a creatinine of 1.39, and elevated ESR/CRP at 45 and 10.7 respectively.

A CXR demonstrated bilateral lung opacities (R>L) consistent with pneumonia (Figure 1). A CT pulmonary angiogram demonstrated no PE, and probable multifocal pneumonia (Figure 2).

A 72 year-old man presented to the Emergency Department with a 3 day history of progressive dyspnea on exertion and hypoxia. He has a history of COPD and wears 2LPM of O2 at baseline, but was now using 4-6LPM to maintain his oxygen saturations. He also noted a cough productive of black-red sputum and wonders if it may be bloody.

He had recently undergone a left total knee replacement 1.5 months prior, which was complicated by a joint infection that grew out methicillin sensitive Staphylococcus aureus. For unclear reasons, the patient was started on vancomycin for this infection. This was changed to daptomycin 9 days prior to admission after he exhibited symptoms consistent with red-man syndrome.

Although eosinophilic pneumonia (EP) can be idiopathic, often an inciting drug can be identified, with antibiotics (ampicillin, sulfonamides, minocycline, nitrofurantoin, daptomycin) and NSAIDs being the most commonly implicated.1

The disease is characterized by fevers, diffuse pulmonary infiltrates, hypoxemia, and >25% eosinophils on BAL. Drug induced EP is suspected when there is: temporally related exposure to a possible drug, no other cause that can be identified, resolution after cessation of drug, and recurrence on re-challenge with the suspected drug (though this is not recommended in clinical practice!).2

EP associated with daptomycin appears to be relatively rare, with 20 confirmed/probable case reports and 38 possible case reports.2 In 2010, the FDA issued a safety announcement highlighting the association of daptomycin with EP and added this to the Adverse Reactions section of the drug label.3

Treatment involves discontinuation of daptomycin often in conjunction with systemic glucocorticoids, though there is no consensus on the appropriate dose or duration of therapy. Most individuals will make a full recovery, though ongoing need for corticosteroid therapy has also been described.4

The mechanism of daptomycin toxicity is unclear. It is known to bind pulmonary surfactant, and it has been postulated to incite an eosinophilic response via accumulation in the alveolar spaces and antigen presentation by macrophages.2

Images courtesy of Intermountain Medical Center

Initial diagnoses thought most likely included: pneumonia (healthcare associated), pulmonary embolism, COPD exacerbation, or heart failure.

The patient was treated for presumed HCAP, with the CTA ruling out significant PE. COPD exacerbation and CHF were felt less likely based on his clinical picture. Despite 2 days of appropriate antibiotics, his clinical status worsened, and the diagnosis of eosinophilic pneumonia was entertained based on his peripheral eosinophilia and exposure to daptomycin.

Bronchoscopy and bronchoalveolar lavage (BAL) demonstrated no growth on cultures, and 34% eosinophils, cementing the diagnosis of eosinophilic pneumonia, likely secondary to daptomycin use. The patient was taken off HCAP therapy and started on systemic corticosteroids, with notable respiratory improvement over the ensuing 5 days.

Figure 1.

Figure 2.

Discussion

Hannah Gaedtke, MDUniversity of Utah-Department of Internal Medicine

Labs, Pathology, ImagingHistory of Present Illness

Exam

Differential Diagnosis

Conclusions

ReferencesMiyakis s, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of Thrombosis and haemostasis, 4: 295-306.Pierangeli SS, Erkan D. Antiphospholipid syndrome treatment beyond anticoagulation: are we there yet? Lupus 2010 19: 475.

Description of Ulcer per dermatology consult:

Right lower posterio-medial leg, large tender malodorous ulcer down to subcutaneous fat with surrounding reticulated/livedo change. Base of ulcer with yellow fibrinous exudate. Anterior of leg with atrophic hypopigmented patches. Mild erythema surrounding wound, no undermined border.

Mr. L is a 76 yo M with a history of atrial fibrillation and chronic systolic heart failure admitted to the internal medicine service from the dermatology clinic for evaluation and management of worsening lower extremity ulcers. The ulcers were located on both lower extremities (right greater than left) at the posterior calf and had been present for approximately 2 months. Mr. L had previously been treated with antibiotic therapy for possible cellulitis without improvement. He had no prior history of skin breakdown or recurrent infections.One week prior to this admission, Mr. L had undergone repeat biopsy of the ulcer which showed microvascular thrombi. The patient was started on warfarin, but noted worsening of his ulcers shortly after. This prompted the patient’s current admission to internal medicine for further evaluation and management.Medications at the time of admission included amiodarone, warfarin, allopurinol. Dapsone was discontinued prior to admission.

Mr. L presented with persistent lower extremity ulcers despite appropriate management of community acquired cellulitis. Biopsy results were concerning for microthrombi which prompted evaluation for coagulopathy. Initial results showed elevated anti-cardiolipin IgG and IgM.

Based on Sapporo Criteria, Mr. L met criteria for diagnosis of antiphospholipid syndrome.

1.Clinical Feature: Biopsy showing microthrombi, Livedo Reticularis

2.Presence of autoantibody: Anti-Cardiolipin Antibodies

Autoantibodies were repeated at 12 weeks and again showed elevated anti-cardiolipin Ab, confirming the diagnosis of antiphospholipid syndrome. ANA was negative and no other clinical or laboratory criteria was found to suggest SLE.

Mr. L was found to have subtherapeutic INR. It was thought that initiating warfarin without heparin bridging may have exacerbated his hypercoagulable state and led to worsening of the ulcers. He was placed on heparin therapy and bridged until warfarin was therapeutic. Ulcers improved following therapeutic anticoagulation.

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Labs:ANA, Protein S/C, Anti-thrombin: WNL Lupus Anticoagulant not detectedBeta 2 glycoprotein IgM, IgG, IgA: WNLAnti-Cardiolipin IgG: 25 (0-14)Anti-Cardiolipin IgM: 80 (0-12)

Biopsy Results: Many of the blood vessels show intraluminal fibrin thrombi. Other vessels show vasculitis with neutrophils and dust in vessel walls.

Lower Extremity Duplex:No thrombus of the right lower extremity.

1. Vasculopathy secondary to hypercoagulable state

2. Vasculitis3. Calciphylaxis

Little Ulcer, Big Problem

Pruritic Purpura and Acute Respiratory FailureVerena C. Haringer, M.D.

University of Utah, Department of Internal Medicine

Case Description

Hospital Course

References1. Falk et al. Granulomatosis with polyangiitis (Wegener’s): an alternative name for Wegener’s

granulomatosis. Arthritis Rheum. 2011 Apr; 63(4):863-4 2. Lee et al. Complications associated with levimasole-contaminated cocaine: an emerging public health

challenge. Mayo Clin Proc. 2012 Jun;87(6):581-63. Peng et al. Culture-negative subacute bacterial endocarditis masquerades as granulomatosis with

polyangiitis (Wegener’s granulomatosis) involving both the kidney and lung. BMC Nephrol. 2012 Dec 26;13:174

A 61 year old white male presented to the Emergency Department with a 6-month history of pruritic purpura in his bilateral lower extremities as well as polyarticular arthralgias and weight loss.

His only past medical history are multiple musculoskeletal injuries and a s/p septic arthritis in both knees. The patient endorses iv drug abuse in the past and cocaine abuse with the last use about 1 year prior to admission. His family history is positive for lymphomas in multiple relatives.

On admission he was found to have palpable, macular purpura on the dorsal hands and prominent on his bilateral legs, including the soles of his feet (Fig. 1), a 3 cm mobile, non-tender, soft mass on the right neck, periodontal disease with gingivitis, diffuse small oral ulcers , punctate oral hemorrhages, and an exudate on his right tonsil. Labs showed a WBC of 11.8 with 11% eosinophils, CRP of 10, a CK of 1300 and 5 RBC on UA. CT chest on admission showed scattered ground glass opacities (Fig. 3).

- Lymphoma

- Endocarditis with septic emboli

- Chronic hepatitis with cryglobulinemia

- Henoch-Schönlein purpura preceded by oral infection

- Microscopic polyangiitis

- Churg-Strauss syndrome

- Levimasole-induced vasculitis in a patient with a history of cocaine abuse

- Granulomatosis with polyangiitis (Wegener’s)

Fig. 1 courtesy of Brian J. Horner, M.D.; Fig. 2 courtesy of Scott R. Florell, M.D.; Fig. 3-5 courtesy of the University of Utah Hospital

Extensive work-up revealed anemia, positive Hepatitis B core antigen IgM antibody, elevated rheumatoid factor and positive ANCA-PR3. Urine was initially negative for red cell casts. TTE/TEE showed no evidence of endocarditis, urine was negative for cocaine, SPEP was within normal range, cryoglobulins were negative.

A skin biopsy of the patient’s lower back showed leukocytoclastic vasculitis with IgM and C3 deposition (Fig 2). A biopsy of a lower lip ulcer showed eosinophil-predominant vasculitis.

On Day 11 after admission, the patient had to be transferred to the MICU for acute hypoxic respiratory failure requiring BiPAP treatment. He was found to have ARDS secondary to diffuse pulmonary hemorrhage (Fig. 4). At this time his urine was found to be positive for red cell casts as well as dysmorphic red cells, and the patient underwent renal biopsy which was inconclusive. Due to the acute worsening of the patient’s clinical picture, he was treated with a 3-day course of plasmapheresis and high-dose iv steroids, followed by po steroids and cyclophosphamide which led to an improvement of his respiratory function (Fig. 4).

Discussion

Differential Diagnoses

The overall clinical picture in this middle-aged white male points towards a small vessel vasculitis, most likely granulomatosis with polyangiitis (Wegener’s).

Although it is best to have a confirmation of diagnosis by tissue biopsy at a site of active disease, patients should be treated empirically if the clinical suspicion is high and initiation of therapy is life saving and organ sparing.

Fig. 1

Fig. 3

Fig. 4

Fig. 5

Fig. 2

Behcet’s disease with Crohn’s disease Abdul Haseeb, MD MPH

University of Utah Department of Internal Medicine

Purpose/Methods

Case Discussion

Conclusions

References

To describe the coexistence of “auto-inflammatory” Behcet’s disease with Crohn’s disease and to demonstrate clinical and diagnostic presentations that make it difficult to identify them as separate entities.

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Retrospective chart review and bibliographic database search for relevant studies pertaining to the patient’s clinical presentation.

37-year-old Hispanic male with a known history of Crohn’s disease presents with recurrent oro-genital ulcers, anterior uveitis, and papulopustular lesions. He had frequent Crohn’s flares since his initial diagnosis three years ago, despite being on maintenance mesalamine therapy and corticosteroid use during acute flares. He had failed 6-mercaptopurine treatment in the past due to liver toxicity and Infliximab treatment due to anaphylaxis. In addition to recurrent colitis, the patient presented with a plethora of extraintestinal findings including neutrophilic vasculitis, skin abscesses, sinusitis, nasal polyps, oral ulcers, pulmonary granulomas, granulomas on bone marrow biopsy, splenic granulomas, uveitis, and non-specific arthritis. He underwent an extensive rheumatological work-up and the top two differential diagnoses were Crohn’s disease with extra-intestinal manifestations and Behcet’s disease. Labs were significant for an elevated proteinase-3-antibody, but negative for ANA, and ANCA. Colonoscopy revealed inflammation in the terminal ileum and colitis in the ascending and transverse colon.

Although these findings were consistent with a Crohn’s flare, the patient was concurrently diagnosed with Behcet’s based on his recurrent episodes of oral aphthae, genital aphthae, uveitis, and papulopustular skin lesions. Diagnosis was based on most widely accepted International Study Group (ISG) criteria for Behcet’s disease. He was initially started on Azathioprine, but treatment was complicated with the development of neutrophilic dermatoses leading to a diagnosis of drug induced Sweet’s syndrome. Treatment was finally switched to cyclosporine and low dose prednisone. The patient has shown significant clinical response to this regimen and has had no readmissions with Crohn or Behcets’ flares.

A distinct diagnosis of Behcet’s disease or inflammatory bowel disease can be perplexing with a significant overlap in the systemic and gastrointestinal features of both disorders. Behcet’s disease classified as an auto-inflammatory disease, usually runs an abating course with time compared to lifelong course of Crohn’s. Although intestinal Behcet’s disease accounts only for a minimal 1-2%, the histological features closely resemble Crohn’s on endoscopy. The diagnosis of Behcet’s is based mainly on clinical findings due to lack of pathognomonic laboratory test. A few case reports are published describing the co-existence of Crohn’s disease with Behcet’s; these are mostly from Turkey and along the “silk route.” Familial studies reviewed also suggested a close relation between the two diseases indicating them to be part of spectrum rather than two distinct disease entities. Co-existent Crohn and Behcets’ disease should be considered a diagnostic possibility in patients who present with overlapping symptoms.

1. Akay N, Boyvat A, Heper AO, Soykan I, Arica IE, Bektas M, et al.Behcet's disease-like presentation of bullous pyoderma gangrenosum associated with Crohn's disease. Clin Exp Dermatol. 2006;31(3):384-6.2. Cheifetz AS. MAnagement of active crohn disease. JAMA. 2013;309(20):2150-8.3. Kim ES, Chung WC, Lee KM, Lee BI, Choi H, Han SW, et al. A case of intestinal Behcet's disease similar to Crohn's colitis. J Korean Med Sci. 2007;22(5):918-22.4. Koksal AS, Ertugrul I, Disibeyaz S, Tola M, Kacar S, Arhan M, et al.Crohn's and Behcet's disease association presenting with superior vena cava thrombosis. Dig Dis Sci. 2005;50(9):1698-701.5. Yazici H, Fresko I. Behcet's disease and other autoinflammatory conditions: what's in a name? Clin Exp Rheumatol. 2005;23(4 Suppl 38):S1-2.

Valve Replacement in Infective EndocarditisMark Kaeppler, MD

University of Utah, Department of Internal Medicine

StudiesHPI

Initial Workup

Discussion

References1. The complications of infective endocarditis. A reappraisal in the 1980s. Mansur AJ, Grinberg

M, da Luz PL, Bellotti G. Arch Intern Med. 1992;152(12):2428.2. Neurological manifestations of infective endocarditis. Review of clinical and therapeutic

challenges. Jones HR Jr, Siekert RG. Brain. 1989;112 (Pt 5):1295.3. AHA Scientific Statement: Infective Endocarditis. Baddour, LM, et al. Circulation. 2005; 111:

e394-e434 doi: 10.1161/ CIRCULATIONAHA.105.165564Figure 2 image obtained from: www.vcu.edu

Thank you to Drs. Scott Woller and Corwin Edwards for obtaining the included Echo images

A 76-year-old male with CAD, hypertension and prostate cancer s/p prostatectomy presented with a 6-week history of progressively worsening back pain. This pain was initially associated with fevers and chills. He presented both to an InstaCare and an outside ED, where he was found to have a persistent leukocytosis prior to his current presentation in the IMC ED.

Treatment of the prostate cancer (diagnosed in 1998) included surgery and androgen deprivation therapy.

He denied IV drug abuse. Further questioning also revealed a new complaint of chest pain exacerbated by deep breathing.

Imaging

The patient acutely developed aphasia, R facial numbness and R hand clumsiness. MRI brain demonstrated ischemia within regions of the L frontal lobe and punctate foci within the bilateral parietal lobes consistent with subacute stroke. In the following days, two further ASSERT calls were performed for similar symptoms. He was otherwise hemodynamically stable. Left heart catheterization was performed, demonstrating obstructive disease within the LAD.

By hospital day #9, the patient underwent mitral valve replacement and CABG (LIMA to LAD). Five days s/p CT surgery, he was discharged without further complication.

Clinical Course

The patient was found to be hypothermic to 34.9 degrees Celsius and tachycardic to 109 bpm. Physical examination demonstrated a 3/6 holosystolic ejection murmur best heard at the apex that radiated to the axilla. Lower extremity strength was rated as 5/5 throughout with normal sensation and 2+ patellar reflexes.

A chest X-ray was normal. MRI of the lumbar spine demonstrated osteomyelitis/discitis. EKG demonstrated significant ST segment depression consistent with coronary ischemia (Figure 1).

Blood cultures were obtained before the initiation of Vancomycin and Ceftriaxone. TTE was performed on the day of admission and TEE a day later (Figures 3 & 4). Microbiology results yielded identification of Streptococcus sanguinis (Figure 2).

Diagnosis#1. Infective endocarditis of the mitral valve, #2. L4-L5 osteomyelitis/discitis, #3. Acute coronary syndrome

Despite substantial improvement in morbidity and mortality since the advent of modern antibiotics, infective endocarditis (IE) continues to carry a high in-hopsital death rate (18-23%) and at 6-months after presentation (22-27%). Furthermore, as many as 50% of patients with IE suffer at least one complication as a direct result of this blood borne infection1.

This patient presented with sepsis in the setting of a new systolic murmur, prompting further evaluation by echocardiogram due to suspicion of IE. Neurologic complications—principally stroke/embolism among the ICA distribution—are common, occurring in 20-40% of cases of IE2. Treatment with prolonged courses of IV antibiotics remains the cornerstone of management of this disease.

Additionally, valve replacement is an important consideration in severe cases of IE, which requires coordination between Medicine and Surgery. It should be emphasized that the decision to undergo valve replacement should be individualized, but a few generally agreed upon indications for valve replacement include3:

•CHF•≥2 major embolic events•Vegetations >10 mm•Fungal IE

Figure 1: EKG demonstrating ST segment depression in precordial leads V3-V6.

Figure 4: TEE Doppler image demonstrating severe mitral regurgitation associated with the vegetation.

Potassium 3

Albumin 2.8

Hgb 11.1

WBC 16,000

ESR 40

CRP 20

Figure 3: TEE image demonstrating a large mobile vegetation present on the anterior leaflet of the mitral valve.

Figure 2: Blood cultures revealed the presence of Gram-positive cocci in chains.

Dental Appliances in the Treatment of OSASurabhi Kasera*, Scott Hollingshaus MD #, Krishna M. Sundar MD #, Gary Lowder DDS+, Julia Whitaker MD#

*Washington University in St. Louis, Departments of #Medicine & +Dentistry, University of Utah

Methods

Introduction

Objectives

Results

Conclusions References1.Use of Flow-Volume Curves to Predict Oral

Appliance Treatment Outcome in ObstructiveSleep Apnea, American Journal of Respiratoryand Critical Care Medicine 2007; 175: 726-730

1.Efficacy of an Adjustable Oral Appliance andComparison with Continuous Positive AirwayPressure for the Treatment of ObstructiveSleep Apnea Syndrome, Chest 2011; 140:1511-1516

1. Assess follow-up visit frequency, compliance withprovider visits, and long-term care for patients on a dentalappliance received through the SWC.

2. Assess efficacy of TAP III appliance based on patient-reported efficacy and objective follow-up measures.

Dental appliances are recommended for patients with mild tomoderate obstructive sleep Apnea (OSA) that are intolerantto continuous positive airway pressure (CPAP) therapy. TheSleep Wake Center (SWC) has a dental appliance programthat custom-fits appliances for referred patients. This studymeasured the efficacy and follow-up of the TAP III dentalappliance given to patients for OSA or upper airwayresistance syndrome (UARS) in the last 2 years.

Data on patients that received the TAP III device at the SWCwithin the last 2 years (since inception of EPIC electronicmedical records) were reviewed. Demographic data andreason for dental referral were obtained from the medicalrecords. Duration and frequency of follow-up after dentalappliance application was obtained from EPIC. TAP IIIappliance efficacy in patients was assessed using thefollowing:

-Patient and provider-reported subjective assessments of TAP III appliance efficacy.-Oximetry and PSG findings while using the dental appliance.

Statistical analysis using a student’s t-test was done to findsignificant differences in TAP III efficacy with age, sex, BMI,etc. The results of this analysis was used to developprotocols for future follow-up of patients following dentalappliance application.

1. Efficacy of dental appliances is increased in obese subjects. This has been noted inprior studies as well 1-2.

2. For patients receiving dental appliances at the SWC, significant deficiencies in follow-up care were noted in the following ways:

a. Lack of follow-up with referring provider and with dentist fitting the appliance

b. Lack of pre-defined objective testing and validated questionnaires to assessefficacy of dental appliance

c. Lack of comprehensive program aimed at improving BMI along with dentalappliance therapy for OSA or UARS patients

0

5

10

15

20

25

30

35

40

Effective Ineffective

BM

I

Figure 1 Baseline data for patients given TAP III appliance

Figure 2 Follow-up durations of dental visits and visits with referring provider at SWC Figure 4 Obesity and dental appliance efficacy, p < .05, student’s t-test

Figure 3 Compliance in patients with OSA and UARS

Primary Sclerosing Cholangitis in the Setting of Normal Liver Chemistries Can Be Associated with Severe Ductal Disease and Dominate Strictures

Thomas Queen, MD, Kristen Cox MS, RN, Douglas G. Adler, MD Division of Gastroenterology, University of Utah Health Sciences Center, Salt Lake City, UT

INTRODUCTION

Primary sclerosing cholangitis (PSC) is a chronic progressive diseasecharacterized by inflammation, fibrosis and stricturing within the intra andextrahepatic biliary ducts.

It is commonly associated with abnormal liver function tests such as alkalinephosphatase, AST, ALT and total bilirubin.

A subset of PSC patients will present with normal laboratory studies.

OBJECTIVE

The aim of this study is to evaluate patients with PSC with normal liverfunction tests.

METHODS

We conducted a retrospective study of PSC patients with normal liverchemistries to evaluate their clinical course, endoscopic, and pathologicfindings.

This study was approved by the institutional review board at the Universityof Utah School of Medicine, Salt Lake City, Utah.

We reviewed electronic medical records, procedure reports, imagingstudies, and pathology reports on patients with known or suspected PSCbetween the period of February 2000 to April 2013.

We also evaluated a prospectively evaluated database of PSC patients.

Patients in this study were diagnosed with PSC by laboratory studies, liverbiopsy, MRCP, ERCP, or a combination thereof.

RESULTS

There were 102 PSC patients in our PSC database from 2000 to 2013.

11 patients had normal liver chemistries at time of presentation (8M, 3F, mean age 47.1Y)

5 patients had IBD: 3 out of 5 had Crohn’s disease ( 1 had colitis), 2 out of 5 had ulcerative colitis.

On CT scan, 8 out of the 11 patients had evidence of cirrhosis. 8 out of the 11 patients underwent MRI/MRCP and 5 of these patients had

ductal findings suggestive of PSC. 1 patient had an MRI/MRCP that was suggestive of PSC and

cholangiocarcinoma.

All 11 patients underwent ERCP which confirmed the diagnosis of PSC.

All 11 patients had intrahepatic ductal disease manifesting as innumerable strictures and pruning.

4 patients were felt to have dominant strictures: 3 of these dominant strictures were in the common hepatic duct and 1 was in the common bile duct.

3 patients were felt to have mild PSC, 6 were felt to have moderate PSC, and 2 were felt to have severe PSC.

There were no complications following ERCP.

8 patients underwent tissue sampling by brushings and/or biopsy during ERCP.

3 patients were not felt to warrant tissue sampling. 1 patient had a mass lesion at the common hepatic duct that to date has

yielded only benign brushing, histology, and FISH results . The 1 patient with the dominant CBD stricture had brushing that showed

atypical cells suspicious for malignancy and positive FISH study. This patient underwent a pancreaticoduodenectomy for presumed cholangiocarcinoma. Final pathology showed evidence of high grade dysplasia but no cancer.

None of the remaining patients who underwent tissue sampling had positive FISH testing or positive brushings for malignancy.

CONCLUSIONS

PSC patients with normal serum liver chemistries has not been previouslywell described.

PSC patients can have cirrhosis and significant ductal disease, includingdominant strictures and abnormal tissue samples, in the setting of normalliver chemistries.

Patients with PSC and normal liver chemistries were less likely to have IBDand colitis than were patients with PSC and abnormal labs.

All patients tolerated ERCP exams without difficulty and had nocomplications: this may be explained, at least in part, by undergoing ERCP byexperienced operators.

No patient has had significant progression of disease over a mean follow upperiod of 50 months. This is in contrast to most PSC patients who can beexpected to have progression when followed over the same timeframe.

Severe ductal disease seen in a patient t with PSC with normal labs

Case PresentationIntroduction Discussion

• Zygomycosis is a devastating fungal infection, mostly seen in immunocompromised persons and diabetics

• Mostly associated with rhino-orbital-cerebral and pulmonary infections but occasionally can be found in other organ systems

• Mortality remains extremely high despite treatment

Zygomycosis• Zygomycetes is a class of fungi include the following

species: Mucor, Rhizomucor, Rhizopus, Absidia • Angioinvasion leading to tissue necrosis is a hallmark

of zygomycosis.• Healthcare-associated infections have been reported• Gastrointestinal mucormycosis thought to be

secondary to translocation of ingested spores• Diagnosis relies upon identification of organisms by

histopathology• Fungal cultures often negative• Treatment involves aggressive surgical debridement

and antifungal therapy• Duration of therapy is variable and cure requires

recovery of neutrophil function• Prognosis is very poor despite early appropriate

treatment

A 46 year old previously healthy female underwent idarubicin and cytarabine induction chemotherapy for newly diagnosed AML M2. Prophylactic treatment with levofloxacin, penicillin, acyclovir, and micafungin was initiated.

On day #7 She developed neutropenic fever and vancomycin and cefepime were empirically started with evidence for central venous catheter (CVC) exit site infection. Blood cultures were negative. Fungal biomarkers were obtained on day #11 and yielded a negative 1,3 Beta D-glucan and a weakly positive Galactomannan initially thought to be a false positive from total parenteral nutrition.

On day #16 the patient developed worsening abdominal pain. Micafungin dosing was increased and metronidazole was added. On day #17 the patient developed elevated LFTs (normal on day #14) and liver failure. Micafungin was replaced with liposomal amphotericin B.

CT imaging demonstrated mild colitis of the descending and sigmoid colon along with multiple new large hepatic and intra-abdominal hypodense masses extending into the suprahepatic IVC thought to be leukemic tumors vs. infectious etiology, most likely mucormycosis.

She rapidly developed septic shock, ascites, encephalopathy, respiratory failure, and renal failure requiring transfer to the intensive care unit, intubation, and hemodialysis. Surgery was not possible due to progressive decline. Her LFTs continued to increase consistent with fulminant hepatic necrosis. Care was withdrawn at the family’s request and the patient expired on day #21.

Autopsy limited to the liver demonstrated massive hepatonecrosis secondary to portal vein thrombosis and extensive venous thrombosis with broad, irregularly shaped, largely aseptate hyphae, some with right angle branching, consistent with mucormycosis. Leukemic infiltrates into the liver were not identified. Mechanism of hepatic involvement of remains unexplained but may be related to extension from colitis and/or dissemination from CVC exit site infection.

Budd-Chiari syndrome from Zygomycosis/Mucormycosis

• Fewer than 15 cases reported in the literature• Mostly in patients with hematological malignancies

(AML, ALL), solid organ transplant recipients, and diabetics

• Pooled mortality > 50% despite treatment with amphotericin

A B

*

Figure 1. Patient’s axial (a) and coronal (b) CT imaging demonstrating multiple large hepatic masses

including invasion into the inferior vena cava (*) consistent with hepatic mucormycosis.

Figure 2. Extensive hepatic portal vein and inferior vena cava zygomycosis with broad, irregularly branched, aseptate hyphae demonstrated via Grocott-Gömöri’s methenamine silver (A,B) and

Hematoxylin and eosin (C,D) staining at 400x and 1000x respectively.

A B

C D

Table 1. Patient’s lab results on days #1, #14 and #17.

We present a case of fatal hepatic necrosis from Budd-Chiari syndrome attributed to angioinvasive mucormycosis in a patient undergoing chemotherapy for AML. Diagnosis was confirmed only at time of autopsy, but imaging helped narrow the differential when vascular invasion was seen.

Despite timely diagnosis and initiation of systemic antifungal therapy this patient expired. Surgery was not an option given hemodynamic instability, extensive liver involvement and chemotherapy-induced pancytopenia.

Budd-Chiari Syndrome Secondary to Hepatic Zygomycosis in a Neutropenic Patient

Craig D. Robison,1 Bert K. Lopansri1,2

1Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah; 2Department of Infectious Disease, Intermountain Healthcare, Salt Lake City, Utah

Day # 1 14 17WBC (K/μL) 4.5 0.2 0.1Hgb/Hct (g/dL; %) 9.9/29 9.527.3 8.6/24.9

Plts (K/μL) 94 43 9

Na+ (mmol/L) 139 140 134K+ (mmol/L) 4.1 3.6 5.2Cl- (mmol/L) 102 101 101CO2

- (mmol/L) 27 31 7BUN/Cr (mg/dL) 12/0.52 10/0.30 29/1.48Glu (mg/dL) 88 132 84

Alk Phos (U/L) 107 53 493AST (U/L) 23 33 22,614

ALT (U/L) 25 55 8,904T Bili (mg/dL) 0.6 0.5 5.7INR 1.1 1.1 4.0

Hepatitis Panel Neg Neg

Craig D. Robison2, MD; Heidi T. May1, MSPH; Benjamin D. Horne1, PhD, MPH; Donald L. Lappe1, MD; Joseph B. Muhlestein1,2, MD; Jeffrey L. Anderson1,2, MD

1Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah; 2Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah

ResultsBackground• Contrast-induced nephropathy (CIN) is a

complication of cardiac catheterization• Angiotensin converting enzyme inhibitors (ACE-I)

and angiotensin receptor blockers (ARB) are frequently prescribed in those undergoing cardiac catheterization

• Studies evaluating ACEI/ARB use and cardiac catheterization thus far have produced mixed results on the effect of these medications on contrast-induced nephropathy.

Objective• To evaluate the association between ACE-I and ARB

administration and development of contrast induced nephropathy following cardiac catheterization

Methods

Conclusions• ACE-I/ARBs following cardiac catheterization

associated with reduced contrast-induced nephropathy

• Consistent even after adjustment for cardiovascular risk factors and differences in creatinine

• No difference in creatinine changes and mortality at 1 year in all patients

• No difference in creatinine at 1 year in patients with contrast-induced nephropathy

• 5,091 patients in the Intermountain Heart Collaborative Study Registry (Salt Lake City, UT) undergoing cardiac catheterization

• Evaluate for administration of ACE-I/ARB prior to discharge following admission for cardiac catheterization

• Require baseline creatinine < 2.5 mg/dL• Follow-up for one year • Evaluate for development of CIN within 10 days:

• Increase in baseline creatinine of ≥ 25% mg/dL OR• Absolute increase of ≥ 0.5 mg/dL

• Evaluate for persistent CIN between 6-12 months:• Persistent Δ in Creatinine ≥ 0.5 mg/dL from baseline

• Perform multivariable logistic regression analysis, adjusting for cardiovascular risk factors, baseline creatinine, contrast amount, medications, and CAD status

• Include secondary outcomes at 1 year of creatinine increase and all-cause mortality

Discussion• ACE-I/ARB administration was associated with a

decreased incidence of CIN despite more comorbidities and more contrast used.

• Literature reports evidence both for and against a renoprotective effect of ACE-I/ARBs in the development of contrast-induced nephropathy.

• Possible renoprotective mechanisms include opposing arteriolar vasoconstrictive effects of contrast media and attenuating contrast-induced renal tubular cell apoptosis.

• Most other studies are limited by small sample sizes and short follow-up.

• Randomized controlled trials are needed to clarify conflicting results in the literature.

ACE-I/ARB Administration following Cardiac Catheterization Is Associated with Reduced Contrast-Induced Nephropathy

References1. Patel K, King CA, Jovin IS. Angiotensin-converting enzyme inhibitors and their effects on

contrast-induced nephropathy after cardiac catheterization or percutaneous coronary intervention. Cardiovascular Revascularization Medicine. 2011;12:90-93.

2. Rim MY, Ro H, K WC, et al. The Effect of Renin-Angiotensin-Aldosterone System Blockade on Contrast-Induced Acute Kidney Injury: A Propensity-Matched Study. Am J Kidney Dis. 2012;60(4):576-582.

3. Rosenstock JL, Bruno R, Kim JK, et al. The effect of withdrawal of ACE inhibitors or angiotensin receptor blockers prior to coronary angiography on the incidence of contrast-induced nephropathy. Int Urol Nephrol. 2008;40(3):749-755.

4. Cirit M, Toprak O, Yesil M, et al. Angiotensin-converting enzyme inhibitors as a risk factor for contrast-induced nephropathy. Nephron Clin Pract 2006;104:20-7.

Characteristics No ACE-I/ARB (n=2463) ACE-I/ARB (n=2628) p-Value

Age (years) 65.1±13.3 66.0±12.7 0.02Sex (male) 63.8% 67.3% 0.008Hypertension 57.1% 68.5% <0.0001Dyslipidemia 54.9% 62.4% <0.0001Diabetes 24.4% 30.3% <0.0001Family History CAD 33.6% 37.4% 0.005Tobacco Abuse 12.3% 12.9% 0.52Renal Failure 1.5% 1.1% 0.17Prior MI 14.0% 17.2% 0.002Prior CVA 6.7% 5.8% 0.18Prior CAD 57.1% 61.9% <0.0001A-Fib History 19.8% 18.9% 0.42

Presentation <0.0001Stable Angina/Other 64.2% 49.7%

Unstable Angina 24.7% 30.0%NSTEMI/STEMI 11.1% 20.3%

IABP 2.4% 2.9% 0.23Pulmonary Edema 4.4% 3.7% 0.17

PCI 30.7% 53.2% <0.0001Drug Eluting Stent,

n=215564.2%

(485/756)64.0%

(896/1399) 0.96

Bare Metal Stent, n=2155

43.1% (326/756)

43.9%(614/1399) 0.73

Total Contrast (mL) 131.2±102.7 (median107)

168.1±114.0 (median150) <0.0001

Baseline Creatinine (mg/dL) 1.12±0.38(median 1.00)

1.09±0.32(median 1.01) 0.02

Follow-up Creatinine (mg/dL) 1.22±0.50(median 1.10)

1.18±0.43(median 1.10) 0.02

Creatinine Change (mg/dL) 0.10±0.34(median 0.06)

0.09±0.33(median 0.05) 0.54

Characteristics No ACE-I/ARB(n=2463)

ACE-I/ARB(n=2628) p-Value

CIN 16.7% (412/2463) 11.0% (290/2628) <0.0001Persistent CIN 8.0% 7.4% 0.44CIN or Persistent CIN 21.3% 16.3% <0.0001

Death at 1 year 3.8% (89/2369) 3.2% (82/2544) 0.31MI at 1 year 8.4% (199/2369) 13.5% (344/2544) <0.0001CVA at 1 year 3.2% (75/2369) 2.8% (71/2544) 0.44HF admit at 1 year 12.4% (293/2369) 13.1% (334/2544) 0.43Revasc at 1 year 23.7% (531/2239) 20.0% (487/2438) 0.002New onset A-Fib at 1 year 20.5% (389/1902) 13.0% (268/2063) <0.0001

Multivariable Regression OR 95% CI P-Value

CIN 0.70 (0.59-0.84) <0.0001Persistent CIN 0.99 (0.80-1.24) 0.97CIN or Persistent CIN 0.81 (0.70-0.94) 0.006

Table 1. Cohort characteristics. CAD = Coronary Artery Disease; MI = Myocardial Infarction; CVA = Cerebrovascular Accident; A-Fib = Atrial Fibrillation; NSTEMI = Non-ST Elevation Myocardial Infarction; STEMI = ST-elevation Myocardial Infarction; IABP =

Intra-Aortic Balloon Pump; PCI = Percutaneous Coronary Intervention

Table 2. Primary and secondary outcomes at 1 year. CIN = Contrast Induced Nephropathy; MI = Myocardial Infarction; CVA = Cerebrovascular Accident; HF =

Heart Failure, Revasc = Revascularization; A-Fib = Atrial Fibrillation. Multivariable regression analysis for primary outcomes adjusted by baseline

characteristics.

Characteristics No ACE-I/ARB ACE-I/ARB p-ValueBaseline Creatinine (mg/dL)

1.14±0.41(median 1.09)

1.05±0.36(median 1.00) 0.006

Follow-up Creatinine (mg/dL)

1.37±0.58(median 1.20)

1.31±0.53(median 1.20) 0.16

Creatinine Change (mg/dL)

0.23±0.40(median 0.20)

0.26±0.39(median 0.20) 0.55

Table 3. Sub-group analysis for patients who developed contrast-induced nephropathy (No ACE-I/ARB: n=412, ACE-I/ARB: n=290).

p-Value for comparison of log-transformed variables.

Figure 1. Kaplan-Meier 1 year event free survival for (A) Death, (B) Myocardial Infarction, (C) Revascularization, and (D) New Onset Atrial Fibrillation for patients

receiving ACE-I/ARB and controls.

A B C D

Drug Rash Jennifer A Springer, MD

University of Utah Department of Internal Medicine/Intermountain Medical Center

ImagesHPI

Hospital course

Discussion

Diagnosis

References1. “Severe Adverse Cutaneous Reactions to Drugs” NEJM Nov 19942. “Cutaneous Adverse Reactions Associated with Calcium Channel Blockers” Arch

Intern Med 1989 3. “Xarelto (Rivaroxaban) Prescribing information” Janssen Pharmaceuticals Aug

2013 4. Emedicine.medscape.com5. Uptodate.com

All non-essential medications held. Dermatology consulted.

Treated with PO and topical steroids.

Xarelto discontinued, treated DVT with heparin drip and restarted Coumadin.

Swab of leg pustule grew MRSA. MRSA cellulitis treated with Cefotaxime.

Patient remained hemodynamically stable. WBC trended up to a max of 30,000/uL before trending down, no eosinophilia.

Rash quickly resolved, patient had near complete desquamation of epidermis.

61 yo F presented to clinic with a full body rash and fevers.

Patient was diagnosed with a DVT, treated with Coumadin and Lovenox.

One week later she developed skin lesions concerning for skin necrosis; anticoagulation was changed to Xarelto.

Two weeks after starting Xarelto, she was started on Diltiazem for HTN.

The next day she developed a full body rash that started in the extremities and spread to her trunk. The rash was pruritic and associated with fevers. Patient stopped Diltiazem but rash continued to worsen.

Past medical history significant for CAD, DM, COPD, HTN, hepatitis C, chronic kidney disease and multiple drug allergies -mostly to antibiotics.

Most likely causative agents are Xarelto and Diltiazem. The onset of the rash was later than would be expected for Xarelto but sooner than would be expected for Diltiazem.

There are reports of SJS/TENS from Diltiazem and rare reports of SJS/TENS from Xarelto.

If there was no involvement of oral mucosa, the diagnosis would be Acute Generalized Exanthematous Pustulosis (AGEP). Patient did not have elevation of liver enzymes or other evidence of systemic involvement to raise concern for DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). Vasculitities are common with hepatitis C, the status of her hepatitis is unknown, but there was no evidence of vasculitis on exam or biopsy.

There is mixed data for the use of oral steroids to treat drug rashes.

Toxic Epidermal Necrosis (TENS)

Exam: T 37.7, HR 94, BP 146/75, RR 16, O2 sat 95% on 4L NCMorbidly obese female, skin had a maculopapular rash that coalesced into erythematous plaques on the trunk with skin desquamation. Lower extremities had bullae and pustules. 0.5 cm ulceration under tongue.

Labs: Na 134, K 4.7, Cl 94, Bicarb 31, BUN 42, Cr 1.69, Glu 232Ca 9.1, Prot 7.6, Alb 3.7, AST 55, ALT 33, Alk Phos 128, Bili 0.8 WBC 18, Hgb 11.2, Plt 378CRP 10.8, ESR 66

Biopsy:Spongiform eosinophilic dermatitis with dermal perivascular neutrophils consistent with drug rash

Exam and Labs Hospital Course

The patient was a previously healthy 63 year-old woman who presented with clinical stigmata of Henoch-Schönlein Purpura (HSP)including non-blanchable palpable purpura of her lower extremities, hematuria and proteinuria, GI involvement (mouth ulcers) andarthralgias with joint swelling. In addition to physical exam findings and abnormal UA, patient had elevated inflammatory markers with skin biopsy showing small vessel vasculitis with IgA and C3 deposition confirming leukocytoclastic vasculitis (LcV)-HSP.

HSP is a systemic, immune complex–mediated, leukocytoclastic vasculitis that presents acutely with an incidence in the adult population of 2-5/100,000 yearly. It is usually associated with a history of an upper respiratory illness (which this patient did not have) and is by far predominately a pediatric disease. Patients with Henoch-Schönlein purpura always present with a purpuric rash, 75% develop arthritis, 65% have GI involvement (usually abdominal pain) and 50% develop renal disease. It is usually a self limited disease (90%) treated with supportive care and oral steroids for joint pain alone. End-stage renal disease is a fairly uncommon occurrence (5%) although it is more likely to occur in the adult population.

Other forms of LcV were considered in our differential. Our patient did not have an elevated ANA or Hep C titer, making lupus or cryoglobulinemia unlikely. She also did not have signs of systemic infection or a history of new medications as etiologies for small vessel vasculitis. Of note however, patient’s recent exposure to pesticides and fertilizer prompted the question whether this could be a chemical/environmental hypersensitivity vasculitis. There have been several studies including a systematic review and two case-control studies that show an association between organic solvents, silica, and allergens found in the farming industry with primary vasculitis. Although this evidence does not show causation of farming chemicals and IgA vasculitis, such chemicals should be considered when working patients up for vasculitis.

Small Vessel Vasculitis—No Small Thing

Special thanks to Dr. Corwin Edwards, Dr. Myung Lee, Dr. Alalia Berry and Dr. Christian Perez for really letting me be a part of Medicine as a student.

REVIEW OF SYSTEMS

HISTORY OF PRESENT ILLNESS DIAGNOSTIC WORK UP DISCUSSION

References

Miguel G. Teixeira, BS, MSIV. Internal Medicine. University of Utah, Salt Lake City, UT.

Patient is a 63 year old previously healthy woman from Wyoming with a recent exposure to pesticides and fertilizers who presents to the ED with complaints of a painful and swollen bilateral purpuric rash in her lower extremities. She reports she noticed small "red spots" that were non-blanchable on the dorsum of her feet approximately one week ago. These spread to her legs and thighs with progressively worsening edema. She took Benadryl and ibuprofen without relief of her pain or swelling. Patient was seen by a family medicine physician and ED in Wyoming and was given Lortab for pain and Lasix for diuresis. She reports these gave her symptomatic relief, but noticed her entire legs became red and then purple with weeping serous fluid bullae and vesicles throughout. She admits to experiencing new joint pains including her ankles, knees and hands. These pains are worse in the morning. Patient denies a history of chronic sinusitis, cough, hemoptysis, dyspnea and gross hematuria. She also denies a history of asthma or GI complaints including any abdominal pain or melena. She denies any fevers, chills or night sweats, and has no risk factors for sexually transmitted diseases. She has not taken any new medications before onset of symptoms and denies any family history of rheumatologic diseases. A full review of systems was conducted and was positive for painful mouth sores, otherwise negative.

Tonsillectomy, right ankle surgery with post-op allergy to hardware and subsequent removal.No DM, CAD, Hep B/C, autoimmune disorders including lupus, rheumatoid arthritis or renal disease

PAST MEDICAL HISTORY

SOCIAL HISTORY

FAMILY HISTORY

MEDICATIONS AND ALLERGIES

15 pack year smoker. Currently smokes 3 cigarettes/daily. No EtOH or IV drug use. She lives in WY. Monogamous relationship with male partner.

No history of DVTs, cancer, lupus or other autoimmune/dermatologic disease.

Calcium, vitamin D. Lortab prn and Lasix started one week prior to presentation. Allergies: Titanium.

A

B

D

C

PHYSICAL EXAMVital Signs: T 37.3 HR 93 RR 20 BP 113/53 SpO2 92% RAGeneral: Alert and Oriented x4. NAD. Patient is tearful.HEENT: No scleral icterus. No conjunctivitis. No rhinorrhea. Small 2-5mm erosions (A) on the soft palate, upper gingiva and lower lip mucosa.Neck: Supple without lymphadenopathy.Heart: Regular rate and rhythm, no murmurs or gallops.Lungs: CTAB, no wheezes or crackles.Abdomen: Soft, non-distended, non-tender. Normoactive bowel sounds. BACK: No CVA tenderness. No point tenderness along the spine.Skin: Discrete, small purpuric macules in palmer aspect of digits. (B) Many non-blanchable palpable purpuric maculopapular lesions on both feet extending to the thighs with several weeping bullae and vesicles with serous fluid. (C, D) Minimal tenderness to palpation. Bilateral peripheral edema up to knees. Right medial thigh incision with stiches in place from biopsy.

Photomicrograph of skin biopsy of patient (F, G) shows neutrophilicinfiltration into the dermis and fibrinoidvasculitis. Immuno-fluorescence microscopy (E)showing deposition of IgA.IF slide (E) is similar to patient’s actual slide and is courtesy of the Univ. of Utah dept. of Dermatology teaching slides.

E

GF

SKIN BIOPSY by punch technique

LABS14.5

25942.6

9.9142 99 25

1361.06284.0

ANA negative, RF 15H, c-ANCA negativeHep C negativeCyrofibrinogen negative

Tox Screen: Negative other than for opiatesUA: Hgb +, Protein 1+, WBC 8/hpf, RBC 3/hpf

ESR 34CRP 14.5INR 1.2Lactate 1.5 Normal Differential

Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, Garcia-Fuentes M, Gonzalez-Gay MA. Henoch-Schonleinpurpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. May 1997;40(5):859-64. .Chartapisak W, Opastirakul S, Hodson EM, Willis NS, Craig JC. Interventions for preventing and treating kidney disease in Henoch-Schonlein Purpura (HSP). Cochrane Database Syst Rev. Jul 8 2009;CD005128. Gedalia A. Henoch-Schonlein purpura. Curr Rheumatol Rep. Jun 2004;6(3):195-202.Hogan, SL et al. Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin J Am Soc Nephrol. 2007 Mar;2(2):290-9. Epub 2007 Feb 7.Lane SE, et al. Are environmental factors important in primary systemic vasculitis? A case-control study. Arthritis Rheum. 2003 Mar;48(3):814-23.Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D. Henoch-Schonlein Purpura in adults: outcome and prognostic factors. J Am Soc Nephrol. May 2002;13(5):1271-8. Reamy BV, et al. Henoch-Schönlein purpura. Am Fam Physician. 2009 Oct 1;80(7):697-704.Saulsbury FT. Clinical update: Henoch-Schonlein purpura. Lancet. Mar 24 2007;369(9566):976-8.Szer IS. Henoch-Schonlein purpura. Curr Opin Rheumatol. Jan 1994;6(1):25-31. William, JR. Environmentally Triggered Small Vessel Vasculitis. Annals of Allergy, 38: 245-251, Apr. 1977.

HLH is a syndrome characterized by a constellation of 8 clinical criteria that include: fever >38.5, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen, lymph nodes or liver, low or absent NK-cell activity, elevated ferritin and sCD24 levels1. The genetic form of this disease is inherited in an autosomal recessive manner which most often presents in the pediatric population, but has been initially diagnosed in adulthood2.

Specific molecular mutations include PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A, and BIRC4. Although multiple mutations have been identified, they share a common phenotype of impaired cytotoxic function of NK and T cells. The genes may affect granule-dependent lymphocyte cytotoxicity by impairing trafficking, docking, exocytosis priming or membrane fusion of cytolytic granules. The genetic defect may also impair the pathway by loss of functional perforin2. This leads to the impaired elimination of activated macrophages by NK and T cells. These persistent macrophages not only phagocytize normal hematopoietic cells but also produce excess cytokines that lead to tissue damage throughout the body.

More commonly, adult HLH is secondarily acquired after a strong immunological activation. The most common triggers are infectious (viral, more so than bacterial or fungal), hematologic malignancy such as leukemia or lymphoma, and autoimmune disease. In our patient’s case we felt that she most likely had a macrophage activating syndrome triggered by her known psoriatic arthritis. Therefore she was treated with steroids in hopes of controlling both her rheumatologic condition and HLH. Inadequate response would require standard induction per the HLH-94 protocol with dexamethasone and etoposide3. Antagonists to IL-1 and IL-6 have been reported to be helpful in patients with HLH secondary to rheumatologic disease as well2. Untreated, the average survival of patients with HLH is 2 months. With treatment however, a survival rate of 55% after a mean follow-up of 3.1 years is reported2.

Patients with HLH can present in many forms: fevers of unknown origin, hepatitis with acute liver failure, bone marrow failure, multiple skin manifestations, pulmonary dysfunction, sepsis-like physiology, cardiac and neurological abnormalities. Our patient obtained an initial diagnosis of CNS tuberculosis, leading to exacerbation and delay in treatment of her HLH. We present this case to increase the recognition of HLH. Prompt recognition and treatment are critical for this otherwise uniformly fatal disease.

When Macrophages Attack!Madeline Torres BS, Matthew Feurer, MD, Shiven Patel, MD

University of Utah Health Sciences Center, Dept. of Internal Medicine, Division of Hematology, Salt Lake City, Utah

T emp la t e & pr i n t i ng b y Med i c a l Gr ap h i c s & Ph o t og r a p hy • Un iv e r s i t y o f U t a h S c h oo l o f Med i c i n e • 80 1 . 58 7 . 343 5 / b a r b a r a . s t e p ha n@hs c .u t a h . ed u 8 / 20 12

After extensive medical evaluation, three diagnostic possibilities were raised: CNS tuberculosis (TB), Adult-onset Still’s disease, and Hemophagocytic Lymphohistiocytosis (HLH). Given the concern for TB she was started on pyrazinamide, rifampin ethambutol and isoniazid. Immunosupressants that would have been appropriate for treatment of the other possible diagnosis were held given concern that these medicines would worsen a tuberculosis infection. Our patient represented two weeks later with a deteriorating clinical status. It was felt at that time that she most likely did not have TB and her care was focused on HLH that was likely triggered from a rheumatologic disorder. She was started on daily dexamethasone 10mg/m2. Clinical parameters such has joint pain, rash, fever curve, and splenomegaly were monitored for improvement. Abnormal laboratory parameters such as platelet count, elevated PT and aPTT, liver function tests, ferritin, and soluble IL-2 receptor levels were closely monitored for normalization.

References

DiscussionLaboratory DataCase Presentation

Fig 1 and 2: Hemophagocytic macrophages identified on bone marrow aspiration

8.33314.8

2516

16

104

3.0

135

0.748

130

2.65.6 23

9.1

0.8181

Serum IL-2 R 2390 pg/mLM.TB amp CSF negativeHistoplasma Y/M CSF

<1:2, negative

CSF %PMN 4%CSF appearance

Clear, colorless

CSF glucose 41 mg/dLCSF RBC 2CSF WBC 2CSF totalprotein

22 mg/dL

A 45-year-old Mexican female with past medical history of hyperlipidemia, hypertension, psoriatic arthritis, and drug-induced lupus presented to the ED with worsening joint pain, fever, chills, night sweats, and blurry vision over a 5 month period. She also complained of hair loss, fatigue, shortness of breath, nausea/vomiting, and a recent 15 pound weight loss on review of systems. Physical exam was notable for tenderness to palpation in both knees and bilateral DIP joints. She had a tender nodule on her left fourth DIP and psoriatic type rash on the extensor surfaces of her fingers bilaterally and elbows. She also had a diffuse erythematous rash covering arms and legs.

Diagnostic Workup Imaging

1. Henter J-I, Elinder G, O ¨ st Å, and the FHL Study Group of the Histiocyte Society. Diagnostic guidelines for Hemophagocytic lymphohistiocytosis. Semin Oncol 18:29–33, 1991.2. Michael B. Jordan, Carl E. Allen, Sheila Weitzman, Alexandra H. Filipovich, Kenneth L. McClain. How I treat Hemophagocytic lymphohistiocytosis Blood. 2011 October 13; 118(15): 4041–4052. Prepublished online 2011 August 9. doi: 10.1182/blood-2011-03-2781273. Henter J-I, Arico M, Egeler M, et al. HLH-94: A treatment protocol for Hemophagocytic Lymphohistiocytosis. Med Pediatric Oncol 1197;28:342-347

Ferritin 53612 ng/mLFibrinogen 123 mg/dLD-dimer 7.8 u/mLTriglycerides 397 mg/dLPT 28.3 secINR 2.7 ratioPTT 35 secIgA 125 mg/dLIgG 1710 mg/dLIgM 367 mg/dLHep A Ab, IgM Negative

Fig 3: Bilateral hand x-ray demonstrating erosions involving DIPs.

Fig 4: Axial abdominal CT scan with splenomegaly measuring up to 14.3 cm in diameterDiagnosis

Hemophagocytic Lymphohistiocytosis

References

Gluteal Diffuse Large B-cell Lymphoma presenting with HypercalcemiaKhine Win, MD

University of Utah, Department of Internal Medicine

Diagnostic Lab and ImagingHistory of Present Illness

Physical Exam

Conclusion

1. Seymour, J.F., Grill, V., Martin, T.J., et al. Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein. Leukemia, 7, 1672-1675 (1993).

2. Clines, G.A., Guise, T.A. Hypercalcemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblatic metastasis to bone. Endocrine-Related Cancer, 12, 549-583 (2005).

3. Hewison, M., Kantorovich, V., Liker, H.R., et al. Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. Journal of Bone and Mineral Research, 18, 579-582 (2003).

4. Matsuhashi, T., Tasaka, T., Uehara, E., et al. Diffuse large B-cell lymphoma presenting with hypercalcemia and multiple osteolysis. Leukemia and Lymphoma, 45, 397-400 (2004).

5. Roodman, G.R. Pathogenesis of myeloma bone disease. Leukemia, 23,435-441 (2009). 6. Kearns, A.E., Khosla, S., Kostenui, P.J. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in

health and disease. Endocrine Reviews, 29, 155-192 (2008).7. Sargent, J.T., Smith, P.O. Haematological emergencies managing hypercalcemia in adults and children with haematological disorders. British

Journal of Haematology, 149, 465-477 (2010).

• A large, firm, fixed mass on the left buttock protruding laterally and posteriorly mildly tender to palpation

• Pertinent findings during the neurological exam Alert and oriented Decreased sensation to the light touch in both

legs up to the knees Normal reflexes Normal rectal tone

• A 59 year-old man with no significant past medical history presented with four weeks history of: Bilateral leg weakness Left buttock pain and swelling Constipation Mild confusion Weight loss

• Previously treated with prednisone and narcotics as outpatient without any improvement

• Malignancy-associated hypercalcemia can be life-threatening without the urgent intervention.

• As we are learning more about the molecular pathophysiology of the bone resorption, many new targeted therapies for the malignancy-associated hypercalcemia, such as monoclonal anti-RANKL antibody (denosumab) and the decoy receptor (osteoprotegerin), have been identified.

• Trials to compare the new targeted therapies with the traditional bisphosphonate therapy such as zolendronate, are underway.

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>X< = Patient Result (Ca 14.4, PTH 7)

p = Primary Hyperparathyroidisms = Secondary Hyperparathyroidismh = Hypoparathyroidismm = Hypercalcemia of Malignancy

CT pelvis showed the marked asymmetry of the pelvis with soft tissue attenuation mass on the left buttock, extending medially.

PET CT showed a large hypermetabolic mass in the left pelvis, along with the hypermetabolic lymph nodes in the peri-aortic region of the retroperitoneum.

No distant metastasis.

H & EH & E

CD20+CD20+

CD45+CD45+

Discussion

All biopsy and radiographic images were obtained through the courtesy of Dr. Corwin Edwards and Intermountain medical center.

• The large gluteal mass biopsy showed the diffuse large B-cell lymphoma (DLBCL), confirmed with positive CD20 and CD45 antigens. Fortunately, he has the localized disease on PET CT scan with no bone marrow involvement, based on the normal bone marrow biopsy and flow cytometry.

• Severe hypercalcemia at presentation with very low parathyroid hormone level indicated the malignancy-associated hypercalcemia. He was treated with IV fluid hydration, zolendronic acid and calcitonin. His calcium level was normalized at discharge.

• Hypercalcemia is not a common presentation for non-Hodgkin lymphoma such as DLBCL. Only up to 13% of incidence was reported previously in the literature. Elevated parathyroid hormone related protein (PTHrP) and bone metastases are the two most common etiologies responsible for malignancy-associated hypercalcemia. Interestingly, our patient has no bone metastases and low PTHrP level at presentation.

• Even though PTHrP is the most common humoral mediator in all malignancies, the ectopic calcitriol was reported to be a key mediator responsible for the malignancy-associated hypercalcemia in 30-40% of non-Hodgkin lymphoma. Calcitriol may be secreted by the lymphoma-associated macrophages and increased the intestinal absorption of calcium, leading to hypercalcemia. Unfortunately, the calcitriol level was not measured during the admission.

• The receptor activator of nuclear factor κB (RANK) and its ligand, RANKL, are known to be involved in the osteoclastic bone resorption, releasing calcium from the bone. RANKL is secreted by the activated lymphocytes and its expression was upregulated by the PTH, PTHrP, calcitriol and prostaglandins. Other cytokines such as IL-1, IL-6, tumor necrosis factor-1α (TNF-1α), macrophage inflammatory protein-1 alpha (MIP-1α), MIP-1β were also reported to increase the local osteolysis in diffuse large B-cell lymphoma cells.