Mimics Test Taking Tip Test Taking

10 – Syndromes that Masquerade as Infections Speaker: Karen C Bloch, MD, MPH, FIDSA, FACP

Disclosures of Financial Relationships with Relevant Commercial Interests 10 •None Syndromes that

Masquerade as Infections With Special Thanks to Dr. Bennett Lorber!

Karen C. Bloch, MD, MPH, FIDSA, FACP Associate Professor, Division of Infectious Diseases Vanderbilt University Medical Center 7/1/2019

Mimics 2018 ID Board Content Medical Content Category % of exam

• Many conditions masquerade as infections. Bacterial Diseases 27% HIV Infection 15% • Often with fever Antimicrobial therapy 9% • Sometimes focal abnormality Viral Diseases 7% Travel and Tropical Medicine 5% – Cellulitis Fungi 5% – Pneumonia Immunocompromised Host (non HIV) 5% Vaccinations 4% – Lymphadenopathy Infection Prevention and Control 5% –Etc General Internal Medicine, Critical Care & Surgery 18% Total 100%

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• Just as for infections, look for “buzz words” • For infections: and “hooks” If I say “rabbit”, you say…..

• For infections: If I say “rabbit”, you say….. TULAREMIA

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I say ”Chitlins” I say ”Chitlins”

You say….. You say…..

YERSINIA

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I say ”Bull’s-eye rash” I say ”Bull’s-eye rash”

You say….. You say….. Lyme disease (or Erythema migrans or STARI)

My Approach to Mimics Warm Up! • Think like an internist! • I’ll use cases to illustrate what kinds of diseases and questions you might encounter on the Board Exam. • Goal is to cover lots of cases rather than in-depth discourse

Question 1 Question 2 A young man has oral and genital ulcers. You Sweet Syndrome is most likely to occur in a suspect Behçet’s disease. Which one of the patient with which one of the following illnesses? following findings is most consistent with that diagnosis? A. Ulcerative colitis A. Evanescent, salmon-colored rash B. Adult onset Still’s Disease B. High ferritin C. Acute leukemia C. Saddle nose deformity D. Systemic lupus D. Pustule at site of venipuncture E. Ankylosing spondylitis E. Posterior cervical adenopathy

Question 3 Now on to our discussion, A patient has a slowly enlarging ulcerated skin lesions on starting with a case. his shin after being hit by a soccer ball. Which one of the following is the most likely diagnosis?

A. Pyoderma gangrenosum B. Ecthyma gangrenosum C. Erythema nodosum D. Sweet Syndrome E. Behçet’s disease

Case 1 Case 1 • 26yo man with presents with a 1-month h/o • Exam: T=38.4⁰C, HR=118bpm, no fever, night sweats and fatigue. He was lymphadenopathy, palpable spleen tip evaluated by his PCP with unrevealing appreciated. bloodwork, and a negative monospot test. He was diagnosed with a viral illness, but symptoms • Labs: 13 ALT=38 have persisted. He lives in Indiana with his wife AST=200 2.7 53 and 2 yo son. They have 2 cats. 0.79 Alk Phos=494 39 Bili total=1.9 Ferritin=35,148 mg/ml

Question 4 Hemophagocytic Lymphohistiocytosis

• What is the most appropriate next study? • Immune activation syndrome – Primary: Familial due to genetic mutation A. Flow cytometry of whole blood B. ANA profile – Secondary: Most commonly triggered by C. EBV serologies infections (EBV or other herpes group viruses, D. Soluble IL-2 receptor alpha level HIV, histoplasmosis, Ehrlichia, etc) or E. Toxoplasma titer malignancy (lymphoma, leukemia)

HLH: Diagnostic Criteria HLH Clues • Requires >=5/8 • EBV or other infection with progressive – Fever symptoms – Splenomegaly – Cytopenias (any line) – Hypertriglyceridemia – Ferritin >500 mg/mL • Massively elevated ferritin – Elevated soluble IL-2 receptor alpha (aka CD25) – Low NK cell activity – Hemophagocytosis on pathology • Cytopenia with negative infectious evaluation

Case 2 • Exam: T=104.2⁰ F. Tonsilar swelling and erythema is present, • A 39-year-old woman is seen on day 4 of with tender cervical LN. Spleen hospitalization for high fever and leukocytosis. tip is palpable. The R wrist is The fever had been present for 3 ½ weeks and swollen and painful. A rash is was accompanied by severe arthralgias of the noted on the trunk and knees, wrists and ankles as well as myalgias. A extremities, most prominently severe sore throat was present during the first under the breasts and in the area week of the illness. of her underwear waistband.

• Labs: Question 5 Ferritin 3600 ng/ml (nl 40-200) WBC 32,200 (89% neutrophils) AST and ALT 3x normal • The most likely diagnosis is? ESR and CRP 5x normal A. Lymphoma ANA and RF negative B. Adult Still’s Disease Throat and blood cultures negative C. Acute Rheumatic Fever • On afternoon rounds with the attending, the fever D. Cryoglobulinemia resolved with Tylenol and the rash is no longer present. E. Kikuchi’s Disease

Adult Still’s Disease (Adult Onset JRA) Adult Still’s

Yamaguchi Criteria: (5 features with 2 major criteria) • Buzz words and associations: evanescent, salmon-colored rash Major: Minor: • Other clues: 1. Fever >39⁰C for >week 1. Sore throat Multi-system illness 2. Arthritis/arthralgia >2 wks 2. Lymphadenopathy Elevated ferritin 3. Nonpruritic mac-pap rash 3. Lg Liver or spleen Pharyngitis during febrile episodes 4. Abnl LFTs or LDH Koebner phenomenon = rash elicited by 4. Leukocytosis >10K with 5. Negative ANA & RF >80% granulocytes. stroking skin or areas of pressure.

Case 3 • Exam: afebrile. • A 24-year-old man is referred from the ER for ulcers of Left eye is inflamed and there is a hypopyon. the mouth and penis. Three months ago he came to the Numerous ulcers on the oral mucosa. U.S. from Japan to attend graduate school. No adenopathy. There is a 0.5cm ulcer on the penis. A 6mm papulo-pustular lesion is present in the right • He has a history of intermittent, painful oral ulcers for 3-4 antecubital fossa; the patient says that is where they years. Four days ago he developed a painful ulcer on drew blood yesterday in the ER. the penile shaft. Had a similar lesion 2 months earlier. • Rest of the exam is normal. Takes no medicines and denies sexual contact for the • Labs: Hb 12.1; WBC 13,750. HIV negative past 5 years.

Question 6 Behçet’s disease • Pleomorphic vasculitis with clinical diagnosis • The most likely diagnosis is? Recurrent oral ulcers (>3 per year) PLUS 2 of the following recurrent genital ulcers A. Syphilis eye (uveitis, retinitis, hypopion) or skin lesions (EN, papules) B. Behçet’s disease pathergy (red papule developing 24-48 hrs after needlestick) • Think “silk road” (Asia->Mediterranean) C. Herpes simplex virus infection • Less common manifestations D. Sarcoidosis – GI disease (abdo. Pain, bloody diarrhea) – CNS disease (aseptic meningitis) E. Cytomegalovirus infection – Arterial and venous thrombosis • Treatment: colchicine

Behçet’s disease Case 4 • Buzz words and associations: • A 38-year-old woman with AML is admitted with fever. Mucosal ulcers on mouth and/or genitals She underwent induction chemotherapy 2 weeks prior, PLUS…. complicated by neutropenic fever. Following marrow recovery, she was d/c to home. The day of admit she GI symptoms (vs CMV) developed fever without localizing symptoms. CBC Aseptic meningitis (vs HSV) showed a white blood cell count of 12,250 with 20% bands. Visual changes • Exam: T 101.4; P 98; otherwise unremarkable. Pathergy (needle or IV site) • Blood cultures were sent, and she was admitted and Asian or Mediterranean ancestry started on broad spectrum empiric antibiotics.

• HD 2: Fever persists, with interval development of raised, red-purple, tender, HD 3: Fever persists; some of the papules non-pruritic papules and nodules on her develop a plaque-like appearance face, neck and the dorsum of her hands.

HD 4: biopsy: dense dermal perivascular infiltrates of neutrophils without evidence of vasculitis; stains for organisms negative.

Question 7 Sweet Syndrome • AKA acute febrile neutrophilic dermatosis • Which one of the following is the most • Three variants: – Idiopathic or “classical”->50% (IBD, post viral illness, preg, etc) likely diagnosis? – Malignancy associated~20% (may precede dx, AML most frequent) A. Ecthyma gangrenosum – Drug induced-G-CSF most common, usually 2 wk after exposure • Fever universally present B. Pyoderma gangrenosum • Rarely oral ulcers or extra-cutaneous disease characterized C. DRESS by neutrophilic infiltrate on path • Labs notable for leukocytosis with left shift, inc ESR & CRP D. Leukemic infiltrates • Path diagnostic—Neutrophilic infiltrate without vasculitis E. Sweet syndrome

Sweet Syndrome Sweet Syndrome • Buzz words and associations: • Lesions appear abruptly and usually tender. Acute • May be single or multiple, Febrile often involving dorsum of Neutrophilic (periph and path) hand. Dermatosis • Red, violaceous, or yellow center Be suspicious in patients with malignancy (esp AML, past • Nodular or plaque-like or present), IBD, recent URI, vaccination, pregnancy, or • Central umbilification with colony stimulating factor use in preceding 2 weeks target appearance

Case 5 •Exam: • A 33-year-old recent immigrant from Central T 100.2; skin lesion on leg (see image) America is seen for a chronic ulcer of the leg. Slight, diffuse abdominal tenderness. • The ulcer has progressively enlarged over 3 months. Otherwise unremarkable. after he bumped his leg on a table. Several courses of oral antibiotics have been given with no response. • Labs: • For the past year he has been troubled by an “upset Hb 12.4; WBC 11,150, ESR=79, stomach” = intermittent abdominal cramps, frequent CRP=110 diarrhea; and, on 2 occasions, blood in the stool. UA normal He has also had intermittent fever, sometimes accompanying diarrhea, sometimes not. Basic metabolic panel normal Chest x-ray normal

Leg lesion Question 8 Which one of the following is the most likely diagnosis? A. Ulcerative colitis B. Cutaneous leishmaniasis C. Amebic colitis D. Necrotizing fasciitis E. Squamous cell cancer Painful and irregularly shaped ulcer with undermined borders

Pyoderma gangrenosum Pyoderma Gangrenosum • Another neutrophilic dermatosis; fever variably present • Buzzwords & Hooks • Papule at site of often trivial trauma, progressing – Minor trauma to a painful ulcer with violaceous or red border (Pathergy) frequent and necrotic base – Painful, progressive undermined ulcer • >50% of cases occur with systemic illnesses (but with violaceous edges may precede dx, or occur independent of flares) and necrotic base

– Concomitant IBD, By Crohnie - Own work, Public Domain, – IBD (MOST COMMON COMORBIDITY; UC>Crohn’s) https://commons.wikimedia.org/w/index.php?curid=3938746 – Inflammatory arthritis arthritis, neoplasm – Solid organ or heme malignancy

Case 6 • Exam: A 79-year-old woman is seen for 3 weeks of fever T 102.2, P 104, BP 124/84 and fatigue. Except for hypertension, she has no Slight tenderness over left scalp medical problems. Has noted jaw discomfort when mitral regurgitant murmur rest of exam normal chewing food, and 1 week ago had a brief episode of double vision. One week before she became ill she • Labs: attended a wedding at which she ate pork from a Hb 9.8; WBC 9800, normal diff whole pig that was roasted on a spit over an open UA normal fire. basic metabolic panel normal sedimentation rate 147

Giant Cell Arteritis Question 9 • GCA (AKA temporal arteritis)= pan-arteritis of extracranial branches of the carotid. Which of the following is most likely to yield a diagnosis? • A disease of the older adult: Almost all >50years • Clinical findings: Fever, HA, scalp or TA tenderness, A. Anti-neutrophil cytoplasmic antibody (ANCA) jaw claudication, amaurosis fugax B. Taenia solium serology • Marked inc ESR/CRP suggestive, TA biopsy C. Blood cultures diagnostic D. Arteriography • Immediate steroid therapy indicated if visual changes E. Temporal artery biopsy to prevent blindness (won’t affect biopsy yield for up to two weeks).

Giant Cell Arteritis Giant Cell Arteritis & PMR Buzz words and associations: Buzz words and associations: – Half of all patients with polymyalgia rheumatic (PMR) Age >50 years; fever (FUO) and: have concomitant GCA scalp tenderness – Fever not prominent (may be low grade) in absence diplopia or transient visual loss of GCA – Aching and morning stiffness in proximal muscles of jaw or tongue fatigue or shoulder and hip girdle pain while chewing – Gel phenomenon high sedimentation rate

Takayasu Arteritis Case 7 • Another large vessel vasculitis involving aorta, branches and pulmonary arteries. • A 37-year-old female presents with fever and joint pain. She is a long-distance runner and in • Buzz words and associations: excellent health. – Young woman (>80%), Asian ancestry – Subacute onset of fever, weight loss, arthralgias and myalgias • Three weeks prior she noted R knee pain after a – Carotidynia (pain with palpation), decreased pulses long run. She was treated with steroid injection – Extremity claudication; visual changes; TIAs with transient improvement, but subsequently • Dx: Arteriography developed bilateral ankle pain and redness. She notes subjective chills and sweats. • She does recall several tick bites over the last 2 months

Exam: Question 10 T 101.2; Pulse 72; BP 110/70 Bilateral synovial thickening of ankles with warmth and Which of the following is most likely to be tenderness to passive movement diagnostic? Skin exam with painful pre-tibial nodules Labs: A. Chest x-ray WBC 8.8 (76% segs) B. Serology for Borrelia burgdorferi CRP=167 C. Urine Histoplasma antigen Uric acid=4.4, RF <15, CCP negative D. Arthrocentesis E. Skin biopsy

Sarcoidosis Erythema nodosum

• A common mimicker with protean presentations Infectious causes Non-Infectious causes • Extrapulmonary presentations in ~1/3 of cases • Streptococcal infection •Sarcoid • Lofgren Syndrome • Mycoplasma •IBD – Clinical diagnosis: Triad of hilar LAN, acute arthritis, EN – Women, ankles (>90%), fevers common • Granulomatous infections • Lymphoma • BUZZ WORDS – Histo/blasto/cocci/TB • Behcet disease – Hilar LAN, EN, parotid enlargement, uveitis • Bartonella • Medications – Aseptic meningitis with basilar enhancement • Yersinia, Salmonella, –OCP – Non-caseating granulomas Campylobacter GE – Sulfonamides & PCN

Case 8 •Exam: • A 19-year-old recent immigrant from Iraq is T 102.2; pulse 114; no rash hospitalized for 2 day history of fever and severe Abdominal guarding, rebound abdominal pain tenderness, hypoactive bowel sounds. • He says he has had similar episodes on at least • Labs: 3 previous occasions over the past 7 years. Hb 12.4; WBC 16,650; UA normal basic At the first episode he underwent metabolic panel normal appendectomy; the removed appendix was no occult blood in stool normal. Other episodes resolved spontaneously CT of abdomen and pelvis normal after 2-3 days.

Question 11 Familial Mediterranean Fever

• Hereditary auto-inflammatory disease The most likely diagnosis is: • Sporadic, recurrent attacks of fever & serositis A. Hereditary angioneurotic edema (peritonitis, pleuritis, arthritis), manifesting as pain. • Dx: genetic testing B. Familial Mediterranean fever • Buzz words and associations: - C. Systemic lupus erythematosus – Periodic episodes (fever PLUS…) D. Crohn’s disease – Colchicine responsive illness – Certain ethnic groups: Armenians, Turks, Sephardic Jews, N. E. Acute intermittent porphyria Africans, Arabs, Greeks, Italians, Ashkenazi Jews in U.S.

Case 9 •Exam: T 101.4; unilateral anterior and posterior cervical • A 26-year-old medical enlarged lymph nodes, mobile, firm, and student presents with fever mildly tender. Otherwise unremarkable. and cervical adenopathy. • Labs: • She was completely well Hb 13.9; WBC 4,900 (9% atypical lymphocytes) until 9 days ago when she Basic metabolic panel normal had the acute onset of fever Chest x-ray normal and vague neck discomfort. She had no sore throat and ESR=72 no dental or scalp problems. Monospot: Negative

• Serologic studies: Question 12 EBV consistent with prior infection Which one of the following is the most likely CMV, Toxoplasma, Bartonella titers negative diagnosis? RF, ANA, ds-DNA negative A. Cat Scratch Disease • Lymph node pathology: B. Adult Still’s Disease necrotizing lymphadenitis with histiocytic infiltrate and phagocytosed debris. C. Sarcoidosis D. Kikuchi Disease Stains for AFB and fungi negative. E. Non-Hodgkin Lymphoma

Kikuchi Disease Kikuchi’s Disease • AKA acute necrotizing histiocytic lymphadenitis • Diagnosis by lymph node biopsy: • Self-limited condition of unknown cause – necrotizing histiocytic infiltrate (not neutrophils) • Typically young women and fragments of nuclear debris. • No racial or ethnic proclivity (more common in Asia) • fever & cervical LAN (esp posterior, usually unilateral). • Buzz words and associations: • May also see morbiliform exantham, rarely extra cervical – Acute onset fever and cervical adenopathy in young LAN, aseptic meningitis, uveitis. woman • Variably leukopenic and atypical lymphocytes (25% of – Atypical lymphocytes (mono-like syndrome) cases). – Path: necrotizing adenitis with histiocytosis

Case 10 • Exam: Temp 101.5; RR 24; • A 41-year-old woman is seen for fever, diffuse wheezing; palpable purpura with worsening respiratory symptoms, an abnormal nodules on elbows and legs. chest x-ray, and a rash. • Labs: WBC 15,230 (22% eosinophils). • She has long-standing asthma. • CT scan: bilateral peripheral infiltrates. She uses an inhaler several times a day and • Skin nodule Bx: granulomas was recently placed on a leukotriene receptor antagonist. She is being tapered off steroids which she has taken for several months.

Question 13 Churg-Strauss Syndrome • AKA eosinophilic granulomatosis with polyangiitis (EGPA) Which one of the following is the most likely • Multisystem, small vessel vasculitis with allergic rhinitis, diagnosis? asthma, peripheral and lung eosinophilia. A. Strongyloidiasis • Most often involves lung and skin, but can involve heart, GI tract, and nervous system. B. Disseminated histoplasmosis • Presence of blood eosinophilia and peripheral pulmonary C. Sarcoidosis infiltrates in setting of difficult to control asthma D. Allergic bronchopulmonary aspergillosis • Tapering of steroids often “unmasks” EGPA E. Churg-Strauss syndrome • May be p-ANCA positive.

Churg-Strauss Syndrome Case 11 • A 38-year-old man is seen for a 6-week history of • Buzz words and associations: cough accompanied by intermittent fever and – Longstanding asthma night sweats. – New infiltrates and eosinophilia (>10%) as • He has had nasal stuffiness for 4-5 months with steroids being tapered. occasional epistaxis. – Rash (tender nodules on extensor surfaces, • He lives in Philadelphia, and 6 months ago purpura, ecchymosis) traveled to Cincinnati, OH on business. – Fever UNCOMMON (until late) • He has no pets and takes only an OTC decongestant

Exam: Question 14 • T 100.2; RR 18; Saddle nose deformity with perforation of nasal • The diagnosis will most likely be supported septum; lungs clear; rest of exam normal. by which one of the following? A. c-ANCA • Labs: B. Anti-glomerular basement membrane Ab WBC 6,900 with normal differential; UA 30-50 RBC; BMP normal C. Histoplasma urine antigen Chest CT: bilateral nodules with cavitation. D. Angiotensin converting enzyme (ACE) E. Pulmonary angiogram

Granulomatosis with polyangiitis (GPA) Granulomatosis with polyangiitis (formerly Wegener’s) •Dx: • Systemic vasculitis of medium and small arteries. Clinical picture and antineutrophil cytoplasmic antibody (ANCA) plus biopsy. • Primarily involves the upper and lower respiratory IFA: c-ANCA. tracts and kidneys (Pulmonary-Renal Syndrome). ELISA: anti-proteinase 3 (PR3-ANCA, >80% ) or • Limited to upper respiratory tract or lungs in 25% anti-myeloperoxidase (MPO-ANCA). (most often young women). • Buzz words and associations: • Variably involves joints, eyes, skin, and nervous Nasal symptoms (Saddle nose and perforation) system. CT nodules Respiratory symptoms and abnormal UA (hematuria)

Case 12 Case 12 Exam: • A 42-year-old man is seen for his third episode Afebrile of cellulitis of the external ear. Right auricle is inflamed and tender. • Two previous episodes involving the same ear, Ear lobe is spared. 2 and 5 months ago, responded very slowly to No regional adenopathy. antibiotics. He has a saddle-nose deformity; • He has a several year history of chronic nasal the nasal mucosa is normal. stuffiness and had an episode of knee arthritis in • Labs: the past year, but is otherwise well. Mild, normocytic, normochromic anemia; otherwise normal.

Question 15

The most likely diagnosis is? A. Invasive external otitis B. Leprosy C. Granulomatosis with polyangiitis D. Relapsing polychondritis E. Congenital syphilis

Relapsing Polychondritis Saddle-nose Deformity

• Immune-mediated condition associated Lepromatous leprosy with inflammation of cartilaginous Syphilis structures, particularly ears (can be bilateral), nose, eyes, joints, and Leishmaniasis airways. Relapsing polychondritis • Clinical diagnosis. Granulomatosis with polyangiitis

Relapsing Polychondritis That’s all! • Buzz words and associations: Recurrent “cellulitis” (cartilage inflammation) Saddle-nose Cauliflower ear Sparing of ear lobe Parasternal joint involvement