American College of PhysiciansCase Presentation

University of MiamiJackson Memorial Hospital

Emmanuel Coronel M.D. PGY 2 - Internal MedicineJorge Cabrera M.D PGY 3 - Internal MedicineFaisal Yamani M.D. PGY 2 - Pathology

Initial Presentation

Chief Complaint: Syncope

Hi t f P t Ill 40 / bl k ith h/ HIV/AIDS tHistory of Present Illness: 40 y/o black woman with a h/o HIV/AIDS, acute cholestatic hepatitis, GERD. Went to her regular clinic appointment, she was doing well, went to the lab after her clinic visit and while getting blood drawn she felt lightheaded, nauseous and had a syncopal episode

Remembered she woke up smelling iodine

Denies tongue biting bowel/bladder incontinenceDenies tongue biting, bowel/bladder incontinence

No witnessed seizures, not post-ictal

Right after brought to the ED

Review of Systems

Constitutional

Respiratory

Cough

Appetite loss, fever 101.1 one night prior

No shortness of breath

Gastrointestinal

Allergies: Bactrim

Weight loss (35 pounds in the last 5 months)

Cardiovascular

Diarrhea, pale stool

G/U

Meds: Not on HAART stopped one month prior admission, magnesium oxide, potassium, ursodiol, metoclopramide, Ca d o ascu a

No chest pain, palpitations

G/U

Dark brown urine

N l i

u sod o , etoc op a de,atovaquone

Neurologic

Normal

Past Medical History

1.HIV diagnosed in 1992, CD4 97/9%/0.1 (1 week prior admission), She has been on HAART for the last 3 ears compliant b t stopped 1 month ago d e to li er disease OIʼs Thr sh in 3 earsthe last 3 years, compliant but stopped 1 month ago due to liver disease. OIʼs: Thrush in 3 years prior.

2.Acute cholestatic hepatitis likely AIDS cholangiopathy versus drug-induced. Complicated with AKI probably from acute liver disease (4 months prior)AKI, probably from acute liver disease. (4 months prior)

3.Esophageal strictures diagnosed 13 years prior, She has had several esophageal dilation procedures over the years.

4.GERD Diagnosed in 7 years ago.

5.Hemorrhoids

6.HPV diagnosed in 13 prior, with carcinoma in situ, s/p LEEP procedure.

Surgical History

1. LEEP procedure 13 years prior admission and esophageal dilations- multiple over the years

2. LN bx of R axilla, first 4 years and second 1 year prior. Negative for malignancy,

3. BM biopsy 1 year prior admission: Normal

4. GI: Liver Biopsy 1 month prior: Profound paucity of bile ducts associated with marked cholestasis. Mild portal fibrosis consistent with HIV cholangiopathy vs. HAART induced.Had a colonoscopy 1 month prior, showed chronic colitis , EGD mild erosive gastritis.

Family History

• Mother - Breast Ca at age 20 s/p bilateral mastectomy; Was 55 and living

• Father - deceased at 50 due to complications of AIDS, Hx of HTN and DM

Social HistorySocial History

• Tobacco NEG, ETOH NEG, Drugs NEG, No sexual partners in last year, worked as security officer, lived with sister and 2 nephews.

Physical Exam

Skin: Dry, marked jaundice

Vital signs

T: 37 C / 99 F

HEENT: Jaundiced sclerae, dry oral mucosa

Cardiovascular: Heart: RRR, no MRG.

RR: 20 breaths/min. saturating 95% in room air

BP: 108/67mmHg. P: 74 per minute, not orthostatic

Respiratory: CTAB

Abdomen: +BS, benign, not distended, no tenderness. Liver enlarged, palpable,

General Appearance: Thin debilitated woman lying in bed

g p phemorrhoids on rectal exam. Sacral decubitus ulcer, 1cm, stage II

Neurologic: alert and oriented, Cranial nerves intact, motor and sensory intact.

77

Labs and Imaging HD 1

On AdmissionOn Admission

Na 137 K 3.2 Cl 97 HCO3 20

On Admission

TB 34.3

BUN 23 Cr 1.99 (normal BL)

WBC: 1.4 HGB: 6.9 HCT: 18.5 PLT: 450

AST 175 ALT 57 AP 1,112

Cholesterol 321 TG 800 HDL 26450

Lymphocytes 92% Normal CXR, normal EKG

Clinical Course HD 1

• Syncope: Anemia/hypovolemia > transfused 2 units PRBCs, fluids

• Neutropenia/Anemia: Consult hematology, last BM normal, likely AOCD or chronic GIB. Ordered iron studies, guaiac negative stool

• AKI: Likely prerenal, Urine electrolytes, fluids

• HIV : Continued atovaquone for PCP PPXHIV : Continued atovaquone for PCP PPX

• Cholestasis: Consulted hepatology, not decompensated with HE, ascites, varices

Clinical Course

HD 2 - HD 4

WBC 0.6---->0.5

PLT 328---->174

Bcx + GPC in clusters and started Cefepime + Vancomycin

IVF > Cr started trending down

HD 5

Ferritin 100,000 Iron 176 (H) TIBC 127 (L) WBC 0.4 PLT 112

Clinical Course

HD 6 - 8

PLT 54k----> 21k (NL fibrinogen, d-dimmer)

Cr still trending down 1.1

Clinically deteriorating, lethargic, weaker, started to become febrile (neutropenic fever)

Abdominal pain obtained a CT abdomen

Repeat BM biopsy

CT Abdomen

CT Abdomen

Bone Marrow Biopsy

Hemophagocytes

Clinical Course

HD 9 - 14

Severe LGIB---->MICU

Non verbal just screaming in painDeveloped fungemia bacteremia septic shock on pressors and developedDeveloped fungemia, bacteremia, septic shock on pressors and developed multiorgan failure. Died on day 14

EGD and colonoscopy, no source. Mesenteric angiogram normal. CT Brain normal, Neuro recommended LP and CSF was normal, EBV Negative

Hemophagocytic L h hi ti t iLymphohistiocytosis

(HLH)(HLH)

Hemophagocytic Lymphohistiocytosisy p y

Also called hemophagocytic syndrome. Syndrome of toxic immune activation driven by the interaction of T cells and innate immune cellsactivation driven by the interaction of T cells and innate immune cells

Hallmark of HLH is hemophagocytosis

HLH is increasingly recognized in adults, including those with predisposing genetic lesions

Historically been divided into primary and secondary forms, it is better viewed as a singular syndrome, associated with a continuum of risk factors

Risma, hemophagocytic lymphohistiocytosis: updates and evolving concepts, Curr Op in Pediatr, Feb 2012, 24:9 - 15

Hemophagocytic Syndrome PathophysiologyPathophysiology

Perforin-dependent cytotoxicity pathway, is an essential function of natural killer (NK) cells d t t i T l h t ALTERED i HLH i ff ti !and cytotoxic T lymphocytes. ALTERED in HLH, ineffective!

Severe immune dysregulation occurs when perforin- mediated cytotoxicity is completely absent, can also happen the other way…

Perforin gene mutations (PRF1). Four other genes in the degranulation pathway have been implicated: UNC13D, STXBP2, Rab27a, and STX11

Lykens et al has demonstrated that in an animal model perforin deficient miceLykens et al. has demonstrated that, in an animal model, perforin deficient mice challenged to a virus developed HLH. The essential immunologic signature of HLH is an excess of acutely activated T cells. HLH is a unique disorder of ʻtoxicʼ T-cell activation. Also MyD88 – TLR – IL-1 signaling is also involved in this syndrome meaning innate immunity (e g macrophages NK cells) is affectedinnate immunity (e.g macrophages, NK cells) is affected

Pachlopnik et al. Inherited defects in lymphocyte cytotoxic activity. Immunol Rev 2010; 235:10 – 23. Lykens, et al. Perforin is a critical physiologic regulator & of T-cell activation. Blood 2011; 118:618 – 626.

Hemophagocytic Syndrome PathophysiologyPathophysiology

Basically what happens is that in severe inflammatory states cells secrete proinflammatory cytokines, such as interferon γ tumor necrosis factor α interleukin (IL) 6interferon γ, tumor necrosis factor α, interleukin (IL)-6, IL-10, and M-GSF, which lead to defects in perforin function and dysfunction of NK-cell, Macrophage and Citotoxic T cells resulting in pancytopenia, tissue necrosis and multi-organ failure…

Hemophagocytic Syndrome

Trigger can be a gene mutation and a predisposing factor (inherited) or secondary to infections, malignancy, rheumatologic disease

All these conditions can cause a severe inflammatory state – Cytokine storm syndrome > HLH

Treatment depends on the causeTreatment depends on the cause

Genetic = BM transplantation

Secondary = Treat the predisposing factor + Immunosuppression - HLH 94Secondary Treat the predisposing factor Immunosuppression HLH 94 8 weeks of dexamethasone and etoposide w/wo intrathecal MTX

Rare syndrome and there are case reports that associate HLH with HIV, chronic, subacute, recurrent forms of disease.subacute, recurrent forms of disease.

ImashukuS.TreatmentofEpstein‐Barrvirus‐relatedhemophagocyticlympho‐ histiocytosis (EBV‐HLH); update 2010. J Pediatr Hematol Oncol. 2011;33:35‐39.

S i l Th k t D L iSpecial Thanks to Dr. Luis Espinoza

Faisal Yamani- Pathology

Jorge Cabrera - Medicine

Thank you for your attention!Thank you for your attention!