The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
...
Another Day,
Another Fever
Gigi Blanchard, MD
July 11,2014
HPI
• 59yo with AIDS (CD4 = 14/14% and VL <20) and
NHL presented to the ED with acute onset AMS,
fever and SOB
• NHL dx’d ...
HPI
• Recently treated for pna before driving from AZ
to San Diego for vacation
• Chest CT in April in AZ: RUL and LLL inf...
ROS
• GEN: fever x 1 day; No NS or weight loss
• HEENT: No HA; no sinus pain/drainage; no visual sx; no
odynophagia or dys...
PMHx & FHx
• AIDS - Atripla
• NHL
• Hepatitis B
• Entecavir added when in NY
• Adrenal Insuff
• CMV colitis
• Anemia and t...
• Meds prior to admission:
• Atripla
• Entecavir
• Valganciclovir 900mg qday
• Fluconazole 100mg qday
• Hydrocortisone 40m...
Shx
• Tob: 1PPD; min etoh; no drugs; married
• Travel Hx: Had worked for an airline
• Every country in South America x Par...
ED Course
• Became hypotensive and obtunded -> intubated
• Tm 100; T low 96.4
• Labs:
• Cr = 1.15 GFR >60
• AST/ALT = 19/1...
ICU Course
• Started on azithro, pip/tazo, vancomycin, Septra
and fluconazole
• Continued on valganciclovir 900mg daily
• ...
Hospital Course
• Sputum/saliva
• Enterobacter cloacae – moderate
• MSSA – heavy
• Strep Pna – heavy
• Bronch cx grew yeas...
Hospital Course cont’d
• Azithromycin and SMX/TMP d/c’d
• Weaned off pressors by day 6
• Extubated day 7
• Afebrile for da...
PE
• T 99.5 BP 64-123/45-67 P 90-127 RR 13-37
• GEN: intubated and sedated; anasarcic
• HEENT: limited exam but no obvious...
Labs
• CBC
• WBC = 1.5, S 68%, B 20% ANC = 1.3
• H/H = 6.8/20.5 (retic 1.8%) Plt = 7
• Chemistries essentially unremarkabl...
Labs
• INR = 1.4 PTT = 31.9
• Fibrinogen = 596 -> 452 -> 273 (nl 200 - 450)
• D-dimer = 8614
• PPP - negative
• Ferritin =...
Micro/Serology
• Blood cx negative 5/22, 5/27, 5/29/5/30
• AFB blood and sputum cx negative
• Fungal blood cx not done
• U...
What is the cause of his fever
and pancytopenia?
• Lymphoma – another recurrence
• Castleman’s Disease
• Fungal infection ...
What to do next?
• H/O is concerned about HLH
• Fever and pancytopenia
• Elevated TG
• Elevated ferritin
• BMbx performed ...
Do you agree with treating him
for HLH?
• No – He’s got plenty of reasons to be febrile &
pancytopenic with elevated ferri...
Ferritin
• Storage protein for iron (4000 atoms of iron)
• Produced in hepatocytes and in any cell that
stores iron (macro...
Elevated Ferritin Ddx
• Iron Overload
• Hereditary hemochromatosis
• Transfusions
• Inflammation
• Rheumatologic diseases ...
Hemophagocytic
LymphoHistiocytosis (HLH)
• AKA Macrophage Activation Syndrome in ass’n
with rheumatologic diseases
• Hemop...
HLH - Intro
• First described in 1939 as histiocytic medullary
reticulosis
• aka Viral Ass’d Hemophagocytic Syndrome
• Mos...
Immunology Review
Immunology review:
The Macrophage
• Monocytes are made in the bone marrow
• Within 24hours, enter tissues
• Differentiate ...
Immunology Review
Macrophage Functions
• Phagocytosis/Janitor – engulf and digest
senescent cells & remove cellular debris
• Clear 200 billi...
Macrophage Functions
• Immune regulation – dampen the immune
response and limit inflammation
• Down regulates production o...
Cytokines & Chemokines
• Cytokine: any small protein made by a cell that
affects the behavior of other cells. They act via...
Cytokines & their actions
Cytokine Produced
by
Local Effects Systemic Effects
IL-1
MΦ
Activates lymphocytes,
Local tissue ...
Immunology Review – NK cells
• Natural Killer cells 10-15% of lymphocytes
• Lymphocytes that originate in the BM and devel...
Immunology Review - CTL
• Cytotoxic T lymphocytes are activated T cells that
lyse autologous cells such as macrophages
bea...
IL-2 (aka T-cell growth factor)
& IL-2 receptor (CD25)
• T cells produce IL-2 to make themselves
proliferate and different...
NK and CTLs
• NK and CTLs normally eliminate MΦ
• NK/CTLs create a pore in the MΦ membrane
using a protein called perforin...
HLH - Pathogenesis
• NK & CTLs become unable to create a hole in
the target cell and/or unable to deliver cytotoxic
molecu...
HLH Pathophysiology
• Defective triggering of apoptosis of MΦ and
reduced T-cell and NK cytotoxicity
• Failure to control ...
HLH Pathophysiology
• Activated histiocytes infiltrate organs
• Hemophagocytosis and infiltration with cytokine
storm resu...
IL-18 & CD25
• Both correlate significantly with disease activity
• IL-18 (made by MΦ) induces CTL to secrete IFN-γ
• IFN-...
Bone marrow
aspirate Histiocytes
Erythroid precursors
(nucleated RBCs)
Dysplastic erythroid
precursor
(trilobed nucleus)
D...
Clinical Presentation
• Fever
• Resp problems (ARDS) including need for
ventilation
• Severe hypotension – requiring press...
Lab findings in HLH
• Anemia & Thrombocytopenia
• Very high serum ferritin
• High LFTs: AST, ALT, GGT, LDH and bilirubin
•...
Diagnostic Criteria (5 out of 8)
• Fever ≥ 38.5 (101.3)
• Splenomegaly
• Cytopenias (need 2 out of 3)
• Hgb < 9; Plt <100,...
Making the Diagnosis
• Extremely difficult!
• Rare
• Variable presentation
• Non-specific findings
• Hemophagocytosis is n...
HLH - Triggers
• Viral illness
• Herpes viruses
• HSV, VZV (HHV3), EBV (HHV4), CMV (HHV5), HHV8
• EBV Latent membrane prot...
HLH - Triggers
• Bacteria (salmonella typhi)
• Parasites
• Toxoplasmosis
• Leishmaniasis
• Fungi
• TB
HLH - triggers
• Autoimmune disease
• Juvenile idiopathic arthritis (Still’s disease)
• SLE, RA, PAN, Sarcoidosis
• Malign...
HLH – Malignancy triggers
• HLH can precede the diagnosis or occur after the
diagnosis
• Can also occur during chemo
• Usu...
HLH and HIV
• Has been reported at all stages of HIV
• Case reports in acute seroconversion illness
• CD4 median ~ 250 (ra...
HLH and HIV Triggers
• Herpes viruses are most common trigger in HIV
• EBV ass’n most common
• HHV8 – cases had high viral...
Labs to get for HLH
• CBC with diff
• PT/PTT, INR = 1.4
• Fibrinogen
• D-dimer
• Ferritin
• LFTs: AST,ALT, GGT, T Bili alb...
More Labs to Get
• Blood, urine and sputum cx
• Fungal and AFB cx
• EBV serology and viral load
• CMV serology and viral l...
Even more studies
• CT of Chest/Abdomen/Pelvis
• Lymph node biopsy
• Bone Marrow Bx
Treatment of HLH
• HLH-94: International treatment protocol by the
Histiocyte Society in 1994
• 8 week induction with dexa...
Treatment of HLH today
• HLH-2004 protocol
• Etoposide, cyclosporine and dexamethasone
• IVIG – 0.5g/kg/day for 2 days
• A...
Back to the Case
• Treated with IVIG (1gm/kg) x 2 days
• Histo urinary antigen negative
• HHV8 virus not detected
• EBV PC...
Abd CT
BMbx
• Hypercellular marrow with dysplastic erythroid
precursors
• Occasional hemophagocytosis
• B-cell lymphoma
• Focal n...
Bone marrow
aspirate Histiocytes
Erythroid precursors
(nucleated RBCs)
Dysplastic erythroid
precursor
(trilobed nucleus)
D...
Dysplastic erythroid
precursor
(nuclear bleb)
Anucleated
red blood cells
Hemosiderin granules
Diagnostic Criteria (5 out of 8)
• Fever ≥ 38.5 (101.3)
• Splenomegaly
• Cytopenias (need 2 out of 3)
• Hgb < 9; Plt <100,...
What’s your diagnosis?
Take Home Points
• Consider HLH in pts with SIRS/Sepsis who are not
responding to broad spectrum antibiotics (check
ferrit...
JP
JP 1 year later
JP 1 year later
Thank you
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Another Day, Another Fever
Upcoming SlideShare
Loading in...5
×

Another Day, Another Fever

260

Published on

Gigi Blanchard, MD, from UC San Diego Owen Clinic, presents "Another Day, Another Fever" at AIDS Clinical Rounds

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
260
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
6
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Another Day, Another Fever

  1. 1. The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission. AIDS CLINICAL ROUNDS
  2. 2. Another Day, Another Fever Gigi Blanchard, MD July 11,2014
  3. 3. HPI • 59yo with AIDS (CD4 = 14/14% and VL <20) and NHL presented to the ED with acute onset AMS, fever and SOB • NHL dx’d ’06 complicated by relapse 3/13 • Chemo 4/13 • Relapse with CNS involvement 7/13 • Autologous SCT at Sloan-Kettering ~ 10/13 • Complicated by CMV colitis • Transfusion dependent since SCT • Plts q 3weeks; PRBC monthly; GCSF prn • Relapse 1/14 to skull – s/p XRT
  4. 4. HPI • Recently treated for pna before driving from AZ to San Diego for vacation • Chest CT in April in AZ: RUL and LLL infiltrates c/w atypical pna • Levofloxacin for 2 weeks • Repeat CT showed improvement • On the night of arrival in SD, fell out of bed and was altered in the AM • Presented for eval of acute onset AMS, fever and SOB
  5. 5. ROS • GEN: fever x 1 day; No NS or weight loss • HEENT: No HA; no sinus pain/drainage; no visual sx; no odynophagia or dysphagia • HEME: no epistaxis; no oral bleeding; + easy bruising • PULM: + SOB; No cough • CV: No chest pain, orthopnea or PND; + pedal edema • GI: No abd pain; no N/V/D; no blood in stools or melena • GU: no dysuria or discharge; no hematuria; no frequency or urgency • Neuro: Neuropathy to mid-shin • Musculoskeletal: no joint or muscle pain • Skin: No rash
  6. 6. PMHx & FHx • AIDS - Atripla • NHL • Hepatitis B • Entecavir added when in NY • Adrenal Insuff • CMV colitis • Anemia and thrombocytopenia • Peripheral Neuropathy • GERD • Fhx: Non-contributory
  7. 7. • Meds prior to admission: • Atripla • Entecavir • Valganciclovir 900mg qday • Fluconazole 100mg qday • Hydrocortisone 40mg bid • Atovaquone • Omeprazole • Pregabalin • GCSF • Megace • Morphine • NKDA
  8. 8. Shx • Tob: 1PPD; min etoh; no drugs; married • Travel Hx: Had worked for an airline • Every country in South America x Paraguay, Throughout Mexico 18months ago • Europe • Hong Kong 2-3 years ago • Bangkok, Thailand and Cambodia 3 years ago • Egypt • Australia and New Guinea 3.5 years ago
  9. 9. ED Course • Became hypotensive and obtunded -> intubated • Tm 100; T low 96.4 • Labs: • Cr = 1.15 GFR >60 • AST/ALT = 19/15; Albumin = 3.1 • WBC = 1.0 S 8%, B 8% ANC = 160 • H/H = 10.3/31.8; Plt = 37 • CXR: bibasilar infiltrates/trace effusions
  10. 10. ICU Course • Started on azithro, pip/tazo, vancomycin, Septra and fluconazole • Continued on valganciclovir 900mg daily • Head CT: Sinusitis but o/w nl • Chest CT: • Multifocal pneumonia • Severe centrilobular and paraseptal emphysema • Bronch: • Diffusely inflamed airways • Moderate amount of thin, purulent secretions
  11. 11. Hospital Course • Sputum/saliva • Enterobacter cloacae – moderate • MSSA – heavy • Strep Pna – heavy • Bronch cx grew yeast, not cryptococcus • 1 colony of MSSA • AFB smear and cx negative at 10days • Cytology negative for PCP
  12. 12. Hospital Course cont’d • Azithromycin and SMX/TMP d/c’d • Weaned off pressors by day 6 • Extubated day 7 • Afebrile for days 2-4 days • Then daily fevers • 100.4-102.2 • CBC improved briefly; no longer neutropenic • Called out to floor team ~ 36 hours • Resp failure – re-intubated
  13. 13. PE • T 99.5 BP 64-123/45-67 P 90-127 RR 13-37 • GEN: intubated and sedated; anasarcic • HEENT: limited exam but no obvious thrush • CV: RR no M • PULM: CTA B/L anteriorly • ABD: soft, NT, ND, NABS; no HSM • SKIN: petechiae; violaceous plaque/nodule on R 5th toe c/w KS • Neuro: unable to assess
  14. 14. Labs • CBC • WBC = 1.5, S 68%, B 20% ANC = 1.3 • H/H = 6.8/20.5 (retic 1.8%) Plt = 7 • Chemistries essentially unremarkable • Nl renal function; Nl AG • AST/ALT = 86/54 • AlkΦ = 770 GGT = 1086 (nl <60) • T/Dbili = 1.3/0.9 • LDH = 888 (nl 135-225)
  15. 15. Labs • INR = 1.4 PTT = 31.9 • Fibrinogen = 596 -> 452 -> 273 (nl 200 - 450) • D-dimer = 8614 • PPP - negative • Ferritin = 8508 • Haptoglobin = 332 (nl up to 200) • CRP = 16.6
  16. 16. Micro/Serology • Blood cx negative 5/22, 5/27, 5/29/5/30 • AFB blood and sputum cx negative • Fungal blood cx not done • Urine cx negative • CMV PCR negative • Cryptococcal Antigen negative • Cocci ID/CF neg • Quantiferon negative
  17. 17. What is the cause of his fever and pancytopenia? • Lymphoma – another recurrence • Castleman’s Disease • Fungal infection – histoplasmosis? Penicillium? • Drug Fever • Malaria, Leishmaniasis or some other exotic infection • Other
  18. 18. What to do next? • H/O is concerned about HLH • Fever and pancytopenia • Elevated TG • Elevated ferritin • BMbx performed and results pending • They recommend etoposide and steroids • High mortality if not treated promptly • Do you agree?
  19. 19. Do you agree with treating him for HLH? • No – He’s got plenty of reasons to be febrile & pancytopenic with elevated ferritin • Yes – He meets criteria and he’s got little to lose • What’s HLH?
  20. 20. Ferritin • Storage protein for iron (4000 atoms of iron) • Produced in hepatocytes and in any cell that stores iron (macrophages and hepatocytes) • Serum ferritin mirrors tissue stores in normal conditions • Acute Phase Reactant • Cytokines (IL-1, IL-6) increase production of ferritin -> increased storage of iron • Hides it from invaders • Low serum iron in chronic inflammation
  21. 21. Elevated Ferritin Ddx • Iron Overload • Hereditary hemochromatosis • Transfusions • Inflammation • Rheumatologic diseases - Still’s disease; SLE • Malignancy • Infections – Histoplasmosis & TB • Liver disease • Chronic viral hepatitis • Alcoholic liver disease & Non-alcoholic steatohepatitis (NASH) • HLH
  22. 22. Hemophagocytic LymphoHistiocytosis (HLH) • AKA Macrophage Activation Syndrome in ass’n with rheumatologic diseases • Hemophagocytosis: the pathologic finding of activated macrophages (MΦ) engulfing RBC, WBCs, platelets and their precursors • A syndrome of extreme inflammation and tissue destruction d/t pathologic immune activation • The excessive inflammation is thought to be caused by a lack of normal down regulation of activated MΦ d/t defective CTL/NK cells
  23. 23. HLH - Intro • First described in 1939 as histiocytic medullary reticulosis • aka Viral Ass’d Hemophagocytic Syndrome • Most frequently affects infants 0-18 mo • Can affect anyone of any age • Familial and sporadic forms • Infection is a common trigger of both forms • Aggressive and life-threatening • Prompt initiation of treatment is essential for survival
  24. 24. Immunology Review
  25. 25. Immunology review: The Macrophage • Monocytes are made in the bone marrow • Within 24hours, enter tissues • Differentiate from circulating peripheral-blood mononuclear cells (PBMCs) to specific type of mononuclear phagocytic cell or macrophage w/in the tissue • Lives w/in the tissues for days to months
  26. 26. Immunology Review
  27. 27. Macrophage Functions • Phagocytosis/Janitor – engulf and digest senescent cells & remove cellular debris • Clear 200 billion RBCs/day • Recycle ~ 3kg of iron per year • Synthesize ferritin • Innate Immunity/1st Responder • Phagocytosis – engulf and digest pathogens and cancer cells • Antigen Presentation Cells • Secrete cytokines that stimulate lymphocytes & other immune cells to respond to pathogens
  28. 28. Macrophage Functions • Immune regulation – dampen the immune response and limit inflammation • Down regulates production of pro-inflammatory cytokine IL-12 • Makes anti-inflammatory cytokine IL-10 • Wound-healing • makes precursors of collagen – contribute to the production of the extracellular matrix • Stimulates fibroblast proliferation and survival
  29. 29. Cytokines & Chemokines • Cytokine: any small protein made by a cell that affects the behavior of other cells. They act via specific cytokine receptors on the cells they affect. • Interleukin: cytokine made by lymphocyte • Chemokine: A type of cytokine that attracts WBCs to sites of infection. Small chemoattractant protein that stimulates the migration and activation of cells, especially phagocytic cells and lymphocytes.
  30. 30. Cytokines & their actions Cytokine Produced by Local Effects Systemic Effects IL-1 MΦ Activates lymphocytes, Local tissue destruction Fever Production of IL-6 IFN-γ T-cells NK cells Macrophage activation TNF-α MΦ Increases vascular permeability Increased entry of IgG ,complement & cells to tissues Increased fluid drainage to lymph nodes Increases NK cells’ killing 20-100 fold Fever Shock IL-6 MΦ T-cells Lymphocyte activation Increased antibody production Fever Induces acute-phase protein production IL-12 MΦ Activates NK cells to secrete IFN-γ/TNF-α Induces differentiation of T cells IL-18 MΦ Activates NK cells to secrete IFN-γ/TNF-α Induces CTL to secrete IFN-γ
  31. 31. Immunology Review – NK cells • Natural Killer cells 10-15% of lymphocytes • Lymphocytes that originate in the BM and develop outside the thymus • First line of defense b/c they can destroy another cell w/o prior sensitization (Innate immunity) • They are activated by IFN and macrophage-derived cytokines • Produce IFN-γ which primes MΦ to secrete pro- inflammatory cytokines • NK eliminate damaged, stressed or infected host cells such as MΦ, typically in response to viral infection or malignancy
  32. 32. Immunology Review - CTL • Cytotoxic T lymphocytes are activated T cells that lyse autologous cells such as macrophages bearing foreign antigens • Adaptive Immune Response • IL-2 is necessary for the growth, proliferation and differentiation of T-cells to b/c effector cells • Antigen binding to T-cell stimulates secretion of IL2 and expression of IL2 receptors
  33. 33. IL-2 (aka T-cell growth factor) & IL-2 receptor (CD25) • T cells produce IL-2 to make themselves proliferate and differentiate • The IL-2 receptor has 3 chains: α, β, γ • Resting T cells – IL2 receptor has only β & γ chains • binds IL-2 w/ moderate affinity • Activated T cells also produce α chain of IL-2 receptor (aka CD25) • Add’n of α-chain creates receptor bind with much higher affinity • 1 T cell can give rise to 1000s in 2-3 days
  34. 34. NK and CTLs • NK and CTLs normally eliminate MΦ • NK/CTLs create a pore in the MΦ membrane using a protein called perforin • Deliver cytotoxic granules into the MΦ • Granules contain proteases such as granzyme B that can initiate cell death, often through apoptosis
  35. 35. HLH - Pathogenesis • NK & CTLs become unable to create a hole in the target cell and/or unable to deliver cytotoxic molecules • Familial forms of HLH involve genetic defects in the perforin gene which encodes a membranolytic protein • Other mutations involve granule exocytosis • Priming for exocytosis • Membrane fusion of cytolytic granules
  36. 36. HLH Pathophysiology • Defective triggering of apoptosis of MΦ and reduced T-cell and NK cytotoxicity • Failure to control infections with intracellular pathogens • Prolonged antigen presentation to CD8+ • Excessive activation of T cells, which leads to increased cytokine secretion and hyperactivation of MΦ • Increased cytokines induce end-organ dysfunction and immune dysregulation
  37. 37. HLH Pathophysiology • Activated histiocytes infiltrate organs • Hemophagocytosis and infiltration with cytokine storm result in: • Organomegaly, • Multi-organ dysfunction, • Life-threatening cytopenias • Cause of HLH in adult/acquired forms is unknown • Unidentified genetic predisposition?
  38. 38. IL-18 & CD25 • Both correlate significantly with disease activity • IL-18 (made by MΦ) induces CTL to secrete IFN-γ • IFN-γ mediates macrophage activation • MΦ excessively phagocytose erythrocytes, leukocytes, platelets and their pre-cursors in the RES - hemophagocytosis • IL-18 has been shown to modulate the synthesis of ferritin by monocytes/MΦ in vitro • CD25 – IL-2 receptor α chain that puts CTL into overdrive
  39. 39. Bone marrow aspirate Histiocytes Erythroid precursors (nucleated RBCs) Dysplastic erythroid precursor (trilobed nucleus) Degenerated cells (artifact) Myeloid precursors Nucleus of histiocyte
  40. 40. Clinical Presentation • Fever • Resp problems (ARDS) including need for ventilation • Severe hypotension – requiring pressors • Hepatomegaly & Splenomegaly • Neuro findings: • Seizures • AMS c/w encephalitis • Demyelinating peripheral neuropathy d/t diffuse MΦ infiltration of the nerve sheath • Skin: rash, petechiae, purpura, edema,erythroderma
  41. 41. Lab findings in HLH • Anemia & Thrombocytopenia • Very high serum ferritin • High LFTs: AST, ALT, GGT, LDH and bilirubin • GGT is especially sensitive d/t biliary tract infiltration by lymphocytes and MΦ • Increased TGs • D/t cytokine inhibition of lipoprotein lipase • May not be elevated until the liver has been affected for some time • Elevated d-dimer
  42. 42. Diagnostic Criteria (5 out of 8) • Fever ≥ 38.5 (101.3) • Splenomegaly • Cytopenias (need 2 out of 3) • Hgb < 9; Plt <100, ANC <1000 • Hypertriglyceridemia &/or Hypofibrinogenemia • Fasting TG > 265 Fibrinogen < 150 • Hemophagocytosis in BM, spleen, LN or liver • Low or absent NK-cell activity • Elevated soluble CD25 • Ferritin > 500 ng/mL (3000 is better value)
  43. 43. Making the Diagnosis • Extremely difficult! • Rare • Variable presentation • Non-specific findings • Hemophagocytosis is neither specific or sensitive • May be absent early in the disease (up to 20%) • Counter-intuitive dx of immune activation • Expect rising white count, plts & fibrinogen
  44. 44. HLH - Triggers • Viral illness • Herpes viruses • HSV, VZV (HHV3), EBV (HHV4), CMV (HHV5), HHV8 • EBV Latent membrane protein-1 activates and stimulates MΦ to phagocytose hematopoietic cells • EBV+/T-lymphoma cells secrete high levels of TNF-α, IFN-γ, and IL-1 • Parvovirus • HIV • Measles • H1N1 influenza
  45. 45. HLH - Triggers • Bacteria (salmonella typhi) • Parasites • Toxoplasmosis • Leishmaniasis • Fungi • TB
  46. 46. HLH - triggers • Autoimmune disease • Juvenile idiopathic arthritis (Still’s disease) • SLE, RA, PAN, Sarcoidosis • Malignancies, most commonly lymphoid cancers • Lymphomas • Leukemias • Myeloid malignancies • Solid tumors • ½ of adult HLH is ass’d with cancer • Those with malignancy still had acute infectious trigger
  47. 47. HLH – Malignancy triggers • HLH can precede the diagnosis or occur after the diagnosis • Can also occur during chemo • Usually T/NK cell lymphomas and leukemias • May be d/t release of TNF-α, IFN-γ and CD25 from neoplastic cells, causing MΦ activation
  48. 48. HLH and HIV • Has been reported at all stages of HIV • Case reports in acute seroconversion illness • CD4 median ~ 250 (range 63-500) • 100% survival • D/t cytokine alteration ass’d with viremia? • Usually advanced AIDS • 20% survival • Triggered by OI • HLH IRIS • Subclinical HLH in HIV pts? • Autopsy study from 1985 of 56 AIDS pts • 20% had e/o hemophagocytosis
  49. 49. HLH and HIV Triggers • Herpes viruses are most common trigger in HIV • EBV ass’n most common • HHV8 – cases had high viral loads of HHV8 • 4/5 had cutaneous KS • 3 cases reported of Castleman’s disease • CMV • AFB: MAI, TB, M kansasii • Histoplasmosis, Penicillium marneffi, Cryptococcus, and Candidal fungemia • Pneumocystis, Toxo
  50. 50. Labs to get for HLH • CBC with diff • PT/PTT, INR = 1.4 • Fibrinogen • D-dimer • Ferritin • LFTs: AST,ALT, GGT, T Bili albumin, LDH • Serum Triglycerides • Soluble IL-2 receptor (CD25)
  51. 51. More Labs to Get • Blood, urine and sputum cx • Fungal and AFB cx • EBV serology and viral load • CMV serology and viral load • HHV-8 viral load • Adenovirus and parvovirus • Cryptococcal antigen • Toxo serology
  52. 52. Even more studies • CT of Chest/Abdomen/Pelvis • Lymph node biopsy • Bone Marrow Bx
  53. 53. Treatment of HLH • HLH-94: International treatment protocol by the Histiocyte Society in 1994 • 8 week induction with dexamethasone, etoposide and intrathecal methotrexate for pts with CNS disease or CSF abnormalities • At the end of 8 weeks, weaned off if possible • If not, continued until stem cell transplant • HLH 2004 • Added cyclosporine to etoposide and dexamethasone
  54. 54. Treatment of HLH today • HLH-2004 protocol • Etoposide, cyclosporine and dexamethasone • IVIG – 0.5g/kg/day for 2 days • Anakinra (Kineret) – IL-1 R inhibitor • Treat the trigger • Consider HAART if not already on it • Case reports of TNF-α blockade with inflixamab in refractory cases • Splenectomy • Stem cell transplant in genetic HLH
  55. 55. Back to the Case • Treated with IVIG (1gm/kg) x 2 days • Histo urinary antigen negative • HHV8 virus not detected • EBV PCR + (Quantitative not done) • IL-2 receptor (CD25) = 1721 pg/ml (nl < 1033) 6/1 6/2 6/3 6/4 6/5 6/6 6/7 Ferritin 8508 4723 5387 3769 2578 IVIG IVIG Tmax 99.5 101.2 100.2 99.9 100.6 101.3 102.4
  56. 56. Abd CT
  57. 57. BMbx • Hypercellular marrow with dysplastic erythroid precursors • Occasional hemophagocytosis • B-cell lymphoma • Focal non-caseating granulomas with no fungal or mycobacteria identified
  58. 58. Bone marrow aspirate Histiocytes Erythroid precursors (nucleated RBCs) Dysplastic erythroid precursor (trilobed nucleus) Degenerated cells (artifact) Myeloid precursors Nucleus of histiocyte
  59. 59. Dysplastic erythroid precursor (nuclear bleb) Anucleated red blood cells Hemosiderin granules
  60. 60. Diagnostic Criteria (5 out of 8) • Fever ≥ 38.5 (101.3) • Splenomegaly • Cytopenias (need 2 out of 3) • Hgb < 9; Plt <100, ANC <1000 • Hypertriglyceridemia &/or Hypofibrinogenemia • Fasting TG > 265 Fibrinogen < 150 • Hemophagocytosis in BM, spleen, LN or liver • Low or absent NK-cell activity • Elevated soluble CD25 • Ferritin > 500 ng/mL (3000 is better value)
  61. 61. What’s your diagnosis?
  62. 62. Take Home Points • Consider HLH in pts with SIRS/Sepsis who are not responding to broad spectrum antibiotics (check ferritin) • Consider HLH if ferritin is elevated • If you have a pt with HLH, check an HIV test!
  63. 63. JP
  64. 64. JP 1 year later
  65. 65. JP 1 year later
  66. 66. Thank you
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×