Case Conference

1
Case Conference

• Toby Fugate, D.O.

2
DisclosuresSection of Infectious Diseases

• Kevin High, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Astellas Pharma US, Inc.
• Consultant Merck Co., Inc.
• Speakers Bureau Pfizer Pharmaceuticals
• James Peacock, M.D.
• Ownership in Common Stock Pfizer
  Pharmaceuticals
• Sam Pegram, M.D.
• Grant/Research Support Roche, Bristol-Myers
  Squibb, Gilead, Schering-Plough, Tibotec
  Pharmaceuticals
• Consultant Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Gilead,
  Roche
• Speakers Bureau Abbott Laboratories,
  GlaxoSmithKline, Boehringer Ingelheim, Merck,
  Pfizer Pharmaceuticals

3
Disclosure (continued)Section of Infectious
Diseases

• Aimee Wilkin, M.D.
• Grant/Research Support Abbott Laboratories,
  GlaxoSmithKline, Tibotec Pharmaceuticals,
  Bristol-Myers Squibb Company, Gilead
• Christopher Ohl, M.D.
• Grant/Research Support Cubist Pharmaceuticals,
  Gene-Ohm Sciences, Merck Pharmaceuticals
• Speakers Bureau/Consultant Ortho-McNeil
  Pharmaceuticals, Cubist Pharmaceuticals,
  Sanofi-Aventis Pharmaceuticals, Pfizer
  Pharmaceuticals, Bayer Pharmaceuticals

4
Disclosure (continued)Section of Infectious
Diseases

• Tobi Karchmer, M.D.
• Grant/Research Support Gene-Ohm Sciences
• Speakers Bureau Pfizer Pharmaceuticals, Cubist
  Pharmaceuticals, Cepheid,
• Gene-Ohm Sciences
• Consultant C.R. Bard
• Robin Trotman, D.O.
• Speakers Bureau Pfizer Pharmaceuticals

5
58 year old male

• Diagnosed with hepatitis C, genotype 1a
• HCV viral load 700,000
• Fibrosis stage 1-2 by biopsy
• Started therapy on 7/15/05 with Pegasys 180
  micrograms weekly and Ribavirin 1200 mg daily
• Developed ribavirin associated anemia requiring
  Procrit and eventually blood transfusions
• Off treatment from 12/18/05 until 1/10/06
• Combination treatment re-initiated with lower
  dose ribavirin (1000 mg daily)

6
58 year old male

• Past Medical History
• Hepatitis C
• PUD

• Past Surgical History
• Cholecystectomy
• Tonsillectomy

7
58 year old male

• Medications
• Pegaysis
• Ribavirin
• Saw Palmetto
• Gingo Biloba
• St Johns Wort

• Allergies
• Sulfa

8
58 year old male

• Social History
• Smokes one pack of cigarettes per day
• No ETOH/IVDA
• Blood transfusion in the 1970s

• Family History
• Mother died of CHF
• Father an alcoholic

9
VA Infectious Disease Clinic

• 2/28/06
• Gradual onset of LE weakness over a period of 3-4
  days
• Unable to ambulate without assistance
• No recent GI symptoms, fevers, or UR tract
  symptoms
• Influenza vaccine 10/27/05
• Recent uncomplicated biliary stenting at
  Asheville VA for CBD stones

10
Admission to VAMC

• Lumbar Puncture
• Glucose 62 (serum 93)
• Protein 101 (serum 7.5)
• WBC 0
• RBC 0
• Grams Stain negative/Culture no growth
• EMG/NCV c/w Guillain Barre
• Weakness worsened
• Transferred to WFUBMC

11
EMG/NCV

• The EMG/NCV study is abnormal.
• F-wave latencies were moderately to severely
  prolonged in all motor nerves studied
• There was noted, significant segmental conduction
  slowing in conduction block in all of the motor
  nerves in the lower extremities studied
• These findings are most consistent with a
  multifocal, segmental, demyelinating
  polyneuropathy affecting the motor nerves more
  significantly than the sensory nerves
• These findings along with the clinical history
  are most consistent with acute inflammatory
  demyelinating polyneuropathy ( Guillain-Barré
  syndrome)

12
Treatment at WFUBMC

• Neurology Service Admission on 3/3/05
• Administered IVIG for 5 days
• Weakness improved somewhat
• Transferred back to VAMC on 3/8/06
• Weakness worsened again
• Re-admission to Neurology Service at WFUBMC on
  3/14/06
• Underwent plasmapheresis five times
• Improvement in weakness
• Transfer back to VAMC on 3/23/06

13
What is the etiology of GBS in this patient?
14
Conditions Associated with GBS

• Approximately 2/3 of pts give a history of an
  antecedent respiratory or GI infection
• Campylobacter infection
• Myoplasma infection
• Haemophilus influenzae infection
• EBV infection
• CMV infection
• Lyme disease
• HSV infection
• HIV infection
• Hodgkins disease
• Systemic lupus erythematosus
• Sarcoidosis

15
Other Associations?

• Influenza vaccine
• Quadrivalent meningococcal conjugate vaccine (A,
  C, Y, W135)
• Epidural anesthesia
• Treatment with thrombolytic agents
• Treatment with isotretinoin

16
Is there an association between Hepatitis C and
GBS?
17
Sporadic Non-A, Non-B (NANB) Hepatitis and EBV
Hepatitis Associated with GBS.

• Three cases of GBS complicating NANB hepatitis
• CSF studies and nerve conduction studies were
  consistent with GBS
• Other causes (Hep A, Hep B, Mycoplasma, CMV, EBV,
  Q fever, influenza, adenovirus, Coxsackie B
  virus, HSV) were ruled out
• No mention of ruling out Campylobacterhowever,
  no pt had GI symptoms
• One case of GBS associated with recent EBV
  infection (EBV IgM positive)

Macleod et al. Arch Neurol, 1987
18
Akute Polyneuritis bei Hepatitis-nonA-nonB.

• 26 year old male developed GBS
• About one week after the onset of GBS, he
  developed icteric non-A, non-B hepatitis
• A febrile URI preceded the onset of GBS by 1-2
  weeks

Schuchardt et al. Deutsche Medizinische
Wochenschrift, 1984
19
GBS as the presenting manifestation of hepatitis
C infection.

• 35 year old woman with symptoms of GBS
• CSF studies and never conduction studies
  consistent with GBS
• LFTs and gamma-glutamyl transpeptidase minimally
  elevated
• Alk phos and bilirubin were both normal
• Hepatitis C serology positive
• Other serological tests negative (CMV,
  picornavirus, adenovirus, HSV, lymphocytic
  choriomeningitis virus, mumps, VZV, influenza,
  RSV, rubella)
• Liver biopsy findings of lymphocytic infiltration
  and minimal piecemeal necrosis were consistent
  with resolving acute hepatitis
• Authors suggest LFTs and HCV serology in all pts
  with GBS

Klippel et al. Neurology, 1993.
20
Is there an association between Hepatitis C
treatment (IFN and ribavirin) and GBS?
21
GBS, a possible side effect of buffy coat
transfusion and IFN-alpha therapy in relpased CML
after bone marrow transplantation.

• 29 yr old male with Ph positive CML diagnosed
  12/1987
• Received non-T-cell-depleted BMT from
  HLA-identical brother in 2/1989
• All Neurological investigations (neurologic
  status, electroencephalogram, sight) before and
  four weeks after BMT were normal
• No signs of GvHD

Schwarzer et al. Annals of Oncology, 1995.
22
GBS, a possible side effect of buffy coat
transfusion and IFN-alpha therapy in relpased CML
after bone marrow transplantation.

• 1/1992, clinical, cytological and chromosomal
  signs of relapse detected
• Pt treated with IFN-alpha 2b
• Due to lack of response, he received 5
  transfusions of fresh buffy coat (BCT) prepared
  from peripheral blood of his BM donor
• No signs of GvHD
• Anemia, leukopenia and thrombocytopenia noted
  over the next three months
• Five months after BCT, IFN-alpha was discontinued
• Shortly after discontinuation of IFN-alpha, the
  pt developed GBS

23
GBS, a possible side effect of buffy coat
transfusion and IFN-alpha therapy in relpased CML
after bone marrow transplantation.

• Nerve conduction studies consistent with GBS
• No mention of CSF studies
• No viral or bacterial etiology could be found
• Following serologies (both IgM and IgG) were
  negative Parvo B19 virus, CMV, rubella, EBV,
  and measles
• HIV 1 and 2 ELISA negative as well
• Authors assumed that GBS was associated with
  IFN-alpha and/or donor lymphocyte transfusion.
  However, an unknown infectious agent cannot be
  excluded.

24
Buffy Coat Transfusion (Donor Leukocyte Infusion)

• A form of adaptive immunotherapy in which the
  leukemic pt who has previously received an
  allogenic BMT is infused with leukocytes obtained
  from a leukopharesis procedure from the original
  BM donor.
• Used to treat relapsed of acute or chronic
  myeloid leukemia

25
GBS after simultaneous therapy with suramin and
IFN-alpha

• In August 1998, 37 yr old female with history of
  pulmonary adenocarcinoma admitted with GBS (CSF
  findings and nerve conduction studies were c/w
  GBS)
• From March to June 1998, the pt had been treated
  with suramin and INF-alpha 2b infusions
• From May to June1998, she received IFN-alpha 2a
  infusions
• LFTs were elevated and hepatitis serology was
  negative
• ANCA and anti-smooth muscle antibody patterns
  indicated autoimmune liver disease
• Muscle disease, infections, myasthenia and
  antibody-mediated paraneoplastic disease were
  excluded (no other details given)
• The time between the end of suramin treatment and
  the beginning of GBS render suramin unlikely as
  the only inductor of GBS
• Cases of GBS due to suramin evolve during
  treatment
• Authors concluded that IFN is the more likely
  inductor of all symptoms in our case.

Bachmann et al. European Journal of Neurology,
2003
26
Suramin

• Suramin inhibits a number of growth factors and
  enzymes essential to cell proliferation including
  platelet-derived growth factor, fibroblast growth
  factor, DNA polymerase, glycerol phosphate
  oxidase, reverse transcriptase, and various
  lysosomal enzymes. Suramin may also have some
  angiogenic inhibitory activity.

27
What about ribavirin?What the herbal supplements?

• Medline search was unrevealing

28
Case Two
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51 year old male with HIV

• Diagnosed in 1991
• CD4 nadir 270 in 2000
• Most recent CD4397 and HIV VL
• Currently treated with Viread, Epivir, Reyataz
  and Norvir

30
51 year old male with HIV

• PMHx
• HIV
• Recurrent thrombosis
• LLE DVT/PE 1995
• LLE DVT 1996
• Superficial venous thrombosis
• Heterozygous prothrombin 20210 mutation
• Depression

• PSHx
• Tonsillectomy

31
51 year old male with HIV

• Medications
• COUMADIN 2 MG QD
• FIBERCON QD
• VIREAD 300 MG QD
• EPIVIR 150 MG 2 QD
• REYATAZ 150 MG 2 QD
• NORVIR 100 MG QD
• AMITRIPTYLINE 25 MG
• 1-2 QHS

• Allergies
• NKDA

32
51 year old male with HIV

• Social History
• Smoker

• Family History
• Two aunts with aneurysms

33
Question

• Is HIV a hypercoagulable state?

34
(No Transcript)
35
Wasif et al. AIDS Patient Care and STDs 2001
15 311-320
36
Degree of Immunosuppression

• Chart review of 131 HIV pts from 1993 to 1998
• Thrombosis dx by venous plethysmography or
  venogram for DVT and by VQ scan or angiography
  for PE
• Divided pt based on CD4 count
• 9 of 37 pts with CD4complications
• 1 of 94 pts with CD4200 had thrombotic
  complications

Wasif et al. AIDS Patient Care and STDs 2001
15 311-320
37
Protein S (PS) Deficiency

• 65 of HIV-infected pts were found to have some
  degree of PS deficiency
• Decrease plasma free PS levels were noted in HIV
  pts as compared with control pts (56 vs 105.3,
  p0.0001)
• Free PS levels were significantly lower in pts
  with AIDS when compared with pts without AIDS
  (37.6 vs 69.8, p0.0001)
• Low plasma free PS levels correlated with low CD4
  counts (p0.0002)

Bissuel et al. J of Acquir Immune Defic Syndr
1992 5 484-489
38
Protein S (PS) Deficiency

• Vitamin K-dependent protein
• Synthesized by endothelial cells, hepatocytes,
  and megakaryocytes
• Cofactor of protein C in the proteolysis of
  activated factors V and VIII
• Circulates in two forms
• Inactive form when bound to C4b-binding protein
• Active form
• C4b-binding protein is an acute-phase reactant
• Increased levels during acute inflammatory
  processes (opportunistic infections)

39
Protein C Deficiency

• Decreased levels of functional protein C (110)
  and antigenic protein C (89) identified in HIV
  pts
• These levels significantly correlated with
  immunosuppression
• Recall, protein C is a vitamin K-dependent
  protein that functions as a natural anticoagulant
  by inactivating the procoagulant cofactors Va and
  VIIIa

Saif et al. AIDS Patient Care and STDs 2001 15
15-24
40
Heparin Cofactor II (HCII) Deficiency

• Compared 96 HIV pts with 96 aged/gender matched
  controls
• Significantly lower plasma HCII levels in HIV vs
  HIV- pts (0.75 /- 0.24 vs 0.99 /- 0.17,
  p
• Proportion of individuals with HCII deficiency
  was significantly higher in HIV vs HIV- (38 vs
  2.1)
• HCII deficiency was significant in AIDS pts as
  compared to HIV pts

Toulon et al. Thromb Haemost 1993 70 730-735
41
Heparin Cofactor II (HCII) Deficiency

• HCII is a specific thrombin inhibitor (activity
  enhanced by heparin)
• Mechanism of HCII deficiency in HIV/AIDS
• Reduced synthesis
• Presence of an inhibitor
• Endothelial cell abnormalities that may promote
  distribution of HCII from the circulation into
  extravascular spaces

42
Antithrombin (AT) Deficiency

• Several case reports of AT deficiency in HIV pts
  who experienced thrombotic events
• Recall, AT is a hepatocyte-synthesized serine
  protienase inhibitor that irreversibly
  neutralizes factors IIa, Xa IXa, XIa and XIIa)

Thaler et al. Clin Hematol 1981 10
369-390 Demers et al. Ann Intern Med 1992 116
754-761
43
Antithrombin (AT) Deficiency

• Mechanisms
• Decreased protein synthesis (liver disease and
  malnutrition)
• Protein-losing nephropathies (HIV nephropathy) or
  enteropathies
• Consumptive states (malignancies, DIC surgery)

44
Antiphospholipid Syndrome

• Recall, antiphospholipid syndrome is due to the
  appearance of circulating autoantibodies to
  anionic phospholipids
• Lupus anticoagulant
• Anticardiolipin antibody
• Prevalence of lupus anticoagulant in HIV pts
  53-70
• Prevalence of anticardiolipin antibodies 46-90
• Association of lupus anticoagulant with
  thrombosis in HIV pts is relatively rare
• Anticardiolipin antibodies have occasionally been
  associated with thrombotic complications in pts
  with HIV (TIAs, thrombotic strokes, avascular
  necrosis, and skin necrosis)

Perkocha et al. Am J Hematol 1988 29
94-105 Aboulafia et al. Hematol Oncol Clin North
Am 1991 5 195-209
45
Antiphospholipid Syndrome

• Proposed mechanisms
• Immunological imbalance due to destruction of CD4
  lymphocytes or defective T cell regulation of B
  cells
• Leads to polyclonal stimulation of B cells
  (polyclonal hypergammaglobulinemia)
• Antiphospholipid antibodies may represent a class
  of natural autoantibodies that have an important
  scavenging function for damaged cells and
  cellular debris
• May represent adaptive immunity against damaged
  self-components

46
Disorders of Plasmin

• Case report of increased levels of plasminogen
  activator inhibitor reported in HIV-infected with
  thromboembolism
• Feffer et al. Southern Med J 1995 88 1126-1130

47
Low-grade DIC

• Mentioned briefly in Feffer et al
• Idea supported by elevated D-dimer and decreased
  levels of protein C

48
HIV-associated Malignancy

• Case report of superior sagittal sinus thrombosis
  associated with primary central nervous system
  lymphoma
• Doberson et al. Arch Pathol Lab Med 1994 118
  844-846
• Case report of DVT and PE in the setting of
  Kaposis Sarcoma
• Kaufmann et al. JAMA 1991 266 2834
• Other AIDS-related malignancies NHL, anal
  carcinoma, and cervical carcinoma

49
HIV Nephropathy

• Characterized by nephrotic syndrome (protienuria,
  edema, hematuria /- azotemia)
• Associated with several disorders of hemostasis
  (secondary thrombocytosis, qualitative platelet
  defects, increased plasma levels of factor
  V/VIII/fibrinogen, fibrin polymerization defect,
  lower fibrinolytic activity, and decreased plasma
  levels of protein S/antithrombin)
• Case report of antithrombin and protein S
  deficiencies in a pt with HIV nephropathy
  resulting in thrombotic events
• Culpepper et al. Am J Med Sci 1992 303
  402-404

50
HIV-associated Autoimmune Hemolytic Anemia (AIHA)

• Associated with an increased risk of
  thromboembolism, particularly during the acute
  phase of hemolysis after RBCs have been
  transfused
• Two case reports of PE in the context of
  transfusion and AIHA
• Saif et al. Connecticut Med 1998 62 67-70
• Bilgrami et al. Transfusion 1994 34 248-251

51
HIV-associated Autoimmune Hemolytic Anemia (AIHA)

• Underlying mechanism unclear
• It is possible that RBC transfusion in
  HIV-infected pt with severe AIHA potentiates the
  hypercoagulable state and produces occulsion in
  an already compromised vascular bed
• These pts may be unusually susceptible to
  transfusion-related complications such as DIC
  and/or hypercoagulability , because they already
  have circulating antigen-antibody complexes and
  their ability to clear the additional complexes
  induced by transfusion is compromised

52
Opportunistic Infections and Thrombosis

• CMV infection
• Peripheral thrombophlebitis, stokes, digital
  infarcts, PE, cerebral venous thrombosis
• May infect endothelial cells predisposing to
  thrombosis
• Demonstration of CMV in digital infarcts as well
  as within blood in AIDS pts with thromboses
• Smith et al. Arch Dermatol 1995 131 357-358

53
Opportunistic Infections and Thrombosis

• PCP
• Positive antiphospholipid antibodies and/or
  positive lupus anticoagulant antibodies found in
  up to 96 of patients with PCP and AIDS
• Aboulafia et al. Hematol Oncol Clin North Am
  1991 5 195-209
• HIV itself
• Central retinal vein occlusions, stroke, cerebral
  venous thrombosis
• Endothelial cell infection by HIV-1 may
  contribute to vascular disease by causing
  vascular thrombosis and endothelial proliferation
• Friedman et al. Arch Ophthalmo 1995 113
  1184-1188

54
Protease Inhibitors and Thromboembolism

• Report of seven HIV-infected pts on PIs who
  developed 11 episodes of unexplained DVT or PE
• Mean CD4 count was 166 and HIV VL 160,000
• Thromboembolism occurred after a mean period of
  72 days after initiation of PI therapy
• Henry et al. Lancet 1998 351 1328

55
Question

• Is there a relationship between HIV and
  prothrombin 20210 mutation?

56
Medline Search

• Unrevealing