Disclosures for J. Evan Sadler

1
Disclosures for J. Evan Sadler
2
Tick bites and fever

• HPI 64 wf was outside, later had up to 35
  ticks on her skin. Developed daily fevers to 101
  F, chills, sweats for 5 days, mild confusion,
  headache. Seen in MBS ER.
• ROS petechiae and bruises diffusely, mainly on
  upper extremities. No other rashes. Generalized
  body aches.
• PH RA, right forearm rheumatoid nodule resected
  2005, on methotrexate until a few wks ago,
  inactive. DM type 2. DJD. Hypothyroid on
  replacement. H/o morbid obesity, lost 150 over 1
  year on phentermine by hx.
• SH Married, lives at home with husband. 90 pack
  year cigarettes
• PE 100.2 F, 90, 114/70, 18. Chest tender
  diffusely. Decreased breath sounds. Abd no
  masses. Skin ecchymoses both forearms,
  petechiae on abdomen.

3
Tick bites and fever

• Lab Admission Hgb 11.5, normal indices, WBC
  2.7 (98 neuts), plt 40K, PT 12.8, PTT 42.7, AST
  877, ALT 416, Na 129, Blood CS NG, ANA C diff negative.
• Course For presumed tick-borne infection and
  sepsis, received doxycycline 100 mg iv q12h,
  Zosyn 4.5 g q8h, Vanc 1 g q12h, Diflucan 100 mg
  qd. Dopamine transiently for hypotension.
  Persistent fever to 102 F. Head CT old lacunar
  infarct.
• Hgb 10.3, WBC 1.1, plt 28K, LDH 3648, AST 1911,
  ALT 808, TP 4.1, Alb 1.7, anti-SM 140, Ferritin
  32500, Lyme antibody negative, E. chaffeensis
  A. phagocytophila titers negative, anti-mitochondrial antibody negative.
  Abd sono no hepatosplenomegaly, trace ascites
• Transferred to BJH Medicine service after 3 days

4
Tick bites and fever

• PE 38.4 C, 64, 128/70, 16, 100 RA. 76.1 kg
  (108 kg 11/07, 120 kg 4/03). Comfortable. ENT
  petechiae in oropharynx. Chest clear. Abd no
  hepatomegaly, possible spleen tip. Skin UE and
  LE ecchymoses and petechiae, sparing soles and
  palms. Lymph no adenopathy. Neuro alert,
  pleasant, oriented x 3. Nonfocal. No Babinski.
• Lab None yet.
• Problems Fever, pancytopenia, purpura,
  transaminitis, hypoalbuminemia, hypoproteinemia,
  hyperferritinemia, hyponatremia. (Hypothyroidism,
  type 2 DM, DJD, h/o RA, h/o obesity)
• Differential Diagnosis?

5
BJH Day 1

• Infection Blood and urine cultures, CXR, titers
  for EBV, CMV, parvovirus
• Pancytopenia Retic count, haptoglobin, Coombs,
  Heme consult for BM exam
• Transaminitis RUQ sono with dopplers
• Possible HLH Lipid panel, fibrinogen, soluble
  CD25, soluble CD163
• Rx Doxycycline, Cefepime, Vanc

6
Ehrlichiosis?

• Ehrlichia chaffeensis human monocytic
  ehrlichiosis (HME)
• Anaplasma phagocytophilum human granulocytic
  anaplasmosis (HGA)
• Epi May through August, when various ticks are
  out. Same vectors also transmit Borrelia
  burgdorferi (Lyme disease) and tick-borne
  encephalitis viruses.

7
Ehrlichioses in Humans
Cases of human monocytic ehrlichiosis (HME) and
human granulocytic anaplasmosis (HGA) reported in
the United States since 1986. The data reflect
information available until January 2006 data
for the year 1998 were unavailable. (Dumler et
al, CID 2007 45 (Suppl 1) S45-51)
8
Symptoms, Signs, Laboratory Findings
9
Complications of Ehrlichiosis
10
Diagnosis
11
Diagnosis
E. chaffeensis (A and C Wright stain) and A.
phagocytophilum (B and D Hema-3 stain) morulae
(arrows) in (A), neutrophils (B), DH82 canine
histiocytic cell culture (C), and human HL-60
cell culture (D). Original magnification, 260.
(Panel A courtesy of A. Marty.)
12
Treatment
All causes of Ehrlichiosis respond to
tetracyclines, usually with improvement in 24-48
hours although response can be prolonged if
treatment is delayed. Post therapy relapse has
never been reported.
13
Hemophagocytic Lymphohistiocytosis?

• Primary
• Autosomal recessive mutations in perforin or
  exocytosis machinery, presenting in infancy or
  early childhood
• Treated with intensive chemo-immunotherapy in
  anticipation of HSCT
• Secondary
• Synonym Macrophage Activation Syndrome (MAS)
• Associated with infections (IAHS), malignancy
  (e.g., LAHS), autoimmune diseases (JRA, AOSD)
• Uncontrolled immune activation, inflammatory
  cytokines, impaired NK and CTL activity

14
Hemophagocytic Lymphohistiocytosis?
X
?
?
?
?
X
15
Extremely Elevated Ferritin
Lee et al, Am J Med 1995 98 566-571 1826
determinations, 122 1000 ng/ml, 95 different
patients
16
Extremely Elevated Ferritin
Takahashi et al, Int J Hematol 2001 74
209-213 52 adult patients with HPS, treated
mostly with steroids and for their underlying
disease
17
Extremely Elevated Ferritin
Koduri et al, CID 1995 21 1463-5 6 patients
with AIDS, disseminated histo, RHPS
18
Extremely Elevated Ferritin
McKenzie and Means, CID 1997 24 519-520 7392
determinations, 26 patients 10,000 ng/ml, 8 HIV
19
Day 1
20
Day 2
Afebrile. Good O2 sats on room air. Bone Marrow
Performed CT chest abdomen pelvis no
adenopathy, normal spleen and liver. Ground glass
appearance LUL concerning for atypical pneumonia
21
Day 3
Afebrile. Alert, intermittently disoriented to
place. CPK 197 U/L (20-170), ESR 25 mm/hr HIV
negative Ammonia 22
Day 4
Afebrile. Alert, oriented to person only Soluble
CD163 2528 ng/ml (369-1377) Vanc and Cefipime
stopped
Blood Immune Competence Panel (Day 1 sample)
23
Day 5
Afebrile. Intermittently somnolent, oriented to
first name barely. Increasing purpura UE,
palpable? Skin biopsy done LP Protein 51, 26
cells (7N, 89L, 4M). PCR VZV, HSV, Toxo, CMV
negative EBV positive. Fungal, bacterial, AFB,
crypto negative. Flavivirus IgM neg
24
Day 6
Afebrile. Alert, oriented to person, place. Skin
biopsy noninflammatory purpura. Interface
dermatitis with basal vacuolar alteration,
scattered dyskeratosis, minimal superficial
perivascular lymphocytic infiltrate. Seen in
dermatomyositis, erythema multiforme, SLE. MRI
head with/without contrast old small R frontal
infarct, otherwise normal
25
Day 7
Afebrile. Alert, oriented to person, place,
date Hgb 8.3, WBC 5.6, plt 291, Alk Phos 61, AST
39, ALT 146, ferritin 707, Discharged to
home Missing data sCD25, convalescent
titers Follow up seeing her LMD, had a
mammogram, complains of arthritis in her
shoulder.
26
Hospital Course
27
Hospital Course
28
Hospital Course
29
Summary

• Did she have IAHS, without a finding of
  hemophagocytosis?
• Many consistent clinical and laboratory features
• Tick-borne Ehrlichia or virus?
• Immunosuppressed by methotrexate? Seems remote in
  time and unlikely.
• Childhood HLH is not like acquired hemophagocytic
  syndromes in adults.
• Extreme hyperferritinemia may be a nonspecific
  sign of systemic inflammation.
• Treatment of underlying disease may be sufficient
  for adult patients who do not have substantial
  organ dysfunction.