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Fever of Unknown Origin. Ayesha Kelly & Jen Rochette 6/25/08. 4/28/08. 52yo F with history of mild COPD presents with fever x3 days N/V, abd pain, HA for preceding 3 months Tick exposure 5 days prior to admission Fevers 102-104F beginning 3 days prior to admission

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fever of unknown origin

Fever of Unknown Origin

Ayesha Kelly & Jen Rochette

6/25/08

4 28 08
4/28/08
  • 52yo F with history of mild COPD presents with fever x3 days
  • N/V, abd pain, HA for preceding 3 months
  • Tick exposure 5 days prior to admission
  • Fevers 102-104F beginning 3 days prior to admission
  • On admission found to have neutropenia (WBC 2.1, ANC 0)
  • Worked up & treated for rickettsial disease
6 13 08
6/13/08
  • Readmitted from ID clinic for intermittent fever x2 weeks
  • Also c/o HA, back pain, night sweats, RLQ pain, constipation alternating with diarrhea, nausea, fatigue
slide4
PMH
    • Mild COPD
    • Colonoscopy 2007: 1 polyp removed
    • Normal mammogram 2008
  • Meds
    • MVI, B12, prn albuterol
  • Allergies
    • Sulfa (reaction unknown)
slide5
SH
    • Lives in Mebane with husband
    • Filtered well water
    • Works at UNC Student Stores
    • Daughter & son-in-law run organic chicken & beef farm
    • Husband works at golf course & is exposed to chemicals on daily basis
    • 1 dog, no other close animal contact
    • No recent travel
    • 60pack year smoking history, recently reduced to 1-2 cigarettes/day; occasional EtOH, denies other drugs
slide6
FH: non-contributory
  • ROS as per HPI
    • Increased DOE
    • Denies LAD, rash, cough, URI symptoms
slide7
VS: 39.5, 122/80, 103, 22, 95%RA
  • Gen: NAD, pallor
  • HEENT: dry MM, posterior pharynx erythematous
  • Pulm: CTAB with fair air movement
  • CV: tachycardic, reg rhythm, no M/R/G
  • Abd: normoactive BS, tenderness RLQ, no rebound/guarding, no masses, no hepatosplenomegaly
slide8
Chem 10: wnl
  • 2.5>11.3/31.3<423
    • ANC 0.1
  • UA neg
  • Utox: + MJ & cocaine
  • CRP 19, ESR 37
abdominal ct
Abdominal CT

Mild inflammatory stranding in the sigmoid colon

slide12
Old labs:
    • CSF: OP, cell count, culture, crypto Ag, VDRL, HSV neg
    • Serum:
      • Neg: ehrlichia, CMV PCR, HIV, EBV PCR, brucella, francisella
      • Pos: Parvo c/w past infection, 4-fold increase in RMSF, ANA
slide13
New labs:
    • CSF: OP, cell count, culture, crypto Ag, VDRL, HSV neg
    • Serum:
      • fungal cx & blood rare pathogen cx neg to date
      • ANA, HIV, EBV, CMV, blood cx x2, urine cx neg
    • Bone aspirate:
      • AFB cx neg to date
      • Bone marrow cx neg
bone marrow aspirate
Bone marrow aspirate
  • Maturation arrest in the myeloid line
  • Mild eosinophilia (7%)
  • Flow cytometry normal, no monoclonal large granular lymphocytes
diagnosis and treatment
Diagnosis and Treatment
  • Neupogen 480 mcg sc qd to shorten length of neutropenia
  • Protective precautions for neutropenia (hygiene, mask, avoiding uncooked & unwashed foods, avoiding sick contacts, etc.)
  • Outpatient EGD to look for gastric ulcers
  • Outpatient colonoscopy to screen for Clostridium septicum
cyclic neutropenia17
Cyclic Neutropenia
  • Rare congenital neutropenia
    • First recognized in 1910
  • Regular oscillations in neutrophils, PLTs, monocytes, eosinophils, lymphocytes, & reticulocytes
    • Typically 21 day cycles (14-28d)
    • Neutrophils fluctuate between normal & <500
    • Marrow may appear hypoplastic with promyelocyte arrest during periods of neutropenia
      • See lots of promyelocytes but few more mature cells
cyclic neutropenia19
Cyclic Neutropenia
  • Childhood onset
    • More common
    • Familial pattern, AD
    • Symptoms tend to regress after puberty
  • Adult onset
    • Associated with clonal proliferation of CD56+ large granular lymphocytes (NK cell LGL leukemia)
pathogenesis
Pathogenesis
  • Defect at level of stem cell
    • Multiple cell lines
    • Can be transferred from affected bone marrow donor to recipient
  • Mutation in Neutrophil Elastase gene
    • Chromosome 19p13.3
    • Several different mutations affecting enzyme’s active site possible
      • Gain of function
    • Synthesized primarily at the promyelocytic stage
    • Hypothesized to cause accelerated apoptosis of developing neutrophil precursors and/or enzymatic antagonism of G-CSF
diagnosis
Diagnosis
  • Documentation of ANC below 500/uL on at least 3-5 consecutive days per cycle of each of 3 regularly spaced cycles
  • Monitor neutrophil count 3 times/week for 6-8 weeks
manifestations
Manifestations
  • Severe neutropenia 3-5 days during each cycle
  • Malaise, fever, aphthous stomatitis, LAD, ulcers of GI tract, serious cutaneous/subcutaneous infections
  • Most common infections: bacterial
    • Staph spp.
    • Gram negatives
  • Association with Clostridium septicum
treatment
Treatment
  • G-CSF is treatment of choice for adult-onset
    • Required higher doses compared to pts requiring G-CSF for other reasons
    • May be augmented when combined with SCF
  • Neutrophil oscillation may persist but neutropenic periods shortened
  • Recovery: cell density arises as wave traveling through myeloblasts  promyelocytes  myelocytes  neutrophils