Fever of Unknown Fever of Unknown OriginOrigin

Ayesha Kelly & Jen RochetteAyesha Kelly & Jen Rochette

6/25/086/25/08

4/28/084/28/08

52yo F with history of mild COPD presents 52yo F with history of mild COPD presents with fever x3 dayswith fever x3 days

N/V, abd pain, HA for preceding 3 monthsN/V, abd pain, HA for preceding 3 months Tick exposure 5 days prior to admissionTick exposure 5 days prior to admission Fevers 102-104F beginning 3 days prior to Fevers 102-104F beginning 3 days prior to

admissionadmission On admission found to have neutropenia On admission found to have neutropenia

(WBC 2.1, ANC 0)(WBC 2.1, ANC 0) Worked up & treated for rickettsial diseaseWorked up & treated for rickettsial disease

6/13/086/13/08

Readmitted from ID clinic for Readmitted from ID clinic for intermittent fever x2 weeksintermittent fever x2 weeks

Also c/o HA, back pain, night Also c/o HA, back pain, night sweats, RLQ pain, constipation sweats, RLQ pain, constipation alternating with diarrhea, nausea, alternating with diarrhea, nausea, fatiguefatigue

PMHPMH– Mild COPDMild COPD– Colonoscopy 2007: 1 polyp removedColonoscopy 2007: 1 polyp removed– Normal mammogram 2008Normal mammogram 2008

MedsMeds– MVI, B12, prn albuterolMVI, B12, prn albuterol

AllergiesAllergies– Sulfa (reaction unknown)Sulfa (reaction unknown)

SHSH– Lives in Mebane with husbandLives in Mebane with husband– Filtered well waterFiltered well water– Works at UNC Student StoresWorks at UNC Student Stores– Daughter & son-in-law run organic chicken & Daughter & son-in-law run organic chicken &

beef farmbeef farm– Husband works at golf course & is exposed to Husband works at golf course & is exposed to

chemicals on daily basischemicals on daily basis– 1 dog, no other close animal contact1 dog, no other close animal contact– No recent travelNo recent travel– 60pack year smoking history, recently reduced 60pack year smoking history, recently reduced

to 1-2 cigarettes/day; occasional EtOH, denies to 1-2 cigarettes/day; occasional EtOH, denies other drugsother drugs

FH: non-contributoryFH: non-contributory

ROS as per HPIROS as per HPI– Increased DOEIncreased DOE– Denies LAD, rash, cough, URI Denies LAD, rash, cough, URI

symptomssymptoms

VS: 39.5, 122/80, 103, 22, 95%RAVS: 39.5, 122/80, 103, 22, 95%RA Gen: NAD, pallorGen: NAD, pallor HEENT: dry MM, posterior pharynx HEENT: dry MM, posterior pharynx

erythematouserythematous Pulm: CTAB with fair air movementPulm: CTAB with fair air movement CV: tachycardic, reg rhythm, no M/R/GCV: tachycardic, reg rhythm, no M/R/G Abd: normoactive BS, tenderness RLQ, Abd: normoactive BS, tenderness RLQ,

no rebound/guarding, no masses, no no rebound/guarding, no masses, no hepatosplenomegalyhepatosplenomegaly

Chem 10: wnlChem 10: wnl 2.5>11.3/31.3<4232.5>11.3/31.3<423

– ANC 0.1ANC 0.1 UA negUA neg Utox: + MJ & cocaineUtox: + MJ & cocaine CRP 19, ESR 37CRP 19, ESR 37

Chest XRayChest XRay

Mild inflammatory stranding in the sigmoid colon

Abdominal CTAbdominal CT

DiscussionDiscussion

Old labs: Old labs: – CSF: OP, cell count, culture, crypto CSF: OP, cell count, culture, crypto

Ag, VDRL, HSV negAg, VDRL, HSV neg– Serum: Serum:

Neg: ehrlichia, CMV PCR, HIV, EBV PCR, Neg: ehrlichia, CMV PCR, HIV, EBV PCR, brucella, francisella brucella, francisella

Pos: Parvo c/w past infection, 4-fold Pos: Parvo c/w past infection, 4-fold increase in RMSF, ANAincrease in RMSF, ANA

New labs:New labs:– CSF: OP, cell count, culture, crypto Ag, CSF: OP, cell count, culture, crypto Ag,

VDRL, HSV negVDRL, HSV neg– Serum: Serum:

fungal cx & blood rare pathogen cx neg to datefungal cx & blood rare pathogen cx neg to date ANA, HIV, EBV, CMV, blood cx x2, urine cx negANA, HIV, EBV, CMV, blood cx x2, urine cx neg

– Bone aspirate:Bone aspirate: AFB cx neg to dateAFB cx neg to date Bone marrow cx negBone marrow cx neg

Bone marrow aspirate Bone marrow aspirate

Maturation arrest in the myeloid Maturation arrest in the myeloid lineline

Mild eosinophilia (7%)Mild eosinophilia (7%) Flow cytometry normal, no Flow cytometry normal, no

monoclonal large granular monoclonal large granular lymphocyteslymphocytes

Diagnosis and Diagnosis and TreatmentTreatment Neupogen 480 mcg sc qd to shorten Neupogen 480 mcg sc qd to shorten

length of neutropenialength of neutropenia Protective precautions for neutropenia Protective precautions for neutropenia

(hygiene, mask, avoiding uncooked & (hygiene, mask, avoiding uncooked & unwashed foods, avoiding sick unwashed foods, avoiding sick contacts, etc.)contacts, etc.)

Outpatient EGD to look for gastric Outpatient EGD to look for gastric ulcersulcers

Outpatient colonoscopy to screen for Outpatient colonoscopy to screen for Clostridium septicumClostridium septicum

Cyclic NeutropeniaCyclic Neutropenia

Cyclic NeutropeniaCyclic Neutropenia

Rare congenital neutropeniaRare congenital neutropenia– First recognized in 1910First recognized in 1910

Regular oscillations in neutrophils, PLTs, Regular oscillations in neutrophils, PLTs, monocytes, eosinophils, lymphocytes, & monocytes, eosinophils, lymphocytes, & reticulocytesreticulocytes– Typically 21 day cycles (14-28d)Typically 21 day cycles (14-28d)– Neutrophils fluctuate between normal & Neutrophils fluctuate between normal &

<500<500– Marrow may appear hypoplastic with Marrow may appear hypoplastic with

promyelocyte arrest during periods of promyelocyte arrest during periods of neutropenianeutropenia

See lots of promyelocytes but few more mature See lots of promyelocytes but few more mature cellscells

Cyclic NeutropeniaCyclic Neutropenia

Childhood onsetChildhood onset– More commonMore common– Familial pattern, ADFamilial pattern, AD– Symptoms tend to regress after Symptoms tend to regress after

pubertypuberty Adult onsetAdult onset

– Associated with clonal proliferation of Associated with clonal proliferation of CD56+ large granular lymphocytes (NK CD56+ large granular lymphocytes (NK cell LGL leukemia)cell LGL leukemia)

PathogenesisPathogenesis

Defect at level of stem cellDefect at level of stem cell– Multiple cell linesMultiple cell lines– Can be transferred from affected bone marrow Can be transferred from affected bone marrow

donor to recipientdonor to recipient Mutation in Neutrophil Elastase geneMutation in Neutrophil Elastase gene

– Chromosome 19p13.3Chromosome 19p13.3– Several different mutations affecting enzyme’s Several different mutations affecting enzyme’s

active site possibleactive site possible Gain of functionGain of function

– Synthesized primarily at the promyelocytic stageSynthesized primarily at the promyelocytic stage– Hypothesized to cause accelerated apoptosis of Hypothesized to cause accelerated apoptosis of

developing neutrophil precursors and/or enzymatic developing neutrophil precursors and/or enzymatic antagonism of G-CSFantagonism of G-CSF

DiagnosisDiagnosis

Documentation of ANC below Documentation of ANC below 500/uL on at least 3-5 500/uL on at least 3-5 consecutive days per cycle of consecutive days per cycle of each of 3 regularly spaced cycleseach of 3 regularly spaced cycles

Monitor neutrophil count 3 Monitor neutrophil count 3 times/week for 6-8 weekstimes/week for 6-8 weeks

ManifestationsManifestations

Severe neutropenia 3-5 days during Severe neutropenia 3-5 days during each cycleeach cycle

Malaise, fever, aphthous stomatitis, Malaise, fever, aphthous stomatitis, LAD, ulcers of GI tract, serious LAD, ulcers of GI tract, serious cutaneous/subcutaneous infectionscutaneous/subcutaneous infections

Most common infections: bacterialMost common infections: bacterial– Staph spp.Staph spp.– Gram negativesGram negatives

Association with Clostridium septicumAssociation with Clostridium septicum

Management of Management of Infection RiskInfection RiskANCANC Risk ManagementRisk Management

>1500>1500 NoneNone

1000-1000-15001500

No significant difference in management; Fever No significant difference in management; Fever can be managed as outptcan be managed as outpt

500-500-10001000

Increased risk of serious infection; Fever may or Increased risk of serious infection; Fever may or may not be able to be managed as outptmay not be able to be managed as outpt

<500<500 Significant risk of serious infection; Fever should Significant risk of serious infection; Fever should always be managed as inpt with IV antibiotics; always be managed as inpt with IV antibiotics; Few clinical signs of infectionFew clinical signs of infection

<200<200 Very significant risk of serious infection; Fever Very significant risk of serious infection; Fever should always be managed as inpt with IV should always be managed as inpt with IV antibiotics; Few/no clinical signs of infectionantibiotics; Few/no clinical signs of infection

TreatmentTreatment

G-CSF is treatment of choice for adult-onsetG-CSF is treatment of choice for adult-onset– Required higher doses compared to pts requiring Required higher doses compared to pts requiring

G-CSF for other reasonsG-CSF for other reasons– May be augmented when combined with SCFMay be augmented when combined with SCF

Neutrophil oscillation may persist but Neutrophil oscillation may persist but neutropenic periods shortened neutropenic periods shortened

Recovery: cell density arises as wave Recovery: cell density arises as wave traveling through myeloblasts traveling through myeloblasts promyelocytes promyelocytes myelocytes myelocytes neutrophils neutrophils