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FRACP Lecture SeriesFRACP Lecture Series

Nalini PatiNalini PatiNalini PatiNalini PatiConsultant haematologistConsultant haematologist

AGENDAAGENDALecture 1 Lecture 1 –– Bleeding disordersBleeding disorders

Lecture 2 Lecture 2 –– Neutropenia and ThrombocytopeniaNeutropenia and Thrombocytopenia

For each of these conditions the following should be addressedFor each of these conditions the following should be addressedClinical presentationClinical presentationppInitial investigationsInitial investigationsInitial managementInitial managementPotential complicationsPotential complicationsTherapeutic optionsTherapeutic optionsIndications for referral Indications for referral

InvestigationsInvestigationsScreening Screening investigationsinvestigations

FBEFBE

PFA PFA –– 100100

Blood groupBlood groupVon Willebrand’s Von Willebrand’s

APTTAPTTPT / INRPT / INRFibrinogenFibrinogenTCTTCT

screenscreen

Factor XIIIFactor XIII

HaemophiliaHaemophilia

What haemophilia was.What haemophilia was.

What haemophilia is.What haemophilia is.

What are the main problems with What are the main problems with haemophilia today.haemophilia today.

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HaemophiliaHaemophilia

XH X

Carrier Woman Healthy Man

X Y

Carrier Girl Healthy Girl Haemophilic Boy Healthy Boy

XH

X X X XH

Y X Y

HaemophiliaHaemophilia

X XH

Healthy Woman Haemophilic Man

X Y

Carrier Girl Carrier Girl Healthy Boy Healthy Boy

XH

X XH

X X Y X Y

Haemophilia Haemophilia –– World World PerspectivePerspective

An estimated 250,000 patients in the world An estimated 250,000 patients in the world population.population.

Only about 50 000 receive specificOnly about 50 000 receive specificOnly about 50,000 receive specific Only about 50,000 receive specific treatment.treatment.

Australia has approximately 1800 patients Australia has approximately 1800 patients with haemophiliawith haemophilia

Haemophilia Management 2008Haemophilia Management 2008Clotting factor replacement is the cornerstone of Clotting factor replacement is the cornerstone of treatmenttreatmentRecent (October 2004) Federal and State Government Recent (October 2004) Federal and State Government consensus to fund recombinant FVIII and FIX for all consensus to fund recombinant FVIII and FIX for all patients with haemophilia in Australiapatients with haemophilia in AustraliaClotting factor needs to be given directly into the into Clotting factor needs to be given directly into the into veinsveinsFactor replacement can be given for treatment AND Factor replacement can be given for treatment AND prevention (prophylaxis) of bleedsprevention (prophylaxis) of bleeds

Haemophilia ProphylaxisHaemophilia Prophylaxis

ProphylaxisProphylaxisRegular infusions of (recombinant) clotting Regular infusions of (recombinant) clotting factor concentrate to prevent joint and muscle factor concentrate to prevent joint and muscle bleedsbleedsMajority of children begin prophylaxis after the Majority of children begin prophylaxis after the first or second joint bleed first or second joint bleed The use of early prophylaxis has significantly The use of early prophylaxis has significantly reduced the complication of joint diseasereduced the complication of joint disease

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FVIII and FIX InhibitorsFVIII and FIX Inhibitors

Most serious complication Most serious complication FVIII or FIX proteins recognised as “foreign” FVIII or FIX proteins recognised as “foreign” Stimulating immune response and formation of Stimulating immune response and formation of IgGIgGIgG IgG Occurs in 30% patients severe haemophilia A Occurs in 30% patients severe haemophilia A and 5% patients haemophilia Band 5% patients haemophilia B

FVIII and FIX InhibitorsFVIII and FIX InhibitorsRenders treatment and prophylaxis ineffectiveRenders treatment and prophylaxis ineffective

Limited treatment options and return to the Limited treatment options and return to the “natural history of haemophilia” “natural history of haemophilia”

Current treatment option to treat haemorrhage in Current treatment option to treat haemorrhage in patients with haemophilia (rFVIIa patients with haemophilia (rFVIIa –– NovoVII) NovoVII) particularly expensiveparticularly expensive

Haemophilia 2008Haemophilia 2008

Whilst inhibitors in haemophilia are still a Whilst inhibitors in haemophilia are still a major problem, the modern management major problem, the modern management of haemophilia prevents the traditional of haemophilia prevents the traditional complications of joint diseasecomplications of joint diseasecomplications of joint diseasecomplications of joint diseaseThe availability of recombinant clotting The availability of recombinant clotting factor concentrate limits the risk of factor concentrate limits the risk of transfusion transmitted viral diseasetransfusion transmitted viral disease

Structure of Haemophilia Structure of Haemophilia Care in AustraliaCare in Australia

National Blood Authority provides funds for National Blood Authority provides funds for clotting factor concentrate clotting factor concentrate

30% state / 70% federal30% state / 70% federalManagement run through haemophiliaManagement run through haemophiliaManagement run through haemophilia Management run through haemophilia individual treatment centersindividual treatment centers

Di i T itiDiagnosis Transition

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Di i T itiDiagnosis Transition

< 12 months of age

• Addressing psychological impact of X linked recessive disorder

Di i T iti

12 – 24 months of age

• Onset of joint bleeds

Diagnosis Transition

Di i T iti

2 years – 5 years

• Commencement of home based therapy

Diagnosis Transition Di i T itiDiagnosis Transition

> 5 years

• Are boys with hemophilia as active, fit and happy as their peers?

Modern Morbidities of HaemophiliaModern Morbidities of Haemophilia

Impact on family functioningImpact on family functioningSupport of home based therapySupport of home based therapy

Complications of central venous linesComplications of central venous linesActivity levelsActivity levels

Bone densityBone densityMaintenance of Healthy WeightMaintenance of Healthy Weight

Maximizing Education PotentialMaximizing Education Potential

Virchow’s Triad in HaemophiliaVirchow’s Triad in Haemophilia

Vessel Wall

Thrombosis

Blood composition

Blood Flow

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Activity LevelsActivity Levels

In the modern era of haemophilia In the modern era of haemophilia management, are boys with haemophilia management, are boys with haemophilia as active as their peers?as active as their peers?What are the implications of reducedWhat are the implications of reducedWhat are the implications of reduced What are the implications of reduced levels of activity in boys with haemophilia?levels of activity in boys with haemophilia?

Bone densityBone densityMaintenance of Healthy WeightMaintenance of Healthy Weight

Bone DensityBone Density

Importance of musculoImportance of musculo--skeletal integrity skeletal integrity (including maintaining adequate bone (including maintaining adequate bone density) density) Patients with haemophilia may be at risk ofPatients with haemophilia may be at risk ofPatients with haemophilia may be at risk of Patients with haemophilia may be at risk of developing reduced bone densitydeveloping reduced bone density

Reduced weight bearing exerciseReduced weight bearing exerciseProlonged periods of immobilityProlonged periods of immobility

Figure 1 Bone mineral density (BMD) of lumbar spine and total body and bone mineral apparent density (BMAD) of lumbar spine plotted by age in boys and girls. The bold line represents the

fitted line, the thin lines represent {+/-}2 SD.

van der Sluis, I M et al. Arch Dis Child 2002;87:341-347

Bone DensityBone Density

Bone DensityBone Density Maintenance of Healthy WeightMaintenance of Healthy Weight

Obesity is a major public health problemObesity is a major public health problemGreater access to calorie dense foodsGreater access to calorie dense foodsReduced activity (greater access to sedentary Reduced activity (greater access to sedentary pastimes)pastimes)pastimes)pastimes)

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Risk FactorsRisk Factors Maintenance of Healthy WeightMaintenance of Healthy Weight

Are boys with haemophilia more prone to Are boys with haemophilia more prone to becoming overweight?becoming overweight?

Predisposed to becoming overweight on the Predisposed to becoming overweight on the basis of reduced physical activitybasis of reduced physical activitybasis of reduced physical activitybasis of reduced physical activity

Maintenance of Healthy Weight in Maintenance of Healthy Weight in HaemophiliaHaemophilia

Implications for patients with haemophilia Implications for patients with haemophilia and obesity significantand obesity significant

Complicated venous accessComplicated venous accessIncreased clotting factor usageIncreased clotting factor usageExacerbation of established joint diseaseExacerbation of established joint disease

Changing Morbidities of Changing Morbidities of HaemophiliaHaemophilia

As a result of the major advances in As a result of the major advances in haemophilia care there is the opportunity haemophilia care there is the opportunity to focus on a different range of coto focus on a different range of coto focus on a different range of coto focus on a different range of co--morbiditiesmorbidities

von Willebrand’s diseasevon Willebrand’s disease

Von Willebrand diseaseVon Willebrand diseaseType 1Type 1

80%80%Mild to moderate quantitative reductions in VWF Mild to moderate quantitative reductions in VWF levelslevels

T 2T 2Type 2Type 220%20%Qualitative defectsQualitative defects

Type 3Type 3Virtual deficiency of VWFVirtual deficiency of VWF

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Type 1 VWDType 1 VWD

Prospective studies have suggested 1% of Prospective studies have suggested 1% of population affectedpopulation affected

T ti f l t 1 i 10 000T ti f l t 1 i 10 000Tertiary referral centres 1 in 10,000Tertiary referral centres 1 in 10,000

Type 1 VWDType 1 VWD

VWD is an VWD is an inheritedinherited diseasedisease that causes that causes bleedingbleeding and type 1 VWD is a and type 1 VWD is a quantitative quantitative deficiency of VWF.deficiency of VWF.

Type 1 VWD (ISTH)Type 1 VWD (ISTH)

All of the following criteria must be metAll of the following criteria must be metA significant history of mucocutaneous A significant history of mucocutaneous bleedingbleedingLaboratory tests compatible with type I VWDLaboratory tests compatible with type I VWDLaboratory tests compatible with type I VWDLaboratory tests compatible with type I VWDEither a positive family history or an Either a positive family history or an appropriate genetic mutationappropriate genetic mutation

Von Willebrand Disease in the Von Willebrand Disease in the NeonateNeonate

VWF:Ag and CBA increased in the VWF:Ag and CBA increased in the neonatal populationneonatal populationneonatal populationneonatal population

Reach adult levels by 6 months of ageReach adult levels by 6 months of age

Royal Children’s Hospital Royal Children’s Hospital VWDVWD

Vast majority of patients have Type 1 Vast majority of patients have Type 1 VWDVWDType 2 VWDType 2 VWDType 2 VWDType 2 VWD

? 4 patients? 4 patientsType 3 VWDType 3 VWD

1 patient1 patient

Royal Children’s Hospital Type Royal Children’s Hospital Type 1 VWD1 VWD

Patients referred from surgical services, Patients referred from surgical services, adolescent gynaecology and external adolescent gynaecology and external general practitionersgeneral practitionersg pg pRoutine investigationsRoutine investigationsFamily testing performed as routineFamily testing performed as routineDDAVP challenge performed as routineDDAVP challenge performed as routine

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DDAVP challengeDDAVP challengeRelative contraindication in children less than 2 Relative contraindication in children less than 2 years of ageyears of ageThirty minute infusion of 0.3 mcg / kg (maximum Thirty minute infusion of 0.3 mcg / kg (maximum 20 mcg)20 mcg)VWF A t 30 i t 1 h d 4 hVWF A t 30 i t 1 h d 4 hVWF:Ag at 30 minutes, 1 hour and 4 hoursVWF:Ag at 30 minutes, 1 hour and 4 hoursRestriction of fluid input over 12 hours following Restriction of fluid input over 12 hours following infusioninfusion

One patient (10 months of age) developed seizures One patient (10 months of age) developed seizures secondary to hyponatramia following treatment with secondary to hyponatramia following treatment with DDAVPDDAVP

Management of VWDManagement of VWDNon transfusional therapiesNon transfusional therapies

DDAVPDDAVPSustain increase in FVIII / VWF 8 Sustain increase in FVIII / VWF 8 –– 10 hours10 hoursGiven 12 Given 12 –– 24 hourly depending on documented 24 hourly depending on documented responseresponseresponseresponseTachyphylaxis after 4 dosesTachyphylaxis after 4 doses

AntifibrinolyticsAntifibrinolyticsTransfusional therapiesTransfusional therapies

BIOSTATE (AHF)BIOSTATE (AHF)

BiostateBiostate

Plasma derived FVIII / VWFPlasma derived FVIII / VWFRatio of FVIII : VWF of 2:3 (product insert Ratio of FVIII : VWF of 2:3 (product insert suggests Biostate ratio of 1:2)suggests Biostate ratio of 1:2)20 000 units on stock at all times at RCH20 000 units on stock at all times at RCH20 000 units on stock at all times at RCH20 000 units on stock at all times at RCH

ThrombocytopeniaThrombocytopenia

InheritedInherited

Acquired (ITP)Acquired (ITP)

Case Case

3 week old male infant presenting with 3 week old male infant presenting with marked thrombocytopenia in the setting of marked thrombocytopenia in the setting of possible vascular tumour of lower limbpossible vascular tumour of lower limb

Antenatal historyAntenatal historyLargely unremarkableLargely unremarkableMother on aspirin for recurrent miscarriagesMother on aspirin for recurrent miscarriagesConsanguineous parentsConsanguineous parents

Case Case

Family historyFamily historyNo significant history of bleeding, known No significant history of bleeding, known platelet disordersplatelet disordersYoungest of five childrenYoungest of five childrenYoungest of five childrenYoungest of five childrenPrevious six miscarriagesPrevious six miscarriages

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Case Case

Presenting historyPresenting historyPresented at birth with large, fleshy Presented at birth with large, fleshy vascular(?) lesion affecting the lower limbvascular(?) lesion affecting the lower limbReferred to paediatricianReferred to paediatricianReferred to paediatricianReferred to paediatrician

Possible kaposiform haemangioendothelioma Possible kaposiform haemangioendothelioma (KHE)(KHE)Treated with corticosteroidsTreated with corticosteroidsReferred to haematology due to persistent Referred to haematology due to persistent thrombocytopeniathrombocytopenia

Case Case

Initial investigationsInitial investigationsSlightly anaemic, neutropenic and markedly Slightly anaemic, neutropenic and markedly thrombocytopenicthrombocytopenicNo evidence of coagulation activationNo evidence of coagulation activationUltrasound showed lesion in right cerebral Ultrasound showed lesion in right cerebral hemisphere, confirmed on MRI as bleed hemisphere, confirmed on MRI as bleed (antenatal)(antenatal)Managed with platelet transfusion with good Managed with platelet transfusion with good responseresponse

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Case Case

ProgressProgressPersistent marked thrombocytopenia despite Persistent marked thrombocytopenia despite involution of vascular lesioninvolution of vascular lesionRepeated bone marrow examination showingRepeated bone marrow examination showingRepeated bone marrow examination showing Repeated bone marrow examination showing normocellular bone marrow but (?) decreasing normocellular bone marrow but (?) decreasing megakaryocytes (confirmed on megakaryocytes (confirmed on immunohistochemistry CD61)immunohistochemistry CD61)Patient “well” and not bleedingPatient “well” and not bleeding

Congenital Thrombocytopenia: “Tools” Congenital Thrombocytopenia: “Tools” available for assessmentavailable for assessment

Platelet count & sizingPlatelet count & sizingReticulated platelets Reticulated platelets Electron microscopyElectron microscopyBone marrow aspiration and Bone marrow aspiration and ppimmunohistochemistryimmunohistochemistryFlow cytometry for platelet glycoproteinsFlow cytometry for platelet glycoproteinsAssessment of platelet functionAssessment of platelet function

PFA 100PFA 100Aggregometry Aggregometry

Molecular markersMolecular markers

Platelet counting and sizing Platelet counting and sizing (Coulter principle)(Coulter principle)

RBCsRBCs

+ -

Cross section ofCross section ofRBC aperture RBC aperture (60x50 micron)(60x50 micron)

Oscilloscope screenOscilloscope screenPLTPLT

Platelet Counting & SizingPlatelet Counting & Sizing

Platelet count is not directly measured Platelet count is not directly measured –– derived derived from platelet histogram from platelet histogram

Any particle sized between 2 to 20 fl is counted as a Any particle sized between 2 to 20 fl is counted as a plateletplateletAny particle sized outside of 2 to 20 fl is not counted as Any particle sized outside of 2 to 20 fl is not counted as a plateleta platelet

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Reticulated PlateletsReticulated Platelets“Immature platelets”“Immature platelets”Larger mean platelet volume with higher RNA Larger mean platelet volume with higher RNA contentcontentFlow cytometric method using the membrane Flow cytometric method using the membrane permeable flurochrome thiazole orange topermeable flurochrome thiazole orange topermeable flurochrome thiazole orange to permeable flurochrome thiazole orange to stain RNAstain RNASensitivity improved by using gating Sensitivity improved by using gating techniques incorporating CD61techniques incorporating CD61Reported as a percentage (lack of widely Reported as a percentage (lack of widely accepted standardization of normal values)accepted standardization of normal values)

Reticulated PlateletsReticulated Platelets

May have a role in the distinguishing May have a role in the distinguishing patients with ITP / consumptive states patients with ITP / consumptive states from those with decreased platelet from those with decreased platelet production production

May have a role in the predictive value for May have a role in the predictive value for marrow recovery following chemotherapymarrow recovery following chemotherapy

Not currently available at RCHNot currently available at RCH

Bone Marrow AspirationBone Marrow Aspiration

Performed under general anaestheticPerformed under general anaestheticLimited morbidityLimited morbidityProvides quantitative information with Provides quantitative information with li it d lit ti i f ti ( l tili it d lit ti i f ti ( l tilimited qualitative information (correlation limited qualitative information (correlation of function with signs of dysplasia / of function with signs of dysplasia / abnormal forms etc.)abnormal forms etc.)

Electron MicroscopyElectron Microscopy

Provide assessment of platelet Provide assessment of platelet ultrastructureultrastructureSomewhat helpful in the assessment of Somewhat helpful in the assessment of platelet function disordersplatelet function disordersplatelet function disordersplatelet function disordersAvailable in Melbourne through University Available in Melbourne through University of Melbourneof Melbourne

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Flow cytometry for platelet Flow cytometry for platelet glycoproteinsglycoproteins

Diagnostic in select group of patients with Diagnostic in select group of patients with characteristic disorderscharacteristic disorders

Glanzman’s thrombocythaemia (deficient Glanzman’s thrombocythaemia (deficient GPIIb/IIIa)GPIIb/IIIa)GPIIb/IIIa)GPIIb/IIIa)Bernard Soulier syndrome (deficient Ib/IX)Bernard Soulier syndrome (deficient Ib/IX)

Assessment of Platelet FunctionAssessment of Platelet Function

Difficult in ChildrenDifficult in ChildrenLarge volumes of blood requiredLarge volumes of blood requiredGenerally require “normal platelet” countsGenerally require “normal platelet” countsMethods availableMethods available

PFA 100PFA 100Formal aggregometryFormal aggregometry

PFAPFA--100 Closure Time Measurement100 Closure Time Measurement

PROGRESSION OF PLATELET PLUG FORMATIONPROGRESSION OF PLATELET PLUG FORMATIONAT THE PFA-100 APERTUREAT THE PFA-100 APERTURE

PoujolPoujol et al., 1998 et al., 1998

PFA PFA -- 100100

Quantitative, rapid test of platelet function Quantitative, rapid test of platelet function at high shear ratesat high shear ratesPlatelet plug forms under shear stress and Platelet plug forms under shear stress and occludes the aperture which is detected as occludes the aperture which is detected as ppthe closure timethe closure timePublished normal ranges for closure times Published normal ranges for closure times for children for children Available RCHAvailable RCH

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Platelet AggregationPlatelet AggregationGold standard for the investigation of platelet functionGold standard for the investigation of platelet functionInitially devised 40 years ago (Bonn, Nature 1962)Initially devised 40 years ago (Bonn, Nature 1962)Platelet rich plasma placed in an aggregometer cuvette, warmed to Platelet rich plasma placed in an aggregometer cuvette, warmed to 3737ooC in the heating block of the instrument and stirred by means of C in the heating block of the instrument and stirred by means of a small magnetic stir bar. a small magnetic stir bar. Li ht t i i th h th l i it d ti lLi ht t i i th h th l i it d ti lLight transmission through the plasma is monitored continuously on Light transmission through the plasma is monitored continuously on a chart recorder. a chart recorder. The addition of an aggregating agent results in the formation of The addition of an aggregating agent results in the formation of increasingly larger platelet aggregates with a corresponding increasingly larger platelet aggregates with a corresponding decrease in optical density and is recorded as a tracing by the chart decrease in optical density and is recorded as a tracing by the chart recorder.recorder.Minimum count in PRP = 100 X10^9/lMinimum count in PRP = 100 X10^9/l

Platelet AggregationPlatelet Aggregation

Glanzmann's thrombasthenia (A), BernardGlanzmann's thrombasthenia (A), Bernard--Soulier Soulier syndrome (B), syndrome (B),

Approach to “Congenital” Approach to “Congenital” ThrombocytopeniaThrombocytopenia

1.1. Rule out secondary causesRule out secondary causes2.2. Congenital thrombocytopeniaCongenital thrombocytopenia

a.a. Syndromic thrombocytopenia Syndromic thrombocytopenia bb NonNon -- syndromic thrombocytopeniasyndromic thrombocytopeniab.b. Non Non syndromic thrombocytopeniasyndromic thrombocytopenia

Associated with macrothrombocytopeniaAssociated with macrothrombocytopeniaBernard SoulierBernard SoulierMYH9 related conditionsMYH9 related conditions

Associated with normal sized plateletsAssociated with normal sized platelets

Secondary ThrombocytopeniaSecondary Thrombocytopenia

Majority of cases of Majority of cases of thromobocytopenia occuring thromobocytopenia occuring in neonates are a result of a in neonates are a result of a clearly apparent underlying clearly apparent underlying systemic illnesssystemic illness

NumberNumber

Congenital InfectionsCongenital Infections(CMV Toxoplasmosis (CMV Toxoplasmosis Rubella)Rubella)

7070

yyFetal platelet counts in Fetal platelet counts in 5914 consecutive fetal 5914 consecutive fetal blood samples blood samples Thrombocytopenia Thrombocytopenia (<150X10^9/l) present in(<150X10^9/l) present in

247 of these cases 247 of these cases (4.1%)(4.1%)

(Hohlfeld et al 1994)(Hohlfeld et al 1994)

Immune causesImmune causes(anti HPA1a / HPA5b, (anti HPA1a / HPA5b, anti HLA, maternal ITP)anti HLA, maternal ITP)

6363

Chromosomal Chromosomal abnormalityabnormality(Trisomy 13, 18, 21)(Trisomy 13, 18, 21)

4343

OtherOther 6262

1. Syndromic Congenital 1. Syndromic Congenital ThrombocytopeniaThrombocytopenia

Wiskott Aldrich / Xlinked Wiskott Aldrich / Xlinked thrombocytopeniathrombocytopeniaTARTARMYH9 MYH9 –– related disease related disease Familial platelet disorder and Familial platelet disorder and predisposition to AML (FPD/AML) predisposition to AML (FPD/AML) (Ho et (Ho et al, Blood 1996)al, Blood 1996)

Non Non -- Syndromic Congenital Syndromic Congenital ThrombocytopeniaThrombocytopenia

Associated with normal sized plateletsAssociated with normal sized plateletsCAMT CAMT

Autosomal recessiveAutosomal recessiveIsolated hypomegakaryocytic thrombocytopenia at Isolated hypomegakaryocytic thrombocytopenia at birthbirth15 families15 familiesDeficiency in the expression of TPO receptor Deficiency in the expression of TPO receptor

Other (?)Other (?)

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Immune Thrombocytopenia Immune Thrombocytopenia PurpuraPurpuraPurpuraPurpura

Case ACase A

2 ½ old boy2 ½ old boyPreviously wellPreviously wellUrgent referral to clinic with bruisingUrgent referral to clinic with bruisingPlatelet count < 10 X 10^9/l with otherwise Platelet count < 10 X 10^9/l with otherwise normal blood countnormal blood countExamination unremarkableExamination unremarkable

Case ACase A

What investigations need to be What investigations need to be performed?performed?

Wh t t t t i i d?Wh t t t t i i d?What treatment is required?What treatment is required?

What advice is given to the parents?What advice is given to the parents?

Case BCase B12 year old girl12 year old girlPresents from country general practitionerPresents from country general practitionerDiagnosis of ITP made 6 weeks prior (platelet Diagnosis of ITP made 6 weeks prior (platelet count 4 X 10^9/l, borderline haemoglobin 114 g/l count 4 X 10^9/l, borderline haemoglobin 114 g/l ( l 115( l 115 135) d l135) d l(normal range 115 (normal range 115 –– 135) and normal 135) and normal examination)examination)Moderate bruising but no active bleedingModerate bruising but no active bleedingComes following 6 weeks of steroids with Comes following 6 weeks of steroids with Cushingoid featuresCushingoid featuresRepeat platelet count 10 X 10^9/l with persistent Repeat platelet count 10 X 10^9/l with persistent borderline haemoglobin and lymphopeniaborderline haemoglobin and lymphopenia

Case BCase B

What investigations are now necessary?What investigations are now necessary?

What treatment is recommended?What treatment is recommended?

What advice is given to the patient?What advice is given to the patient?

Case CCase C

4 year old boy with Down’s syndrome4 year old boy with Down’s syndromePresents with marked bruising, active Presents with marked bruising, active mucosal bleeding and platelet count < 10 mucosal bleeding and platelet count < 10 X 10^9/l (and mild normochromic X 10^9/l (and mild normochromic ((normocytic anaemia with reticulocytosis)normocytic anaemia with reticulocytosis)Develops headache, focal neurological Develops headache, focal neurological signs and intracranial haemorrhage signs and intracranial haemorrhage requiring urgent neurosurgeryrequiring urgent neurosurgery

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Case CCase C

Why does this patient manifest significant Why does this patient manifest significant bleeding symptoms despite the “same bleeding symptoms despite the “same degree of thrombocytopenia”degree of thrombocytopenia”

What treatments are recommended in the What treatments are recommended in the setting of urgent splenectomy?setting of urgent splenectomy?

Case DCase D

10 month old boy10 month old boyPreviously wellPreviously wellMorphologically normalMorphologically normalPresents with acute onset of increased Presents with acute onset of increased bruising and marked thrombocytopeniabruising and marked thrombocytopeniaAlready walking but unsteadyAlready walking but unsteady

Case DCase D

Below what age is the diagnosis of ITP Below what age is the diagnosis of ITP less likely?less likely?

Th th t h l tTh th t h l t h t ih t iThe mother wants a helmet The mother wants a helmet –– what is your what is your advice?advice?

Case ECase E

15 year old girl15 year old girlLong standing history of ITP Long standing history of ITP

diagnosed at 7 years of agediagnosed at 7 years of ageS l t t 7 5 fS l t t 7 5 fSplenectomy at 7.5 years of ageSplenectomy at 7.5 years of ageLimited further followLimited further follow--upup

Presents with exacerbation of Presents with exacerbation of menorrhagia associated with iron menorrhagia associated with iron deficiency anaemiadeficiency anaemia

Case ECase E

Parents want another splenectomy Parents want another splenectomy –– what what investigations are recommended to investigations are recommended to identify accessory spleens / splenunculi?identify accessory spleens / splenunculi?

What treatments are recommended to What treatments are recommended to manage menorrhagia in this patient?manage menorrhagia in this patient?

Facts about ITPFacts about ITP

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Facts about ITPFacts about ITP

Imbach et al., Lancet 1985;2:464-68

Randomised study

NeutropeniaNeutropeniaClassification of NeutropeniaClassification of Neutropenia

NEUTROPENIA CAUSED BY INTRINSIC DEFECTS IN NEUTROPENIA CAUSED BY INTRINSIC DEFECTS IN

GRANULOCYTES OR THEIR PROGENITORSGRANULOCYTES OR THEIR PROGENITORS

Reticular dysgenesisReticular dysgenesisC li t iC li t iCyclic neutropeniaCyclic neutropeniaSevere congenital neutropenia (including Kostmann's Severe congenital neutropenia (including Kostmann's syndrome)syndrome)ShwachmanShwachman--Diamond syndromeDiamond syndromeAlbinism/neutropenia syndromes (including ChédiakAlbinism/neutropenia syndromes (including Chédiak--Higashi)Higashi)Familial benign neutropeniaFamilial benign neutropeniaBone marrow failure syndromes (congenital and acquired)Bone marrow failure syndromes (congenital and acquired)

NEUTROPENIA CAUSED BY NEUTROPENIA CAUSED BY EXTRINSIC FACTORS (Infection / EXTRINSIC FACTORS (Infection /

Drugs)Drugs)Autoimmune neutropeniaAutoimmune neutropeniaNeonatal immune neutropenia with immune dysfunctionNeonatal immune neutropenia with immune dysfunctionNeutropenia associated with metabolic diseasesNeutropenia associated with metabolic diseasesNeutropenia associated with metabolic diseasesNeutropenia associated with metabolic diseasesNutritional deficienciesNutritional deficienciesSequestrationSequestrationBone marrow infiltrationBone marrow infiltrationChronic idiopathic neutropenia (may also be intrinsic)Chronic idiopathic neutropenia (may also be intrinsic)Types of neutropenia are listed in order of discussion in Types of neutropenia are listed in order of discussion in the text.WHIM, warts, hypogammaglobulinemia, the text.WHIM, warts, hypogammaglobulinemia, infections, myelokathexis.infections, myelokathexis.

NeutropeniaNeutropenia

Severe congenital neutropenia Severe congenital neutropenia (Kostmann’s syndrome)(Kostmann’s syndrome)Cyclic neutropeniaCyclic neutropeniaS h Di d dS h Di d dSwachman Diamond syndromeSwachman Diamond syndromeGSD1bGSD1bAssociated with immunodeficiencyAssociated with immunodeficiency

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Neutropenia Neutropenia -- approachapproach

Age at presentationAge at presentationDepth of neutropeniaDepth of neutropeniaAssociation with bacterial infectionsAssociation with bacterial infections

Evaluation of neutropeniaEvaluation of neutropenia

History and physical examination with emphasis History and physical examination with emphasis on (1) related phenotypic abnormalities; (2) h/o on (1) related phenotypic abnormalities; (2) h/o bacterial infection (including evaluation of the bacterial infection (including evaluation of the gingiva and perineum); (3) evaluation of gingiva and perineum); (3) evaluation of lymphadenopathy, hepatosplenomegaly lymphadenopathy, hepatosplenomegaly Drug exposure, history of periodontitis, dental Drug exposure, history of periodontitis, dental abscesses, or tooth abscesses, or tooth Family history Family history Race and ethnic background Race and ethnic background

Neutropenia: EvaluationNeutropenia: Evaluation

White blood and differential counts obtained White blood and differential counts obtained twice weekly for 6 to 8 weeks twice weekly for 6 to 8 weeks Direct and indirect antiglobulin Direct and indirect antiglobulin serum immunoglobulinsserum immunoglobulinsserum immunoglobulins serum immunoglobulins HIV testing HIV testing Other viral studiesOther viral studies-- CMV, EBV, ParvoCMV, EBV, ParvoANAANABone marrow aspiration and biopsy with Bone marrow aspiration and biopsy with cytogenetics cytogenetics

Investigations contd..Investigations contd..

Vitamin B12, folate, and copper levels. Vitamin B12, folate, and copper levels. Radiographic studies of the femoral Radiographic studies of the femoral heads, rib cage, and spine may be useful heads, rib cage, and spine may be useful in the diagnosis of Shwachmanin the diagnosis of Shwachman DiamondDiamondin the diagnosis of Shwachmanin the diagnosis of Shwachman--Diamond Diamond syndrome syndrome Pancreatic exocrine functionsPancreatic exocrine functionsMetabolic screeningMetabolic screening

Principles of Therapy for Principles of Therapy for NeutropeniaNeutropenia

Underlying cause and severity. Underlying cause and severity. The major concern in neutropenic patients The major concern in neutropenic patients is the development of serious pyogenic is the development of serious pyogenic infectioninfectioninfection. infection. Fever may often be the only indication of Fever may often be the only indication of infection as very less local signsinfection as very less local signsOrganisms involved are usually from the Organisms involved are usually from the skin or GI tractskin or GI tract

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FEBRILE NEUTROPENIAFEBRILE NEUTROPENIA

J Age- 4 1/2 yrs

Diagnosis-Acute Lymphhoblastic leukaemia

(FAB – L2)

Date of diagnosis –26 December2004

Symptoms-Recurrent fever

Bone pains 3 wksBone pains 3 wks

Extreme lethargy

Investigations- Peripheral smear, bone marrow confirmed diagnosis of acute lymphoblastic leukaemia (FAB L2)

INTP - PPO, PHO, IAP.P4 – 3/19

Risk factorsRisk factors-- Male, high TLC andMale, high TLC andsignificant organomegalysignificant organomegalyNo lymphadenopathyNo lymphadenopathy

ManagementManagement –– Chemotherapy with 4 week, 5 drugsChemotherapy with 4 week, 5 drugsInduction protocol. Induction protocol.

Marrow on D28Marrow on D28 –– M1 (remission status)M1 (remission status)

Next phaseNext phase -- I 2I 2-- RadiationRadiationCNS prophylaxis CNS prophylaxis Standard drugs. Standard drugs.

However,7 days into I2 phase of therapy he was brought with However,7 days into I2 phase of therapy he was brought with history of fever,lethargy and refusal to eat.He also had cough history of fever,lethargy and refusal to eat.He also had cough and looked toxic.and looked toxic.

INTP - PPO, PHO, IAP.P4 – 4/19

Examination :Examination : Mucositis in the mouth andMucositis in the mouth andthroat & B/L coarse crepitations in the lungs.throat & B/L coarse crepitations in the lungs.No hepatosplenomegaly.No hepatosplenomegaly.

InvestigationsInvestigations:: Blood counts, Peripheral blood Blood counts, Peripheral blood smear, Xsmear, X--ray, CRP, blood and urine cultures ray, CRP, blood and urine cultures

INTP - PPO, PHO, IAP.P4 – 5/19

The smear and count reports were as follows-

Hb 8 g/L

Total WBC=1.3 X 109/L

N 08%

L 78%

M 08%M 08%

E 06%

ANC=0.1 X 109/L

Platelets=36 X 109/L

CRP - 96INTP - PPO, PHO, IAP.P4 – 6/19

The peripheral smear of this child is shown below. What can you see in this slide?

INTP - PPO, PHO, IAP.P4 – 7/19

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The smear shows significant neutropenia. The smear shows significant neutropenia.

The large cell on the left is a band form and the The large cell on the left is a band form and the one on the right is a myelocyte. Both cells one on the right is a myelocyte. Both cells show toxic granulations. This picture suggests a show toxic granulations. This picture suggests a shift to the left indicative of sepsis.shift to the left indicative of sepsis.pp

The next slide shows a normal peripheral The next slide shows a normal peripheral smear.smear.

Can you make out the difference?Can you make out the difference?INTP - PPO, PHO, IAP.P4 – 8/19

INTP - PPO, PHO, IAP.P4 – 9/19

The child was subjected to radiological The child was subjected to radiological investigation and the X investigation and the X –– ray was as below:ray was as below:

INTP - PPO, PHO, IAP.P4 – 10/19

The X The X –– ray shows bilateral soft infiltrates suggestive of ray shows bilateral soft infiltrates suggestive of bronchopneumonia.bronchopneumonia.

As the recordings of temperature revealedAs the recordings of temperature revealedcontinuous fever of more than 38 degrees C, thecontinuous fever of more than 38 degrees C, thechild was immediately started on empirical antibioticchild was immediately started on empirical antibioticchild was immediately started on empirical antibiotic child was immediately started on empirical antibiotic

therapy.therapy.

What would your choice of antibiotics be in this What would your choice of antibiotics be in this situation?situation?

What are the standard dosages of these drugs?What are the standard dosages of these drugs?

INTP - PPO, PHO, IAP.P4 – 11/19

Febrile neutropeniaFebrile neutropenia

Neutropenia:Neutropenia: ANC < 500 cells / cmm. ANC < 500 cells / cmm. Temperature:Temperature:

single observation of > 38.3single observation of > 38.3°°CC

sustained temp > 38.0sustained temp > 38.0°°C, >1 hrC, >1 hr

< 36< 36°°C with clinical deterioration C with clinical deterioration (HR > 90, RR > 20, BP<90) (HR > 90, RR > 20, BP<90)

Associated risk factorsAssociated risk factors

Degree of neutropenia (<500/Cmm)Degree of neutropenia (<500/Cmm)

Prolonged neutropenia ( > 7Prolonged neutropenia ( > 7--10 days)10 days)

Co morbid medical problemCo morbid medical problem-- exampleexample--Continued cancerous stateContinued cancerous state

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Low Risk PatientsLow Risk PatientsAnticipated short duration of neutropenia (<10d)Anticipated short duration of neutropenia (<10d)No Co morbid Medical ConditionNo Co morbid Medical ConditionControlled oncological statusControlled oncological statusOptionsOptions::Oral antibioticsOral antibiotics

CefiximeCefiximeCefiximeCefiximeCiprofloxacin + ClindamycinCiprofloxacin + ClindamycinCipro+ AmoxyCipro+ Amoxy--clavclav

Parental MonotherapyParental MonotherapyTo continue 7 days as OPD CareTo continue 7 days as OPD CareIf C/S If C/S --ve ve –– switch to oral drugsswitch to oral drugs(Ref: Malik et al , Am j med,98:224,1995).(Ref: Malik et al , Am j med,98:224,1995).

High Risk PatientsHigh Risk Patients

Granulocytopenia >10daysGranulocytopenia >10days

Proven source of infectionProven source of infection

Co morbid medical conditionCo morbid medical condition

If afebrile by day 14If afebrile by day 14-- stop antibioticsstop antibiotics

If febrile on day 3If febrile on day 3-- repeat Blood C/S on D4repeat Blood C/S on D4

(Ref: Malik et al , Am j med,98:224,1995).

IDSA Guide LinesIDSA Guide Lines-- 20022002(Walter et al)(Walter et al)Careful Physical ExaminationCareful Physical Examination

Initial evaluationInitial evaluation--To risk stratificationTo risk stratification-- determine whether determine whether

Vancomycin is needed in the initial trt.Vancomycin is needed in the initial trt.yyExamination sites :Examination sites :-- Oral cavityOral cavity

Perianal areaPerianal area

Exit sites of linesExit sites of lines

Blood Cultures Blood Cultures -- Minimum of 2 sets of culturesMinimum of 2 sets of cultures-- If has indwelling line If has indwelling line –– one set from one set from the lumen & the other from the the lumen & the other from the periphery.periphery.

Urine c/sUrine c/sEven if growth < 10Even if growth < 1055 of a single organism isof a single organism is-- Even if growth < 10Even if growth < 105 5 of a single organism isof a single organism issignificant significant

Chest radiotherapy.Chest radiotherapy.Assessable sites.Assessable sites.Tunnel sites should be aspirated / culturedTunnel sites should be aspirated / culturedExit sitesExit sites

Infectious cause is established in 30Infectious cause is established in 30--50% of pts.50% of pts.

Serial surveillance cultures (Serial surveillance cultures (Walsh etal Walsh etal Medicine 65, 265, 1996)Medicine 65, 265, 1996)

Not recommended routinely in neutropenia Not recommended routinely in neutropenia pts.pts.Useful in Useful in

P t t d t i ( 3P t t d t i ( 3 4 k )4 k )Protracted neutropenia ( > 3Protracted neutropenia ( > 3--4 weeks)4 weeks)High incidence of virulent organismsHigh incidence of virulent organisms

The blood culture, sample for which was collected at admission, revealed a significant growth of an organism after 48 hrs as seen on the blood agar plate below:

INTP - PPO, PHO, IAP.P4 – 12/19

22

The organism grown was identified as Haemophilus The organism grown was identified as Haemophilus influenzae which was found to be sensitive to a influenzae which was found to be sensitive to a number of antibiotics. The plate below shows the number of antibiotics. The plate below shows the sensitivity of the organism to ceftazidimesensitivity of the organism to ceftazidime..

INTP - PPO, PHO, IAP.P4 – 13/19

The general condition of J remained stable for the next five The general condition of J remained stable for the next five days, but fever persisted. Blood cultures showed the days, but fever persisted. Blood cultures showed the following:following:--A repeat count done on D5 after admission revealed Hb of A repeat count done on D5 after admission revealed Hb of 6gm%6gm%TLC of 0.9 N4 L88 M02 E06TLC of 0.9 N4 L88 M02 E06ANC =0.3ANC =0.3Platelets = 16 000/ cummPlatelets = 16 000/ cummWith the counts as above, platelet and RBC transfusions With the counts as above, platelet and RBC transfusions were considered.were considered.What is the role of these transfusions in a What is the role of these transfusions in a situation such as this?situation such as this?What is the threshold for platelet transfusion in a What is the threshold for platelet transfusion in a child whose general condition is stable and who is child whose general condition is stable and who is not bleeding?not bleeding?

INTP - PPO, PHO, IAP.P4 – 15/19

However, clinical examination revealed no evidence However, clinical examination revealed no evidence of bleeding and the mucositis had not worsened.of bleeding and the mucositis had not worsened.

A repeat of the chest X ray did not reveal any further A repeat of the chest X ray did not reveal any further deterioration.deterioration.

Considering the clinical picture,what steps would one Considering the clinical picture,what steps would one take now ? take now ? What is the role of packed cell RBC transfusion in a What is the role of packed cell RBC transfusion in a child with thrombocytopenia?child with thrombocytopenia?Would you consider empirical antifungal therapy Would you consider empirical antifungal therapy now? Why?now? Why?What drug would you use? What drug would you use?

INTP - PPO, PHO, IAP.P4 – 16/19

Goals for empirical treatmentGoals for empirical treatment

To protect against the early morbidity To protect against the early morbidity and mortality.and mortality.

GmGm--veve organism organism –– most common & most most common & most virulent virulent

All i h ld GAll i h ld G iiAll regimen should cover GAll regimen should cover G--veve organisms organisms with broad spectrum coverage for Gmwith broad spectrum coverage for Gm+ve+ve

organism.organism.

Essential Properties of Empirical Essential Properties of Empirical RegimesRegimes

Broad spectrum of activity that includes Broad spectrum of activity that includes Pseudomonas aeruginosa Pseudomonas aeruginosa

Ability to achieve high serum bactericidal Ability to achieve high serum bactericidal levelslevelslevelslevels

Effective in the absence of neutrophilsEffective in the absence of neutrophils

Low potential for the emergence of resistanceLow potential for the emergence of resistance

Acceptable toxicity profileAcceptable toxicity profile

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AminoglycosideAminoglycoside--Based Combination Based Combination RegimesRegimes

Aminoglycoside + AntiPseudomonal Aminoglycoside + AntiPseudomonal ±± Additional AntiAdditional Anti--GramGram--PositivePositive

beta beta –– LactamLactam

GentamicinGentamicin ExtendedExtended--spectrum penicillin Isoxozolylspectrum penicillin Isoxozolyl--penicillinpenicillinTobramycinTobramycin CarbenicillinCarbenicillin NafcillinNafcillinAmikacin Amikacin TicarcillinTicarcillin OxacillinOxacillin

AzlocillinAzlocillin ororMezlocillinMezlocillinPiperacilli First generation cephalosporinPiperacilli First generation cephalosporin

CephalothinCephalothinCefazolinCefazolin

ThirdThird--generation cephalosporin orgeneration cephalosporin orCeftazidimeCeftazidime VancomycinVancomycin

CefoperazoneCefoperazoneoror

AztreonamAztreonam

Regimen without AminoglycosideRegimen without Aminoglycoside

Combination of two beta lactam antibioticsCombination of two beta lactam antibioticsExample . Piperacillin + CeftazidimeExample . Piperacillin + Ceftazidime

Single agent with Aminoglycoside / Extended spectrumSingle agent with Aminoglycoside / Extended spectrumpenicillin / Vancomycin penicillin / Vancomycin –– should notshould not be used.be used.Drugs as monotherapyDrugs as monotherapy

1. Ceftazidime1. Ceftazidime2. Meropenem / Imipenem2. Meropenem / Imipenem3. Cefoperazone3. Cefoperazone4. Cefepime / Cefpirom4. Cefepime / Cefpirom

Defervesence Defervesence Ultimate outcome ComparableUltimate outcome Comparable

((Ref : friefeld et al, J Clin OncolRef : friefeld et al, J Clin Oncol 13:165, 1995)13:165, 1995)

Patients require frequent Patients require frequent modificationsmodifications

With a documented source of infectionWith a documented source of infection

P t t d l t i ( 1 k)P t t d l t i ( 1 k)Protracted granulo cytopenia ( > 1 week)Protracted granulo cytopenia ( > 1 week)

Continued Oncological statusContinued Oncological status

Use of Vancomycin in the Initial Use of Vancomycin in the Initial RegimesRegimes

No change in morbidityNo change in morbidityLess use of Amphotericin BLess use of Amphotericin BNo change in Febrile episodesNo change in Febrile episodesIncreases V R E emergenceIncreases V R E emergenceIncreases V R E emergenceIncreases V R E emergenceC D C RecommendationsC D C Recommendations::

*Not to be included in initial regimes unless *Not to be included in initial regimes unless culture proven by 3culture proven by 3rdrd dayday

* Not to be used prophylactically for central line * Not to be used prophylactically for central line infectioninfection

(Ref Karp et al, Am J of medicine 81:237, 1986)(Ref Karp et al, Am J of medicine 81:237, 1986)

CiprofloxacinCiprofloxacin

As monotherapy causes breakthrough As monotherapy causes breakthrough infection with streptococcus infection with streptococcus reserved for M D R statereserved for M D R state

(Ref: Meunier e tal Antimicrobiol agent chemother (Ref: Meunier e tal Antimicrobiol agent chemother 35:873, 1991)35:873, 1991)

Would you consider colony stimulating factors? Would you consider colony stimulating factors? How are they used?How are they used?

The boy was given a packed cell transfusionThe boy was given a packed cell transfusion

What is the volume of blood to be transfused?What is the volume of blood to be transfused?

and started on antifungal therapy with flucanazoland started on antifungal therapy with flucanazoland started on antifungal therapy with flucanazol.and started on antifungal therapy with flucanazol.

What is the dose of fluconazole? Amphotericin B?What is the dose of fluconazole? Amphotericin B?

GG--CSF was considered but not started.CSF was considered but not started.

Why?Why?INTP - PPO, PHO, IAP.P4 – 17/19

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Antifungal TreatmentAntifungal TreatmentIndicationIndication::

Persistence of fever on day 5Persistence of fever on day 5--77Anti fungalsAnti fungals

Itraconazole/Fluconazole Itraconazole/Fluconazole Patient received Fluconazole Prophylaxis Patient received Fluconazole Prophylaxis --

Amphotenicin BAmphotenicin BAmphotenicin BAmphotenicin BBenefits of empirical antifungalsBenefits of empirical antifungals--

Early clinical DefervesenceEarly clinical DefervesenceLess morbidityLess morbidity

RationaleRationaleEarly treatment of sub clinical infectionEarly treatment of sub clinical infectionSuppression of fungal overgrowth accompanyingSuppression of fungal overgrowth accompanyingAntibiotics therapyAntibiotics therapy(Ref(Ref--Pizzo et al, Am J med 1982,72;101).Pizzo et al, Am J med 1982,72;101).

Colony Stimulating FactorsColony Stimulating FactorsIndicationsIndications::1.Worsening course1.Worsening course2.Predicted prolonged neutropenia2.Predicted prolonged neutropeniaEffectsEffects::Reduce duration of antibioticsReduce duration of antibioticsReduce duration of antibioticsReduce duration of antibioticsNo change in mortalityNo change in mortality

DosageDosage :G:G--CSFCSF--5ug/Kg,GM5ug/Kg,GM--CSFCSF--250/m250/m22

ProphylaxisProphylaxis: (ASCO guidelines: (ASCO guidelines--if the chance of if the chance of FN>40%,prior h/o severe infectionFN>40%,prior h/o severe infection))

(Ref:(Ref:--J Clin Oncol 1996,14:1957J Clin Oncol 1996,14:1957--60,ASCO guidelines,200060,ASCO guidelines,2000))

Because GBecause G--CSF is useful when started early with CSF is useful when started early with neutropenia and has a limited role when neutropenia neutropenia and has a limited role when neutropenia is fully established. Besides, is fully established. Besides, it is expensive.it is expensive.

The general condition of J gradually The general condition of J gradually Improved.He became afebrile after the 9Improved.He became afebrile after the 9thth day of day of pp yyantibiotics and 4antibiotics and 4thth day of antifungals. His mucositis day of antifungals. His mucositis improved and his cough reduced.improved and his cough reduced.

His XHis X-- ray done on the 14ray done on the 14thth day after admission is day after admission is shown next.shown next.

INTP - PPO, PHO, IAP.P4 – 18/19

INTP - PPO, PHO, IAP.P4 – 19/19

PCP ProphylaxisPCP Prophylaxis

Started in 1980’s after isolation of HIVStarted in 1980’s after isolation of HIVIncidence of PCP infection without prophylaxis Incidence of PCP infection without prophylaxis (Meyer’s et (Meyer’s et al)al)

ALLALL--2222--43%,RMS43%,RMS--25%,BMT25%,BMT--16%,16%,SCIDSCID--27%,Solid tumors27%,Solid tumors--4040--50%50%

Standard trtStandard trt--TMPTMP--SMX BD SMX BD --3times / wk (3times / wk (Ioannidis et alIoannidis et al--metametaanalysis)analysis)

OthersOthers--DapsonDapson--2mg/kg2mg/kg--Aerosolised PentamidineAerosolised Pentamidine--monthlymonthly--limted use in limted use in

children children -- AtovaquoneAtovaquone

Granulocyte TransfusionGranulocyte TransfusionIn use since 1970In use since 1970Lots of studies in favour and against Lots of studies in favour and against (Higby et al Vs (Higby et al Vs Winston et al)Winston et al)Donors treated with G CSF and corticosteroidsDonors treated with G CSF and corticosteroidsAdequate cell doseAdequate cell dose 1x 101x 10 of PMN cellsof PMN cellsAdequate cell doseAdequate cell dose--1x 10 1x 10 1010 of PMN cellsof PMN cellsMatched donors (ABO compatible ,No need for HLA)Matched donors (ABO compatible ,No need for HLA)Needs further studyNeeds further studyIDSA IDSA –– 2002 :Not to be used routinely2002 :Not to be used routinely

25

Antibacterial ProphylaxisAntibacterial Prophylaxis

C t i lControversial

IDSA-Not indicated

Antibacterial ProphylaxisAntibacterial Prophylaxis

Regimens aim at total reduction of endogenous gut Regimens aim at total reduction of endogenous gut flora is not recommendedflora is not recommendedSelective gut decontamination (against aerobic and Selective gut decontamination (against aerobic and fungal) by fungal) by Van der et alVan der et al using TMP/SMXusing TMP/SMXFluoroquinolones Fluoroquinolones ––mostly used in adults.mostly used in adults.

Not recommended by IDSA. Not recommended by IDSA. Comparative studies Comparative studies ––no overall benefit than simple no overall benefit than simple infection prevention protocols such as hand washinginfection prevention protocols such as hand washing

When can we consider discharging J?When can we consider discharging J?

What is the ANC at which the child can be safelyWhat is the ANC at which the child can be safelydischarged?discharged?

What prophylactic therapy would you advise J’s mother What prophylactic therapy would you advise J’s mother to give him at home?to give him at home?

What is the dosage and frequency of administration?What is the dosage and frequency of administration?

What are the other preventive measures that should be What are the other preventive measures that should be followed?followed?

When would you like to review him again?When would you like to review him again?

INTP - PPO, PHO, IAP.P4 – 2/19

On Day 3On Day 3

Duration of TherapyDuration of Therapy

If afebrile by D 3 with ANC >0.5 stop If afebrile by D 3 with ANC >0.5 stop antibiotic on day 7.(To be institutionalized)antibiotic on day 7.(To be institutionalized)

If ANC < 0.5 continue antibioticIf ANC < 0.5 continue antibiotic

If has persistent fever and ANC >500/cmm If has persistent fever and ANC >500/cmm stop antibiotic on D 7.stop antibiotic on D 7.

If ANC < 0.5 on D 5 If ANC < 0.5 on D 5 –– cont for 14 dayscont for 14 days

All febrile neutropenia All febrile neutropenia –– are infectiveare infective

Rationale:Rationale:No mechanism to differentiate No mechanism to differentiate 55% infective pts did not have any source.55% infective pts did not have any source.

26

Thank youThank youThank youThank you