AGENDA

FRACP Lecture Series z Lecture 1 – Bleeding disorders

z Lecture 2 – Neutropenia and Thrombocytopenia

z For each of these conditions the following should be addressed Nalini Pati z Clinical presentation z Initial investigations Consultant haematologist z Initial management z Potential complications z Therapeutic options z Indications for referral

Investigations Haemophilia z Screening z PFA – 100 z What haemophilia was. investigations z Blood group z FBE z z Von Willebrand’s What haemophilia is. screen z APTT z What are the main problems with z PT / INR z Factor XIII haemophilia today. z Fibrinogen z TCT

1 2 Haemophilia

Carrier Woman Healthy Man

XH X X Y

X X X X X Y X Y H H

Carrier Girl Healthy Girl Haemophilic Boy Healthy Boy

Haemophilia Haemophilia ––WorldWorld

Healthy Woman Haemophilic Man Perspective z An estimated 250,000 patients in the world population.

X X X Y H z Only about 50, 000 receive specific treatment.

X X X X X Y X Y z Australia has approximately 1800 patients H H with haemophilia

Carrier Girl Carrier Girl Healthy Boy Healthy Boy

Haemophilia Management 2008 Haemophilia Prophylaxis z Clotting factor replacement is the cornerstone of z Prophylaxis treatment z Regular infusions of (recombinant) clotting z Recent (October 2004) Federal and State Government consensus to fund recombinant FVIII and FIX for all factor concentrate to prevent joint and muscle patients with haemophilia in Australia bleeds z Clotting factor needs to be given directly into the into veins z Majority of children begin prophylaxis after the first or second joint bleed z Factor replacement can be given for treatment AND prevention (prophylaxis) of bleeds z The use of early prophylaxis has significantly reduced the complication of joint disease

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

FVIII and FIX Inhibitors Haemophilia 2008 z Renders treatment and prophylaxis ineffective z Whilst inhibitors in haemophilia are still a major problem, the modern management z Limited treatment options and return to the of haemophilia prevents the traditional “natural history of haemophilia” complications of joint disease z Current treatment option to treat haemorrhage in z The availability of recombinant clotting patients with haemophilia (rFVIIa – NovoVII) factor concentrate limits the risk of particularly expensive transfusion transmitted viral disease

Structure of Haemophilia Care in Australia z National Blood Authority provides funds for clotting factor concentrate z 30% state / 70% federal z Management run through haemophilia Diagnos is TitiTransition individual treatment centers

4 12 – 24 months of age • Onset of joint bleeds

Diagnos is TitiTransition Diagnos is TitiTransition

< 12 months of age • Addressing psychological impact of X linked recessive disorder

2 years – 5 years • Commencement of home based therapy

Diagnos is TitiTransition Diagnos is TitiTransition

> 5 years • Are boys with hemophilia as active, fit and happy as their peers?

Modern Morbidities of Haemophilia Virchow’s Triad in Haemophilia

z Impact on family functioning Vessel Wall z Support of home based therapy z Complications of central venous lines z Activity levels z Bone density z Maintenance of Healthy Weight Thrombosis z Maximizing Education Potential

Blood Blood composition Flow

5 Activity Levels Bone Density

z In the modern era of haemophilia z Importance of musculomusculo--skeletalskeletal integrity management, are boys with haemophilia (including maintaining adequate bone as active as their peers? density) z What are the implications of reduced z Patients with haemophilia may be at risk of levels of activity in boys with haemophilia? developing reduced bone density z Bone density z Reduced weight bearing exercise z Maintenance of Healthy Weight z Prolonged 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. Bone Density

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

Bone Density Maintenance of Healthy Weight

z Obesity is a major public health problem z Greater access to calorie dense foods z Reduced activity (greater access to sedentary pastimes)

6 Risk Factors Maintenance of Healthy Weight

z Are boys with haemophilia more prone to becoming overweight? z Predisposed to becoming overweight on the basis of reduced physical activity

Maintenance of Healthy Weight in Changing Morbidities of Haemophilia Haemophilia z Implications for patients with haemophilia and obesity significant z As a result of the major advances in haemophilia care there is the opportunity z Complicated venous access to focus on a different range of co- z Increased clotting factor usage morbidities z Exacerbation of established joint disease

Von Willebrand disease

z Type 1 z 80% z Mild to moderate quantitative reductions in VWF von Willebrand’s disease levels z T2Type 2 z 20% z Qualitative defects z Type 3 z Virtual deficiency of VWF

7 Type 1 VWD Type 1 VWD z Prospective studies have suggested 1% of z VWD is an inherited disease that causes population affected bleeding and type 1 VWD is a quantitative deficiency of VWF. z Terti ary ref erral cent res 1 i n 10 , 000

Type 1 VWD (ISTH) Von Willebrand Disease in the Neonate z All of the following criteria must be met z A significant history of mucocutaneous bleeding z VWF:Ag and CBA increased in the z Laboratory tests compatible with type I VWD neonatal population z Either a positive family history or an appropriate genetic mutation z Reach adult levels by 6 months of age

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

z Vast majority of patients have Type 1 z Patients referred from surgical services, VWD adolescent gynaecology and external ggpeneral practitioners z Type 2 VWD z ? 4 patients z Routine investigations z Type 3 VWD z Family testing performed as routine z 1 patient z DDAVP challenge performed as routine

8 DDAVP challenge Management of VWD z Relative contraindication in children less than 2 z Non transfusional therapies years of age z DDAVP z Thirty minute infusion of 0.3 mcg / kg (maximum z Sustain increase in FVIII / VWF 8 – 10 hours 20 mcg) z Given 12 – 24 hourly depending on documented response z VWF:A g at 30 mi nut es, 1 h our and 4 hours z Tachyphylaxis after 4 doses z Restriction of fluid input over 12 hours following z Antifibrinolytics infusion z Transfusional therapies z One patient (10 months of age) developed seizures z BIOSTATE (AHF) secondary to hyponatramia following treatment with DDAVP

Biostate Thrombocytopenia z Plasma derived FVIII / VWF z Inherited z Ratio of FVIII : VWF of 2:3 (product insert suggests Biostate ratio of 1:2) z Acquired (ITP) z 20 000 units on stock at all times at RCH

Case Case z 3 week old male infant presenting with z Family history marked thrombocytopenia in the setting of z No significant history of bleeding, known possible vascular tumour of lower limb platelet disorders z Youngest of five children z Previous six miscarriages z Antenatal history z Largely unremarkable z Mother on aspirin for recurrent miscarriages z Consanguineous parents

9 Case z Presenting history z Presented at birth with large, fleshy vascular(?) lesion affecting the lower limb z Referred to paediatrician z Possible kaposiform haemangioendothelioma (KHE) z Treated with corticosteroids z Referred to haematology due to persistent thrombocytopenia

Case

z Initial investigations z Slightly anaemic, neutropenic and markedly thrombocytopenic z No evidence of coagulation activation z Ultrasound showed lesion in right cerebral hemisphere, confirmed on MRI as bleed (antenatal) z Managed with platelet transfusion with good response

10 Case Congenital Thrombocytopenia: “Tools” available for assessment z Progress z Platelet count & sizing z Reticulated platelets z Persistent marked thrombocytopenia despite involution of vascular lesion z Electron microscopy z Bone marrow aspiration and z Repeated bone marrow examination showing immunohistochemistry normocellular bone marrow but (?) decreasing megakaryocytes (confirmed on z Flow cytometry for platelet glycoproteins immunohistochemistry CD61) z Assessment of platelet function z PFA 100 z Patient “well” and not bleeding z Aggregometry z Molecular markers

Platelet counting and sizing Platelet Counting & Sizing (Coulter principle)

z Platelet count is not directly measured – derived RBCs from platelet histogram z Any particle sized between 2 to 20 fl is counted as a + - platelet z Any particle sized outside of 2 to 20 fl is not counted as a platelet

PLT Cross section of Oscilloscope screen RBC aperture (60x50 micron)

11 Reticulated Platelets z “Immature platelets” z Larger mean platelet volume with higher RNA content z Flow cytometric method using the membrane permeable flurochrome thiazole orange to stain RNA z Sensitivity improved by using gating techniques incorporating CD61 z Reported as a percentage (lack of widely accepted standardization of normal values)

Reticulated Platelets Bone Marrow Aspiration z May have a role in the distinguishing z Performed under general anaesthetic patients with ITP / consumptive states z Limited morbidity from those with decreased platelet production z Provides quantitative information with lim ite d qua lita tive in forma tion (corre la tion of function with signs of dysplasia / z May have a role in the predictive value for marrow recovery following chemotherapy abnormal forms etc.) z Not currently available at RCH

Electron Microscopy

z Provide assessment of platelet ultrastructure z Somewhat helpful in the assessment of platelet function disorders z Available in Melbourne through University of Melbourne

12 Flow cytometry for platelet glycoproteins z Diagnostic in select group of patients with characteristic disorders z Glanzman’s thrombocythaemia (deficient GPIIb/IIIa) z Bernard Soulier syndrome (deficient Ib/IX)

Assessment of Platelet Function PFAPFA--100100 Closure Time Measurement z Difficult in Children z Large volumes of blood required z Generally require “normal platelet” counts z Methods available z PFA 100 z Formal aggregometry

PROGRESSION OF PLATELET PLUG FORMATION AT THE PFA-100 APERTURE PFA - 100

z Quantitative, rapid test of platelet function at high shear rates z Platelet plug forms under shear stress and occludes the aperture which is detected as the closure time z Published normal ranges for closure times for children z Available RCH

Poujol et al., 1998

13 Platelet Aggregation Platelet Aggregation z Gold standard for the investigation of platelet function z Initially devised 40 years ago (Bonn, Nature 1962) z Platelet rich plasma placed in an aggregometer cuvette, warmed to 37oC in the heating block of the instrument and stirred by means of a small magnetic stir bar. z Light t ransmi ssi on th rough th e pl asma i s monit ore d con tinuous ly on a chart recorder. z The addition of an aggregating agent results in the formation of increasingly larger platelet aggregates with a corresponding decrease in optical density and is recorded as a tracing by the chart recorder. z Minimum count in PRP = 100 X10^9/l z Glanzmann's thrombasthenia (A), BernardBernard--SoulierSoulier syndrome (B),

Approach to “Congenital” Secondary Thrombocytopenia Thrombocytopenia 1. Rule out secondary causes z Majority of cases of Number 2. Congenital thrombocytopenia thromobocytopenia occuring Congenital Infections 70 in neonates are a result of a a. Syndromic thrombocytopenia clearly apparent underlying (CMV Toxoplasmosis Rubella) b. Non - syndromic thrombocytopenia systemic illness z Fetal platelet counts in Immune causes 63 Associated with macrothrombocytopenia 5914 consecutive fetal (anti HPA1a / HPA5b, z Bernard Soulier blood samples anti HLA, maternal ITP) z Thrombocytopenia z MYH9 related conditions Chromosomal 43 (<150X10^9/l) present in abnormality Associated with normal sized platelets 247 of these cases (4.1%) (Trisomy 13, 18, 21) Other 62 (Hohlfeld et al 1994)

1. Syndromic Congenital Non - Syndromic Congenital Thrombocytopenia Thrombocytopenia z Wiskott Aldrich / Xlinked z Associated with normal sized platelets thrombocytopenia z CAMT z TAR z Autosomal recessive z MYH9 – related disease z Isolated hypomegakaryocytic thrombocytopenia at birth z Familial platelet disorder and z 15 families (Ho et predisposition to AML (FPD/AML) z Deficiency in the expression of TPO receptor al, Blood 1996) z Other (?)

14 Case A

z 2 ½ old boy Immune Thrombocytopenia z Previously well Purpura z Urgent referral to clinic with bruising z Platelet count < 10 X 10^9/l with otherwise normal blood count z Examination unremarkable

Case A Case B z What investigations need to be z 12 year old girl performed? z Presents from country general practitioner z Diagnosis of ITP made 6 weeks prior (platelet count 4 X 10^9/l, borderline haemoglobin 114 g/l z Wha t trea tmen t is requ ire d? (normal range 115 – 135) an d norma l examination) z Moderate bruising but no active bleeding z What advice is given to the parents? z Comes following 6 weeks of steroids with Cushingoid features z Repeat platelet count 10 X 10^9/l with persistent borderline haemoglobin and lymphopenia

Case B Case C z What investigations are now necessary? z 4 year old boy with Down’s syndrome z Presents with marked bruising, active mucosal bleeding and platelet count < 10 z What treatment is recommended? X 10^9/l (and mild normochromic normocytic anaemia with reticulocytosis) z What advice is given to the patient? z Develops headache, focal neurological signs and intracranial haemorrhage requiring urgent neurosurgery

15 Case C Case D z Why does this patient manifest significant z 10 month old boy bleeding symptoms despite the “same z Previously well degree of thrombocytopenia” z Morphologically normal z Presents with acute onset of increased z What treatments are recommended in the bruising and marked thrombocytopenia setting of urgent splenectomy? z Already walking but unsteady

Case D Case E z Below what age is the diagnosis of ITP z 15 year old girl less likely? z Long standing history of ITP z diagnosed at 7 years of age z The moth er wan ts a h e lme t – whtihat is your z SlSplenec tomy a t75t 7.5 years o f age advice? z Limited further followfollow--upup z Presents with exacerbation of menorrhagia associated with iron deficiency anaemia

Case E Facts about ITP z Parents want another splenectomy – what investigations are recommended to identify accessory spleens / splenunculi? z What treatments are recommended to manage menorrhagia in this patient?

16 Facts about ITP

Randomised study

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

Classification of Neutropenia Neutropenia NEUTROPENIA CAUSED BY INTRINSIC DEFECTS IN GRANULOCYTES OR THEIR PROGENITORS

z Reticular dysgenesis z CliCyclic neu tropen ia z Severe congenital neutropenia (including Kostmann's syndrome) z ShwachmanShwachman--DiamondDiamond syndrome z Albinism/neutropenia syndrsyndromomeses (including Chédiak-Chédiak-Higashi)Higashi) z Familial benign neutropenia z Bone marrow failure syndromes (congenital and acquired)

NEUTROPENIA CAUSED BY EXTRINSIC FACTORS (Infection / Neutropenia Drugs) z Severe congenital neutropenia z Autoimmune neutropenia (Kostmann’s syndrome) z Neonatal immune neutropenia with immune dysfunction z Cyclic neutropenia z Neutropenia associated with metabolic diseases z ShSwachman DiddDiamond syndrome z Nutritional deficiencies z Sequestration z GSD1b z Bone marrow infiltration z Associated with immunodeficiency z Chronic idiopathic neutropenia (may also be intrinsic) z Types of neutropenia are listed in order of discussion in the text.WHIM, warts, hypogammaglobulinemia, infections, myelokathexis.

17 Neutropenia - approach z Age at presentation z Depth of neutropenia z Association with bacterial infections

Evaluation of neutropenia Neutropenia: Evaluation z History and physical examination with emphasis z White blood and differential counts obtained on (1) related phenotypic abnormalities; (2) h/o twice weekly for 6 to 8 weeks bacterial infection (including evaluation of the z Direct and indirect antiglobulin gingiva and perineum); (3) evaluation of z serum immunoglobulins lymphadenopathy, hepatosplenomegaly z HIV testing z Drug exposure, history of periodontitis, dental abscesses, or tooth z Other viral studiesstudies--CMV, EBV, Parvo z ANA z Family history z Bone marrow aspiration and biopsy with z Race and ethnic background cytogenetics

Principles of Therapy for Investigations contd.. Neutropenia z Vitamin B12, folate, and copper levels. z Underlying cause and severity. z Radiographic studies of the femoral z The major concern in neutropenic patients heads, rib cage, and spine may be useful is the development of serious pyogenic in the diagnosis of Shwachman-Diamond infection. syndrome z Fever may often be the only indication of z Pancreatic exocrine functions infection as very less local signs z Metabolic screening z Organisms involved are usually from the skin or GI tract

18 J Age- 4 1/2 yrs Diagnosis-Acute Lymphhoblastic leukaemia (FAB – L2) FEBRILE NEUTROPENIA Date of diagnosis –26 December2004 Symptoms-Recurrent fever Bone pains 3wks3 wks Extreme lethargy

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

INTP - PPO, PHO, IAP. P4 – 3/19

Risk factors- Male, high TLC and significant organomegaly Examination : Mucositis in the mouth and No lymphadenopathy throat & B/L coarse crepitations in the lungs. Management – Chemotherapy with 4 week, 5 drugs No hepatosplenomegaly. Induction protocol. Marrow on D28 – M1 (remission status)

Next phase --II 2- Radiation Investigations: Blood counts, Peripheral blood CNS prophylaxis smear, XX--ray,ray, CRP, blood and urine cultures Standard drugs. However,7 days into I2 phase of therapy he was brought with history of fever,lethargy and refusal to eat.He also had cough and looked toxic.

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 4/19 P4 – 5/19

The smear and count reports were as follows- The peripheral smear of this child is shown below. What can ¾ Hb 8 g/L you see in this slide? ¾ Total WBC=1.3 X 109/L ¾ N 08% ¾ L 78% ¾ M 08% ¾ E 06% ¾ ANC=0.1 X 109/L ¾ Platelets=36 X 109/L ¾ CRP - 96

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 6/19 P4 – 7/19

19 The smear shows significant neutropenia.

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

The next slide shows a normal peripheral smear.

Can you make out the difference?

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 8/19 P4 – 9/19

The child was subjected to radiological investigation and the X – ray was as below: The X – ray shows bilateral soft infiltrates suggestive of bronchopneumonia.

As the recordings of temperature revealed continuous fever of more than 38 degrees C, the child was immediately started on empirical antibiotic therapy.

What would your choice of antibiotics be in this situation? What are the standard dosages of these drugs?

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 10/19 P4 – 11/19

Associated risk factors Febrile neutropenia

z Degree of neutropenia (<500/Cmm) z Neutropenia: ANC < 500 cells / cmm. z Temperature: single observation of > 38.338.3°°CC z Prolonged neutropenia ( > 7-7-1010 days)

sustained temp > 38.038.0°°C,C, >1 hr z Co morbid medical problemproblem--exampleexample-- < 36°36°CC with clinical deterioration Continued cancerous state (HR > 90, RR > 20, BP<90)

20 Low Risk Patients High Risk Patients

z Anticipated short duration of neutropenia (<10d) z Granulocytopenia >10days z No Co morbid Medical Condition z Controlled oncological status z Options: z Proven source of infection Oral antibiotics Cefixime Ciprofloxacin + Clindamycin z Co morbid medical condition Cipro+ AmoxyAmoxy--clavclav z Parental Monotherapy z If afebrile by day 1414-- stop antibiotics To continue 7 days as OPD Care If C/S -ve-ve – switch to oral drugs (Ref: Malik et al , Am j med,98:224,1995). z If febrile on day 33-- repeat Blood C/S on D4 (Ref: Malik et al , Am j med,98:224,1995).

IDSA Guide LinesLines--2002 (Walter et al) z Blood Cultures Careful Physical Examination - Minimum of 2 sets of cultures - If has indwelling line – one set from z Initial evaluation-evaluation-ToTo risk stratification the lumen & the other from the - determine whether periphery. Vancomycin is needed in the initial trt. z Urine c/s - Even if growth < 105 of a single organism is z Examination sites ::--OralOral cavity significant ‰ Chest radiotherapy. Assessable sites. Perianal area Tunnel sites should be aspirated / cultured Exit sites

Exit sites of lines Infectious cause is established in 3030--50%50% of pts.

The blood culture, sample for which was collected at Serial surveillance cultures (Walsh etal admission, revealed a significant growth of an organism Medicine 65, 265, 1996) after 48 hrs as seen on the blood agar plate below:

z Not recommended routinely in neutropenia pts. z Useful in z PPtrotract tded neut ropeni i(a ( > 3 -44k) weeks) z High incidence of virulent organisms

INTP - PPO, PHO, IAP. P4 – 12/19

21 The organism grown was identified as Haemophilus influenzae which was found to be sensitive to a The general condition of J remained stable for the next five days, but fever persisted. Blood cultures showed the number of antibiotics. The plate below shows the following:following:-- sensitivity of the organism to ceftazidime. A repeat count done on D5 after admission revealed Hb of 6gm% TLC of 0.9 N4 L88 M02 E06 ANC =0.3 Platelets = 16 000/ cumm With the counts as above, platelet and RBC transfusions were considered. What is the role of these transfusions in a situation such as this? What is the threshold for platelet transfusion in a child whose general condition is stable and who is not bleeding?

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 13/19 P4 – 15/19

However, clinical examination revealed no evidence Goals for empirical treatment of bleeding and the mucositis had not worsened. A repeat of the chest X ray did not reveal any further deterioration. Considering the clinical picture,what steps would one To protect against the early morbidity take now ? and mortality. What is the role of packed cell RBC transfusion in a child with thrombocytopenia? Would you consider empirical antifungal therapy now? Why? What drug would you use?

INTP - PPO, PHO, IAP. P4 – 16/19

Essential Properties of Empirical Regimes

--veve z Broad spectrum of activity that includes z Gm organism – most common & most Pseudomonas aeruginosa virulent

z Ability to achieve high serum bactericidal levels z All reg imen s hou ld cover G--veve organiiisms with broad spectrum coverage for Gm+ve z Effective in the absence of neutrophils organism.

z Low potential for the emergence of resistance

z Acceptable toxicity profile

22 AminoglycosideAminoglycoside--BasedBased Combination Regimen without Aminoglycoside Regimes z Combination of two beta lactam antibiotics Aminoglycoside + AntiPseudomonal ± Additional AntiAnti--GramGram-- Positive Example . Piperacillin + Ceftazidime beta – Lactam Single agent with Aminoglycoside / Extended spectrum penicillin / Vancomycin – should not be used. Gentamicin ExtendedExtended--spectrumspectrum penicillin Isoxozolyl-Isoxozolyl-penicillinpenicillin Tobramycin Carbenicillin Nafcillin Drugs as monotherapy Amikacin Ticarcillin Oxacillin 1. Ceftazidime Azlocillin or 2. Meropenem / Imipenem Mezlocillin Piperacilli First generation cephalosporin 3. Cefoperazone Cephalothin 4. Cefepime / Cefpirom Cefazolin Defervesence ThirdThird--generationgeneration cephalosporin or Ceftazidime Vancomycin Ultimate outcome Comparable Cefoperazone or ((RefRef : friefeld et al, J Clin Oncol 13:165, 1995) Aztreonam

Use of Vancomycin in the Initial Patients require frequent Regimes modifications z No change in morbidity z Less use of Amphotericin B z With a documented source of infection z No change in Febrile episodes z Increases V R E emergence z PtProtract tded granul o cyt openi i(a ( > 1 wee k) ¾ C D C Recommendations:

z Continued Oncological status *Not to be included in initial regimes unless culture proven by 3rd day * Not to be used prophylactically for central line infection (Ref Karp et al, Am J of medicine 81:237, 1986)

Would you consider colony stimulating factors? Ciprofloxacin How are they used? The boy was given a packed cell transfusion z As monotherapy causes breakthrough infection with streptococcus What is the volume of blood to be transfused? z reserved for M D R state and started on antifungal therapy with flucanazol.

(Ref: Meunier e tal Antimicrobiol agent chemother What is the dose of fluconazole? Amphotericin B? 35:873, 1991) GG--CSFCSF was considered but not started.

Why? INTP - PPO, PHO, IAP. P4 – 17/19

23 Antifungal Treatment Colony Stimulating Factors z Indication: z Indications: Persistence of fever on day 55--77 1.Worsening course ‰ Anti fungals 2.Predicted prolonged neutropenia Itraconazole/Fluconazole Patient received Fluconazole Prophylaxis - z Effects: Amphotenicin B Reduce duration of antibiotics z Benefits of empirical antifungals-antifungals- No change in mortality Early clinical Defervesence z Dosage :G:G--CSFCSF--5ug/Kg,GM5ug/Kg,GM--CSFCSF--250/m250/m2 Less morbidity z Prophylaxis: (ASCO guidelinesguidelines--ifif the chance of Rationale FN>40%,prior h/o severe infection) z Early treatment of sub clinical infection z Suppression of fungal overgrowth accompanying Antibiotics therapy (Ref:(Ref:--JJ Clin Oncol 1996,14:19571996,14:1957--60,ASCO60,ASCO guidelines,2000) (Ref(Ref--PizzoPizzo et al, Am J med 1982,72;101).

¾ Because GG--CSFCSF is useful when started early with neutropenia and has a limited role when neutropenia is fully established. Besides, it is expensive.

¾ The general condition of J gradually Improved.He became afebrile after the 9th day of antibiotics and 4th day of antifungals. His mucositis improved and his cough reduced.

¾ His XX-- ray done on the 14th day after admission is shown next.

INTP - PPO, PHO, IAP. INTP - PPO, PHO, IAP. P4 – 18/19 P4 – 19/19

PCP Prophylaxis Granulocyte Transfusion z In use since 1970 z Started in 1980’s after isolation of HIV z Lots of studies in favour and against (Higby et al Vs z Incidence of PCP infection without prophylaxis (Meyer’s et Winston et al) al) z Donors treated with G CSF and corticosteroids ALLALL--2222--43%,RMS43%,RMS--25%,BMT25%,BMT--16%,16%, SCIDSCID--27%,Solid27%,Solid tumorstumors--4040--50%50% z Adequate cell dose-1x 10 10 of PMN cells Standard trt--TMPTMP--SMXSMX BD --3times3times / wk (Ioannidis et al--metameta z Matched donors (ABO compatible ,No need for HLA) analysis) z Needs further study Others--DapsonDapson--2mg/kg2mg/kg z IDSA – 2002 :Not to be used routinely --AerosolisedAerosolised PentamidinePentamidine--monthlymonthly--limtedlimted use in children - Atovaquone

24 Antibacterial Prophylaxis Antibacterial Prophylaxis

z Regimens aim at total reduction of endogenous gut flora is not recommended z Selective gut decontamination (against aerobic and fungal) by Van der et al using TMP/SMX CtControvers ilial z Fluoroquinolones –mostly used in adults. Not recommended by IDSA. Comparative studies ––nono overall benefit than simple IDSA-Not indicated infection prevention protocols such as hand washing

When can we consider discharging J? OnOn Day Day 3 3 What is the ANC at which the child can be safely discharged?

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

What is the dosage and frequency of administration?

What are the other preventive measures that should be followed? When would you like to review him again?

INTP - PPO, PHO, IAP. P4 – 2/19

Duration of Therapy

z If afebrile by D 3 with ANC >0.5 stop z All febrile neutropenia – are infective antibiotic on day 7.(To be institutionalized)

z If ANC < 0.5 continue antibiotic z Rationale: z If has persistent fever and ANC >500/cmm No mechanism to differentiate stop antibiotic on D 7. 55% infective pts did not have any source.

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

25 Thank you

26