IHA – case study

Somjai Kanjanapongkul QSNICH

CASE 1

Identification data ผ ปวยเดกชาย อาย 3 ป 4 เดอน ภมล าเนา จ.เพชรบรณ Admission date 13/7/60 – refer มา ดวยเรอง DRESS • 6 d PTA มไขชก นอน รพจ. ตรวจพบ UTI ไดรบยา ceftriaxone phenobarbital

loading dose and depakin • 3 dPTA เรมมอาการเจบปาก มารดาสงเกตวามแผลทรมฝปากบน กนไดนอย มผน

แดงบรเวณแกมทงสองขาง ยงมไข ปสสาวะปกต ไมมไอ ไมเหนอย • 1 dPTA ผนแดงบรเวณใบหนาเรมลอก รมฝปากลอก ตวแดงทงตว ขาสองขางบวม

เทาๆกน มไข ขอ refer PH : U/D Epilepsy (Dx ตอนอาย 2 ป รกษาท รพ.ชนแดน จ.เพชรบรณ) on

Depakine(200 mg/ml) 1 ml oral bid pc, Iron deficiency anemia – on Eurofer 3 ml oral OD

: แพยา ibuprofen - DRESS

Physical Examination

• BT38.9 C PR140/min RR26/min BP 110/78 mmHg

• General appearances : A Thai boy with good consciousness

• HEENT : mild pale conjunctivae, no icteric sclerae, circumoral crusting, no strawberry tongue, no injected conjunctivae

• Skin : generalized erythroderma with desquamation on face, trunk, back, perianal area, buttock and all extremities

• Liver – just palpable

• Otherwise-unremarkable

Problem lists

• Fever with generalized erythroderma

• U/D Epilepsy

• History of DRESS (Ibuprofen)

• History of AED used (Phenobarbital, Depakine)

• Histroy of ATB used (Ceftriaxone)

Laboratory Investigation รพช รพด

8/7/60 11/7/60 13/7/60

Hb 10.6 9.1 8.2

Hct 33.3 26.7 25.3

WBC 19200 10930 5090

PMN 36 81 43

Lymp 53 9 38

Mono 5 0 6

Eo 4 8 11

Platelet 438000 227000 168000

Lab

• Dengue NS1Ag – neg

• Dengue IgM – neg

• Dengue IgG – neg

• ESR 25

• CRP 26.6

• Reticulocyte count 0.2%

Management

– Ceftriaxone (75mg/kg/day)

– Cloxacillin (200mg/kg/day)

– Clindamycin (40mg/kg/day)

– Special mouth wash

– Atarax

– Bactoban

Epilepsy - Continue Depakine 1 ml oral bid pc

14/7/61 17/7/61 18/7/61 19/7/61

Hb 8.3 7.6 8.5 9.1

Hct 24.8 23 25.3 26.6

WBC 6130 8680 17150 14020

PMN 45 34 63 65

Lymp 34 40 19 30

Eo 0 Band 3 Band 6 0

Mono 15 12 8 5

Plt 148000 297000 342000 356000

• Consult Skin (19/7/60)

– R/O Exfoliative dermatitis

– Hydrocortisone (5mg/kg/dose) q 6 hr 20/7/60

– CPM 0.1 mg/kgdose q 6 hr

– Skin biopsy – Consistent with exfoliative dermatitis

–Off Phenobarb, Depakine, Ceftriaxone

Progression

22/7/60 : 18.00

• ซม หมดสต ประมาณ 10 วนาท ไมมเกรงกระตก เรยกไมรตว หลงจากนนตนรตวด รองไห

• V/S BT 37.70 C PR 133/min BP 95/44 RR 26/min

• HEENT : marked pale conjunctivae , no icteric sclerae

• Retain Foley cath – ได urine สแดง

• UA -Sp 1.020, blood 4+, WBC 0-1, RBC 1-2, Protein 3+, Urobil 1+, leukocyte – trace, Epi 0-1

• Depakine level : 48.2

• CBC : Hb 2.4 g/dl, Hct 6.6%, WBC 29,570 (N50, L44, M5, E1%, NRC 14/100 WBC) platelet 352,0000/ cu mm.

• Coagulogram : PT 14 , INR 1.18, PTT 20.1, aPTT ratio 0.76

• Direct Coomb’s test : Positive 3+

• Mycoplasma IgM - equivocal

Imp: AIHA – severe anemia

Positive DAT may result from: – Autoantibodies to intrinsic red cell antigens

– Circulating Alloantibodies bound to transfused donor cells

– Alloantibodies in donor plasma containing products reacting with transfused recipient’s cells

– Maternal Alloantibodies that cross the placenta and bind to fetal red cells

– Antibodies against drugs on red cells

– Non-red cell immunoglobulins bound to red cell (e.g. IVIG)

– A positive DAT does not mean decreased red cell lifespan and therefore a history and physical is needed to determine the significance of a positive DAT

Questions to ask…

• Decreased red cell survival?

• Has the patient been recently transfused? – Red cells, plasma containing products

• Is the patient on any medications that can cause a positive DAT and hemolysis (e.g. penicillin, aldomet, cephalosporins)?

• Has the patient received a transplant?

• Is the patient receiving IVIG?

• Is the patient pregnant? Is the patient a newborn infant?

Classification

• Warm Autoimmune (WAIHA) – 70-80%

• Cold Autoimmune (CAIHA) – 20-30%

• Mixed – 7-8%

• Paroxysmal Cold Hemoglobinuria – rare in adults

• Drug Induced Hemolytic Anemia

Coombs’ positive with Spherocytes Autoimmune hemolytic anemia

Warm AIHA

• Abrupt onset

• IgG

• Anti-Rh, e, C, c, LW, U

• Jaundice

• Splenomegaly

• SLE, CLL, Lymphoma

• Drugs: methyl-dopa, mefenamic acid, cimetidine, cefazolin

Cold AIHA

• Insidious onset

• IgM, complement

• Anti-I, I, Pr

• Cold agglutinin titer

• Absent jaundice

• Mycoplasma

• Virus

Warm Auto

• Most are idiopathic (30%)

• Older patients

• Secondary (acute or chronic) (70%)

– Malignancy esp. lymphoproliferative disorder

• predominantly B-cell lymphomas

– Rarely carcinoma

– Autoimmune disorders (e.g. SLE)

WAIHA Serologic Investigation

• DAT+ – Anti-IgG only 20-60%

– Anti-C3d only 7-14%

– Both 24-63%

• Antibody screen+

• All panel cells+

• Autocontrol+

• 50% of patients will have autoimmune antibody left over in the serum (DAT should be 4+)

Cold Auto

• 16-32% of all Immune Hemolysis

• Idiopathic (10%) Cold Agglutinin Disease

• Secondary forms (90%);

– Postinfectious

• Mycoplasma

• CMV

• EBV; Infectious mononucleosis

– Lymphoproliferative disorders • E.G. B-cell lymphomas; sometimes intravascular

CAIHA Serologic Investigation • Spontaneous agglutination in EDTA tube;

difficulties with ABO typing

• DAT+

– >90% positive for C3d only

– Antibody is usually IgM, binds in cold (periphery), then dissociates in warm

– C3d may or may not shorten red cell survival

• Antibody Screen+

• Determine underlying alloantibodies using autoabsorption techniques

CAIHA Serologic Investigation

• Specificity is I, IH or I (academic interest only)

– Adult cells: I

– Cord cells: I

• Cold Agglutinin titers and thermal amplitude studies

Cold Auto Treatment

• Again, with severe anemia or unstable disease, transfusion can be life threatening

• Keep the patient warm

• Transfuse through a blood warmer

• Folate and B12

• Treat underlying disease

• Steroids usually poor response

Cold Auto Transfuse

• ABO/Rh compatible units

• Rule-out underlying alloantibodies and give antigen negative units

• Crossmatch in warm

• Again, transfuse through a blood warmer while keeping the patient warm

Coombs’ positive with Spherocytes Other immune hemolytic anemia

Alloantibody hemolytic anemia

• Transfusion reaction

• Feto-maternal incompatibility (Kleihauer-Betke test)

Drug related Hemolytic anemia

• Toxic immune complex (drug+Ab+C3)

- Quinine, Quinidine, Rifampin, INH, Sulfonamides,

Tetracyclin

• Hapten formation (anti-IgG)

- PCN, methicillin, ampicillin

DIHA

• Three types:

– Haptenic (e.g. penicillin)

– Immune Complex

– Induction of Autoimmunity (e.g. aldomet, L-dopa, procainamide)

Haptenic (e.g. Penicillin, Cephalosporins)

• Drug Coats cell; antibody directed against drug/red cell membrane

• DAT+ for IgG and possibly complement

• Eluate negative

• Nonreactive for unexpected antibodies

• Antibody eluted off red cells reacts with cells+drug but not cells alone

• Hemolysis develops gradually

• Discontinue the drug and red cell survival increases

Paroxysmal Cold Hemoglobinuria

• Idiopathic (rare)

• Post-infectious (more common)

• Occasionally seen in syphilis

• Biphasic Hemolysin – IgG antibody that binds in the cold and fixes

complement

– At Warm temperatures, IgG dissociates and complement remains

PCH Serologic Investigation

• DAT+ (>50%)

– Usually IgG; sometimes C3d

• Eluate often negative

• Antibody screen w+

• Antibody is panagglutinin with P or IH specificity

• Donath-Landsteiner Test positive

Donath-Landsteiner Test (Biphasic Hemolysis)

30’@4ºC

60’@37 ºC

90’@4 ºC 90’@37 ºC

Patient

Serum + - -

Patient Serum

Normal fresh

serum + - -

Normal

Fresh - - -

PCH

• Transfusion can be life threatening in the setting of severe anemia or clinical instability

• Support with transfusions; B12 and folate

• Corticosteroids not helpful

• Treat underlying disorder

• ABO/Rh compatible units

22/7/60 23/7/60 24/7/60 26/7/60 27/7/60

Hb 2.4 8 11

Hct % 6.6 23.5 31 31 32

WBC 29,570 16,020 12,930

PMN 50 52 62

Lymp 44 30 36

Mono 5 16 2

Eo 1 1 0

NRC 14

Plt 352,000 298000 585000

*PRC 5.8 ml/kg , Dexa 0.6 mkd iv

DCT 3+ Pred 2 mkd po

*Hemoglobin Level and Symptoms

HGB (GM%) SYMPTOMS

9-11 MINIMAL

7.5 EXERTIONAL DYSPNEA

6.0 WEAKNESS

3.0 DYSPNEA AT REST

2-2.5 HEART FAILURE

LINMAN NEJM 279:812, 1968

RBC Transfusion Volume

• Usual: Up to 15cc/Kg in 3-4 hours

• Unusual: Acute Hemorrhage: replace ongoing losses

Chronic Anemia, Heart Failure, îBP :*2cc/Kg/Gm Hb (= Hb levelx2/kg)

:Diuretic

:partial exchange/blood leting

Management

• PRC transfusion (2 cc x Hb x BW) x I • Off Hydrocortisone ( due to DRESS ) Dexamathasone 0.6

mg/kg/day iv x 4 days Pred 2 mkd po • Folate supplement • Off Ceftriaxone, Cloxacillin, Clindamycin • Meropenem 100 mg/kg/day • Vancomycin 40 mg/kg/day • Epilepsy – Rivotril (0.5) ½ tab oral hs D/C 28/7/60

CASE 2

Patient profile

ผ ปวยเดกชายไทยอาย 9 ป 8 เดอน ภมล าเนา จงหวดฉะเชงเทรา • Admission date: 25 เมษายน 2561 CC : อาเจยนมาก 4 เดอนกอนมาโรงพยาบาล admit เพอปรบ feeding

ทาง NG tube

• U/D spastic CP with GDD with NP incoordination with GERD On Omeprazole 5ml bid ac, Domperidone 4ml tid ac, Depakin syr.

1ml bid, Risperidone(1)1/4 hs, Baclofen 1tab od, Rivotil(0.5) ½ bid, ZnSO4 1cap od, MTV 1tab od

Progression

Admission date 25/4/61 : ไดปรบเวลาใหอาหารปนนานขนเปน30minutes/feed สามารถรบfeed ไดหมด ไมมอาเจยนอก

26/4/61 : หลงนอนโรงพยาบาล มไข ไอมากขน มเสมหะ หายใจครดคราด

BT38.7c PR122/min RR 26/min BP118/79mmHg

Lung: fine crepitation RL

CXR: peribronchial thickening and reticular opacity at perihilar

Dx: pneumonia

Mx: ceftriaxone 75 mg/kg/day start 26/4/61

Progression

2/5/61 ไขสง ซมลง ปสสาวะสน าตาลเขม ดซดลงมาก

BT38.7c PR144/min RR44/min BP84/40mmHg PE: stuporous, marked pallor, anicteric sclerae

Lungs: equal breath sound, fine crepitation BL

PBS 25/04/61 02/05/61

Hb 14.5 g/dL 5.1 g/dL

HCT 41.8 % 14.4 %

MCV 74.6 fL 100 fL

WBC 12,160 /uL 33,120 /uL

Platelet 285,000 /uL 171,000 /uL

Neutrophil 60 % 50 %

Lymphocyte 33 % 44 %

Monocyte 5 % - %

Eosinophil 2 % 1 %

Atypical lymp

- % 1 %

Basophil - % 1 %

result

Blood group A

Rh Positive

Direct coombs’ test Positive 2+

Indirect coombs’ test Positive (weakly)

Antibody screening test Positive

Serum identification Auto Anti-i

Antibody titration Auto control 2+

Mycoplasma IgM : Positive

Urine Analysis result

color brown

Sp.gr. 1.025

pH 6.5

WBC 0-1/HPF

RBC 5-10/HPF

Epithelium 0-1/HPF

Blood 4+

Protein 4+

Nitrite neg

Urobilinogen neg

Bilirubin neg

Problems

• Pneumonia • Septic shock with DIC (aPTT 39, PT26.4, INR 2.5,

TT 30, D-dimer 58,343 ng/ml) • Transaminitis • AKI (BUN 48.75/ Cr 2.2) with oliguria (0.5

ml/kg/hr) and Hyperkalemia ( K 7.39) • Severe anemia – AIHA

• U/D severe CP (bed ridden) and epilepsy มารดาตดสนใจไมท า CVVH ใหเปน palliative with full

medication

Management

On ETT

NSS 360ml iv in 20min x3 dose

Levophed 0.1 mcg/kg/min

PRC , FFP, CPP

Vitamin K 10 mg iv

Meropenem 60 mg/kg/day

Start Dexamethazone 0.6mg/kg/day *F

Correct hyperkalemia

*F : suggest methyprednisolone

Week 1

05

10152025303540

Hct

Hct

PRC 2dose Dexa

0.6mkday

PRC 1dose Dexa 0.6mkday

Dexa 0.6mkday

DCT 2+

Week 2

0

5

10

15

20

25

30

Hct

Hct

PRC 1dose Pred 2mkday

Pred 2mkday

Week 3

05

10152025303540

Hct

Hct

PRC 1dose

Reintubation ↓Dexa

0.3mkday

Pred 2mkday

Week 4

05

10152025303540

Hct

Hct

PRC 1dose Dexa 0.6mkday

DCT weakly +

CASE 3

ผ ปวยหญงอาย 9 ป 11 เดอน Admit 24/3/2558

CC : เหนอย 2 ชวโมง กอนมาโรงพยาบาล

PI : 2 ชวโมงกอนมาโรงพยาบาลหลงจากไปวงเลนกบเพอนกลบมาดเหนอย มหนาซด เรมมไข กนยาลดไขแลวไขลง ไมมไอหรอมน ามก ไมเจบคอ มคลนไสแตไมอาเจยน ไมมถายเหลว ไมปวดทอง ไมมผน ปสสาวะสสม อจจาระปกตด มารดาจงพามาโรงพยาบาล Rheumatologist ตรวจพบซดมาก ใหนอน รพ.

PH : เคยผาตดไสตง เคยผาตดไต Rt UPJ obstruction S/P pyeloplasty with DJ stent โรงพยาบาลจฬาลงกรณ

: TB abdomen admit ดวยเรองปวดทอง, prolonged fever with failure to thrive, recurrent groin abscess (รกษาเปน TB infection 2IRZE+10IR รกษาครบ กค ป 2556)

: R/O Barchet’s disease DDx Chron’s disease มผนแดงในปากและอวยวะเพศเปนๆหายๆ

Physical examination

V/S : BT 37.2 c BP 116/56 mmHg PR 160 bpm RR 30 /m, Height 120 cm BW 19.7 kg

: A thai girl , good consciousness , well co-operative , marked pallor, mild icteric sclera ,tonsils and pharynx not inject , chain of cervical LN enlargement both sides diameter 0.5 cm

Abdomen: active bowel sound, soft, not tender, liver 2 FB BRCM and spleen 3 FB BLCM

Otherwise is unremarkable

Laboratory

• Electrolytes :normal • CBC : Hb 4.3 g/dl, Hct 13% WBC 15,910( N70, L26,

M4%) platelets 279,000 • TFT : TB 4.32 DB 1.07 AST 60 ALT 16 • UA : amber color sp.gr 1.010, blood 2+, protein trace,

leukocyte trace ,RBC1-2 , nitrite +

• Reticulocyte count 0.36 % • G6PD normal • DCT 3+ ICT 4+ • PBS : rouleux formation ,decrease RBC , spherocyte 2+

,polychromacia 2+

Progression

Hematological condition

Date Clinical Lab Management

24/3/2558 ไข ซด เหนอยเพลย Ward - GM for PRC หาเลอดไมได consult hematologist 17 น

Hct 13 % แรกกรบ - Start Prednisolone (2 mkd) -FU – Hct 23 น = 8% ยงหาเลอดใหไมได ทก unit 3-4+ *a

- Cefotaxime

25/3/2558 Alteration of conciousness ยาย PICU

-on Et-tube ยาย PICU

-Metylprednisolone (30 MKDay) 25-25/3/58 -PRC 5 ml/kg/dose x 2/day 25-27/3/58: Hct 6-14%

28/3/2558 Sepsis with DIC – Meropenem+Vanco Amlodipine Hyperglycemia- on RI

-IVIG (1g/kg/day) x 2 days 28-29/3/58 –Hct 9-13% -PRC 5 ml/kg/dose x 1/day

30/3/2558 -Prednisolone (2MKDay) 30-31/3/58 Hct 13-22% -PRC 5 ml/kg/dose x 2/day

1/4/2558 Start Ampho B 3/4/58 BMA : decrease cellularity ,erythroid hyperplasia, M:E:L 68:8:23 absent megakaryocyte 6/4/58 – cardiac arrest

-Prednisolone (5CPR) 1-6/4/58 – Hct 8.6-15% – PRC 1-3/day*b

*a :Learning point Don’t wait to transfuse

• Transfusion can be life saving in the setting of WAIHA and severe anemia or unstable clinical/cardiac status

• Do not wait for “compatible blood”

• Do not wait for underlying alloantibodies to be worked up (several hours) when the anemia is severe and life threatening

• “Least incompatible”?

Selection of Blood

• ABO compatible

• Negative for alloantibody and autoantibody specificity

• Phenotype identical

• All units will be incompatible ? least incompatible

Date Clinical Lab Management

7/4/2558 Post cardiac arrest Plan ให rituximab มารดาขอตดสนใจ

-Metylprednisolone (30MKDay)7-9/4/58 -Hct 8-15% -Need PRC transfusion supprot

9/4/2558 -Bone marrow biopsy:Trilineage hypercellular marrow with normoblastic erythroid poliferative , no malignancy or granuloma

-Hydrocortisone 9-19/4/58

10/4/2558 Refractory AIHA -Rituximab 300mg #1 @ Hct 18% -Hct 15-20% - PRC 1/day

17/4/2558 -Rituximab 300mg #2 -Hct 15-17% -PRC 1/day

19/4/2558 -Prednisolone (6CPR) 19/4/58จนถงวนนด -PRC,,platlet

Date Clinical Lab Management

21/4/2558 ตนด มปญหาไมหลบกลางคน - Off ET-tube - Hct 17-21%

24/4/2558 -Rituximab 300mg #3 -วนสดทายทได PRC

28/4/2558 -ยายออกจาก PICU

-Hct 23-25%

1/5/2558 -Rituximab 300mg #4 @ Hct 26% -Hct 26-41%

20/5/2558 ตนด กนได พดคยรเรอง -D/C นด 2 สปดาห -Prednisolone (6CPR)

Thank you