Diagnosis, Management and Prevention of Acute Hemolytic Anemia in Infants, Children and Adolescents

➡️Introduction

Acute hemolysis is a common presentation in the Emergency room and General

Pediatrics clinic visits. For most parts of the world, the guideline recommendations are

targeting specific disease entities after initial diagnosis. The purpose of developing the

Egyptian guidelines are to identify strategies and comprehensive actions needed to help

general Pediatricians in the initial approach and management of children presenting with

acute hemolytic episode till reaching a diagnosis and referring the patient to the pediatric

hematologist

 ➡️Scope

This guideline focuses on diagnosis, prevention and management of the most common causes of acute hemolytic anemia where early interventional treatment can reduce the risk or extent of end-organ failure;” Glucose-6-phosphate-dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia and hemolytic uremic syndrome” in infants (beyond the neonatal period), children and adolescents 

➡️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1- Laboratory diagnosis of G6PD deficiency. A British Society for Haematology Guideline.

Br J Haematol. 2020;189(1):24-38 [1].

2- Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005 Oct 1;72(7):1277-82 [2].

3-The diagnosis and management of primary autoimmune haemolytic anaemia.

 Br J Haematol. 2017;176(3):395-411 [3].

4- Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association. Blood Transfus. 2017;15(3):259-267 [4] 

5- 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017;65(12):1963-1973 [5].

6- Hemolytic uremic syndrome in a developing country: Consensus guidelines.

 Pediatr Nephrol. 2019 Aug;34(8):1465-1482 [6].

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -    Adoption for most of the guideline recommendations.

         -    Development of Good Practice Statements

➡️Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following three sub-sections:

A. Diagnosis of acute hemolytic anemia

The guideline covers how to diagnose and differentiate between different causes of acute hemolytic anemia in infants (beyond the neonatal period), children and adolescents.

This section includes recommendations and good practice statements on first level testing in patient presented with AHA, indication and timing for reassessment and when and which further testing are needed.  

B. Management of the most pressing causes of AHA namely Glucose-6-phosphate-dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia and hemolytic uremic syndrome.

This section includes recommendations and good practice statements on first line therapy in AIHA, indication of and precautions during packed red cells transfusion, and follow up plans for patients with G6PD and AIHA  

C. Prevention of acute hemolytic anemia due to Glucose-6-phosphate-dehydrogenase (G6PD) deficiency, autoimmune hemolytic anemia and hemolytic uremic syndrome.

This section includes recommendations and good practice statements on which drug to be avoided in patients with G6PD, and indications for empiric antibiotics in children with diarrhea to avoid the development of HUS 

We can summarize the guidelines’ recommendations for acute hemolytic anemia in the following: 

➡️For diagnosis of Acute Hemolytic Anemia:

▪️  We suggest that First level testing for any patient presented with acute hemolysis includes: * CBC with red cell morphology on peripheral smear, * Reticulocyte count, * Indices of hemolysis (indirect bilirubine, LDH), * Urine analysis, * Direct and indirect antibody test (DAT, Coombs test), * Blood group, [Very Low], Liver transaminases and kidney function (blood urea and serum creatinine). [Low, Conditional]

·       We recommend that; If G6PD assay was done during a hemolytic episode of unknown cause, re-assay is warranted to ensure the diagnosis of G6PD deficiency is not missed. [Low, Strong}

▪️   We suggest that a normal G6PD activity during a hemolytic episode should be repeated after 2 months in absence of clinical and laboratory evidence of hemolysis. [Very Low]

▪️    We recommend that G6PD can be diagnosed with a quantitative spectrophotometric analysis or, more commonly, by a rapid fluorescent spot test.[Low, Strong]

▪️  We recommend against relying on screening tests for female patients. Measure G6PD activity by quantitative spectrophotometric assay directly. [Low, Strong]

▪️   We recommend that quantitative assay must be carried out if the screening test is abnormal or borderline. [Low, Strong]

▪️   We recommend that the final G6PD activity should be interpreted in the lights of the reticulocyte count measured on the same sample. [Low, Strong]

▪️    We recommend that samples with very low mean corpuscular hemoglobin (MCH) may give G6PD activity levels above the expected value. [Very Low, Strong]

▪️    We suggest G6PD testing in the following situations; * Favism (hemolysis with fava beans intake), * Hemolysis associated with “oxidant” drugs (Table in implementation tools) or infection, * Abnormal red-cell morphology (Basket cells/ positive Heinz body stain), * Hemoglobinuria, or * Hemolysis with previous history of neonatal pallor/jaundice. [Very Low]

▪️     We recommend that in case of AIHA at a minimum, the DAT should include monospecific anti-IgG and anti-C3d. [Low, Strong]

▪️     We recommend that in case of DAT-negative hemolysis: In patients with unexplained hemolysis and a negative screening DAT, retest with a column agglutination DAT method that includes monospecific anti-IgG, anti-IgA and anti-C3d. [Moderate, Strong]

▪️   We suggest that retest was also negative, consider preparing and investigating a red cell eluate. [Low, Conditional].

▪️    We recommend that the next test to be done before starting treatment; * Immunological markers: ANA, Anti DNA, C3, Antiphospholipid, * Total serum immunoglobulins, * CD markers and * Double negative α/β T cells if hepatosplenomegaly. [High, Strong]

▪️    We suggest that bone marrow aspiration is only recommended in the presence of another associated cytopenia or persistent reticulocytopenia or on suspicion of neoplasia or myelodysplasia. [Very Low]

▪️    We suggest the following initial laboratory panel for patients with suspected post diarrheal hemolytic uremic syndrome; • Complete blood count (hemoglobin <10 g/dl, hematocrit <30%, platelet count <150,000/μl), • Peripheral smear (fragmented red cells - schistocytes ≥ 2%), • Lactate dehydrogenase (LDH > 450 IU/l), • Haptoglobin (undetectable), • Kidney function tests (increased serum creatinine by 50% over baseline level). [Very Low]

For management of Acute Hemolytic Anemia:

▪️  We recommend that if anemia is life threatening, transfuse with ABO, Rh and K matched red cells. [Low, Strong]

▪️  We suggest that transfusion can be avoided in hemodynamically stable patients with regular monitoring until no evidence of hemolysis. [Low, Conditional]

▪️   We suggest to Transfuse if - Hb < 5 g/dl or - Hb is < 7g/dl with cardiac decompensation. GPS

▪️   We suggest to consider the use of a blood warmer for transfusion in patients with cold AIHA (CHAD, mixed AIHA and PCH). [Low, Conditional]

▪️  We suggest the following dose: 3-5 ml/Kg of packed RBCs fully compatible ABO, Rh, K, leucodepleted filtered blood. Transfuse slowly over 4 hours. [Very Low]

▪️  We recommend that the First line therapy of AIHA is prednisolone1-2 mg/kg /day. [Moderate, Strong]

▪️    We suggest that the second line therapy for AIHA should be considered if: - No response to steroids after 3 weeks, - Relapse during or after steroid reduction. And Refer to Hematologist. [Low, Conditional]

▪️   We suggest to consider IV Ig or plasma exchange for severe or life-threatening anemia. [Low, Conditional]

▪️  We recommend for patients with AIHA should receive folic acid supplementation. [Low, Strong]

▪️   We recommend that All patients should receive oral calcium and vitamin D supplements while taking corticosteroids (typically 1200–1500 mg calcium and 800–1000 units’ vitamin D). [High, Strong]

▪️   We recommend follow up by CBC and reticulocyte count every 2-4 weeks when indicated by treating physician. And that G6PD enzyme assay should be tested after complete recovery of the hemolytic attack and patient discharge. [Low, Strong]

➡️For prevention of Acute Hemolytic Anemia:

▪️   We suggest that Patients with G6PD deficiency should avoid exposure to oxidant drugs and ingestion of fava beans. And that patients with suspected G6PD deficiency should avoid exposure to oxidant drugs and ingestion of fava beans till diagnosis. [Low]

▪️    We recommend against the use of antimicrobial therapy in children with infections attributed to certain strain of STEC that produce Shiga toxin 2 (or if the toxin genotype is unknown). [Moderate, Strong]

▪️  We recommend that in immunocompetent children, empiric antimicrobial therapy for bloody diarrhea while waiting for results of investigations is not recommended, except for: * Infants <3 months of age with suspicion of a bacterial etiology. * Ill immunocompetent children with fever, abdominal pain, bloody diarrhea, and bacillary dysentery presumptively due to Shigella. [Low, Strong] * People who have recently travelled internationally with body temperatures ≥38.5°C and/or signs of sepsis. [Low, Conditional]

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/