Childhood Anaemia

Background/Epidemiology

  • Not uncommon
  • Can be a cause of growth failure and slow development
  • Can be defined as either <5th centile for age OR (easier)
    • <140g/l in a newborn; <110g/l in children 6 month – 4 years; <115g/l in children 5-11 years and <120g/l in children >12

Aetiology/Risk factors

  • Remember that anaemia is not a diagnosis but a sydrome of signs which usually has an underlying cause.
    • In children, usually either decreased RBC production or increased turnover
  • Risk factors
    • Decreased RBC production
      • Chronic disease e.g. renal disease, hypothyroidism, chronic inflammation/infection, IBD/Coeliac disease
      • Iron Deficiency
      • Poor diet
      • Prematurity
    • Increased RBC turnover
      • Drugs e.g. sulfamethoxazole, nitrofurantoin, phenytoin
      • Family history e.g. Thalassaemia, sickle cell,
      • Mechanical heart valve

Causes and Presentation

  • Neonate
    • Haemorrhage (e.g. placental abruption; traumatic haematoma; subgaleal (scalp) haematoma; maternal-foetal and twin-twin transfusion)
      • ~5-10% of severe neonatal anaemia; usually normocytic with initially normal reticulocyte count (increasing); check Kleihauer-Betke test in maternal-foetal haemorrhage
      • Tachypnoea, pallor, irritability, poor feeding.  In severe cases, shock and cardiorespiratory collapse
    • Isoimmunisation (e.g. ABO incompatibility/Rh incompatibility)
      • ~10/10,000 births (Rh incompatibility)- half of which develop anaemia
      • Jaundice with mild anaemia; severe cases may present with hydrops fetalis (severe oedema)
      • Positive Coombs test; raised bilirubin; normocytic anaemia with raised reticulocytes
    • Congenital Haemolytic anaemia (e.g. Spherocytosis, G6PD deficiency)
      • Hyperbilirubinaemia and moderate jaundice
      • May show poikilocytosis (spiky RBCs), reticulocytosis, Heinz bodies and Bite cells or Spur cells
    • Congenital Infection (e.g. Parvovirus B19; HIV; syphilis; rubella; sepsis)
    • Rarely- congenital disorders such as Diamond-Blackfan syndrome (very rare; causes macrocytic anaemia); Fanconi anaemia
  • Infancy- toddler
    • Iron Deficiency (e.g. poor diet, chronic occult blood loss (excessive cow’s milk consumption, IBD, Meckel’s diverticulum))
      • Not uncommon in this age group (up to 15%)
      • Usually asymptomatic; severe cases can present with fatigue, pallor, shortness of breath
      • Microcytic, hypochromic anaemia; low iron (low ferritin and iron saturation; with raised transferrin)
    • Chronic/recurrent infection (anaemia of chronic disease)
      • Presents usually with symptoms of infection
      • Normocytic, normochromic anaemia
    • Blood loss (e.g. trauma, GI bleed)
      • Usually presents with acute signs e.g. tachypnoea, tachycardia, pallor, hypotension
      • Haemoglobin may initially be normal but will fall (normocytic, normochromic)
    • Inherited disorders (e.g. Thalassaemia, sickle cell disease)
      • See pages- usually present in the first year of life
    • Other causes
      • RBC enzyme defects (G6PD, pyruvate kinase deficiencies)
      • RBC membrane defects (e.g. spherocytosis)
      • Acquired haemolytic anaemias (e.g. antibody mediated (incompatibility disease); drug-induced; Haemolytic uraemic syndrome; DIC)
      • Leukaemia
  • Late childhood and adolescence
    • Iron deficiency can occur during growth spurts, menstruation, and change of diet (as above)
    • Chronic disease (renal, liver, hypothyroid and others)
    • Blood loss (as above (+ menstruation))
    • Blood disorders; haemolytic anaemias and leukaemias (as above)

Approach to the newborn with anaemia

  • Newborn
    • Take a history of pregnancy/delivery (any suggestion of trauma or maternal-foetal haemorrhage; infections etc)
    • Check reticulocyte count to check marrow function (decreased RBC production e.g. Fanconi anaemia, Diamond Blackfan syndrome, congenital infections)
    • Look for signs of haemorrhage e.g. irritability/low conscious level, tachycardia/tachypnoea, jaundice
      • also check head circumference (subgaleal or intracranial bleed)
    • Check bilirubin (haemolysis) and then Coomb’s test

For older children

  • Take a full history including family, past medical (including pregnancy, neonatal, development etc), travel, social (including diet)
  • Check FBC, reticulocytes and blood film; iron studies; bilirubin; TFTs; and then investigate as required for conditions in the differential diagnosis
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Haemophilia

Haemophilia A

Background/Epidemiology

  • Factor VIII deficiency
    • Factor VIII is primarily synthesised by the liver and endothelial cells and has a half life of ~12 hours.  It is protected from proteolysis in the circulation by binding to von Willebrand factor.
  • Affects 1/10000; most common congenital coagulation factor deficiency
    • Varies in severity according to mutation
      • Severe (<0.01U/ml)
      • Moderate (0.01-0.05U/ml)
      • Mild (>0.05 to 0.4U/ml)
  • X-linked disease with 100% penetrance (i.e. all family members have the same gene)
    • As a result, female carries may also have reduced factor VIII levels compared to the general population
  • families with haemophilia A can be offered prenatal diagnosis (chrorionic villous sampling)

Classical_blood_coagulation_pathway

Presentation

  • Severe disease
    • Usually present with spontaneous bleeding into the skin, muscle and joints; retroperitoneal space and intracranially
  • Moderate/mild disease
    • Similar features but associate with trauma rather than spontaneous
  • Bleeding in the large joints and muscles are the major source of morbidity in patients with haemophilia
    • Recurrent haemarthroses causes synovial atrophy, destruction of cartilage and secondary osteoarthritis
    • Therefore, treatment of any hot, red, swollen joint in these patients needs to be prompt
    • Recognising compartment syndrome is also very important and swift management crucial for retaining function

Investigations

  • Imaging of a baby known to have haemophilia should be performed within the first 24 hours of life to look for signs of intracranial bleeding
  • Coagulation screen and measurement of coagulation factors VIII and IX will usually confirm the diagnosis (although exclusion of vWD type 2N should also be considered prior to definitive diagnosis using assays or molecular genetic testing)
  • Imaging should be used in symptomatic patients to look for location and extent of bleeding

Management

  • Severe disease
    • IV infusion of factor VIII concentrate for episode of bleeding
    • Weekly infusions can be given to children but is generally stopped once the patient has reached maturity
      • Patients receiving transfusions should be offered Hepatitis A and B immunisation
      • Patients may develop antibodies against transfused factor VIII (20%)
        • Alternative treatments include transfusions of activated clotting factors e.g. VIIa; or factor VIII inhibitor bypass activity (FEIBA)
  • Mild-moderate disease
    • Vasopressin receptor agonist DDAVP can also help raise vWF and factor VIII by 3-4 fold
      • Monitor for water retention

Haemophilia B

  • Rarer than Haemophilia A (~1:30000)
  • Essentially the same disease but due to a deficiency of factor IX
    • Also X-linked
    • Also similar presentation and variety of severity (practically indistinguishable)
    • Also treated with factor IX replacement transfusion (less risk of antibody resistance)

Immunodeficiency

Primary immunodeficiencies are genetic/congenital abnormalities of the immune system whilst secondary immunodeficiencies are acquired.

Background

  • There are many primary immunodeficiency disorders- most are inherited genetic disorders and are very rare (symptomatic cases: 1/10000).  Most present in childhood and most present in males (X-linked).

Classification

  • Can be classified as disorders of immune systems:
    • B-cell and Immunoglobulin system- Mainly antibody deficiencies which account for the majority (50%) of cases
      • e.g. Common variable immunodeficiency, Selective IgA deficiency, Bruton’s/X-linked agammaglobulinaemia; Transient hypogammaglobulinaemia of the newborn; IgG deficiency
    • T-cell and cell-mediated immune system- accounts for 30% of cases
      • NB Many of these disorders span both T- and B-cells e.g. Severe combined immunodeficiency; DiGeorge syndrome; Wiskott-Aldrich syndrome; Ataxia-telangiectasia; X-linked hyper-IgM
    • Phagocytic (Polymorphic/mononuclear) system (including macrophage dysfunction)
      • e.g. Chronic granulomatous disease
    • Complement system (mainly complement deficiencies)
  • NB Many disorders span more than one system e.g. Severe combined immunodeficiency (T- and B-cells); DiGeorge syndrome; Wiskott-Aldrich syndrome; Ataxia-telangiectasia; X-linked hyper-IgM

Disorders

Disorders of Humoral Immunity

  • Often present >6 months of age (loss of maternal antibodies), but can present late (into adulthood- see below)
  • Classically present with infections of encapsulated bacteria (tend to fight of viral and fungal infections with an intact innate immune system)
    • Chronic sinusitis / Recurrent acute sinusitis; other recurrent infections e.g. Strep pneumoniae pneumonia; unusual infections e.g. mycobacterial/fungal infections
  1. Common Variable Immunodeficiency
    • Not that common (1/75000); technically group of different disorders (a ‘heterogeneous syndrome’) with variable presentation and outcome
      • e.g. can present in infancy or into adulthood; can present in males and females (although females tend to have a better phenotype)
      • CVID is a diagnosis of exclusion (i.e. other causes of Ig deficiency should be ruled out)
    • Commonly associated with autoimmunity and family history
      • e.g. idiopathic thrombocytopenic purpura; haemolytic anaemia; thyroid disease; vitiligo; diabetes (insulin-dependent); rheumatoid arthritis; SLE; psoriasis; uveitis; IBD (mainly UC)
    • Characterised by failure of B cell differentiation into plasma cells and defective interaction between T- and B-cells
      • Causing reduced levels of immunoglobulin (IgG and IgA > IgM > IgE)
      • Up to half of patients also have associated T-cell dysfunction
  2. Selective IgA Deficiency
    • Most common (1/300-700) but often asymptomatic/undiagnosed (incidence based on blood samples)
    • IgA is found mainly in mucosal membranes and is thought to prevent bacteria from attaching to mucosal surfaces
    • Patients are at increased risk of allergies and autoimmune disease (atopy is common)
    • Patients commonly present with recurrent URTIs, including sinusitis, as well as GI infections
    • Although IgA < 5mg/dl; IgG can be normal and patients can often respond normally to vaccinations.  However, patients can respond abnormally (e.g. anaphylaxis) to blood/blood product transfusions due to the presence of IgA
  • Bruton’s/X-linked Agammaglobulinaemia
    • Caused by mutation/absence of Bruton’s tyrosine kinase (Btk) gene- important in cell signalling pathways involved in B-cell maturation (rare: 1/350000-400000)
      • X-linked (male)
      • Failure of maturation and absence (/minimal levels) of all immunoglobulin (IgG, IgA and IgM)
    • Often present in the first year of life with recurrent otitis media; pneumonia; and sinusitis BUT 20% of children can present later (3-5 years)

Disorders of Innate (+/- Humoral) Immunity

  • Usually more severe than isolated Ig/B-cell disorders, presenting earlier in life with failure to thrive and severe infections
  1. DiGeorge Syndrome
  2. Severe Combined Immunodeficiency 
    • Another syndrome which can manifest from several, usually genetic, disorders- characterised by recurrent, severe and opportunistic infections, failure to thrive and chronic diarrhoea presenting in the young infant (usually a few months after birth).
      • Other signs include rashes, hepatopathy, chest infections (interstitial pneumonia (cf lobar pneumonia), fungal infections
    • Fairly rare at 1/75-100,000.  Almost half of cases are x-linked (far more common in males) and others are autosomal recessive (with Jak3 and ADA deficiency)
      • Most commonly caused by a defect in the γ-chain of the interleukin receptors (X-linked)
    • Can encompass a range of white cell abnormalities
      • Most cause a T-cell defect- usually completely absent.  Many also affect B-cell and NK cell production.  A severe lymphopenia is seen on FBC.
      • Patients often do not mount any immune response to vaccinations and so can get symptoms with certain vaccinations
    • Patients will require IVIg and should be considered for an emergency bone marrow transplant
      • Without treatment, infections will usually kill the patient before they are 2 years old.
  3. Wiskott-Aldrich Syndrome
    • X-linked recessive condition characterised by
      • Recurrent bacterial infections of the sinuses/lungs
      • Eczema (resembles atopic dermatitis)
      • Bleeding tendency due to thrombocytopenia and platelet dysfunction.  This can be of the form of bloody diarrhoea, purpuric rash or excessive bruising.
        • NB These patients are also at risk of autoimmune conditions e.g. autoimmune haemolytic anaemia, vasculitides (inc glomerulonephritis); IBD etc as well as non-Hodgkins lymphoma
    • Typically presents in infants/toddlers
    • Caused by a defect of the WAS-protein gene, normal function of which is required for normal antibody, T-cell and platelet function
      • As a result, patients often have low IgG (often normal B-cells- IgM may be affected but this may be a sign of CVID or other syndrome- IgA and IgE may be elevated); low T cell count (particularly CD8+) and low/small platelets
    • Management should involve vaccinations and active management of any infections; may involve transfusions and/or stem cell transplant
      • Most patients survive well into their 20s/30s if treated conservatively.  Stem cell transplant can almost cure this condition and lengthen life span to normal.

Disorders of Phagocytic immunity

  1. Chronic Granulomatous Disease
    • CGD is a group of genetic syndromes in which phagocytes are unable to kill bacteria/fungi that have been ingested.
      • Usually caused by a defective gene encoding NADPH oxidase enzyme responsible for oxygen radical formation
      • Most commonly X-linked or autosomal recessive
    • Usually presents <2 with recurrent bacterial/fungal infections e.g. fungal pneumonia, skin abscesses/infections, lymphadenitis, diarrhoea
      • commonly with Aspergillus fumigatus; Candida albicans and Candida glabrata
    • Granulomas of the skin and GI tract can also be seen
    • Investigations include a phagocytic oxidase activity (Nitroblue tetrazolium- NBT- microscopy stain) test and genetic test
    • Management is usually prophylactic antibiotics and antifungals
      • Co-trimoxazole (Trimethoprim + Sulfamethoxazole- 5mg/kg/day based on trimethoprim) is often used because is reduces bacterial infection without increasing the risk of fungal infections
      • Itraconazole is also used
      • Interferon gamma may also be used to enhance immune function
      • Prednisolone may be used in moderate-severe granulomatous disease, particularly if causing GI symptoms
    • Acute infections should be managed as per case

Disorders of the Complement System

  • Variety of complement deficiencies- each with specific features.  Patients may be at risk of immune complex deposition disorders e.g. SLE, as well as recurrent bacterial infection

When to suspect immunodeficiency

  • Warning History
    • ≥8 ear infections in a year
    • ≥2 serious sinus infections in one year
    • ≥2 episodes of pneumonia in one year
    • ≥2 deep-seated or unusually located infections
    • Recurrent deep skin or organ abscesses
    • Need for IV antibiotics to clear infections
    • Infections with unusual or opportunistic organisms
    • Family History
  • Warning Signs
    • Poor growth/Failure to thrive
    • Absent lymph nodes/tonsils
    • Skin lesions: telangiectasias, petechiae, dermatomyositis, lupus-like rash
    • Ataxia
    • Oral thrush (>1 year old)
    • Oral ulcers
  • If a patient has any one or more of the bold warning signs, and an immunodeficiency is suspected, IgG/IgM/IgA and a FBC can be measured to screen for a primary immunodeficiency

Management

  • Most require high dose and IV antibiotics for treatment of acute infections.  Many will require prophylactic antibiotics too
  • Where appropriate, vaccines should be given
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    • Patients with T-cell deficiencies should receive cytomegalovirus-negative irradiated blood products
  • IVIg should be used to replace immunoglobulin
  • Stem cell/bone marrow transplants can be curative for cellular immunodeficiency

Haemorrhage of the newborn and Vitamin K

Vitamin K is poorly transported across the placenta and breast milk is a poor dietary source.  On top of this, the body is unable to store large amounts of vitamin K.  Vitamin K is important in the production of clotting factors II, VII, IX and X.

As such, newborn infants are at risk of severe bleeding due to lack of vitamin K-

Vitamin K Deficiency Bleeding

‘Types of VKDB’

  • Early- within 24 hours
  • Classic- 1-7 days
  • Late- 7 days- week 12

Risk Factors and Prevention

  • Risk
    • Early VKDB
      • Maternal drugs (particularly anti-TB e.g. rifampicin, isoniazid; anti-epileptics/convulsants; and anti-coagulants) – combined with trauma at delivery can cause severe early VKDB
    • Classic VKBD
      • Drugs (as above)
      • Exclusive breastfeeding in babies who have not had prophylaxis
    • Late
      • Usually caused by malabsorption of vitamin K
        • diarrhoeal disease
        • can be due to undiagnosed cholestasis
  • Prevention
    • Vitamin K injection soon after birth (1mg IM) should be given to prevent VKDB

Presentation and Management

  • Common bleeding sites include
    • the GI tract (malaena, haematemesis)
    • skin/mucous membranes (nose, gums)
    • sites of trauma (at delivery- particularly the scalp)
  • More rarely, intracranial bleeding can occur

Management of haemorrhagic disease

  • Subcut Vit K and/or oral vit K
  • If severe (or intracranial) bleeding, fresh frozen plasma can be given with vit K to replace clotting factors
    • Rarely, transfusion may be required.

Rhesus D and Haemolytic disease of the newborn

Epidemiology

  • With advances in Rh D immunisation, haemolytic disease of the newborn is now extremely rare

Background

  • Rhesus antigens are just one of several proteins that can be expressed on red blood cells.  These are genetically predetermined, i.e. you inherit proteins from either parent.
  • In the case of Rhesus, the rhesus D protein can be particularly antigenic and will cause an immune response to occur.
  • If a mum who is Rhesus D -ve carries a child that is Rhesus D +ve, there is a risk that a small amount of foetal blood will cross into the maternal circulation (foeto-maternal haemorrhage, or FMH)
    • This usually occurs in the third trimester/during childbirth
    • The mother’s immune system mounts an immune response and produces anti-D antibodies- once sensitisation has occurred it is irreversible
  • If this is the first pregnancy, then this is not usually a problem for either mother or child.  However, in subsequent pregancies, the immune response will be greater and more rapid.  The result can be destruction of the foetal RBCs and a severe/fatal foetal anaemia.  This can result in neonatal jaundice (secondary to haemolysis)

Risk Factors for FMH

  • Traumatic delivery (inc C-section)
  • Manual removal of the placenta
  • Stillbirths/miscarriage
  • Abdominal trauma during the third trimester
  • Multiple pregnancy

Antenatal screening

  • All pregnant women will have their Rhesus status checked and whether they have antibodies already
    • the latter can be tested with an indirect Coombe’s Test
      • mother’s serum (containing IgG) can be added to Rh+ve RBCs, then added to anti-human IgG which will cause agglutination (only if patient sample is positive for Anti-D
  • Antenatal ultrasound will look for features of hydrops fetalis and foetal anaemia
    • e.g. by doppler USS looking at the middle cerebral artery
    • If there are any concerns, foetal blood sampling could also be done
      • anaemia, abnormal RBCs and a high reticulocyte count are features of anaemia

Presentation after birth

  • In up to 50% of cases, babies may be born normal.  Babies typically develop symptoms within the first 24 hours
    • jaundice (including yellow amniotic fluid and vermix (‘gunk’ on baby’s skin))
    • hepatosplenomegaly
    • hypoglycaemia
    • hydrops fetalis
      • IMPORTANT: babies who appear normal but have identified rhesus incompatibility should be closely observed for up to 2 months
  • Severe disease may result in still birth or require intensive resuscitation

Prevention

  • Rh-ve mothers should be offered an injection of Anti-D antibody at 28 weeks, or when she has any invasive obstetric procedure (e.g. amniocentesis), or if she has any significant risk factors (e.g. abdominal trauma); and finally after delivery
    • This works by binding to the baby’s blood antigens before the mother can mount an immune response

Management of HDN

In utero

  • If the baby is anaemic (confirmed by blood test), transfusion directly to the foetus (via the umbilical vein) with O- cells should be given at around 16-18 weeks
  • These babies should be delivered early (37/8 weeks) if no complications, (earlier- down to 32 weeks, if complications)

 

Post-natal

    • Transfusion may be required
    • Phototherapy for jaundice