L21 Hematological Disease and Immunodeficiencies

Haematological Diseases and Immunodeficiency¹

Overview

This lecture provides an overview of red blood cell disorders, bleeding and platelet abnormalities, haematological malignancies, and immunodeficiencies, with a specific focus on their oral manifestations and implications for dental management.

Learning Outcomes²

Upon completion of this section, students should be able to:

• Gain an understanding of an overview of haematological diseases and immunodeficiency.
• Recognise the oral manifestations and management of patients with these conditions.
• Develop an awareness of when medically compromised patients should be referred to secondary care.
• Develop an awareness of when to consult a physician or specialist regarding systemic conditions that may impact dental treatment.

Anaemia

Anaemia is a term used for either a decrease in the volume of red blood cells (RBC) or in the concentration of haemoglobin.

Pathophysiology³

• Results from decreased production of RBCs or increased destruction or loss (trauma, menstruation, GI bleeding) of RBCs.

General Symptoms

Symptoms are related to the reduced oxygen-carrying capacity of the blood:

• Tiredness and shortness of breath
• Tachycardia and palpitations
• Pallor of the mucous membrane

Iron Deficiency Anaemia

Iron-deficiency anaemia is the most common cause of anaemia and is classified as hypochromic microcytic anaemia.

Causes⁴

• Decreased dietary intake of iron
• Decreased absorption of iron (e.g., Coeliac disease)
• Excessive blood loss (e.g., menstrual or GI bleeding)
• Increased demand for red blood cells (e.g., pregnancy)

Signs and Symptoms

• Fatigue and dyspnoea
• Koilonychia (spoon-shaped nails)
• Pica (craving for specific foods/dirt)
• Blue sclera

Oral Findings

• Pale oral mucosa
• Depapillated atrophic tongue
• Glossodynia (burning sensation)
• Candidiasis and angular cheilitis
• Aphthous-like ulcers

Plummer-Vinson Syndrome

Plummer-Vinson syndrome (also known as Patterson-Brown-Kelly syndrome) is a severe and chronic form of iron deficiency.

Clinical Characteristics

• Typically affects middle-aged females.
• Atrophic glossitis: Smooth, atrophic, and red tongue.
• Pharyngeal and oesophageal webbing: Leads to dysphagia.
• Malignancy Risk: Predisposition to post-cricoid and oral squamous cell carcinoma.

Dental Management Considerations for Anaemia

Anaesthesia⁵

• In poorly controlled anaemia: Use local anaesthesia (LA) without epinephrine, as it may aggravate cardiac symptoms.

Anxiety and Sedation

• Nitrous oxide can be used.
• General Anaesthesia (GA) should be avoided if the Hb level is below 10g/dL.

Medical Referral

• Iron deficiency in men may indicate an occult GI cancer; refer for further evaluation.

Diagnosis of Iron Deficiency

Diagnosis involves a Full Blood Count (FBC): reduced Hb, reduced Mean Corpuscular Volume (MCV), low serum iron/ferritin, and high Total Iron Binding Capacity (TIBC).

Thalassemia

Thalassemia is a hereditary haemoglobinopathy characterised by a reduction in the production of globin chains in the haemoglobin molecule.

Epidemiology and Classification⁶

• More prevalent in Mediterranean, African, and Asian populations.
• Types:
  • Alpha-thalassemia
  • Beta-thalassemia

Pathogenesis

• Caused by deletions or mutations in the alpha or beta globin genes.
• Results in decreased haemoglobin production and the formation of malformed RBCs.
• Severity increases with the number of defective genes.

Systemic Features⁷

• Severe jaundice, pallor, growth retardation, and splenomegaly (typically appearing in the 1st year of life).
• Typical symptoms of anaemia.

Skeletal and Radiographic Findings

Bone expansion occurs as a result of intramedullary haematopoiesis:

• Maxillary protrusion with spacing of teeth.
• Thin cortical plates and spongy marrow.
• Thin, widely spaced trabeculae.
• “Hair-on-end” appearance on a lateral skull radiograph.

Sickle Cell Anaemia

Sickle cell anaemia is a hereditary haemoglobinopathy in which red cells contain an abnormal haemoglobin, HbS.

Pathogenesis⁸

• Autosomal recessive disorder.
• More common in Mediterranean, African, and Far East countries.
• Caused by a point mutation of the beta-globin gene.
• Red cells become rigid and curved (sickle-shaped).
• Deformed sickle cells are highly vulnerable to haemolysis.
• Newborn babies are screened for sickle cell status.
• Deformed cells can block small vessels.
• Diagnosis: Sickle cell solubility test and haemoglobin electrophoresis.

Clinical and Radiographic Findings⁹

• Pallor or jaundice of the oral mucosa.
• Widely spaced trabeculae.
• Step-ladder appearance: Characteristic bone trabeculation seen in periapical (PA) x-rays.
• Mandibular bone pain and osteomyelitis.
• Asymptomatic pulpal necrosis.
• Maxillary protrusion.
• Delayed eruption and dental hypoplasia.

Bleeding and Platelet Disorders

Info

Hemostasis involves vasoconstriction, platelet plug formation, and activation of the coagulation pathway to form a fibrin clot.

Vascular Disorders¹⁰

• Capillary fragility.
  • e.g., Vitamin C deficiency/Scurvy.
• Hereditary haemorrhagic telangiectasia.
  • Also known as Osler-Weber-Rendu Syndrome.

Platelet Disorders

• Abnormal platelet number or function.
  • Quantitative: Thrombocytopenia (low count)
    • Qualitative: Thrombocytopathy (abnormal function, e.g., Aspirin use, Von Willebrand disease).
• Inability to develop a temporary clot.

Coagulation Disorders

• Defects in coagulation leading to an inability to form a definitive clot.
• Inherited: e.g., von Willebrand’s disease, haemophilia.
• Acquired: e.g., liver disease, anticoagulants.

Fibrolytic Disorders

• Inability to destroy free plasmin.

Assessing Risk for Bleeding

Patient History¹¹

• Bleeding problems in relatives (e.g., von Willebrand’s disease, haemophilia).
• History of bleeding after surgery or tooth extractions.
• Bleeding after trauma (cuts).
• Spontaneous bleeding from the nose, mouth, or GI tract.

Medications and Treatments

• Antiplatelets.
• Long-term antibiotic therapy.
• Some herbal preparations.
  • e.g., Ginkgo biloba, Garlic.
• Chemotherapy.

Associated Medical Conditions

• Leukaemia and thrombocytopenia.
• Advanced liver disease.
• Renal failure.

Thrombocytopenia

Thrombocytopenia is defined as low platelet levels in the blood. Clinical evidence is typically not visible until the platelet level falls below 100,000/µl (Normal range: 150,000 to 450,000/µl).

Causes of Decreased Production¹²

• Bone marrow dysfunction or infiltration by malignant cells (leukaemia, myeloma, bone metastasis).
• Toxic effects of chemotherapeutic drugs.
• Liver disease.

Causes of Increased Consumption or Destruction

• Drug-induced immunologic responses (heparin, quinidine, methyldopa).
• Systemic diseases: SLE and HIV infection.
• Vaccinations and viral infections.
• Immune (idiopathic) thrombocytopenic purpura (ITP).

Other Causes

• Increased splenic sequestration (portal hypertension due to liver disease, tumour infiltration).

Oral Manifestations¹³

• Petechiae and ecchymosis.
• Spontaneous gingival bleeding.
• Postoperative bleeding.

Dental Management Considerations

• Obtain a thorough history, clinical exam, and relevant tests (platelet count).
• Refer and consult a haematologist if necessary.
• Use local measures to control bleeding.
• Contraindication: Do not prescribe aspirin.
• Be aware of the risk of infection in patients with bone marrow suppression (e.g., leukaemia).
• Guidelines for Platelet Counts:
  • Count > 50,000/µL: Extractions and minor surgery possible
  • Count > 80,000/µL: Major oral surgery possible
  • Count < 30,000/µL: Only non-surgical procedures
• Use Acetaminophen for pain management instead of Aspirin/NSAIDs.

Local Haemostatic Agents

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Physical and Mechanical Agents¹⁴

• Gauze: 2″×2″ sterile pads; applied with pressure (closing or finger pressure).
• Surgicel®: Oxidized regenerated cellulose; exerts a physical effect by swelling on contact with blood; becomes gelatinous after 24-48 hours.
• Gelfoam®: Absorbable gelatin sponge.
• Atraumatic Technique: Minimally traumatic surgery and precise suturing.

Physiological and Chemical Agents

• Avitene®: Microfibrillar collagen hemostat; attracts platelets and triggers aggregation.
• Thrombostat®: Topical thrombin; converts fibrinogen to fibrin.

Antifibrinolytic Agents

• Tranexamic acid: Competitive inhibitor of plasminogen activation (available as 4.8% mouthwash in Europe; tablets or injections in the USA).
• ε-Aminocaproic acid (EACA/Amicar®): Competitive inhibitor of plasminogen activation; used as a rinse (25% syrup).

Platelet Function Disorders

Inherited Disorders¹⁵

• Von Willebrand’s disease: May also involve a secondary factor VIII deficiency.

Acquired Platelet Dysfunction

• Drug-induced: Aspirin, clopidogrel, NSAIDs, beta-lactam antibiotics (penicillin), calcium channel blockers, and phenytoin.
• End-stage renal disease: Uraemia (high urea levels) can result in circulating toxins that impair platelet function.
• Alcohol ingestion.

Von Willebrand Disease

Von Willebrand disease is the most common inherited bleeding disorder, caused by an inherited gene mutation on chromosome 12 affecting both males and females.

Pathophysiology

• Characterised by deficient or defective von Willebrand factor (vWF).
• vWF serves as a carrier protein for Factor VIII.
• Patients experience both platelet dysfunction and Factor VIII deficiency.

Clinical Features

• Common findings: Ecchymoses and nose bleeds.
• Prolonged bleeding after tooth extraction.
• Severe forms may present with haemarthroses.

Coagulation Disorders

Hereditary Disorders¹⁶

• Von Willebrand’s disease
• Haemophilia:
  • Haemophilia A (Factor VIII deficiency)
  • Haemophilia B (Factor IX deficiency)

Acquired Disorders

• Anticoagulants: Warfarin and Heparin therapy.
• Liver Disease: Viral hepatitis and alcoholism.
• Vitamin K Deficiency: Caused by malabsorption or long-term use of broad-spectrum antibiotics.

Haemophilia A

Haemophilia A is an X-linked recessive disorder characterized by factor VIII deficiency. It primarily affects males, while females are usually carriers. Normal haemostasis requires at least 30% factor VIII activity.

Severity Classification¹⁷

• Mild haemophilia: Factor VIII level between 5-30%; patients are often asymptomatic
  • Often asymptomatic until trauma or surgery..
• Moderate haemophilia: Factor VIII level between 1-5%.
• Severe haemophilia: Factor VIII level less than 1
  • Characterized by spontaneous bleeding.%.

General and Oral Findings¹⁸

• Common findings: Ecchymoses, hemarthrosis, and dissecting haematomas.
• Persistent bleeding after dental surgery.
• Bleeding after tooth extraction (may be the first evidence of mild haemophilia).
• Formation of liver clots and haematomas.
• Spontaneous mucosal or gingival bleeding.
• Hemarthrosis of the TMJ (rare finding).

Haemophilia B

Haemophilia B, also known as Christmas disease, is a sex-linked recessive disorder characterised by Factor IX deficiency.

Clinical Profile¹⁹

• Clinical features are identical to Haemophilia A.
  • Inherited as an X-linked recessive trait.
• Classified as mild, moderate, or severe (20-45% of cases are severe).

Diagnosis and Management

• Lab tests: Prolonged PTT (partial thromboplastin time) and confirmed Factor IX deficiency.
• Medical management: Factor IX replacement therapy.

Dental Management for Patients on Warfarin

Pre-operative Assessment²⁰

• Determine the reason for anticoagulant therapy.
• Confirm the INR level, ideally within 72 hours of the scheduled procedure.
• Consult with the patient’s physician if necessary.

Clinical Guidelines based on INR

• INR ≤ 3.5: Minor procedures can be performed using local haemostatic measures.
• INR > 3.5: Consult the physician; delay the procedure by 3-5 days and re-confirm the INR level
  • Physician consultation may involve adjusting the dosage..
• Major Oral Surgery: INR should be less than 3.0.

Emergency Measures

• If post-operative bleeding is uncontrollable, Vitamin K or fresh frozen plasma may be used.

Haematological Malignancies

Leukaemia

Leukaemia is a cancer of the white blood cells (WBCs) that affects the bone marrow and circulating blood, involving the exponential proliferation of clonal or lymphoid cells.

Classification²¹

• Acute Leukaemia: Sudden onset and rapid course; involves immature, undifferentiated WBCs.
• Chronic Leukaemia: Slower onset; involves more mature, functional cells.
• Types: ALL, AML, CLL, CML.

Clinical Signs²²

• Mucosal pallor (important sign in children).
• Gingival bleeding, petechiae, or purpura.
• Spontaneous gingival bleeding (a key diagnostic sign)
• Gingival enlargement (soft, boggy, leukemic infiltrates)
• Oral ulcers (herpetic, neutropenic, or drug-induced).
• Oral infections (e.g., candidiasis, CMV).
• Cervical lymphadenopathy.

Specific Pathologies

• Gingival Enlargement: Localised or generalised; caused by leukemic infiltrates. Gingiva appears boggy and bleeds easily.
• Myeloid Sarcoma: A localised mass of leukemic cells that can involve the maxilla, palate, gingiva, tongue, or oral mucosa.

Lymphoma

Hodgkin Lymphoma

Hodgkin Lymphoma (HL) is a B lymphocyte neoplasm that presents as discrete masses in lymphoid organs.

Pathophysiology and Epidemiology

• Contains the characteristic Reed-Sternberg cell (large, bi-nucleated tumour cell
  • Reed-Sternberg cells often have a characteristic "owl-eye" appearance).
• Most common in adolescents and young adults (bimodal incidence: 20-30 and 50-70 years).
• EBV is linked to 40% of cases.

Clinical Presentation

• Typically manifests as painless, firm, enlarged lymph nodes with a rubbery consistency (commonly mediastinal and cervical).
• Oral involvement is rare.
• Systemic symptoms: Pruritus, fatigue, fever, weight loss, and night sweats.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) is a large group of lymphoproliferative disorders derived from B, T, and natural killer cells (B-cell proliferation accounts for 85-90% of cases).

Risk Factors and Age

• Can occur at any age (median age at diagnosis is 67 years).
• Causative agents: Genetic factors, infectious agents, autoimmune diseases (e.g., Sjögren syndrome), and immunodeficiency states (e.g., AIDS).

Risk Factor: Sjögren Syndrome

Patients with long-term Sjögren’s Syndrome have a significantly higher risk of developing Non-Hodgkin Lymphoma.

Clinical Presentation

• Involvement can be nodal (painless, firm enlarged cervical lymph nodes) or extra-nodal.
• Oral Findings:
  • Oral submucosal mass (may or may not be ulcerated).
  • Involvement of salivary glands (especially those affected by Sjögren syndrome).
  • Jaw bone involvement in African children with Burkitt’s Lymphoma.

Multiple Myeloma

Multiple myeloma is a malignant neoplasm composed of plasma cells, occurring as a disseminated disease involving many bones.

Clinical Features

• Typically affects men over 50 years; presents with persistent bone pain.
• Skeletal Involvement: Multiple osteolytic “punched-out” lesions or mottled areas on radiographs. Commonly affects vertebrae, sternum, ribs, and pelvic bones
  • "Punched-out" radiolucencies are especially prominent on the skull.
• Jaw Involvement: Osteolytic lesions of the jaws occur in 30% of patients.
• Systemic Complications:
  • Serum hypercalcaemia and potential pathological fractures.
  • Fever and recurrent infections due to neutropenia.
  • Proteinuria and renal failure.
  • Amyloid deposition in various tissues (heart, liver, nervous tissue).

Radiographic and Oral Findings²³

• “Punched-out” lesions: May cause bone pain, paraesthesia, and cortical enlargement; can be the initial manifestation of the disease.
• Macroglossia: Caused by amyloid deposition in the tongue, leading to pain.
• Haematological signs: Petechiae, pallor, and increased susceptibility to bleeding and infections.

Treatment Complications

• MRONJ (Medication-related osteonecrosis of the jaw): A potentially serious complication of long-term bisphosphonate therapy, commonly observed in the mandible.

• Distinction: Unlike Candida, Hairy Leukoplakia cannot be wiped off.

Immunodeficiency²⁴

Immunodeficiency refers to a state in which the immune system’s ability to fight infectious diseases and cancer is compromised or entirely absent.

Primary Immunodeficiency

Characteristics of Primary Immunodeficiency²⁵

• Genetically based.
• Predominantly involves B-cell or T-cell defects, a combination of both, or selective immunodeficiencies (e.g., IgA deficiency).
• Results in life-threatening conditions.
• Affected individuals tend to die young as a result of recurrent infection.

Clinical Manifestations

• Candida infections are often predominant in these patients.
• Patients are more susceptible to periodontal infections.

Secondary Immunodeficiency²⁶

Secondary immunodeficiency can arise from various underlying conditions and external factors:

• Malignancies
  • Leukaemia, lymphoma, multiple myeloma
• Medications
  • Corticosteroids and immunosuppressants
  • Chemotherapy
• Health and Lifestyle Factors
  • Malnutrition
  • Autoimmune disorders
  • Diabetes mellitus
  • Chronic renal failure
• Environmental and Infectious Factors
  • Radiation
  • Infections (e.g., HIV, TB)

Human Immunodeficiency Virus Infection

Pathophysiology and Transmission²⁷

• Caused by an RNA retrovirus infection.
• Spread through:
  • Sexual contact
  • Parenteral exposure to blood
  • Mother to foetus
• Immune deficiency is due to damage to CD4 T-lymphocytes.

Predisposition to Complications

Infected individuals are predisposed to:

• Viruses and virally induced malignancies
• Fungi
• Mycobacteria
• Autoimmune disease
• Neurological damage

Clinical Stages and Classification

Clinical Progression Stages

1. Stage I: Seroconversion Illness

   • Occurs within 2-3 weeks.
   • Symptoms: Fever, malaise, lymphadenopathy, pharyngitis, mouth ulcers.
   • Antibodies typically develop within 3-6 months.

2. Stage II: Asymptomatic Stage

   • Chronic phase lasting approximately 10 years.

3. Stage III: Persistent Generalized Lymphadenopathy

   • Lasts approximately 10 years.

4. Stage IV (A-E): Symptomatic Stage

   • Diseases involving the entire body.
   • Includes neurological disease, secondary infectious disease, secondary cancers, and other conditions.

Classification of Oral Lesions

• Group I: Lesions strongly associated with HIV infections
  • Example: HIV-associated candidosis
• Group II: Lesions less commonly associated with HIV infection
  • Example: HIV-associated CMV ulcer
• Group III: Lesions possibly associated with HIV infection
  • Example: HIV-associated wart

Oral Manifestations of HIV²⁸

Common oral manifestations observed in HIV disease include:

• Candidiasis
• Hairy leukoplakia
• Kaposi’s sarcoma
• Gingival and periodontal disease
• Ulcers
• Other orofacial conditions

Hairy Leukoplakia

Clinical Features

• Presents as a white patch which cannot be removed.
• Characterized by vertical white folds on the lateral aspects of the tongue.
• Associated with Epstein-Barr Virus (EBV).

Additional Characteristics

• The lesion is not premalignant.
• Usually superimposed by Candida.
• Common in patients with late-stage HIV infection.
• Development may herald the onset of AIDS.

Diagnostic Information

• Diagnosis: Primarily clinical.
• Biopsy: Shows ballooned cells with perinuclear vacuoles; swollen cells contain EBV.

Kaposi’s Sarcoma

Overview

• The most common malignancy in HIV patients.
• Caused by Human Herpesvirus type 8 (HHV-8).
• Arises from vascular endothelial cells.
• Common in homosexuals, though it can occur in all risk groups.

Clinical Presentation

• Involves skin and mucosal surfaces.
• The tip of the nose is a frequent facial site.
• Common oral sites include the hard palate and gingiva.
• Presents as reddish-purple patches that may become nodular and ulcerate.

Diagnosis

• Clinical suspicion must be supported by biopsy.

HIV-Associated Periodontal Diseases

Linear Gingival Erythema

• Characterized by a red band involving the free gingival margins.
• Not related to the accumulation of dental plaque.

Necrotizing Conditions

• Necrotizing Ulcerative Gingivitis: Features punched-out ulceration of the interdental papillae.
• Destructive Periodontitis: Involves necrosis of gingival and periodontal tissues, sometimes resulting in exposure and sequestration of alveolar bone.
  • Necrotizing Ulcerative Periodontitis (NUP) is characterized by rapid bone loss.

HIV-Associated Lymphoma

Clinical Presentation

• Oral lesions present as soft tissue enlargement or ulcerative lesions of the gingiva.
  • Presents as large, ulcerated masses on the gingiva or palate.

Pathological Associations

• Increased incidence of Non-Hodgkin Lymphoma (NHL).
• Some cases are associated with Epstein-Barr Virus (EBV).

Acquired Immunodeficiency Syndrome²⁹

• AIDS is the final stage of HIV disease.
• Clinical Markers:
  • CD4 cell count: <200 cells/mm³
  • CD4 cell %: <14%
• Highly active antiretroviral therapy (HAART) has significantly improved the quality and length of survival for many patients.

Diagnosis and Key Points

Clinical and Laboratory Diagnosis

• Diagnosis may be clear when a patient presents with obvious lesions such as Hairy Leukoplakia (HL), candidiasis, or Kaposi’s sarcoma.
• Serological Confirmation: Necessary via Enzyme-Linked Immunosorbent Assay (ELISA).
• Confirmatory Testing: HIV P24 antibody confirmed by Western Blot.
• Viral Detection: Polymerase Chain Reaction (PCR) is used to detect HIV RNA.

Summary of HIV Infection

• Caused by a retrovirus.
• Transmitted sexually, through IV drug abuse, and via blood & blood products.
• Characterized by progressive deterioration of cell-mediated immunity.
• Oral signs and symptoms may be the initial manifestation of the disease.
• Oral candidiasis is the most prevalent oral lesion.
• Hairy leukoplakia may indicate progression to AIDS.
• Kaposi’s sarcoma and lymphomas often occur in the oral regions.
• Associated with neurological and psychological disorders.
• Death is mainly due to opportunistic infections.

Dental Management of HIV Patients

Responsibilities and Clinical Guidelines

• Referral: Refer to a specialist if a diagnosis has not yet been made.
• Knowledge: Understand the disease progression and management strategies.
• Clinical Care:
  • Provide oral health care, specifically to avoid
    • Avoid aggressive surgery if the patient is severely immunocompromised. causes of infection or pain.
  • Avoid needle stick accidents.
  • Avoid surgery where possible.
  • Treat xerostomia.
• Patient Education: Provide oral health education to the patient.
• Ethics and Safety:
  • Treat the diagnosis with strict confidentiality.
  • Avoid drug interactions with antiretroviral agents.
  • Maintain strict adherence to infection control measures.

Footnotes

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