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Be aware of the range of congenital and acquired immunodeficiency syndromes

Immunodeficiencies may be congenital or acquired and any part of the innate or adaptive immune system may be affected.

Congenital immunodeficiency is relatively rare. They may affect phagocytes, complement production/ activation, B cells, T cells or a combination.

 Acquired immunodeficiency, other than AIDS, may be secondary to other diseases but it is often iatrogenic. Acquired immunodeficiency may affect phagocytes, B cell, T cells or a combination.

    The most important acquired immunodeficiency syndrome is AIDS caused by human immunodeficiency virus (HIV). However, there are many other important causes of acquired immunodeficiency including leukaemia, lymphoma, multiple myeloma, splenectomy, corticosteroid therapy and chemotherapy. 


How are congenital immunodeficencies managed? Give examples of B and T cell deficiency

The congenital immunodeficiencies are rare and their management is specialised. They are the province of the paediatrician and the immunologist.

B-Cell deficiency

  •     X-linked hypogammaglobulinaemia (Bruton syndrome): recessive, early presentation, low IgA and IgM, no tonsils
  •     Mature B cells are not generated => lack of antibodies

T-cell deficiency

  •     DiGeorge Syndrome: CATCH-22 (cardiac abnormality esp tetralogy of Fallot, abnormal facies, thymic aplasia, cleft palate, hypocalcaemia/hypoparathyroidism)
  •     Absent thymus (T cells unable to mature)


Describe SCID, Ataxia Telangiectasia and CGD

Severe Combined Immunodeficiency (SCID)

  •     Recessive, low B and T cells, treated by bone marrow transplant
  •     SCID involves defective antibody response due to direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells.
  •     Most severe form of primary immune deficiency

Ataxia telangiectasia:

  •     Recessive, thymic hypoplasia, low B cells (due to low T helper cells)
  •     Treated by bone marrow transplant

Neutrophil defect

  •     Chronic granulomatous disease
  •     X-linked recessive, persistent infections of skin, respiratory and Gi tract
  •     Neutrophils present but do not function properly – defective bacterial killing by neutrophils (so bacteria cannot be successfully eliminated)
  •     Treated by bone marrow transplant


Describe the management of acquired immunodeficiencies

The major acquired immunodeficiencies will be seen in the context of infectious disease units, haematology, oncology and transplantation


Give examples of acquired B and T cell deficiencies

Acquired B Cell Immunodeficiency

  •     Hypogammaglobulinaemia (low levels of all immunoglobulins) can occur in chronic lymphatic leukaemia and other lymphoproliferative disorders, myeloma (dedicated to the production of 1 immune component at the deteriment of others), nephrotic syndrome (due to loss of immunoglobulins at glomerulus)

Acquired T Cell immunodeficiency

  •     Can occur in HIV, chemotherapy, Hodgkin’s disease, immunosuppression e.g. transplantation

Radiotherapy, Chronic Lymphatic Leukaemia and Malnutrition can reduce both B and T cell levels. 


What's the difference between neutropenia and myelodysplasia?

Neutropenia: not enough neutrophils, risk of developing neutropenic sepsis

Myelodysplasia: present but neutrophils are not functioning


Describe HIV disease

    HIV infection

    Virus infects via CD4 molecule on T helper cells => decreased T helper cells (low CD4 count)

    Affects T and B cell responses

    Lymphopenia and alterations in T cell subsets common

    Opportunistic infections


Describe the range of opportunistic pathogens in HIV


  • Pneumocystis jiroveci (Carinii) – pneumonia
  • Candida albicans – GIT (thrush)
  • Aspergillus fumigatus (very rarely affects healthy people, normally affects immunosuppressed hosts) – pneumonia
  • Histoplasma capsulatum – disseminated
  • Cryptococcus neoformans – meningo-encephalitis, pneumonia


  • Tuberculosis
  • Mycobacterium avium-intracellulare infection (MAI) – atypical mycobacterial infection 


  • Cryptosporidia – GIT
  • Isospora – colon (Cystoisospora belli)
  • Toxoplasma gondii (normally completely silent in healthy people) – CNS, eyes, lymph nodes


  • Cytomegalovirus (CMV) – GIT, CNS etc
  • Herpes zoster – shingles
  • Herpes simplex – muco-cutaneous, can affect eye

    Other bacteria

  • Haemophilus influenzae
  • Streptococcus pneumoniae


Describe Pneumocystis Jiroveci

    Atypical pneumonia in appropriate clinical setting should prompt investigation

    Diagnosis by direct microscopy of broncho-alveolar lavage (inject sterile water during bronchoscopy and collect sample)

    If suspicion is high, treat empirically with cotrimoxazole 


Describe Candida albicans

    Oral/oesophageal disease common

    Occasionally systemic (usually when immune system is really low)

    Diagnosed clinically – white plaques

    Treatment – fluconazole or related drugs


Describe Cytomegalovirus

    Usually reactivation of old infection (e.g. after low-dose steroid treatment)

    Subclinical CMV common in normal people

    Pneumonitis, oesophagitis, colitis, hepatitis

    Treatment – acyclovir/gancyclovir


Describe Herpes Zoster and Herpes Simplex

Herpes zoster

  •     Shingles – reactivation
  •     Vesicular rash
  •     May be extensive and severe
  •     Limited by the midline, e.g. limits by the ophthalmic division of the trigeminal nerve
  •     May involve conjunctivae

Herpes simplex

  •     Skin lesions, encephalitis, systemic
  •     Treatment: acyclovir/gancyclovir
  • Mycobacterium tuberculosis
  •     Common in HIV patients but all immunocompromised patients at risk


Describe MAI and EBV

Mycobacterium avium intracellulare

  •     May cause systemic infection, GI disturbance etc
  •     Large numbers of organisms usually present

Epstein Barr virus (EBV)

  •     Reactivation of infection common
  •     Post-transplant lymphoproliferative disorder
  • B cell proliferation driven by EBV, due to therapeutic immunosuppression after organ transplantation
  • Mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia…may progress to lymphoma
  • May spontaneously regress on reduction or cessation of immunosuppressant medication, and can also be treated with addition of anti-viral therapy. In some cases it will progress to non-Hodgkin’s lymphoma and may be fatal.


Describe the JC and BK viruses

v JJC virus (John Cunningham Virus – JCV)

    Human polyomavirus which is genetically similar to BK and causes progressive multifocal leukoencephalopathy (PML) and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with drugs intended to induce a state of immunosuppression (e.g. organ transplant patients).

v BK(polyoma)virus

    Widespread but many people infected are symptomatic. If symptoms do appear, they tend to be mild: respiratory infection or fever. These are known as primary BK infections.

    The virus then disseminates to the kidneys and urinary tract where it persists for the life of the individual. It is thought that up to 80% of the population contains a latent form of this virus, which remains latent until the body undergoes some form of immunosuppression. Typically, this is in the setting of kidney transplantation or multi-organ transplantation.

    Presentation in these immunocompromised individuals is much more severe. Clinical manifestations include renal dysfunction (seen by a progressive rise in serum creatinine) and an abnormal urinalysis revealing renal tubular cells and inflammatory cells.


What are opportunistic infections and give some examples of opportunistic pathogens

Opportunistic infections are the type of infection that occurs when the immune system is compromised and is related to the defective components. Opportunistic pathogens for the types of immune dysfunction are listed below:

  •     Phagocyte defects: Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Candida albicans, Aspergillus fumigatus,
  •     Complement defects: Streptococcus pneumoniae, other streptococci, Haemophilus influenzae, Neisseria meningitidis
  •     Antibody deficiency: Campylobacter species, Mycoplasma species, Echovirus, Listeria, Legionella, Salmonella, Mycobacterium tuberculosis, Atypical mycobacteria, Herpes zoster, Herpes simplex, CMV, EBV, Measles, Papova viruses, Candida, Cryptococcus, Nocardia, Pneumocystis, Histoplasma


Describe the sites of haemopoiesis in the foetus, child and adult 


  •     0-2 months = yolk sac
  •     2-5 months = liver and spleen
  •     5-9 months = bone marrow


  •     Bone marrow – most bones


  •     Bone marrow: vertebrae, ribs, sternum, sacrum and pelvis, proximal ends of femur (central skeleton)


Describe the structure of bone marrow

    RBC, platelets and most WBC are produced here

    Soft, spongy, gelatinous tissue found in the hollow spaces in the interior of bones

    Consists of stem cells supported by stroma

    Red marrow (medulla ossium rubra) – mainly contains haematopoietic tissue

    Yellow marrow (medulla ossium flava) – mainly fatty tissue

    All marrow at birth is red

    Half of marrow is red in adults, rest converted to yellow marrow (less cellular, more fat spaces)


Outline haemtopoiesis

    Myeloid – white cells

  • Myeloblast (high nuclear/cytoplasmic ratio) => Promyelocyte => Myelocyte => Metamyelocyte => Band cell => Neutrophil
  • Similar process for eosinophils, monocytes and basophils

    Myeloid – red cell

  • Proerythroblasts => Early normoblast => Intermeidate normoblasts => Late normoblasts => Reticulocyte (RNA still present) => Red cell
  • Haemoglobinisation of cytoplasm => nuclear maturation => finally nuclear extrusion 


Describe platelet production

Megakarycotes stay in the bone marrow and produce platelets

    Cells increase in size and replicates its DNA

    Platelets ‘bud’ from the cytoplasm

     Platelet production is controlled by thrombopoietin (TPO)


Describe the spleen including functions

    Surrounded by capsule

    Consists of:

  • Red pulp: sinuses lined by endothelial macrophages and cords (full of reticuloendothelial cells)
  • White pulp: similar structure to lymphoid follicles

    Blood enters via the splenic artery

  • White cells and plasma preferentially pass through the white pulp
  • Red cells preferentially pass through the red pulp

Functions of the spleen (essentially a filter organ)

  •     Sequestration and phagocytosis – old/abnormal (damaged/defective) red cells removed by macrophages
  •     Blood pooling – platelets and red cells can be rapidly mobilised during bleeding (to keep circulating volume up)
  •     Extramedullary haemopoiesis – pluripotential stem cells proliferate during haematological stress or if marrow fails (e.g. myelofibrosis)
  •     Immunological function – 25% of T cells and 15% of B cells are present in the spleen


What are possible causes of splenomegaly?

    Back pressure ~portal hypertension in liver disease

    Overworking red pulp or Overworking white pulp e.g. in malaria

    Reverting to what it used to do ~ extramedullary haemopoiesis

    Expanding as infiltrated by cells which shouldn’t be there

  • Cancer cells of blood origin e.g. leukaemia
  • Other cancer metastases

    Expanding as infiltrated by other material e.g. in Gauchers (genetic disorder in which glucocerebroside accumulates particularly in white blood cells, especially macrophages and collect in the spleen, liver, kidneys, lungs, brain and bone marrow).


Describe different causes for different sizes of splenomegaly. What are symptoms?

    Massive: chronic myeloid leukaemia, myelofibrosis, chronic malaria

    Moderate: as above, also lymphoproliferative disorders, myeloproliferative disorders, liver cirrhosis with portal hypertension

    Mild: as above, also infections including glandular fever, infectious hepatitis, endocarditis, sarcoidosis, AIHA, ITP, SLE

    Symptoms include early satiety, left sided back pain


Describe hyposplenism

    = Lack of functioning splenic tissue

    Causes: sickle cell disease (patients are treated as if the spleen has been taken out as it becomes a withered organ), coeliac disease, splenectomy

    Blood film reveals Howell Jolley bodies (DNA remnants) – cannot be removed.

    Patients at risk of overwhelming sepsis, particularly from encapsulated organisms e.g. Pneumococcus, Haemophilus influenza and Meningococcus 


What is hyposplenism, and what are the different types?

Cytopenia is a reduction in the number of blood cells. It takes a number of forms:

    Low red cell count = anaemia

    Low white blood = leucopenia

    Low neutrophil count = neutropenia

    Low platelet count = thrombocytopenia

    Low red blood cells, white blood cells and platelets = pancytopenia


What is thrombocytopenia and what could it be due to?

Low platelet count (thrombocytopenia) can be either due to reduced production (low number of megakaryocytes) or increased removal (normal concentration of megakarycotes)


What factors in increased removal could lead to thrombocytopenia?

Non-immune destruction

  • E.g. microangiopathic haemolytic states
  • Thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), haemolytic-uraemic syndrome (HUS) etc
  • Usually due to a pathological activation of coagulation => numerous microthrombi are formed in the circulation => this leads to consumption of clotting factors and platelets, and a haemolytic anaemia
  • E.g. cardiopulmonary bypass surgery (platelets become very sensitive, aggregate and stick to tubes and each other)

Immune destruction

  • Immune thrombocytopenic purpura (ITP) is the most common cause – autoantibodies against GP IIb/IIIa and GP Ib/IX (specific glycoproteins)
  • Can be secondary to autoimmune disease e.g. SLE and lymphoproliferative disorders e.g. lymphoma, chronic lymphatic leukaemia
  • Treated with immunosuppression (corticosteroids or IVIG (intravenous immunoglobulin G) first line)
  • Can occur de novo especially in children after URT. Treatment for children tends to be observe as immune destruction is normally self-limiting.
  • Platelet transfusions do not work – as the transfuse platelets get destroyed too

Splenic pooling


What factors in reduced production could lead to thrombocytopenia?

B12/folate deficiency ~ failure of the building blocks

Infiltration of the bone marrow by cancer cells or fibrosis

Aplastic anaemia ~ an empty marrow

Drugs – chemotherapy, antibiotics, including chloramphenicol and co-trimoxazole

Viruses – HIV, infective hepatitis, EBV, CMV


What is Neutropenia and what are possible causes?

    Neutrophil count below <1.5x10^9/L

    Could be due to reduced production or increased removal. Increased removal could be due to immune destruction or splenic pooling

    Reduced production

  • B12/folate deficiency
  • Infiltration by malignancy or fibrosis
  • Aplastic anaemia
  • Drugs – chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDs
  • Viruses
  • Congenital disorders e.g. cyclic neutropenia


What could Pancytopenia be due to?

Pancytopenia can occur due to pooling of blood in the enlarged spleen = hypersplenism. Pancytopenia can be due to reduced production or increased removal (immune destruction or splenic pooling).

    B12/folate deficiency

    Malignancy or fibrosis

    Idiopathic immune aplastic anaemia

    Drugs – chemotherapy, antibiotics, anticonvulsants, psychotropic drugs, DMARDs

    Viruses – EBV, viral hepatitis (non-A, non-B, non-C usually), HIV

    Congenital bone marrow failure e.g. Fanconi’s anaemia, dyskeratosis congenita


Describe Aplastic Anaemia

    Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin (fibrosis)

    Idiopathic aplastic anaemia

  • Thought to be due to T-cell mediated destruction of stem cells (immune condition)
  • No secondary cause found e.g. drugs, congenital disorder, viruses