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.
- X-linked hypogammaglobulinaemia (Bruton syndrome): recessive, early presentation, low IgA and IgM, no tonsils
- Mature B cells are not generated => lack of antibodies
- 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
- Recessive, thymic hypoplasia, low B cells (due to low T helper cells)
- Treated by bone marrow transplant
- 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
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
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
- 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
- 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
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
- 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
- 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).
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)
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
- 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
= 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?
- 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 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
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
- B12/folate deficiency
- Infiltration by malignancy or fibrosis
- Aplastic anaemia
- Drugs – chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDs
- 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).
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
What malignancies can cause Pancytopenia?
- Acute and chronic leukaemia
- Myelodysplastic syndromes – clonal disorder leading to ineffective and disordered haemopoiesis
- E.g. prostate, breast and lung cancer (metastases)
What are the clinical consequences of severe thrombocytopenia?
Severe bleeding after trauma
Intracranial haemorrhage (rare)
Occasionally some haematuria
Describe the consequences of neutropenia?
Severe life threatening bacterial infection
Severe life threatening fungal infection (high cause of mortality)
Neutropenic sepsis is a medical emergency
Describe the symptoms of pancytopenia
Symptoms of anaemia: fatigue, dizziness, chest pain, shortness of breath etc
Symptoms of thrombocytopenia: bleeding, bruising etc
Symptoms of neutropenia: infection, apthous mouth ulcers, fevers etc
Symptoms of underlying cause