Host defence mechanisms and immunodeficiency disorders

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Chapter 59 Host defence mechanisms and immunodeficiency disorders

Steve Wesselingh, Martyn AH. French

There is a coordinated immunological response to infection involving both cellular and humoral components. The outcome of an infection will be determined by the balance between the body’s ability to eliminate invading microorganisms and the microorganism’s virulence. Humans have diverse host defence mechanisms to protect the different anatomical compartments of the body from a great variety of microorganisms (Table 59.1). There are many ways in which the immune system can be defective, leading to an increased propensity to infections. The immune response also needs to be controlled to avoid inappropriate and excessive activation, which may damage the host. A certain degree of host damage is inevitable during the response to infection, particularly if there is systemic activation resulting in disseminated intravascular coagulation (DIC) and an excessive inflammatory response.

Table 59.1 Host defence mechanisms

Physical barriers
Skin and mucosal surfaces
Cilia
Fever
Lysozyme
Lactoferrin
Acute-phase proteins, e.g. C-reactive protein
Fibronectin
Immune system, including secondary mediators
Other mediators of inflammation
Kinins
Vasoactive amines
Coagulation system

INNATE IMMUNE RESPONSES

The immune system is capable of reacting to microorganisms without having been previously exposed to antigens from those microorganisms. This innate immune system consists of plasma proteins, including alternative-pathway components of the complement system and mannose-binding lectin (MBL), a subset of lymphocytes with cytotoxic activity (natural killer or NK cells), and some macrophage functions. Innate immune responses provide a first line of defence against many pathogenic microorganisms.

ACUTE-PHASE REACTION

The acute-phase reaction is a response of the haematopoietic and hepatic systems, involving at least 20 plasma proteins and the cellular components of the blood. The reaction occurs within hours of acute physical stress or infection. The functions of many of these acute-phase proteins remains unclear, but teleologically, they should be assumed to be beneficial to the patient. The falls in haemoglobin, serum iron and albumin are all normal in the acute-phase reaction. Most of the proteins are inflammatory mediators or inhibitors of transport proteins. Fibrinogen, the bulk protein of the coagulation system, is one of the plasma proteins to show the greatest rise in the acute-phase reaction, and is responsible for the elevation in the erythrocyte sedimentation rate. The fall in albumin is due to redistribution and decreased synthesis and generally does not require supplementation.

THE ADAPTIVE IMMUNE SYSTEM

Adaptive immune responses are characterised by specificity, memory, amplification and diversity. The specificity of an immune response against a particular antigenic component of a microorganism, and the memory which results in a prompt response on subsequent exposures, is determined by lymphocytes and antigen receptors on their surface. Amplification and diversity of immune responses are regulated by cytokines, which are secreted by lymphocytes and other cells, and through the effects of various lymphocyte surface molecules, including adhesion molecules and co-stimulatory molecules. Cytokines have various activities, the most important of which are cell activation (e.g. interferon-gamma (IFN-γ)), regulation of immune responses (e.g. interleukin (IL)-10) and proinflammatory effects (e.g. tumour necrosis factor (TNF)) and lymphotoxins).

ANTIGEN PRESENTATION

The most important events in the initiation of an immune response are the processing and presentation of fragments of the microorganism in a form which makes the fragments antigenic to lymphocytes. Major histocompatibility complex (MHC) class I (human leukocyte antigen (HLA)-A, B, C) and class II (HLA-DR, DP, DQ) molecules are the major cell-surface antigen presentation molecules. These molecules also determine the nature of the subsequent response against the antigen. Class I MHC molecules are present on most nucleated cells, and present processed endogenous peptides (such as fragments of viruses) to the antigen receptor (T-cell receptor; TcR) of T cells expressing CD8 molecules. Class II MHC molecules present antigenic fragments of microorganisms which are exogenous to cells and have been taken into the cell by phagocytosis, in the case of macrophages and monocytes, or by binding to antigen-specific surface immunoglobulins (the B-cell antigen receptor), in the case of B cells. Antigens presented on class II MHC molecules bind to TcRs on CD4+ T cells.

T CELLS AND B CELLS

CD8+ T cells have a cytotoxic effect on cells expressing class I MHC-associated viral antigens, resulting in the death of the cell and inhibition of viral replication. Antigen-induced stimulation of CD4+ T cells results in activation of the T cell and the expression of cell-surface molecules and secretion of cytokines with immunoregulatory effects. These immunoregulatory molecules augment the functions of many other cells, including B cells, T cells and macrophages (T-cell help). A response to an antigen directed by CD4+ T cells may also elicit macrophage activation and killing of the microorganism expressing that antigen. Activation of macrophages by CD4+ T cells is critically dependent on the production of IFN-γ.

The activation and proliferation of T cells occur under the influence of cytokines and other regulatory molecules, including co-stimulatory molecules such as the ligand of the B-cell membrane molecule CD40 (CD40L). Proliferating B cells differentiate into plasma cells, which secrete immunoglobulins with antibody activity against the initiating antigen. Nine isotypes of immunoglobulin can be produced, each of which has a different function.

IMMUNOGLOBULINS AND ANTIBODIES

Immunoglobulin M (IgM) is a large pentameric molecule, which is particularly effective as a bacterial agglutinator and activator of the complement system, and has its major effect within the circulation. IgA1 and IgA2 are produced at secretory surfaces, such as the mucosa of the gut and respiratory tract, and also in the breast, where IgA is a major constituent of the colostrum and provides secretory antibody to the gut of the neonate. IgE antibodies are also produced at mucosal surfaces where they form an important part of the immune response against parasitic infections. Antibodies of the IgG1 and IgG3 subclass are particularly effective at activating the complement system and binding to Fc receptors on phagocytic cells. IgG2 antibodies are mainly active against polysaccharide antigens, such as those present in bacterial cell walls. The functions of IgG4 antibodies are unclear.

SECONDARY ANTIBODY FUNCTION

The elimination of a microorganism by antibodies usually requires the activation of a secondary effector mechanism, of which there are several. Antibodies complexed with antigens activate the complement system through the classical pathway. The complement system may also be activated directly by components of microorganisms through the alternative pathway or MBL pathway. Activation of the complement system results in the generation of biologically active molecules, such as C3b, which is an important opsonin, and the activation of the membrane attack complex (MAC), which lyses bacterial cell walls. Like C3b, antibodies of the IgM, IgG1 and IgG3 isotype are also important opsonins. These molecules, when bound to the surface of a microorganism, facilitate their opsonisation and phagocytosis. These effects of complement and antibody are mediated through complement receptors (CRs) and receptors for the Fc portion of the immunoglobulin molecules (Fc receptors) on the surface of phagocytic cells such as neutrophils and macrophages.

DIVERSITY OF IMMUNE RESPONSES

The type of immune response produced against a microorganism varies according to the nature of the infecting organism. Thus, virus-infected cells elicit a cytotoxic CD8+ T-cell response; intracellular pathogens such as mycobacteria and protozoa elicit a CD4+ T-cell response, which results in macrophage activation; encapsulated bacteria elicit an opsonising antibody response; and some bacteria such as Neisseria spp. elicit a complement-activating antibody response, which lyses the cell wall of the bacterium. The nature of the immune response is regulated by cytokines, which provide T-cell help (Th) in the course of an immune response. Thus, IL-2, IL-12 and IFN-γ production induces a predominantly cellular immune response (Th1), whereas the production of IL-4 and IL-13 induces a predominantly antibody-mediated immune response (Th2).

IMMUNE DEFECTS UNDERLYING IMMUNODEFICIENCY DISORDERS

Defects of the immune system may give rise to immunodeficiency disorders, which are generally of five types: antibody deficiency, complement deficiency, cellular immunodeficiency, combined immunodeficiency (T cells, B cells and NK cells) and phagocyte dysfunction.

ANTIBODY DEFICIENCY

A deficient systemic antibody response most commonly results in a lack of opsonising antibody, and a propensity to infections with encapsulated bacteria such as pneumococci or Haemophilus influenzae. Recurrent respiratory tract infections including sinusitis are therefore the most common complication of this type of immune defect. Chronic echovirus infections of the nervous system and infection with some mycoplasmas may also occur in patients with severe primary immunoglobulin deficiency (agammaglobulinaemia).

Deficient secretory antibody responses are common in patients with IgA deficiency, but most affected individuals are able to produce compensatory secretory IgM or IgG antibody responses and do not suffer from infections.

CELLULAR IMMUNODEFICIENCY

Impairment of cell-mediated immune responses leads to an increased propensity to infection with microorganisms which are normally controlled by cellular immune responses (Table 59.2). These microorganisms are often pathogens that replicate intracellularly (intracellular pathogens) and cause persistent (latent) infections that reactivate when the cellular immune response against them becomes ineffective.

Table 59.2 Microorganisms that most commonly cause disease in patients with cellular immunodeficiency

Mycobacteria Mycobacterium tuberculosis
Non-tuberculous mycobacteria
Bacteria Salmonella spp.
Shigella spp.
Listeria monocytogenes
Fungi and yeasts Candida spp. (mucosal infections)
Pneumocystis jiroveci
Cryptococci
Aspergillus spp.
Protozoa Toxoplasma gondii
Cryptosporidia
Viruses Herpes simplex viruses
Cytomegalovirus
Varicella-zoster virus
Epstein–Barr virus
Molluscum contagiosum virus
JC virus (cause of progressive multifocal leukoencephalopathy)

COMPLEMENT COMPONENT DEFICIENCY

Complement-mediated lysis of bacterial cell walls is a critical mechanism in the immune response against certain bacteria, especially Neisseria spp. and related bacteria such as Moraxella spp. and Acinetobacter spp. Deficiency of complement components, particularly MAC components (C5–C9), may therefore result in infection with these bacteria. C3b is an important opsonin and C3 deficiency will often impair phagocytosis of bacteria. Deficiency of classical pathway components may also result in impaired antibody responses.

PHAGOCYTE DEFECTS

Depletion or functional impairment of phagocytes results in an increased propensity to bacterial and fungal infections, particularly infection with Staphylococcus aureus, Gram-negative enteric bacteria, Candida spp. and Aspergillus spp. Fungal and yeast infections are often systemic in patients with severe neutropenia, indicating the importance of phagocytes in the systemic immune response against these microorganisms.

Phagocytosis of a bacterium or fungus by a neutrophil leukocyte or macrophage is dependent on chemotactic attraction of phagocytes to the site of infection, their adhesion to endothelial cells via adhesion molecules such as integrins, binding to opsonins on the microorganism, ingestion and intracellular killing. Intracellular killing involves both oxidative and non-oxidative mechanisms. Primary or acquired defects of phagocytes may result in localised pyogenic infections or pneumonia. However, in the neutropenic patient, localised infections may show little inflammatory reaction and overwhelming systemic infections are common.

IMMUNODEFICIENCY DISORDERS

Immunodeficiency disorders are classified as primary or acquired. Primary immunodeficiency disorders are the result of a developmental anomaly or a genetically determined defect of the immune system. Genetically determined defects are usually of two types:

1 the consequence of an absent or non-functional gene product, which is critical for the normal development or function of a component of the immune system
2 aberrant regulation of lymphocyte differentiation, which is probably determined by the products of several genes and possibly by environmental factors

Immunodeficiency disorders caused by the latter type of defect usually present later in life than congenital immunodeficiency caused by a non-functioning gene product.

Acquired immunodeficiency disorders are more common than primary immunodeficiency disorders and may present at any time after early childhood. Most result from an immune defect that is a consequence of a disease process, infection or complication of a therapeutic procedure such as splenectomy, immunosuppressant therapy or haemopoietic stem cell transplantation (HSCT).

Diagnosis of an immunodeficiency disorder in a patient with an abnormal propensity to infections is dependent on the demonstration of an immune defect, as indicated in Table 59.3.

Table 59.3 Tests of immunocompetence

Antibody-mediated immunity
Serum immunoglobulins, including IgG subclasses
Systemic antibody responses (after vaccination if necessary)
Polysaccharide antigens, e.g. pneumococcal
Protein antigen, e.g. tetanus toxoid
Blood B-cell (CD19+) counts
Cell-mediated immunity
Delayed-type hypersensitivity (DTH) skin test responses to antigens
Blood T-cell (CD3+) and T-cell subset (CD4+ or CD8+) counts
Phagocyte function
Blood neutrophil numbers
Tests of oxidative killing mechanisms, e.g. NBT test
Leukocyte expression of CR3 (a CD18 integrin)
Neutrophil migration assays
Bacteria or Candida killing assays
Complement system
Immunochemical quantitation of individual components
Functional assays of the classical pathway (CH50) or alternative pathway (AH50)

IgG, immunoglobulin G; NBT, nitroblue tetrazolium.

ANTIBODY DEFICIENCY

PRIMARY ANTIBODY DEFICIENCY DISORDERS

Failure of B-cell production or the presence of immature B cells due to a defect of differentiation is the cause of most primary antibody deficiency disorders.1 B cells are absent from blood and secondary lymphoid tissues in patients with X-linked agammaglobulinaemia (XLA) because mutations of the Btk gene on the X-chromosome result in the absence of a B-cell tyrosine kinase necessary for the maturation of pre-B cells to B cells in the bone marrow. In the hyper-IgM immunodeficiency syndrome, B cells are able to differentiate into plasma cells secreting IgM, but not IgG or IgA. The X-linked form of this condition results from mutations in the gene encoding CD40L, which is critical in delivering a T-cell signal to differentiating B cells.

Common variable immunodeficiency (CVID) and IgA deficiency appear to be the consequence of immunoregulatory defects which result in impaired B-cell differentiation. Severe immunoglobulin deficiency (hypogammaglobulinaemia) and systemic antibody deficiency are characteristic of CVID, whereas most individuals with IgA deficiency are asymptomatic. Those IgA-deficient patients who suffer from recurrent infections often have a defect of systemic antibody responses, which commonly manifests as deficiency of an IgG subclass and/or impairment of antibody responses to polysaccharide antigens.2

The immunoregulatory defect underlying CVID and IgA deficiency sometimes results in an increased propensity to autoimmunity, which can include the production of anti-IgA antibodies. These antibodies may be a cause of anaphylactoid reactions to blood products containing IgA.

ACQUIRED ANTIBODY DEFICIENCY DISORDERS

B-cell chronic lymphocytic leukaemia or lymphoma and myeloma are commonly associated with reduced synthesis of normal immunoglobulins, which may result in immunoglobulin and antibody deficiency resulting in bacterial infections.3 A thymoma is a rare cause of immunoglobulin and antibody deficiency, and should be considered in a patient presenting with primary immunoglobulin deficiency after the age of 40.4 Impaired production of antibodies against polysaccharide antigens contributes to the susceptibility of asplenic patients to infection with encapsulated bacteria, such as pneumococci and meningococci, particularly in patients who had haematological malignancy.5

Drugs occasionally affect B-cell differentiation and cause immunoglobulin deficiency, particularly IgA deficiency. The most common offender is phenytoin. Most patients do not have antibody deficiency severe enough to cause infections. Intensive plasmapheresis may also cause severe immunoglobulin deficiency if immunoglobulin replacement is not used.

TREATMENT OF ANTIBODY DEFICIENCY DISORDERS

Infections can be prevented by regular infusions of intravenous immunoglobulin (IVIg) in patients with primary or acquired antibody deficiency. The usual dose is 300–500 mg/kg given monthly. Acute infections should be treated with appropriate antibiotics. The use of IVIg as an adjunct in the management of sepsis, particularly pneumococcal infections, has been suggested. In the absence of documented antibody deficiency there is no evidence to support this practice.

CELLULAR IMMUNODEFICIENCY

PRIMARY CELLULAR IMMUNODEFICIENCY

Complete or partial absence of the thymus gland resulting in depletion of T cells from blood and lymphoid tissue is the characteristic immunological abnormality in children with the Di George syndrome.6 Infections of the type listed in Table 59.2 occur from birth onwards. A less severe defect of cellular immunity is present in patients with chronic mucocutaneous candidiasis. This usually occurs in patients with the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED) syndrome, which results from a disorder of T-cell-processing in the thymus.7

ACQUIRED CELLULAR IMMUNODEFICIENCY

Acquired defects of cellular immunity are by far the most common cause of cellular immunodeficiency. Infection of cells of the immune system by human immunodeficiency viruses (HIVs) 1 and 2 is the most common (see Chapter 60). Less commonly, Hodgkin’s disease, T-cell lymphomas and sarcoidosis may also be complicated by opportunistic infections occurring as a consequence of cellular immunodeficiency. A thymoma is a rare cause of chronic mucocutaneous candidiasis which, like thymoma and immunoglobulin deficiency, occurs later in life.4

Suppression of cellular immune responses is an intended effect of many immunosuppressant drugs used to treat allograft rejection, graft-versus-host disease (GvHD), autoimmune diseases and vasculitis. However, opportunistic infections may be a complication of this type of immunodeficiency, and may cause severe morbidity and death.

TREATMENT OF CELLULAR IMMUNODEFICIENCY DISORDERS

Since most infections complicating cellular immunodeficiency are reactivated latent infections, an important aspect of management is prevention of infection by the use of prophylactic antimicrobial drugs, as exemplified by HIV-induced immunodeficiency.8 In circumstances of acquired cellular immunodeficiency it is essential to take into account the severity and duration of immunodeficiency. It is possible to predict the likelihood of infection and the likely pathogens by determining the degree of cellular immunodeficiency. This allows for appropriate decisions to be made regarding investigations, treatment and prophylaxis.

Acquired cellular immunodeficiency may be corrected, at least temporarily, by removing its cause (e.g. by suppressing HIV infection or ceasing immunosuppressive therapy). Thymus transplantation may be effective in children with thymus aplasia.

COMPLEMENT COMPONENT DEFICIENCY

Deficiency of complement components is an uncommon but often overlooked cause of recurrent bacterial infections.

PRIMARY COMPLEMENT DEFICIENCY

Congenital deficiency of C3 is extremely rare and usually causes a propensity to severe pyogenic infections. Deficiency of MAC components (C5–9) is more common, and should be considered in patients with meningococcal infections, particularly when the infections are recurrent.9 Deficiency of classical pathway components (C1, C2, C4) may also result in an increased propensity to infection with meningococci and some other bacteria, but most affected individuals do not experience recurrent infections.

ACQUIRED COMPLEMENT DEFICIENCY

Disease processes that cause persistent activation of the complement system may cause depletion of complement components, particularly classical pathway components. This can result in infections with Neisseria spp. or related bacteria, and sometimes overwhelming septicaemia when the complement deficiency is severe. Systemic lupus erythematosus, myeloma and chronic atrioventricular shunt infections are rare causes of complement component deficiency.

MANAGEMENT OF PATIENTS WITH COMPLEMENT DEFICIENCY

An awareness of the possibility of complement deficiency is the most important aspect of management. Replacement therapy is not available. If a complement component deficiency is identified, screening of family members should be considered.

PHAGOCYTE DISORDERS

PRIMARY DISORDERS OF PHAGOCYTOSIS

Congenital neutropenias are rare. Defects of phagocyte function usually affect chemotaxis, adhesion or intracellular killing, either alone or in combination. The best-characterised defect of phagocyte adherence results from a congenital absence of the β-subunit of CD18 integrins in patients with leukocyte adhesion deficiency syndrome type 1.10 Defects of intracellular killing are usually caused by a deficiency of microbicidal enzymes. In chronic granulomatous disease (CGD), deficiency of a phagosome enzyme (NADPH oxidase) results in ineffective oxidative killing mechanisms.11 CGD usually presents in childhood but may present in adults, even as late as the seventh decade.12 It should be considered in patients with recurrent abscesses or suppurative lymphadenitis, and in patients with pneumonia caused by Staphylococcus aureus or Aspergillus spp. infection.

ACQUIRED DISORDERS OF PHAGOCYTOSIS

Severe neutropenia may be complicated by bacterial or fungal infections. There are many causes of neutropenia, including autoimmune neutropenia, drug therapy and haematological diseases such as cyclic neutropenia, myelodysplastic syndromes and aplastic anaemia. Cytotoxic chemotherapy, used to treat various malignancies, commonly causes neutropenia, which is often complicated by severe bacterial and fungal infections.

MANAGEMENT OF PHAGOCYTE DISORDERS

Acquired neutropenia may be corrected by removing the underlying cause and/or use of granulocyte colony-stimulating factor (G-CSF). Febrile neutropenia requires investigation for the source of sepsis and empirical antibiotics. If fever persists antifungals should be added. IFN-γ therapy may be effective in patients with CGD.

COMBINED IMMUNODEFICIENCY DISORDERS

Several immunodeficiency disorders result from a combination of immune defects. Some combinations of congenital immune defects are so severe that death is a common occurrence, unless the defect can be corrected. Such conditions are classified as severe combined immune deficiency (SCID) syndromes.

PRIMARY COMBINED IMMUNODEFICIENCY

There are many primary combined immunodeficiency syndromes, which present in early childhood.13 Some are still classified descriptively, but the molecular defects have now been demonstrated for many of them. For example, defective expression of MHC class II molecules, adenosine deaminase (ADA) deficiency, and deficiency of the common γ-chain of the receptor for several interleukins (IL-2, 4, 7, 9, 15, 21) all result in a deficiency and/or functional impairment of B cells, T cells and sometimes NK cells. Deficiency of the interleukin receptor common γ-chain results from mutations of its gene on the X-chromosome and is the underlying defect of X-linked SCID.

TREATMENT OF PRIMARY COMBINED IMMUNODEFICIENCY

HSCT is the treatment of choice for many types of primary SCID, though enzyme replacement therapy can be effective in ADA deficiency and gene replacement therapy has been used to treat X-linked SCID. Antibody replacement with IVIg therapy and prophylaxis for opportunistic infections are also important in primary SCID.

ACQUIRED COMBINED IMMUNODEFICIENCY

Combined immune defects are a characteristic of several acquired immunodeficiency disorders.

Haemopoietic stem cell transplantation

Combined immune defects may result in severe infections in patients who have received an HSCT.14 Following transplantation, the recipient’s immune system is reconstituted with donor cells. A degree of immunocompetence is passively transferred from the donor to recipient by antigen-specific lymphocytes, but as this and any residual immunocompetence of the recipient declines, an immunodeficient state exists until the donor immune system is established. Consequently, both antibody-mediated and cell-mediated immunity are deficient in the first 3–4 months after transplantation and may remain deficient for a longer period of time in patients with GVHD. This combined immune defect is often compounded by neutropenia and/or the effects of corticosteroid or immunosuppressant therapy for GVHD. Defective antibody responses may persist for several years after transplantation, particularly antibody responses against polysaccharide antigens.

Critical illness

Many patients who are critically ill as a result of surgery, trauma, thermal injury or overwhelming sepsis also have acquired immune defects.15 These defects include abnormalities of cellular immunity, immunoglobulin deficiency and impaired neutrophil function. They appear to be associated with an increased propensity to infections and arise from abnormalities that are complex and multifactorial. Impairment of cell-mediated immune responses usually manifests as decreased T-cell proliferation and impaired delayed-type hypersensitivity responses, and probably results from a combination of factors, including the effects of anaesthetic drugs, blood transfusion, negative nitrogen balance and serum suppressor factors, including cytokines such as TNF. Phagocyte defects are mostly due to impairment of neutrophil chemotaxis by serum factors, and impaired intracellular killing. Deficiency of serum immunoglobulins also occurs, especially IgG deficiency, and may be associated with antibody deficiency. Serum leakage is a factor in patients with thermal injuries, and reduced synthesis and increased catabolism of immunoglobulins occur in many critically ill patients.

The correction of immune defects in critically ill patients has been intensely investigated, but no effective treatment regimen has been defined. General measures such as adequate nutrition, achieving a positive nitrogen balance and excision of thermally injured tissue are effective. Biological response modifiers, cytokine and mediator inhibitors, and IVIg therapy have all been evaluated. The number of acute infections, particularly pneumonia, can be reduced by the use of IVIg therapy, but patient survival is not increased. G-CSF levels are increased during critical illnesses and correlate with the severity of illness. Administration of G-CSF has been shown to be safe in intensive care patients with no apparent increases in acute respiratory distress syndrome or multiple-organ dysfunction. However there is no current evidence that the administration of G-CSF improves outcome and until further evidence is presented, G-CSF is not indicated in the treatment of critically ill intensive care unit patients.

Asplenia and hyposplenism

The spleen is an important part of the immune system’s response to infections, particularly blood stream infections. The most important splenic functions in this context are removal of opsonised microorganisms from the blood by splenic macrophages and production of an early antibody response to the polysaccharide antigens of encapsulated bacteria by IgM memory B cells (also known as mantle-zone B cells). In those people in whom the spleen is removed or does not function, best-practice guidelines recommend lifelong education, vaccination and appropriate use of antibiotics. The risk of severe life-threatening infection related to splenectomy alone is in the order of 1 in 500 per annum with 50% mortality. The most common organisms identified with overwhelming postsplenectomy infection (OPSI) include encapsulated bacteria, such as pneumococcus, Haemophilus infiuenzae and meningococcus, for which vaccines are available. Other bacteria, which are sometimes important, include group A Streptocccus, Capnocytophagia canimorsus following dog bites, Salmonella, Enterococcus and Bacteroides.

Pneumococcus, Haemophilus infiuenzae and meningococcus vaccines including regular boosters and annual infiuenza vaccine are recommended. This is consistent with US guidelines and broadly with UK guidelines, which make the last bacterial vaccine optional. Second, chemoprophylaxis with penicillin for at least 2 years after splenectomy, if the patient is not allergic, should be considered.

SUMMARY: APPROACH TO THE IMMUNODEFICIENT PATIENT

1 Determine: (a) type of immunodeficiency; (b) degree of immunodeficiency; and (c) duration of immunodeficiency.
2 Predict: (a) the likelihood of infection; and (b) the type of infection.
3 Commence: (a) empirical; and (b) prophylactic therapy.
4 Targeted diagnostic tests.

REFERENCES

1 Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med. 2000;343:1313-1324.

2 French MA, Denis K, Dawkins RL, et al. Infection susceptibility in IgA deficiency: correlation with low polysaccharide antibodies and deficiency of IgG2 and/or IgG4. Clin Exp Immunol. 1995;100:47-53.

3 Tsiodras S, Samonis G, Keating MJ, et al. Infection and immunity in chronic lymphocytic leukemia. Mayo Clin Proc. 2000;75:1039-1054.

4 Tarr PE, Sneller MC, Mechanic LJ, et al. Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature. Medicine (Baltimore). 2001;80:123-133.

5 Cherif H, Landgren O, Konradsen HB, et al. Poor antibody response to pneumococcal polysaccharide vaccination suggests increased susceptibility to pneumococcal infection in splenectomized patients with hematological diseases. Vaccine. 2006;24:75-81.

6 Hong R. The DiGeorge anomaly. Clin Rev Allergy Immunol. 2001;20:43-60.

7 Collins SM, Dominguez M, Ilmarinen T, et al. Dermatological manifestations of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-1093.

8 Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med. 2000;342:1416-1429.

9 Fijen CA, Kuijper EJ, te Bulte MT, et al. Assessment of complement deficiency in patients with meningococcal disease in The Netherlands. Clin Infect Dis. 1999;28:98-105.

10 Bunting M, Harris ES, McIntyre TM, et al. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands. Curr Opin Hematol. 2002;9:30-35.

11 Winkelstein JA, Marino MC, Johnston RBJr., et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79:155-169.

12 Schapiro BL, Newburger PE, Klempner MS, et al. Chronic granulomatous disease presenting in a 69 year old man. N Engl J Med. 1991;325:1786-1790.

13 Buckley RH. Advances in the understanding and treatment of human severe combined immunodeficiency. Immunol Res. 2001;22:237-251.

14 Ninin E, Milpied N, Moreau P, et al. Longitudinal study of bacterial, viral, and fungal infections in adult recipients of bone marrow transplants. Clin Infect Dis. 2001;33:41-47.

15 Napolitano LM, Faist E, Wichmann MW, et al. Immune dysfunction in trauma. Surg Clin North Am. 1999;79:1385-1416.

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