2 Secondary immunodeficiency and other host-defence syndromes

Classification of secondary immunodeficiency

Human immunodeficiency virus 1 and 2

Epstein–Barr virus

Other viral infections

Acute bacterial infections

Chronic bacterial sepsis

Bronchiectasis

Fungal and parasitic infections

Malignancy

Myeloma

Lymphoma: Hodgkin’s disease

Non-Hodgkin’s lymphoma

Chronic lymphocytic leukaemia (CLL)

Chronic myeloid leukaemia (CML) and myelodysplastic syndromes

Acute leukaemias

Bone marrow and stem cell transplantation

Acute leukaemias

Extremes of age: prematurity

Extremes of age: the elderly

Transfusion therapy

Chronic renal disease (nephrotic syndrome and uraemia)

Protein-losing enteropathy and liver disease (cirrhosis)

Metabolic disorders

Diabetes mellitus

Iron deficiency and nutritional status

Asplenia

Drugs and toxins

Burns

Thoracic duct drainage

Cardiac surgery in children

Physical and environmental factors

Proteus syndrome

Yellow nail syndrome

Cilial dyskinesia (Kartagener’s syndrome)

Young’s syndrome

Cystic fibrosis (CF)

Alpha-1-antitrypsin deficiency (α1-AT deficiency)

Acute bacterial infections:

Chronic bacterial and parasitic infections:

Malignancy.

Plasma cell tumours and related problems:

Lymphoma/leukaemia:

Extremes of age:

Transfusion therapy:

Drugs and biologicals:

Physical therapies:

Nutrition:

Chronic renal disease:

Gastrointestinal disease:

Metabolic disease:

Toxins:

Splenectomy:

Cardiac surgery (thymectomy).

Other host-defence disorders:

Burns.

Myotonic dystrophy.

It also infects other CD4⁺ cells (macrophages, dendritic cells) and other cells expressing CD4-like surface proteins (neuronal cells).

Macrophage tropic viruses use CCR5, and infect T cells poorly; T-cell tropic viruses use CXCR4 for entry and form syncytia.

Resistance to viral infection is associated with polymorphism in the chemokine receptors.

A viral isolate entering T cells via CD8 has been described.

Uptake of virus into phagocytic cells may be augmented by antibody, and complement. HIV activates complement.

High levels of viral replication may take place in lymph nodes.

Initial viraemia after infection is controlled by CD8⁺ cytotoxic T cells (increased cell numbers). The asymptomatic phase is characterized by strong cytotoxic responses, but viral replication still detectable intermittently, i.e. HIV is not a true latent virus.

The antibody response to major viral proteins appears after a lag phase of up to 3 months and persists through the asymptomatic phase but declines in late-stage disease.

Marked B-cell dysfunction with polyclonal increase in immunoglobulins and the appearance of multiple autoantibodies.

In the seroconversion illness there is a dramatic fall in CD4⁺ T cells and rise of CD8⁺ T cells. The levels of CD4⁺ T cells may drop to a level at which opportunistic infections may occur at this early stage (poor prognostic indicator). Levels then usually recover to within the low normal range. There is then a slow decline of absolute CD4⁺ T-cell count over time (years) following infection.

Passage to the symptomatic phase is characterized by a rapid drop in CD4⁺ T cells, loss of cytotoxic activity, and switch of virus type from slow-growing, non-syncytial-forming strains to rapidly growing, syncytial-forming strains (quasi-species evolving through lack of replicative fidelity and under immunological selection pressure). This is accompanied by the occurrence of opportunistic infections.

Activation of T cells enhances viral replication and hence CD4⁺ T-cell destruction. Therefore opportunistic infections enhance the self-destruction of the immune system. Long-term non-progressors and

patients responding to highly active antiretroviral therapy (HAART) show good proliferative responses to gag proteins. Progression has been associated with a switch from Th1 to Th2 responses.

HIV preferentially infects CD45RO⁺ cells but the depletion of T cells principally affects CD45RA⁺CD62L⁺ naive T cells.

T-cell depletion is caused by increased apoptosis, impaired production (HIV effects on thymus), and destruction of both infected and uninfected cells.

HIV replication is suppressed by natural CCR5 chemokine ligands, RANTES, MIP-1α, and MIP-1β, which are secreted by CD8⁺ T cells. SDF-1α is the natural ligand for CXCR4. High levels of chemokine production have been associated with resistance to infection.

The most accurate monitoring of disease is now available through measurements of viral load by quantitative PCR (viral load).

In the acute seroconversion illness, there is a sharp fall in absolute CD4⁺ T-cell numbers and an increase in CD8⁺ T-cell numbers with T-cell activation markers increased (IL-2 receptor (CD25) and MHC class II (DR)); this normally returns rapidly to normal as evidence of viral replication disappears. Persistent CD4⁺ T-cell lymphopenia after seroconversion illness is a poor prognostic sign indicating rapid progression to terminal illness.

Sequential monitoring of the CD4⁺ T-cell numbers provides guidance on the rate of progression of disease and identifies levels at which therapeutic interventions may be indicated (e.g. Pneumocystis prophylaxis at 0.2×10⁹/L CD4⁺ T cells).

Once the CD4⁺ T-cell count falls below 0.05×10⁹/L, further monitoring is of little clinical value (except psychologically to patients, who view cessation of monitoring as doctors giving up).

Successful treatment with HAART will lead to a rise of CD4⁺ T cells to within the normal range and suppression of viral load.

Immune function will recover in patients with a good response to HAART:

Serum immunoglobulins are usually polyclonally elevated (IgG levels >50g/L may be recorded); serial measurements have no clinical utility. Most of the antibody is either ‘junk’ or relates to an anamnestic response.

Autoantibodies may be detected (including antinuclear and dsDNA antibodies, anti-neutrophil cytoplasmic antibody (ANCA), and anti-cardiolipin). The presence of autoantibodies may cause serious diagnostic confusion, especially if the clinical presentation is atypical.

Rare patients, usually children, may suffer from panhypo-gammaglobulinaemia or specific antibody deficiency, presenting with recurrent bacterial infections; these patients may derive significant benefit from IVIg. It has been more difficult to demonstrate specific antibody defects in adults, although a subpopulation of adult patients do have recurrent sinopulmonary infections with Haemophilus and Pneumococcus: IVIg seems to be less helpful.

Serum β₂-microglobulin levels may be elevated, as a marker of increased lymphocyte turnover; however, the range of elevation in HIV+ patients is small compared with that seen in lymphoproliferative disease, and its value (except where CD4⁺ T-cell counts are unavailable) is small. Serum and urinary neopterin, a marker of macrophage activation, may also be elevated. There is little to choose between these two surrogate markers and viral load is much more clinically relevant.

IVIg may be helpful in certain HIV+ infants, although not in adults.

Other immunotherapies (interferons, IL-2) have been uniformly disappointing and are not used routinely. α-IFN enjoyed a vogue in the treatment of Kaposi’s sarcoma (due to HHV-8), but the latter responds better to cytotoxic therapy and radiation.

Use of passive immunotherapy has been disappointing.

No reliable vaccine is yet available, although trials are continuing on a number of candidate vaccines.

Good virological and immunological response to HAART.

Temporal association with the introduction of HAART, although may be delayed.

Associated with the presence of infection (either recognized or cryptic):

Features include:

Management is aggressive treatment of underlying infection.

Characterized by polyclonal lymphproliferation causing lymphadenopathy, fever, weight loss, leucopenia.

Histology of lymph nodes shows typical ‘onion-skin’ change.

Also seen in SLE, POEMS syndrome, and paraneoplastic pemphigus.

Caused by excessive IL-6 production.

May respond to antiviral drugs (HHV-8, HIV), rituximab, or possibly anti-IL6 monoclonal antibodies.

Following infection there is a B lymphoproliferation, triggered by cross-linking of the CD21, CD19, CD81 complex by the virus, which is controlled rapidly by cytotoxic T cells which form the ‘atypical mononuclear cells’ seen on smears. Both MHC-restricted and unrestricted cells are produced, with the latter directly recognizing a virally induced antigen on the cells (LYDMA (lymphocyte-determined membrane antigen)). The viral BZLF1 protein is a major target antigen.

Viral persistence occurs, with reactivation of infection in the immunocompromised (immunosuppressed patients, transplant recipients, HIV-infected patients), giving oral hairy leucoplakia, lymphocytic interstitial pneumonitis and lymphoma. Nasopharyngeal carcinoma also occurs, although other cofactors are likely to be involved.

In patients with a genetic predisposition (Duncan’s syndrome (XLPS), NK-cell deficiency (see Chapter 1)), severe or fatal infection can occur on first exposure to EBV.

Although infectious mononucleosis (glandular fever) is usually a self-limiting illness, some patients fail to clear the virus and develop an appropriate sequence of IgG antibodies. These patients have persistently positive IgM antibodies to EBV and have chronic symptoms (fatigue, malaise, sore throats).

In the acute phase of EBV infection there is suppression of mitogen and allogeneic responses. NK function is also abnormal even though cell numbers are increased. It has been shown that EBV-transformed cells secrete a homologue of IL-10. Monocyte chemotaxis is also abnormal.

EBV infection may cause severe B-cell lymphoproliferative disease in immunosuppressed patients and in patients after BMT. It also causes B-cell lymphomas, especially in solid organ transplant recipients on long-term immunosuppression.

Initial lymphopenia is followed by lymphocytosis of CD8⁺ T cells, which give rise to the atypical lymphocytes seen on blood films. However, monitoring of lymphocyte subpopulations is of little value, except in unusual variants of EBV infection.

There is usually an acute polyclonal rise in immunoglobulins, which may be associated with the production of autoantibodies.

Vaccines are in development, including peptide vaccines.

Adoptive immunotherapy with EBV-specific CTL is undergoing trials, especially in immunosuppressed or immunodeficient patients.

Early CD8⁺ T-cell lymphocytosis giving atypical lymphocytes on a blood film.

Proliferative responses are reduced during acute infections.

CMV infection of monocytes with production of an IL-1 inhibitor may be important.

Congenital CMV infection leads to a prolonged suppression of T-cell function, and may also suppress antibody production.

In BMT recipients, there may be prolonged suppression of myeloid differentiation.

Reactivation of the disease may occur in the context of immunosuppression (e.g. HIV, drug therapy).

High-titre anti-CMV antibodies in the form of IVIg may help to prevent infection.

Once infection is established treatment with antivirals (ganciclovir, foscarnet, cidofovir) is necessary. Valganciclovir is an oral prodrug.

Hypogammaglobulinaemia and a hyper-IgM syndrome, with transiently reduced CD40 ligand expression, have been reported.

Rubella appears to infect both T and B cells directly.

Acute measles depresses cutaneous type IV reactivity (tuberculin reactivity); this is transient. Similar effects occur with measles vaccines.

NK activity and immunoglobulin production are suppressed.

Acute measles may lead to reactivation of TB because of immunosuppression.

Acute measles may cause:

Early inactivated measles vaccines led to a response predominantly against viral haemagglutinin but not to the fusion protein, sometimes leading to an atypical wild-type infection due to inappropriate immune response.

Congenital infection with HBV leads to tolerance of the virus and chronic carriage.

5% of normal subjects do not make a humoral response to HBV vaccines after the normal 3-dose course (>100U). Where evidence of full seroconversion is required for occupation try the following:

May be seen in immune deficiencies (see Chapter 1)

Full immunological evaluation required.

Some patients have no identifiable immunological defect.

May respond to intralesional α-interferon or systemic γ-interferon-1b.

The potent contact sensitizer diphenylcyclopropenone (diphencyprone) may also be helpful (not readily available).

Cimetidine has been used: this is said to improve cell-mediated immunity by blocking T-cell H₂-receptors.

Imiquimod is a topical agent believed to act by local cytokine induction.

Irritant agents such as 5-fluorouracil and tretinoin can also be used.

Intralesional skin test antigens (mumps, Candida, and Trichophyton) have been used.

Laser surgery is useful, particularly in WAS, as it prevents excessive bleeding.

The role of HPV vaccine is uncertain, but may be beneficial in some cases.

Immunological abnormalities include variable lymphopenia, IgG subclass abnormalities, and atypical anti-nuclear antibodies.

May be transient or persistent.

Lymphopenia affecting CD4⁺ and CD8⁺ cells may be marked. Significant and temporary hypogammaglobulinaemia may be present (?release of immunosuppressive components from bacteria).

Massive acute-phase response with elevation of C-reactive protein (CRP) and other acute-phase proteins (complement, fibrinogen, protease inhibitors, α₂-macroglobulin (IL-6 carrier)), and a reduction in albumin (negative acute-phase protein).

Complement components will be consumed rapidly, but synthesis will be increased (all are acute-phase proteins), so measurements may be difficult to interpret. Functional assays of complement are usually highly abnormal.

Toxic shock may follow certain types of bacterial infection (staphylococci, streptococci) owing to release of ‘superantigenic’ toxins, which activate many clones of T cells directly, bypassing the need for MHC on antigen-presenting cells by binding directly to the T-cell receptor. Effects are likely to be due to cytokine excess.

Monitoring of the acute-phase response (CRP) gives a good indication of response to therapy.

Chronic antigenaemia will cause immune complex reactions and secondary hypocomplementaemia (e.g. subacute bacterial endocarditis (SBE)).

The acute phase becomes a chronic phase: anaemia of chronic disease, iron deficiency due to sequestration (defence against pathogen) (see ‘Iron deficiency and nutritional status’, p.111). There is the risk of amyloid development (see Chapter 14).

T-cell function may be significantly impaired.

Mycobacterial infection causes anergy to PPD and third-party antigens. 10% of TB cases do not respond to tuberculin.

Untreated leprosy is a potent suppressor of cell-mediated immunity: T-cell responses to mitogens and antigens are reduced.

Low complement (C3) and elevated C3d indicates immune-complex reaction (renal involvement likely); monitoring of functional haemolytic complement is not valuable.

Immunoglobulins are usually high (polyclonal stimulation ± monoclonal bands). Electrophoresis also shows elevated α₂-macroglobulin, reduced albumin; beware apparent monoclonal ‘bands’ from very high CRP (use specific antisera on immunofixation to demonstrate this).

Hypogammaglobulinaemia is rare: consider underlying immunodeficiency.

Measurement of in vitro T-cell function and lymphocyte markers is not valuable unless there is a suspicion that the infections are due to an underlying immunodeficiency.

Associated with deficiencies of host defence, but may be idiopathic.

Mucolytics (carbocisteine).

Nebulized antibiotics (colistin).

Treat underlying cause.

Meningococcal polysaccharide, and Salmonella O antigen), presumably through effects on the spleen. There appears to be little interaction between HIV infection and malaria where the two diseases overlap. Tropical splenomegaly due to vivax malaria is associated with a CD8⁺ T-cell lymphopenia and raised IgM.

Trypanosomes suppress cellular responses, but there is often a polyclonal increase of non-specific immunoglobulin, especially IgM.

Visceral leishmaniasis is characterized by a polyclonal hypergammaglobulinaemia, often massive, but with absent cell-mediated immunity until after treatment. Splenomegaly may be massive and there is often lymphopenia. The cachexia and lymphopenia are mediated by release of tumour necrosis factor-α (TNF-α) by infected macrophages.

Many parasites, including malaria and trypanosomes, escape immunological surveillance by antigenic variation. This occurs under selection pressure from the immune system. Other avoidance mechanisms include shedding of surface antigen complexed with antibody.

Autoimmunity may occur as a consequence of the chronic infection. Schistosomiasis is associated with anti-nuclear antibodies including anti-calreticulin antibodies. Onchocerciasis is also associated with anti-calreticulin antibodies (which cross-react with an onchocercal antigen).

Parasitic infections are associated with excess eosinophil and IgE responses.

Malignancy is also increased in patients with autoimmune disease, possibly secondary to immunosuppressive drug therapy, and in transplant patients who are immunosuppressed (skin tumours, carcinoma of the anogenital tract).

Abnormalities of T- and NK-cell function may be due to impaired surveillance or secondary to tumour/treatment.

T-cell defects include reduction of IL-2 and TNF-α production, and activation markers such as CD71 (transferrin receptor).

Cancer cells may release TGF-β, which reduces T-cell proliferative responses and macrophage metabolism, through inhibitors of complement.

Some tumours cause autoimmune responses due to inappropriate expression of antigens. These may lead to paraneoplastic phenomena, such as the Lambert–Eaton myasthenic syndrome (small cell lung carcinoma), due to an autoantibody against voltage-gated calcium channels, and neuronal and retinal autoantibodies in breast, ovarian, and colonic tumours.

Major immunosuppression may result from radio- and chemotherapy. This may be prolonged and lead to secondary infective complications.

Patients with significant and persistent infective problems post-treatment may warrant investigation of cellular and humoral immune function, depending on the type of infections. Lymphocyte surface markers, immunoglobulins, IgG subclasses, and specific antibodies to bacteria and viruses may be appropriate.

Paraneoplastic phenomena may suggest a search for unusual autoantibodies (voltage-gated calcium channels, cerebellar Purkinje cells, retinal antigens) (see Chapter 5).

In vitro stimulation of non-specific killers (LAK cell therapy) by IL-2, using either peripheral blood cells or tumour-infiltrating cells, has also been claimed to be beneficial in small open trials, but is even more toxic.

Other immunotherapies tried have included the use of non-specific immunostimulants such as BCG, Corynebacterium parvum, and Bordetella pertussis, often given intralesionally. Occasionally spectacular results have been achieved.

α-IFN has been used with success in certain lymphoid disorders (hairy cell leukaemia, plateau-phase myeloma).

Monoclonal antibodies are now being introduced targeted against tumour-specific antigens, e.g. CD20 (rituximab) in lymphoma, anti-CD52 in CLL, and anti-Her-2 (trastuzumab) in breast cancer.

Monoclonal antibodies have also been used to target radiopharmaceuticals to tumours where the antibody itself may kill tumour cells poorly (e.g. anti-CD20 monoclonals labelled with yttrium-90).

A major benefit of immunotherapy has been in the use of colony-stimulating factors to protect the bone marrow, allowing higher doses of conventional cytotoxic agents to be used. This approach may increase the risk of secondary myeloid leukaemias.

>10% plasma cells in bone marrow.

Staging of disease depends on bone marrow features, paraprotein level, calcium, and haemoglobin.

There may be a genetic background (HLA-Cw2, -Cw5), and IgA paraproteins may be associated with a translocation t(8;14). Other translocations may occur; Ig gene rearrangements are detectable (FISH is the preferred technique).

Myeloma cells often express lymphocyte and plasma cell antigens simultaneously. Abnormal B cells may be detectable in the peripheral blood, expressing high levels of CD44 and CD54. Cells also express CD56 (NCAM), an adhesion molecule, and soluble levels of NCAM are elevated in myeloma.

IL-6 plays a key role as either an autocrine or a paracrine factor stimulating proliferation. CRP may be raised in consequence. Osteoclast-activating factors are also produced, leading to bone destruction (IL-1, IL-6, TNF-β).

Monoclonal immunoglobulin production parallels the frequency of B cells: 52% IgG; 22% IgA; 25% free light chain only; 1% IgD. IgE myeloma is exceptionally rare and is found with plasma cell leukaemia. Biclonal myeloma and non-secreting tumours may be found.

Synthesis of heavy and light chains is often discordant and whole paraprotein may be accompanied by excess free light chains. Free light chains are readily filtered, but are nephrotoxic. IgD myeloma often presents in renal failure.

Hyperviscosity is common with high levels of IgM and IgA paraproteins, but is rare with IgG and free light-chain paraproteins. IgA frequently polymerizes in vivo (dimers and tetramers).

Paraproteins may have autoantibody activity and may be cryoglobulins (types I and II).

Complexes of paraproteins (especially IgM) with coagulation factors may cause bleeding.

Although myelomatous change probably arises in the spleen or lymph nodes, these are unusual sites for disease, which is usually found in bone and bone marrow. Excess clonal plasma cells will be found in the bone marrow.

Normal humoral immune function is impaired and there is suppression of non-paraprotein immunoglobulin (arrest of B-lymphocyte maturation). Specific antibody responses are poor.

T-cell function is also impaired, leading to viral infections.

Low levels of monoclonal paraproteins are found in other lymphoproliferative conditions, chronic infections, connective tissue diseases, and old age.

Where a paraprotein is present without other features of myeloma (no increase in plasma cells in bone marrow), the term ‘monoclonal gammopathy of uncertain significance’ is applied. A proportion of these patients develop myeloma with time, and all should be monitored at intervals.

Heavy-chain disease is rare (μ, γ, and α); α-heavy-chain disease is the most likely. All are associated with lymphoma-like disease.

POEMS syndrome (polyneuropathy, organomegaly, endocrine abnormalities, monoclonal gammopathy, and skin rashes) appears to be a plasma-cell variant of Castleman’s disease, a hyperplasia of lymph nodes, which may occur with autoimmune diseases (see also Chapter 4). It is associated with high circulating levels of IL-1, IL-6, VEGF, and TNF.

Paraprotein levels are best determined by scanning densitometry, provided that the total protein in serum can be measured accurately. There are difficulties if the M-band overlaps the β-region.

Urinary light-chain excretion may be helpful as a prognostic monitor of tumour cell burden, but there are difficulties in calculating this (see Part 2) and renal function affects the output.

Measurement of serum free light chains is a more sensitive marker of clonality and tumour burden.

Serum β₂-microglobulin is a marker of tumour-cell activity, but has fallen out of favour.

CRP may be a surrogate for IL-6 production.

The degree of humoral immunodeficiency should be assessed by measurement of exposure and immunization antibodies, followed by test immunization with protein and polysaccharide antigens.

Light-chain (AL) amyloid may be a complication.

α-Interferon has a major effect in prolonging the plateau phase.

Thalidomide (and a newer derivative, lenalidomide) has been shown to be valuable, but side effects can be significant.

Bortezomib (Velcade^®) is a proteasome inhibitor which has produced excellent clinical responses. Neutropenia and neuropathy are significant side effects.

HSCT (allogeneic and autologous purged marrow) may also prolong remission, but it is doubtful if it is curative. Colony-stimulating factors should be used with caution as they may enhance tumour cell growth.

Waldenström’s macroglobulinaemia may be treated with fludarabine or cladribine; rituximab is also helpful.

Radiotherapy may be required for localized plasmacytomas.

IVIg may be beneficial in dealing with secondary infective problems but should be used with great caution in patients with renal impairment and those with rheumatoid activity of their paraproteins (both may lead to renal failure). Prophylactic antibiotics may be an alternative.

Plasmapheresis may be required to deal with hyperviscosity and/or cryoglobulinaemia.

Found in 3% of population aged >50.

<10% plasma cells in bone marrow.

Chromosomal abnormalities in bone marrow are common (FISH).

Paraprotein <15g/L.

IgG, IgA paraproteins account for 80%; IgM 17%; small number of light-chain-only MGUS.

Monitor paraproteins at regular intervals—often stable for years

Rising level indicates development of myeloma.

Most MGUS will progress to myeloma, given long enough (>20 years in some cases).

Three major types (nodular sclerosing, mixed cellularity, and lymphocyte depleted) are recognized. Lymphocyte predominant may well be a separate disease, as it occurs later and often relapses to non-Hodgkin’s lymphoma. Staging depends on the number of sites affected and on the presence or absence of constitutional symptoms.

EBV genome is often found in HD, and RS cells are usually positive. RS cells are thought to be the true neoplastic cell, possibly derived from interdigitating reticulum cells.

T- and B-cell numbers are reduced. Immunoglobulins are often raised, especially IgE. 10% of patients will have hypogammaglobulinaemia (severe disease). There may be poor specific antibody responses; primary antibody responses are impaired, whereas secondary responses may be normal.

T-cell proliferation is reduced (reversible by indomethacin, suggesting a possible macrophage defect). Cutaneous anergy is common.

Responses to Pneumovax II^® may be present even if there is a lack of DTH responses.

In some cases the defects have been shown to precede the development of the disease and also to persist long term after successful treatment (although the role of the cytotoxic regimes in this is poorly understood). It is difficult then to distinguish from a primary immunodeficiency complicated by lymphoma.

Bacterial infections are common (Pneumococcus and Haemophilus influenzae), related to poor humoral function and possibly also to poor neutrophil function.

Before CT scanning became widespread, splenectomy for staging was common. This is now only undertaken for symptomatic hypersplenism. Splenectomy has a very significant effect on immune function in lymphoma, and patients may become unresponsive to bacterial vaccines.

There is usually a reactive expansion of CD4⁺ T cells.

Molecular techniques should be used to look for evidence of EBV genome.

HD is associated with an acute-phase response, with elevated ESR, CRP, and caeruloplasmin. This may be a poor prognostic indicator.

All patients with lymphoma should be monitored for evidence of humoral immune deficiency: serum immunoglobulins, IgG subclasses, and specific antibodies. Test immunization is appropriate. Particular attention should be paid to apparently cured patients, who may still have persisting immunodeficiency.

Most regimes are myelosuppressive and impose a temporary secondary defect through neutropenia.

Relapse can be treated with autologous bone marrow transplantation (harvested in remission) or with a stem-cell transplant.

Secondary neoplasms may occur (myelodysplasia, acute myeloid leukaemia); the risk is related to the intensity of treatment.

IVIg may be required for those with a persisting symptomatic humoral defect after treatment.

Tumours are also divided on the basis of their clinical grade (= aggressivity). Low-grade B-cell tumours overlap with chronic lymphocytic leukaemia. Waldenström’s macroglobulinaemia is often referred to as an immunocytic lymphoma. Both T- and B-cell lymphomas are recognized, as well as tumours derived from histiocytic elements.

Retrovirus (HTLV-1) has been associated with T-cell lymphomas in areas where it is endemic (Japan and the Caribbean).

EBV has been associated with certain B-cell lymphomas, particularly associated with immunosuppression, and endemic Burkitt’s lymphoma, which is found in malarial areas. This tumour, but also others, is associated with chromosomal abnormalities, normally translocations t(14;8).

Many other translocations have been identified. It is thought that these translocations allow dysregulated activity of cellular oncogenes, such as bcl-2 and abl, by placing them in proximity to active promoters. In Burkitt’s lymphoma the oncogene is c-myc.

Secondary lymphomas are usually non-Hodgkin’s lymphoma (NHL). These are found with:

In the case of primary immunodeficiency, it is likely that the chronic infections lead to an abortive immune response that predisposes to lymphoma. Perhaps earlier diagnosis and better treatment will prevent this.

Studies of humoral and cellular function have shown abnormalities that have not always correlated with the type of lymphoma. Abnormalities are more likely in high-grade tumours. Both hypo- and hypergammaglobulinaemia may occur and may persist after treatment. Monoclonal bands, often IgMκ, may be found in association with B-cell tumours. Autoantibody activity may be noted.

Acquired angioedema (AAE) (see Chapter 1) is often associated with an underlying B-cell lymphoma with a paraprotein:

As in Hodgkin’s disease, splenectomy may have been undertaken in the past, imposing an additional immunological defect. These patients require careful supervision.

Clonality will be established by molecular techniques looking at Ig and Tcr gene rearrangements.

Humoral immune function should be monitored as for Hodgkin’s disease.

Serial β₂-microglobulin measurements may be helpful as a marker of lymphocyte turnover.

Electrophoresis will demonstrate the presence of paraproteins.

If autoimmune phenomena are present, association with the paraprotein can be shown by light-chain restriction on immunofluorescence.

Sometimes abnormalities of immunoglobulins precede overt disease. In contrast with primary immunodeficiency, IgM disappears first, followed by IgG and IgA.

Autologous bone marrow transplantation may be helpful in relapse. IVIg may be required if there are infective problems.

The monoclonal antibody rituximab, with or without and attached radioisotope, is valuable for treating CD20⁺ lymphomas.

Different variants can be distinguished by flow cytometry.

Bone marrow examination shows an excess of lymphocytes.

Chromosomal abnormalities are common: trisomy 12 and deletions of the long arm of chromosome 13 in B-cell disease, and chromosome 14 abnormalities (inversion or tandem translocation) or trisomy 8q in T-cell disease. Deletions of 17p affecting p53 expression have a poorer prognosis. Recent studies have demonstrated that some CLL patients have an abnormal ATM gene (ataxia telangiectasia mutated).

Recurrent bacterial infections are a major problem.

Humoral function is impaired and response to Pneumovax II^® is a better predictor of infection than total IgG.

Studies of normal B-cell function is difficult in vitro because of the predominance of the aberrant clone.

Electrophoresis may show small bands (usually IgM). T-cell numbers may be increased (CD4⁺ T cells), but function may be poor with low/absent PHA responses.

Viral infections may be a problem: shingles with dissemination, HSV.

Autoimmune phenomena are common: ITP and haemolytic anaemia. Splenectomy may be required and this exacerbates the immune deficit.

Vaccine responses are frequently entirely absent in this situation and patients must have prophylactic antibiotics.

HCL may be associated with vasculitis.

Studies of humoral immune function are necessary and should include test immunization with Pneumovax II^®. As these diseases are chronic, monitoring should be carried out at regular intervals to identify deterioration.

α-Interferon is very effective in HCL. Rituximab or ofatumumab (anti-CD20) is valuable in combination with fludarabine and cyclophosphamide. The humanized monoclonal antibody Campath-1H^® (alemtuzumab) has been used in resistant cases with success, but causes profound immunosuppression. Younger patients may be candidates for HSCT (autologous BMT is not curative).

Recurrent infections may require prophylactic antibiotics or IVIg. Monthly treatment is usually adequate (dose 200–400mg/kg).

There is a high incidence of progression to acute myeloid leukaemia.

Abnormal neutrophil function is well described: neutropenia is common in myelodysplasia. Even if the neutrophil count is normal, function is often not, with abnormalities of adhesion, chemotaxis, phagocytosis, and bacterial killing being well documented. This occurs particularly with monosomy 7 in childhood.

Infections are common.

Certain primary immunodeficiencies are risk factors for ALL (Bloom’s syndrome, ataxia telangiectasia, Schwachmann’s syndrome, xeroderma pigmentosa). Most ALLs are B cell in origin.

T-ALL is associated strongly with HTLV-1 infection in areas where this virus is endemic.

A number of chromosomal translocations have been described, including the Philadelphia translocation (t(9;22)), which is common in adult ALL. Other translocations are well described.

T-ALL is often associated with translocations involving the T-cell receptor genes.

ALL is classified according to the FAB classification, on the basis of cytological appearance, into L1, L2, and L3 types. Immunophenotyping allows the distinction of B-, T-, and null (rare) ALLs.

Acute myeloid leukaemia has also been classified by the FAB group into M0–M7, depending on the predominant cell type identified by morphology and cytochemistry. Cases of AML may be secondary to Wiskott–Aldrich syndrome, Chediak–Higashi syndrome, or Fanconi anaemia, as well as to the use of cytotoxic drugs such as cyclophosphamide.

Occasionally, biphenotypic leukaemias may be detected, defined as the presence of at least two markers from each lineage (e.g. lymphoid and myeloid). They account for 5–10% of acute leukaemias and tend to have a poor prognosis. Often they present as AML, but have evidence of clonal rearrangements of immunoglobulin and Tcr genes.

Secondary immune responses are usually normal.

Non-neoplastic cells are normally present in normal numbers.

Leukaemic clones rarely have functional activity, although there have been reports of cytokine production.

Rare cases may be hypogammaglobulinaemic at presentation.

Chemotherapy is profoundly immunosuppressive, affecting both T- and B-cell function and rendering patients neutropenic. Careful attention to prevention of infection (isolation, irradiation of food, gut decontamination) is essential.

AML is treated similarly with intensive chemotherapy, with the option for BMT/HSCT when remission is obtained. Acute promyelocytic leukaemia associated with the t(15;17) translocation may be treated with all-trans retinoic acid, which allows differentiation of the blocked cells to mature neutrophils, although BMT is still required.

Certain cytokines may have a role as adjunctive agents, allowing intensification of chemotherapy, but with the increased risk of later myeloid lineage leukaemias.

BMT leads to an immediate severe immunodeficiency because of the conditioning required to allow ‘take’. All blood products must be irradiated to prevent viable lymphocytes engrafting and must be CMV^–.

There follows a period of gradually improving immune function while the immune system reconstitutes. This recapitulates immunological ontogeny.

T-cell function reconstitutes early, but full B-cell function may take up to 2 years. IgG2 levels may remain depressed, and there are frequently poor responses to polysaccharide antigens.

Degree of reconstitution is affected by the degree of mismatch and by GvHD.

Return of T-cell function in vitro (positive PHA) is usually taken to define the time when release from isolation is safe, but this is usually the last parameter to normalize. Anti-CD3 stimulation responses usually return early.

Appearance of recent thymic emigrants may be detected by measurement of TRECs (T-cell receptor excision circles) and by the use of CD45RA and CD27 to define naive and effector CD4⁺ T-cell reappearance.

While B-cell function is poor during the acute phase and for the first year thereafter, IVIg prophylaxis is essential.

Return of B-cell function can be monitored by IgA/IgM levels and development of isohaemagglutinins. Reappearance of class-switch memory B cells is also valuable, especially in patients transplanted for hyper-IgM syndromes.

Once off IVIg, a full programme of immunizations should be undertaken, starting with killed vaccines (killed polio, DPT, Hib, and Pneumovax II^®). The response to these can be assessed (pre- and post-levels are required, and remember that antibody from IVIg may persist for up to 6 months or longer).

Once there is a good response to killed/subunit vaccines, live vaccines can be administered (MMR).

Immunological function in chronic GvHD is markedly abnormal, with a persisting risk of invasive infections of all types. The gastrointestinal involvement superimposes a severe nutritional defect, which further reduces immune function.

Immune function gradually develops, although there is usually a physiological trough in IgG levels at around 6 months. If this is prolonged, transient hypogammaglobulinaemia of infancy results (Chapter 1).

Additional protection to the neonatal gut is provided by breastfeeding, particularly in the first few days when the IgA-rich colostrum is produced.

Maternal antibody transfer is an active process in the placenta which begins at around 14 weeks’ gestation and accelerates markedly after 22 weeks. The process can take place against a concentration gradient and is selective for some IgG subclasses; IgG2 is transferred relatively less well.

Antibody-deficient mothers will also be at risk of producing hypogammaglobulinaemic infants, who will require IVIg for the first 6 months of life. Good replacement therapy during pregnancy will obviate the need for this.

Premature delivery interrupts the placental transfer and leaves the infant deficient in immunoglobulins and with a relatively less mature humoral and cellular immune system. Breastfeeding is rarely possible, but oral administration of colostrum is desirable to prevent necrotizing enterocolitis. Infections are often problematic, although other factors, such as ITU nursing, venous and arterial lines, and lung immaturity, all contribute. Group B streptococcal infections are particularly troublesome.

Provided that there are no major complications, the immune system rapidly catches up after delivery and there are rarely long-term sequelae.

Responses to standard immunization schedules may be poor—consider boosters.

Immunization of the premature causes problems in timing, as there may be very poor responses if routine immunizations are given at intervals calculated from date of delivery uncorrected for gestational age.

Thymic function declines, but not as much as previously assumed!

NK-cell numbers increase in the long-lived elderly.

Mucosal immunity seems to be reasonably intact, although the non-specific inflammatory response is reduced.

Aged lymphocytes have metabolic abnormalities such as reduced 5′-nucleotidase activity (also associated with CVID), and there are changes in the expression of surface antigens.

Immunoglobulin levels change with age: IgG and IgA tend to rise while IgM and IgE fall. Primary humoral responses are reduced and secondary responses give lower peak titres and a more rapid fall with time. Antibody affinity may also be poorer. Some studies have shown that vaccine responses in the elderly may be as good as in younger people.

CVID may present for the first time post-retirement, but this diagnosis should only be entertained when other secondary causes have been eliminated.

With increasing age there is an increasing incidence of small monoclonal bands on electrophoresis (MGUS), such that 20% of 95-year-olds will have bands. These are present at low levels and are rarely of great significance.

There is a parallel increase in autoantibodies of all types. These are usually present at low titres and are not associated with disease.

Normal ranges for antibody titres should be adjusted to take account of these changes.

Cell-mediated immunity, as tested by mitogen responses and DTH testing, are also reduced in the elderly. Thymic function is probably better than previously thought and new thymic emigrants can be detected in the elderly.

Biologically, the healthy very elderly (>85 years old) represent a special group. There may be combinations of MHC genes that can be associated with survival (in Japan, a high frequency of DR1 and a low frequency of DR9), but this might be due to selection out of those individuals with less favourable MHC types associated with autoimmune disease.

Coexisting disease imposes additional strains on the immune system (e.g. chronic lung disease from smoking, cardiac failure with pulmonary oedema, and malnutrition). These often tip the balance away from the immune system in favour of invading pathogens.

Diseases such as influenza have a disproportionate effect on the elderly through the risks of secondary bacterial infection and exacerbation of pre-existing underlying diseases. Infections common in early childhood, such as meningitis, are also more common in the elderly.

CMV has been suggested as an important risk factor for immunological decay.

Consideration should also be given to ensuring that other vaccines such as tetanus are kept up to date (this tends to be forgotten in the elderly) as tetanus antibodies may fall below protective levels. Keen gardeners are at most risk.

Immunoglobulin therapy may be required for those with significant symptomatic hypogammaglobulinaemia.

IVIg has complex immunoregulatory properties when used in high doses (Chapter 16).

Crude factor VIII concentrates are immunosuppressive, although this may relate as much to chronic hepatitis due to hepatitis C. High-purity FVIII is much less immunosuppressive.

Other infections transmissible by blood, such as HIV and CMV, can have major immunosuppressive effects.

The use of unirradiated blood in the immunocompromised (with poor/absent cell-mediated immunity (CMI)) may lead to engraftment of viable lymphocytes and the development of GvHD.

Investigation of humoral function is essential if there is significant proteinuria.

In the nephrotic syndrome there is an increased susceptibility to Pneumococcus and other streptococci.

Typical pattern is loss of immunoglobulins in order of ascending molecular weight, depending on the selectivity of the proteinuria, with preferential loss of IgG and then IgA, and preservation of IgM until gross nephrosis ensues.

The IgG synthetic rate is normal or increased and the IgM catabolic rate is normal.

Responses to Pneumovax II^® are poor, but responses to influenza are normal.

Poor neutrophil chemotaxis and opsonization are also described.

Loss of complement proteins such as C3 and factor B may also contribute to poor bacterial handling through decreased opsonization.

Lymphopenia is common, affecting CD4⁺ and CD8⁺ T cells; DTH and mitogen responses are reduced.

Immunoglobulins and specific antibody responses to pneumococcal and hepatitis B vaccines may be low. Double doses of HBV vaccines (40mcg) are advised.

Lymph nodes show a loss of secondary follicles.

Neutrophil function shows defective chemotaxis and phagocytosis, with impaired oxidative metabolism, leading to poor bacterial killing.

Certain types of dialysis membrane (cellophane, now no longer used) activate the alternate pathway of complement, with release of anaphylotoxins and neutrophil activation leading to severe circulatory and respiratory problems.

Dialysis patients often have a CD4⁺ T-cell lymphopenia; increased expression of CD11b/CD18 is seen on neutrophils. Increased T-cell apoptosis may occur.

Increased risk of HPV-induced skin tumours, EBV-induced lymphomas, and B-lymphoproliferative disease.

Por humoral and cellular immune function.

Monitoring is required, especially if irreversible lymphocytoxic agents such as azathioprine are used long-term.

Specific antibody responses may be normal, although they may decline rapidly.

Lymphopenia is associated with dilated or blocked lymphatics (intestinal lymphangiectasia, constrictive pericarditis, right heart failure). This may lead to poor mitogen responses and DTH reactions.

Radiolabelled albumin excretion in the faeces will quantitate the loss.

Full studies of humoral and cellular function are required, together with investigation of the underlying cause (radiology, endoscopy, and biopsy).

Complement components are reduced (decreased synthesis).

Neutrophil phagocytosis and chemotaxis occur.

T-cell function is poor.

Mannosidosis: recurrent severe infections; impaired neutrophil chemotaxis. Poor T-cell responses to PHA and concanavalin A (ConA).

Galactosaemia: increased risk of Gram-negative septicaemia due to abnormalities of neutrophil motility and phagocytosis.

Myotonic dystrophy: hypercatabolism of IgG, but not albumin, IgA, or IgM, may occur, although infections are not usually a major problem.

Sickle cell disease: increased susceptibility to meningitis and septicaemia. There is an acquired splenic dysfunction due to infarction. Tissue hypoxia also contributes to bacterial infection. Serum immunoglobulins and vaccine responses are usually normal, even to polysaccharide antigens. It is recommended that all patients should be treated as other asplenic or hyposplenic patients, and should receive Pneumovax II^® and Hib vaccines and be considered for prophylactic antibiotics.

Coeliac disease: this may be accompanied by splenic atrophy, and these patients should be investigated and treated as other asplenic patients.

Prolidase deficiency: rare autosomal disorder with rashes, skin ulceration, dysmorphic features, splenomegaly, and recurrent infections. It also appears to be associated with a risk of developing SLE. It is diagnosed by the presence of iminopeptiduria.

In established disease, the raised glucose itself interferes with both innate and specific immune functions. Most of the research has been done on chemically induced or genetic diabetes in mice; much less work has been done on human diabetes.

Humoral function is impaired: IgG levels may be reduced, while IgA may be increased. Specific antibody responses may show poor primary immune responses and the non-enzymatic glycation of immunoglobulin may interfere with function. Both T-dependent and T-independent antigens are affected.

Lymphoid organs are essentially normal, but peripheral blood lymphocytes may show variable abnormalities. CMI may be depressed with poor DTH responses, abnormal mitogen responses, and poor cytokine production (IL-2).

Macrophage and neutrophil function is also reduced.

Type I diabetes is strongly associated with coeliac disease; hyposplenia may occur.

Infections with Candida and other fungi, TB, and pneumococci are more common in diabetes. Staphylococcal colonization of the skin is higher in diabetics than in normal individuals.

Abnormalities of immune function are more marked in type I diabetes but correlate poorly with blood glucose levels. It is possible that immune dysfunction relates to glycation of surface antigens on immunologically important cells.

In the USA, regular pneumococcal vaccination is recommended, but this policy has not been adopted in the UK.

Iron deficiency due to loss or inadequate intake impairs neutrophil bactericidal activity, as it is essential for the activity of myeloperoxidase. There is often a T lymphopenia. Immunoglobulins are usually normal but specific antibody production is reduced. All the changes are reversible with iron.

Marasmus is total nutritional deficiency, while kwashiorkor is protein deficiency in a high-calorie diet. Both are usually accompanied by vitamin deficiency.

Increased susceptibility to infection seems to be the rule.

Non-specific barriers are impaired (especially in vitamin A deficiency).

There may be variable abnormalities of neutrophil bactericidal activity, but these may well be secondary to infection.

Immunoglobulins are often normal or high, even if the albumin is low. IgE levels may be elevated, even in the absence of significant parasitic infections, suggesting dysregulation of the Th1/Th2 axis.

Mitogen responsiveness is reduced in kwashiorkor. Lymph nodes show germinal centre depletion and there is thymic atrophy, although the latter is also a feature of infection.

Risk appears to be lifelong and is not limited to the first 2–3 years after splenectomy, as was previously thought.

Degree of compromise also depends on the reason for splenectomy. For example, individuals splenectomized for lymphomas often have a more severe defect than those splenectomized for trauma.

Ideally, all patients undergoing elective splenectomy should be immunized with Pneumovax II^® and Hib vaccine and probably with the quadrivalent meningococcal conjugate vaccine preoperatively. If this is not possible, immunization prior to discharge may be adequate, although responses immediately post-surgery will be reduced.

The value of conjugated pneumococcal vaccines as routine first-line vaccines in asplenic/hyposplenic patients is uncertain.

All asplenic patients should be on prophylactic antibiotics (preferably penicillin V 500mg twice daily); erythromycin can be used for penicillin-allergic patients. Where there is a high level of pencillin-resistant pneumococci (Mediterranean countries), amoxicillin 500mg daily can be used.

Patients should have their antibodies to Pneumovax II^® and Hib measured annually. Those with suboptimal levels should be (re)immunized and the levels rechecked.

Those with poor responses to Pneumovax II^® should receive the conjugated pneumococcal vaccine Prevenar^®.

Repeated doses of Pneumovax II^® close together should be avoided, as this may induce tolerance rather than boost immunity.

Annual influenza immunization is essential to reduce risks of secondary bacterial sepsis.

Asplenic patients may also not maintain adequate levels following vaccination for more than 3–5 years, and regular checks should be carried out to ensure that protection is adequate. Note that the licence for Pneumovax II^® does not indicate that it can be given this frequently. However, provided that steps are taken to avoid immunizing patients with high antibody levels, the risk of adverse events appears to be low.

Dog bites are dangerous and patients must seek immediate assistance. Antibiotic treatment is essential.

Specific advice is required for foreign travel to malarial areas—refer to the Infectious Disease Team for advice.

Illegal drugs have considerable immunosuppressive potential, in part due to contaminants. Cannabis is particularly dangerous to severely immunocompromised patients as it may contain fungal spores.

Alcohol in excess suppresses macrophage function, and as result increases the risk of tuberculosis.

Disruption of the integrity of the normal cutaneous barriers and associated non-specific defences is a serious problem. Complement levels will be reduced by loss.

In severe burns neutrophil function is impaired and there is a lymphopenia, with depletion of lymphoid organs.

DTH, mitogen, and allogeneic responses are reduced.

These changes may be stress-related owing to excessive endogenous steroid production (Curling’s ulcer is also associated) or the release of bacterial products at the burned site.

Immunoglobulin levels fall, often dramatically, because of reduced synthesis and increased loss through exudation. However, there is no benefit from IVIg replacement therapy.

The best treatment is good intensive care and rapid grafting to re-establish normal barrier function.

It usually occurs now as an unintended consequence of radical oesophageal surgery; chylothorax results, usually draining through the surgical drains.

Loss of the circulating lymphocyte pool occurs within 48–72 hours and leads to severe prolonged lymphopenia, followed by severe panhypogammaglobulinaemia.

Opportunist infections (PCP, Candida) occur.

Chylothorax should be drained to the abdominal cavity if possible to allow conservation of lymphocytes. IVIg will be required, together with prophylactic co-trimoxazole, antivirals, and antifungals.

Reconstitution of the immune system depends on thymic function and may take up to 2 years. Once normal lymphocyte numbers are achieved, a programme of re-immunization is required, commencing with killed/subunit vaccines.

Poor development of humoral immune responses.

Test immunization may be required.

Poor antibody function and history of infections are indications for the use of IVIg therapy.

IVIg has also been used in adult cardiac transplant patients with hypogammaglobulinaemia and infections

T-cell proliferative responses to mitogens and antigens remain depressed after irradiation for years.

Lymphopenia, particularly of CD4⁺ T cells, is common; humoral immune function is reduced.

Apoptosis may be increased.

NFκB in T cells is activated by UV light.

Hypoxic therapy has been used as an adjunct to sports conditioning; this is associated with measurable alterations in circulating lymphocyte profiles, although the patterns are not consistent.

A Th1 to Th2 switch and reduced T-cell proliferation have been noted, but this is in part mediated by prostaglandin release from macrophages.

Antibody production is inhibited by β-endorphin (reversible by naloxone).

Prolonged administration of anaesthetic agents in the ITU may contribute to worse immune function.

Preventing tissue hypoxia is crucial (supplemental oxygen).

Hypogammaglobulinaemia has been reported.

Cause uncertain.

Associated with bronchiectasis in 40% of cases.

May respond to high dose vitamin E.

Poor/absent cilial function.

Genetics complex: 38% of dynein mutations are associated with DNAI1 and DNAH5 (the latter is associated with situs inversus).

Clinical features include:

Treatment includes aggressive anti-infective treatment to prevent infection-related lung damage.

Manage asplenia as described above on p.112 (‘Asplenia’).

Possibly secondary to contact with mercury.

Cilial function is normal.

Clinical features include:

Disease is caused by mutations in the CF transmembrane conductance regulator (CFTR, chromosome 7q31.2). Heterozygosity for the mutated gene is common in Caucasian populations.

Many mutations are described: some are compatible with longevity and late presentation.

Genetics should be checked in all patients presenting as adults with bronchiectasis/recurrent chest infections where there is no other explanation, particularly if there are recurrent staphylococcal chest infections.

Coexistent MBL deficiency is associated with worse prognosis.

Aspergillus colonization may occur; development of IgE to Aspergillus is a poor prognostic sign.

Chronic carriage of Pseudomonas and Burkholderia tend to be late events and are poor prognostic indicators. These patients need to be segregated to avoid infecting other patients.

Aggressive antibiotic therapy is required; malabsorption and secondary diabetes are managed normally.

Lung transplantation is successful.

Causes neonatal jaundice, cirrhosis, and liver failure.

Later in life, emphysema (rarely bronchiectasis), especially in smokers, and panniculitis and angioedema.

>80 genetic variants identified by isoelectric focusing (for main types see Table 2.2).

Severe cases have been treated with infusions of α₁-AT.

Smoking avoidance is crucial to prevent accelerated lung damage.