Secondary Immuno-Deficiency and other Host-Defence Syndromes
Introduction
Many disease states have been associated with immune dysfunction of varying degrees of severity and significance; some rare secondary disorders have already been covered in Chapter 1. In this and subsequent chapters the immunological abnormalities will be discussed, together with the value of immunological tests (if any). However, there will not be a detailed discussion of the clinical and non-immunological features of the diseases, and the reader is advised to consult other standard textbooks.
Classification of secondary immunodeficiency
Viral infections:
Acute bacterial infections:
septicaemia.
Chronic bacterial and parasitic infections:
tuberculosis, leishmaniasis.
Malignancy.
Plasma cell tumours and related problems:
Myeloma, plasmacytoma, Waldenström’s macroglobulinaemia
Amyloidosis (see Chapter 14).
Lymphoma/leukaemia:
Hodgkin’s disease, non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, other chronic and acute leukaemias.
Extremes of age:
Prematurity, old age
Transfusion therapy:
whole blood; clotting factors.
Drugs and biologicals:
as an undesirable side-effect; immunosuppressive drugs (see Chapter 16).
Physical therapies:
plasmapheresis and variants, radiation (see Chapter 16).
Nutrition:
starvation, anorexia (see also Chapter 1 for immunological effects of certain inborn errors that affect nutritional status); iron deficiency.
Chronic renal disease:
uraemia, dialysis, nephrotic syndrome.
Gastrointestinal disease:
Protein-losing enteropathies; secondary to cardiac disease.
Metabolic disease:
diabetes mellitus, glycogen storage disease, mannosidosis.
Toxins:
cigarettes, alcohol, other chemicals.
Splenectomy:
in conjunction with other diseases (lymphoma, coeliac disease, sickle-cell disease); traumatic (see Chapter 1 for congenital asplenia).
Cardiac surgery (thymectomy). Other host-defence disorders:
cilial dyskinesia
cystic fibrosis
yellow nail syndrome
Young syndrome
Alpha-1-anti-trypsin deficiency.
Burns.
Myotonic dystrophy.
Human immunodeficiency virus 1 and 2
HIV-1 and HIV-2 are retroviruses, responsible for the acquired immuno-deficiency syndrome (AIDS). For more detailed information on clinical aspects see Oxford Handbook of Genitourinary Medicine 2e.
Immunological features
Virus enters the cells via a cognate interaction of the gp120 env with CD4 and a chemokine receptor, either CxCR4 or CCR5.
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 selfdestruction 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.
Diagnosis and monitoring
Diagnosis depends on the detection of antiviral antibody ± viral antigen, not on immunological markers. Screening tests for anti-HIV antibody are followed up by PCR-based tests. Informed consent must be obtained.
The most accurate monitoring of disease is now available through measurements of viral load by quantitative PCR (viral load).
Lymphocyte surface markers (CD4 count) must not be used as a way of HIV testing without consent.
CD4+ T cell numbers will be reduced and CD8+ T cells increased in most acute viral infections and in seriously ill patients in the ITU setting.
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:
recovery is biphasic
rapid increase in CD4+ T cells in first 3-6 months, mainly CD45RO+ memory T cells (decreased apoptosis and redistribution?)
second phase is due to slower increase in CD54RA+CD62L+ naive T cells owing to increased thymic emigration
rapid increase in CD8+ T cells initially followed by decline
return of cutaneous reactivity to recall antigens.
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 panhypogammaglobulinaemia 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.
Immunotherapy
The mainstay of therapy at present is the use of antiretroviral agents. Mono- or dual-agent therapy is not recommended. Complex multi-agent regimes are now used. The reader is advised to consult the current HIV literature for information on the current state of therapeutic options. Some regimes require strict timing of administration and high levels of compliance. Multiresistant HIV strains have been reported.
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.
Immune reconstitution inflammatory syndrome (IRIS)
Occurs in HIV+ patients with very low CD4+ T-cell counts, especially if on protease inhibitors.
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:
infection-specific features (depending on organ infected)
fever
lymphadenopathy
likely to be due to excessive cytokine release as improved lymphocyte numbers interact with infection
protease inhibitors increase macrophage IL-6 and TNF-α production.
Management is aggressive treatment of underlying infection.
Castleman’s syndrome
Occurs in association with HIV, especially with HHV8 co-infection. Characterized by polyclonal lymphproliferation causing lymphadenopathy, fever, weight loss, leucopenia.
Histology of lymph nodes shows typical ‘onion-skin’ change.
Caused by excessive IL-6 production.
May respond to antiviral drugs (HHV-8, HIV), rituximab, or possibly anti-IL6 monoclonal antibodies.
Epstein-Barr virus
EBV is associated with infectious mononucleosis (glandular fever), Hodgkin’s disease, Burkitt’s lymphoma, and nasopharyngeal carcinoma. Rare EBVpositive T-cell lymphomas have also been described (T/NK—lethal midline granuloma).
Immunological features
EBV is a transforming B-lymphotropic virus of the herpes family, binding to the cells via CD21 (C3d) receptor and MHC class II antigens. This receptor is also expressed on follicular dendritic cells and pharyngeal and cervical epithelium. All these tissues are targets. Pharyngeal epithelium is usually affected first, with infection spreading to B cells in the adjacent lymphoid tissue of Waldeyer’s ring.
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.
Immunological diagnosis
Usual screening test (Monospot) for acute EBV infection relies on the production of heterophile antibodies that agglutinate sheep cells. This test may miss cases. IgM antibodies are detected and are then succeeded rapidly by IgG antibodies to early antigen (EA) and viral capsid antigen (VCA); antibodies to EBV nuclear antigen (EBNA) appear weeks to months after infection.
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.
Immunotherapy
None is required normally. However, in patients with a persistent EBV syndrome, high-dose aciclovir (800mg 5 times daily for 14 days) may lead to remission of symptoms and disappearance of the IgM anti-EBV antibodies.
Vaccines are in development, including peptide vaccines.
Adoptive immunotherapy with EBV-specific CTL is undergoing trials, especially in immunosuppressed or immunodeficient patients.
Other viral infections
Cytomegalovirus
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.
Rubella
Congenital rubella, but not acute infection, causes poor lymphocyte responses (reduced PHA proliferation) and may lead to long-term depressed humoral immune function.
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.
Measles
Measles virus is capable of infecting both lymphoid and myeloid cells.
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:
transient lymphopenia
PHA- and PPD-driven proliferation↓.
transient ↓neutrophil chemotaxis (‘significance).
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.
Influenza virus
Acute influenza may give a marked but transient lymphopenia, accompanied by poor T-cell proliferative responses.
Hepatitis viruses
Non-specific immunosuppressive effects are seen, which may be due to either liver damage or virus.
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:
different brand of vaccine
double dose may be given (40mcg)
double dose of vaccine with γ-IFN-1b 50mcg/m2—in practice give 100mcg (1 vial) and warn subjects of severe flu-like symptoms.
Interleukin-2 (1mU) has also been used successfully.
Disseminated warts (papillomavirus)
May occur as discrete warts or as epidermodysplasia verruciformis (defects in EVER1/EVER2 genes (see Chapter 1)).
May be seen in immune deficiencies (see Chapter 1)
common variable immune deficiency
Wiskot-Aldrich syndrome (WAS) and other combined immune deficiencies
WHIM syndrome.
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.
Post-viral fatigue syndromes
Chronic fatigue syndromes, accompanied by muscle/joint pains and neurocognitive symptoms, may occur after a range of viral infections, including enteroviruses, and vaccines.
Immunological abnormalities include variable lymphopenia, IgG subclass abnormalities, and atypical anti-nuclear antibodies.
May be transient or persistent.
See Chapter 14 for a fuller discussion.
Acute bacterial infections
Acute bacterial sepsis may lead to profound changes in immune function on a temporary basis.
Immunological features
Neutrophil migration and chemotaxis are increased, while phagocytosis is normal or decreased.
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.
Immunological investigation
The most important investigations are microbiological, to identify the pathogen, by culture and rapid antigen or PCR tests.
Monitoring of the acute-phase response (CRP) gives a good indication of response to therapy.
Acute measurement of immunoglobulins and complement is usually misleading and may lead to erroneous diagnoses of antibody or complement deficiency. It is best to leave these investigations until convalescence. Functional assays of complement may take 2-3 weeks to normalize after acute sepsis.
Acute measurement of cytokines in toxic shock is currently impractical and the diagnosis is clinical.
Chronic bacterial sepsis
Immunological features
Hypergammaglobulinaemia is usual, often with small and sometimes multiple monoclonal bands developing which represent the immune response against the pathogen.
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.
Mycobacterial products (arabino-D-galactan) interfere with in vitro proliferative responses to PHA, PWM, and PPD; the effect is possibly via macrophages and may involve prostaglandins (inhibitable by indomethacin).
There is often a lymphopenia.
Persistently raised CRP may also be suppressive.
Miliary TB may cause neutropenia, generalized bone marrow suppression, and leukaemoid reactions.
Untreated leprosy is a potent suppressor of cell-mediated immunity: T-cell responses to mitogens and antigens are reduced.
Defect disappears with appropriate antibiotic therapy and appears to be mediated by a glycolipid.
Underlying bias of the immune system towards either Th1 (cellular) or Th2 (antibody) responses determines whether the response to leprosy is tuberculoid (Th1) or lepromatous (Th2).
Other immunological features include the development of vasculitis (erythema nodosum) and glomerulonephritis (assumed to be due to immune complex with IgG and complement).
Immunological monitoring
Acute-phase markers provide the best guide to progress and response to therapy (but beware of elevations from drug reactions). The erythrocyte sedimentation rate (ESR) is less useful because of its long half-life.
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.
Bronchiectasis
Clinical features
Syndrome of chronic inflammatory/infective airway damage, leading to chronic cough with sputum production.
Associated with deficiencies of host defence, but may be idiopathic.
Causes
See Table 2.1.
Do not use IVIg without evidence of humoral immune deficiency (test immunization required); IgG levels increased in non-immune bronchiectasis.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
