Oxford Handbook of Clinical Immunology and Allergy (3 edn)
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Sarcoidosis
Sarcoidosis is a multisystem disease characterized by non-caseating granulomata.
Presentation
Common presentations include:
asymptomatic bihilar lymphadenopathy
erythema nodosum, arthritis, and hilar lymphadenopathy (Löfgren’s syndrome)
uveo-parotid fever (von Heerfordt’s syndrome)
primary cerebral involvement
multisystem presentation, which can affect all organs in the body.
Other clinical features include erythema nodosum, arthralgias, skin involvement (lupus pernio), and symptoms and signs of hypercalcaemia.
Cause and immunopathogenesis
Formation of non-caseating granulomata is typical, but is not by itself diagnostic.
Differential diagnosis of non-caseating granulomata is extensive and includes:
infections (Toxoplasma, Bartonella)
lymphoma
carcinoma
berylliosis, due to beryllium exposure
vasculitis and connective tissue diseases
Crohn’s disease
chronic granulomatous disease.
Granuloma comprises a central area of macrophages, epithelioid cells, and Langerhans giant cells surrounded by lymphocytes (mainly CD4+ cells and plasma cells), monocytes, and fibroblasts.
Macrophages are activated and release enzymes and 1,25-dihydroxycholecalciferol—hence the tendency to hypercalcaemia.
IL-12 is released; IL-18 associated with granuloma formation.
Peripheral blood lymphopenia (T and B cells), cutaneous anergy, and poor in vitro tests of lymphocyte proliferation.
T cells have an ‘activated’ phenotype, and T-cell receptor studies show skewing of the Vβ chain usage which might be compatible with a response to a single, as yet unidentified, pathogen.
Disease manifestations are of a Th1 phenotype.
Serum immunoglobulins are elevated, and as a result low-level autoantibodies may be present. IgM anti-T-cell antibodies may be detected.
Bronchoalveolar lavage specimens show a lymphocytosis (predominantly CD4+ T cells with high levels of activation and adhesion markers) and monocytes/macrophages (also activated with elevated MHC class II).
Soluble activation markers, such as sIL-2R, are raised.
Investigations (see Box 14.1)
No specific diagnostic tests are available for sarcoidosis.
Raised ACE levels in about 60% of patients (released by epithelioid cells in the granulomata).
Hypercalcaemia (and hypercalciuria).
Serum immunoglobulins show a polyclonal elevation of all classes, but predominantly IgG.
Low-titre rheumatoid factors and anti-nuclear antibodies may be present.
Peripheral blood lymphocyte analysis will show a generalized lymphopenia, with a proportional reduction in all cell types.
DTH testing will show anergy. There is no clinical need to assess lymphocyte proliferation in vitro, although it will be reduced.
Biopsy with appropriate immunohistochemical staining is helpful.
The Kveim test, in which an extract of sarcoid spleen is injected under the skin and biopsied 4–6 weeks later, has been used previously: a granuloma forms at the site of injection. This test, which uses human material, is no longer considered appropriate.
BAL studies are helpful where there is interstitial lung disease, although the changes are not specific.
A gallium-67 scan is helpful in identifying granulomata.
CSF oligoclonal bands may be present (again not specific) in cerebral sarcoidosis.
Lung function testing and appropriate radiological studies are essential.
| Tests for diagnosis | Tests for monitoring |
|---|---|
Serum ACE | Serum ACE |
Vitamin D levels | CRP/ESR |
CRP/ESR | Calcium |
Serum immunoglobulins | FBC |
Calcium and urinary calcium excretion | Cr&E |
FBC | Imaging (CXR, CT, gallium-67) |
Cr&E | |
Imaging (CXR, CT, gallium-67) | |
Biopsy | |
BAL |
| Tests for diagnosis | Tests for monitoring |
|---|---|
Serum ACE | Serum ACE |
Vitamin D levels | CRP/ESR |
CRP/ESR | Calcium |
Serum immunoglobulins | FBC |
Calcium and urinary calcium excretion | Cr&E |
FBC | Imaging (CXR, CT, gallium-67) |
Cr&E | |
Imaging (CXR, CT, gallium-67) | |
Biopsy | |
BAL |
Treatment
Asymptomatic disease picked up by chance on chest radiography; requires no specific treatment.
Treat erythema nodosum with NSAIDs intially.
Symptomatic disease requires low- to moderate-dose steroids.
Occasionally patients require other immunosuppressive drugs as steroid-sparing agents (cyclophosphamide, methotrexate, and azathioprine). Ciclosporin and hydroxychloroquine may be helpful through their effects on T-lymphocyte activation. Infliximab has also been used.
Patients with uveitis may require aggressive treatment to preserve vision.
Progressive lung disease may be an indication for lung transplantation, but disease recurs in 30–80% of cases.
Prognosis
Asymptomatic disease usually resolves spontaneously over several years.
Symptomatic disease is frequently chronic.
Amyloidosis
This group of conditions which cause multisystem disease is often overlooked clinically. The diseases are characterized by the deposition of polymerized proteins in an insoluble β-pleated sheet form, either generally or in a single organ, depending on the type of polymerizing protein (Table 14.1). Once deposits are established, they are virtually impossible to eliminate. Multiple proteins have been associated with amyloid formation. Hereditary forms occur.
| Amyloid protein | Protein precursor |
|---|---|
AL, AH | Light or heavy chain of immunoglobulin |
AA | Serum amyloid A |
Aβ2M | β2-microglobulin |
Acys | Cystatin C |
Alys, AFibA | Lysozyme, fibrinogen Aα |
AIAPP | Islet amyloid polypeptide |
AANF | Atrial natriuretic peptide |
Acal | Procalcitonin |
Ains | Porcine insulin |
ATTR | Transthyretin |
Aβ | Aβ-protein precursor |
AprP | Prion protein |
| Amyloid protein | Protein precursor |
|---|---|
AL, AH | Light or heavy chain of immunoglobulin |
AA | Serum amyloid A |
Aβ2M | β2-microglobulin |
Acys | Cystatin C |
Alys, AFibA | Lysozyme, fibrinogen Aα |
AIAPP | Islet amyloid polypeptide |
AANF | Atrial natriuretic peptide |
Acal | Procalcitonin |
Ains | Porcine insulin |
ATTR | Transthyretin |
Aβ | Aβ-protein precursor |
AprP | Prion protein |
Abbreviated list—27 amyloidogenic protein fibrils have been identified in humans so far.
AL amyloid
Presentation
Typical clinical features include:
hepatosplenomegaly
cardiac failure due to infiltration
malabsorption
nephrotic syndrome
peripheral neuropathy (especially carpal tunnel syndrome)
macroglossia may be present
deposits may occur in the skin
bleeding tendency due to selective absorption of clotting factors.
It is a disease predominantly of older people.
Cause and immunopathogenesis
In this type of amyloid the deposited protein is derived from immunoglobulin light chains (λ:κ = 2:1—the opposite of that found in myeloma).
Often associated with evidence of lymphoproliferative disease.
20% of AL amyloid patients only have myeloma; the rest have other paraproteinaemias.
Rarely, AL amyloid has been associated with heavy-chain deposition.
Investigations (see Box 14.2)
Serum and urine should be checked for the presence of monoclonal immunoglobulins and free light chains: sensitive techniques may be required to demonstrate the paraproteins, which are present in up to 80% of cases.
Paraprotein levels are often low.
Serum-free light-chain analysis is very valuable.
Some paraproteins may not be detected as the light chain is highly abnormal or polymerized in circulation, such that it does not react with the usual antisera, or the band overlaps on electrophoresis with other protein bands.
Biopsy of an affected organ and Congo red staining, which gives apple-green birefringence, is helpful. More specific immunostaining with anti-light-chain antisera may give reactions, although the distorted protein structure may prevent reactivity.
Bone marrow examination is essential.
| Tests for diagnosis | Tests for monitoring |
|---|---|
Serum immunoglobulins and electrophoresis, immunofixation (isoelectric focusing) | Paraprotein quantitation |
Urinary electrophoresis | Serum free light chains |
Paraprotein quantitation | |
Serum free light chains | |
Bone marrow examination | |
Biopsy (Congo red stain) |
| Tests for diagnosis | Tests for monitoring |
|---|---|
Serum immunoglobulins and electrophoresis, immunofixation (isoelectric focusing) | Paraprotein quantitation |
Urinary electrophoresis | Serum free light chains |
Paraprotein quantitation | |
Serum free light chains | |
Bone marrow examination | |
Biopsy (Congo red stain) |
Treatment
No curative treatment, but steroids, melphalan, and colchicine may slow down the rate of progression; symptomatic organ-specific treatment will be required.
HSCT may be necessary.
Iododoxorubicin binds to AL amyloid and promotes resorption.
Bortezomib (Velcade®), a proteasome inhibitor, may be helpful.
AA amyloid
Presentation
Presents predominantly with hepatosplenomegaly, nephrotic syndrome, and malabsorption.
Cardiac and nerve involvement is rare.
Cause and immunopathogenesis
Caused by the polymerization of serum amyloid A protein (SAA), an acute-phase protein, whose levels rise in response to IL-1 and IL-6.
It is a complication of chronic infection or inflammation (TB, bronchiectasis, rheumatoid arthritis, ankylosing spondylitis, etc.).
Investigations
Biopsies will confirm the presence of the amyloid deposits, and the serum will contain high levels of acute-phase proteins (e.g. CRP).
SAA can be measured routinely, especially in amyloidogeneic conditions, such as the autoinflammatory diseases, on treatment.
SAP scans may help localize deposits.
Treatment
Treatment is aimed at the underlying disease to eliminate the drive to high levels of SAA.
Colchicine is a valuable prophylatic agent in some periodic fever syndromes.
Other acquired amyloidoses
Dialysis amyloid
Caused by the polymerization of β2-microglobulin (Aβ2MG).
Related to failure of certain older (cuprophane) haemodialysis membranes to clear β2MG. Current membranes do not have this problem to the same extent.
Widespread deposition of β2MG occurs, but these deposits may resolve slowly with a successful transplant or on switching to dialysis with more permeable membranes.
Serum β2MG levels will rise to very high levels (>20mg/L).
Prion disease
Amyloid deposition has been associated with prions in Creutzfeldt–Jakob disease (CJD), where the prion protein PrP mutates and becomes amyloidogenic.
Alzheimer’s disease
β-amyloid protein has also been identified in certain cases of Alzheimer’s disease and is associated with the typical neurofibrillary tangles.
Protein is derived from a larger precursor amyloid β-precursor protein (AβPP). In Alzheimer’s it appears that the processing is defective, leading to an abnormal β-amyloid.
Diabetes
Amyloid deposits are found in patients with type II maturity-onset diabetes.
Amyloidogenic protein is thought to be islet amyloid polypeptide (IAPP), which is normally co-secreted with insulin.
This type of amyloid may occur in association with insulinomas.
Senile cardiac amyloid
Senile cardiac amyloid is very common in the elderly and is due to deposition of polymerized atrial natriuretic factor.
Medullary thyroid carcinoma
Medullary thyroid carcinoma may be associated with a form of amyloid derived from pro-calcitonin and calcitonin.
Inherited amyloidosis
There are a number of rare inherited amyloid deposition diseases related to rare mutations in proteins. These include:
transthyretin
apolipoprotein A-I
gelsolin
fibrinogen
cystatin C
lysozyme.
Clinical features are variable but renal and neurological involvement, both central and peripheral, are common.
Diagnosis is by identification of the mutated genes.
Familial Mediterranean fever (FMF)
Presentation
Inherited disease, most common in Jews, Arabs, Italians, Turks, and Armenians, especially those living around the Mediterranean basin.
Clinical features include attacks of abdominal pain with high fever, mimicking acute peritonitis but settling over 24–48 hours. Pleuritic chest pain, arthritis (which may be destructive and mimic RhA), and erythematous skin rashes also occur. Pericarditis may occur rarely.
Attacks usually begin before the age of 20 (90% of cases).
Typical attacks last 24–72 hours and can be triggered by physical exertion, stress, and menstruation.
Periodicity is variable and unpredictable.
AA amyloid may be a long-term complication of repeated attacks, especially in Jews.
Cause and immunopathogenesis
Inherited as an autosomal recessive.
Associated with mutations in the MEFV gene (16p13.3), encoding pyrin (also known as marenostrin), a protein that regulates caspase 1 and IL-1 secretion.
Investigations
There is a peripheral blood leucocytosis, mild anaemia, and the ESR and CRP rise during attacks. Fibrinogen levels are high (>g/L).
Serum immunoglobulins are non-specifically polyclonally elevated.
Involved serosal surfaces have an inflammatory infiltrate, mainly neutrophils. Joint fluid also shows a high neutrophil count during an acute attack.
Autoantibodies are not found.
Biopsies need to be considered if AA amyloid is suspected.
Genetic diagnosis is confirmatory.
Treatment
Colchicine in a daily dose of 1–1.5mg will reduce the frequency and severity of attacks markedly and reduce the risk of developing amyloidosis.
Colchicine taken inadvertently by pregnant women may increase the risk of Down’s syndrome.
5–10% of cases are resistant to colchicine.
Anakinra is beneficial.
TNF-receptor-associated periodic syndrome (TRAPS, familial Hibernian fever)
Presentation
Recurrent attacks of pleurisy, peritonitis, pericarditis, erythematous rash, arthritis, and myalgia, beginning in childhood.
Conjunctivitis, rarely uveitis.
15% develop amyloidosis.
Attacks usually prolonged >7 days.
Cause and immunopathogenesis
Dominant mutations in the TFRSF1A gene (12p13), encoding the TNF receptor.
Mutations occur in external domains and prevent the normal shedding of the receptor.
Diagnosis
Demonstration of TNF-R mutations.
Treatment
Corticosteroids are better than colchicine.
Anti-TNF agents (etanercept)—preferred treatment.
Anakinra.
Hyper-IgD syndrome
Clinical features
Rare autosomal recessive syndrome comprises bouts of fever, lymphadenitis, and occasionally oligoarthritis. Diffuse rash.
Peritonitis and pleurisy are common.
Oral and vaginal ulcers may occur.
Attacks last 3–7 days.
Severe immunization reactions are a particular feature.
Cause and immunopathogenesis
Mutations in the MVK gene (12q24) encoding mevalonate kinase.
Predominantly occurs in Dutch and northern Europeans.
24% of cases do not have mutations in the coding part of the gene.
Investigations
Humoral immune responses may be poor, with reduced IgM, raised IgG3, and very high IgD levels. IgA may also be elevated.
IgD can be measured with commercial RID assays.
Treatment
NSAIDs for fever.
Anakinra and anti-IL-1 treatments—preferred option.
Anti-TNFs may be tried.
Statins may have a role (mevalonate kinase is part of the HMG-CoA reductase pathway).
Muckle–Wells and related syndromes
Three hereditary febrile syndromes have been described in association with dominant mutations in the gene C1AS1, coding for cryopyrin.
Muckle–Wells syndrome.
Episodic symptoms lasting up to 48 hours. Urticaria (not associated with cold), arthralgia, myalgia, headache, conjunctivitis, episcleritis. May lead to amyloidosis (25%).
Neonatal-onset multisystem inflammatory disease (NOMID), also known as CINCA (chronic infantile neurological cutaneous and articular syndrome).
Chronic disease, diffuse urticaria, epiphyseal overgrowth, conjunctivitis, uveitis (blindness), sensorineural deafness. Amyloidosis may occur as late feature.
Familial cold autoinflammatory syndrome (FCAS).
Fever, rigors, headache, arthralgia, conjunctivitis, and urticaria in response to cold exposure.
Familial cold urticaria is a milder variant of FCAS which also maps to the C1AS1 gene.
Treatment
NSAIDS are usually used.
Anakinra (IL-1RA) and canakinumab (anti-IL1b) are very effective.
Rilonacept (dimeric fusion protein with binding regions of the IL-1 receptor and the IL-1R accessory protein, fused to IgG1 Fc) appears to be highly effective.
The experimental caspase-1 inhibitor VX-765 has been shown to reduce IL-1 and is undergoing trials.
Periodic fever with aphthous ulcers, pharyngitis, and cervical adenopathy (PFAPA)
A rare syndrome characterized by periodic fever, aphthous ulceration, pharyngitis, and adenitis.
Starts early in childhood but improves as child grows up.
Cause uncertain—no gene identified yet.
Treat with corticosteroids, colchicines, or IL-1 inhibition.
Adenotonsillectomy has resolved some cases.
Schnitzler’s syndrome
A rare syndrome characterized by urticaria, skin papules, intermittent fever, bone pain, arthritis/arthralgia, and monoclonal IgM monoclonal gammopathy.
Severe anaemia of chronic disease is common.
IL-6 levels are elevated.
Evolves into lymphoma or Waldenström’s macroglobulinaemia in 15%.
Treatment may involve corticosteroids, colchicine, thalidomide, or anakinra. Preferred treatment is anakinra.
Anti-TNF therapy may make it worse.
Anti-histamines rituximab and hdIVIg are ineffective.
Blau syndrome
Familial granulomatous arthritis, iritis, cutaneous granulomata.
Overlaps with sarcoidosis and Crohn’s disease.
Associated with mutations in the NOD2 gene.
Deficiency of the IL-1 receptor antagonist (DIRA)
A rare autosomal recessive autoinflammatory syndrome.
Severe anaemia of chronic disease is common.
Sterile multifocal osteomyelitis, periosteitis, and cutaneous pustulosis from birth.
Mutations in IL-1 receptor antagonist gene IL1RN.
Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA)
Autosomal dominant condition.
Presents with early arthritis (destructive), pyoderma gangrenosum (variable), and nodulocystic acne.
Mutations identified in CD2 binding protein 1 gene (CD2BP1) located on chromosome 15.
Treat with anti-TNF or anti-IL-1 agents.
Xanthogranulomatosis
Syndrome is characterized by subcutaneous xanthogranulomatous plaques, typically around the eyes, associated with hard subcutaneous nodules.
There is an association with the development of paraproteins and eventually with lymphomas.
Paraproteins seem to associate with apo-B lipoproteins, which are then taken up by macrophages in the lesions.
Diagnosis is made by appearance and biopsy features.
The disease responds well to corticosteroids.
Regular monitoring of serum immunoglobulins and electrophoresis is required.
Kikuchi’s syndrome
A rare syndrome of lymphadenopathy seen in children and young adults. It is usually self-limiting.
Clinical features include fever, lymphadenopathy, skin rashes, and headache.
May be triggered by viral infections (CMV, EBV, HSV, VZV, parvovirus).
Possible association with autoimmune diseases, including SLE.
May also be a cause of haemophagocytosis.
Responds to NSAIDs; corticosteroids for severe disease.
Satoyoshi syndrome (Komura–Guerri syndrome)
A very rare syndrome of progressive muscle spasms, alopecia, diarrhea, endocrinopathy with amenorrhoea, and skeletal abnormalities, first described in Japan.
Spasms are painful and can affect breathing; myoclonus may occur. There are similarities to stiff person syndrome.
Thought to be autoimmune; may be associated with antibodies to GAD.
Castleman’s syndrome
Syndrome of diffuse lymphadenopathy, fever, malaise, and weight loss.
Many cases appear to be due to HHV-8 infection.
IL-6 levels may be elevated (?direct effect of virus).
Characteristic ‘onion-skin’ appearance in lymph nodes.
Usually treated with corticosteroids; role of anti-virals is uncertain.
Cheilitis granulomatosa (Miescher–Melkersson–Rosenthal syndrome, orofacial granulomatosis)
Rare syndrome presenting with non-tender swelling of the lips (upper lip more common than lower lip).
Initially attacks are intermittent, but eventually the swelling becomes permanent and progressive.
Must be distinguished from angioedema (more persistent).
Attacks of swelling may be accompanied by low-grade fever.
Swellings may also appear on other parts of the face.
Lymph nodes may be enlarged.
Tongue may be fissured.
Facial palsy may occur in one-third.
Biopsies may show granulomata in established cases.
May have a genetic basis but the cause is unknown; may be a localized form of Crohn’s disease.
Consider a labelled white cell scan to look for other evidence of Crohn’s disease
Patch testing may show positive reactions to cinnamon and benzoates, and occasionally metals. Trial of dietary avoidance may help a few patients.
Treatments suggested include clofazimine, metronidazole, intra-lesional steroid, azathioprine, sulfapyridine, dapsone and other antibiotics.
Chronic fatigue syndrome (CFS) 1
Chronic fatigue is a major presentation to doctors; causes are multiple and establishing a diagnosis is time-consuming. CFS is a diagnosis of exclusion. ME (myalgic encephalomyelitis) is an inappropriate term as there is no evidence for an encephalomyelitis. It is not a new syndrome and has been well described from Victorian times onwards (neurasthenia).
Presentation
Significant debilitating fatigue (not tiredness!) lasting beyond 6 months.
About half have a sudden onset, often after an acute infectious event; the remainder have gradual onset (unclear if these types differ).
Excess of ‘major life events’ in the year preceding presentation.
Other symptoms include:
unrefreshing sleep, sleep disturbance
poor short-term memory and poor concentration, word-finding difficulty
non-specific arthralgia, without arthritis
myalgia
headaches
disturbed temperature perception
sore throats and swollen glands
debilitating fatigue
secondary depression
alcohol intolerance
activity makes all symptoms worse.
Weight loss is not a feature and should always prompt a detailed search for an underlying medical or surgical cause.
Patients often self-diagnose CFS/ME. This is dangerous.
Patients may acquire bizarre beliefs about the cause and treatment of their symptoms, obtained from alternative practitioners, lay publications, and the internet. These include:
multiple allergies, including multiple chemical sensitivity
reactions to mercury amalgam fillings
chronic Candida overgrowth.
There is no evidence to support these aetiologies.
Chronic fatigue syndrome is a hotch-potch of miscellaneous syndromes, dependent on the speciality of the ‘expert’! Included within the spectrum are:
irritable bowel syndrome
food allergy
fibromyalgia (FM)
somatization disorder
effort syndrome
over-training syndrome (see ‘Sports immunology 2’, p.358)
patients with otherwise unexplained persistent fatigue and/or atypical pain
patients with significant medical/psychiatric disorders (up to 47% of referrals to hospital).
Differential diagnosis
In hospital practice, up to 47% of patients may turn out to have other medical or surgical problems. The differential diagnosis is long but includes the following.
Chronic infections: EBV, HIV, Coxsackievirus, Toxoplasma, Brucella, Yersinia, Borrelia;
Connective tissue diseases: SLE, Sjögren’s syndrome, rheumatoid arthritis, polymyositis, and polymyalgia rheumatica often have a long prodrome of fatigue;
Other autoimmune diseases: especially thyroid disease, Addison’s disease, diabetes mellitus, pituitary disease.
Gastrointestinal disease: PBC, autoimmune hepatitis, coeliac disease.
Neurological disease: MS, degenerative disease (including CJD), Parkinson’s disease (early stages), primary muscle disease.
Sleep apnoea, other primary sleep disorders including restless legs.
Cardiac disease: cardiomyopathy (alcohol, thiamine deficiency).
Poisoning: carbon monoxide, heavy metals, prescription drugs (e.g. β-blockers, minor opiate analgesics).
Malignancy.
Primary psychiatric disorders: depression (but a secondary depression is common), autistic spectrum disorders, somatization disorder, stress.
Malingering: rare, but usually perpetuated by obvious financial benefit from maintenance of sick role.
UK and US case definitions for CFS
The UK criteria have evolved out of the need to identify homogeneous groups of patients for research trials. Not all patients will fit the criteria.
Severe disabling fatigue affecting physical and mental functioning.
Minimum duration of symptoms—6 months.
Functional impairment—disabling.
Mental fatigue required.
No other symptoms required.
No evidence of other medical illness.
Normal screening blood tests.
The North Americans have a similar but slightly different case definition.
Physical causes of fatigue excluded.
Psychiatric disorders excluded, including:
psychosis
bipolar disorder
eating disorder
organic brain disease.
Epidemiology
Institutional epidemic outbreaks (Royal Free disease). These differ substantially from sporadic disease.
‘Chronic fatigue’, loosely defined, is very common in the community: prevalence of 20–30%.
10–20% of attenders in primary care complain of chronic fatigue (loosely defined).
For 5–10% this will be the primary reason for consultation.
Only a minority fulfil the case definition for CFS (see above).
Female to male ratio 2:1.
The prevalence of CFS/ME is much lower, but similar figures have been obtained from the USA and UK (using the different criteria):
point prevalence, 0.08–1% range using restrictive criteria
point prevalence of up to 2.6% using UK (Oxford) criteria
there are no reliable data on incidence.
It has been estimated that there may be as many as 150 000 cases in the UK.
CFS 2: cause and immunopathogenesis, assessment, and investigations
Cause and immunopathogenesis
Virology
Antecedent history of acute viral infection can be documented in about 50% CFS/ME patients.
Definable fatigue syndromes are well documented after:
Epstein–Barr virus—persistent EBV IgM positive (chronic EBV), only occurs in 10% of EBV-infected individuals
Toxoplasma
cytomegalovirus
other infectious agents (non-specific response)—severe bacterial infections.
Association with enteroviral infections is unproven (VP1 test is not reliable).
Association with XMRV (murine retrovirus) has been shown not be true.
Immunology
No evidence for a primary immunological cause. Identified abnormalities may well be secondary.
Abnormalities described are:
minor abnormalities of IgG subclasses
increased CD5+ CD19+ B cells
poor B-cell function
low levels of autoantibodies (RhF)
reduced CD4+ T cells increased CD8+ T cells
increased markers of T-cell activation
abnormalities of NK cells and monocytes
no clear changes in cytokine production
antibodies against nuclear pore antigens were found in 60–70% of CFS patients in one study.
Significant immunological abnormalities should raise doubts about a diagnosis of CFS.
Genetic abnormalities
Likely to be a genetic predispisition to develop the disease:
other family members may be affected
multiple genes involved (brain, immune system).
Muscle abnormalities
No characteristic abnormalities:
CK may be mildly elevated
NMR studies demonstrate abnormal metabolism, with failure to clear lactate
Cardiomyopathy may occur in a small subset.
Neurological abnormalities
No diagnostic abnormalities. However, a range of abnormalities has been documented, the significance of which is uncertain at present.
MRI scanning may show white matter abnormalities.
Single-photon emission tomography (SPET) reflects abnormalities of regional cerebral perfusion.
SPET abnormalities identified in brainstem; lesser abnormalities are reported in patients with depression.
Autonomic abnormalities are frequent and may occur in other disorders with fatigue (PBC). Postural orthostatic tachycardia syndrome (POTS) is a variant of CFS with marked autonomic abnormalities. Severity of autonomic disorder correlates with fatigue.
Endocrine abnormalities
Dynamic tests of the hypothalamic–pituitary–adrenal axis demonstrate abnormal responses.
Subgroup of CFS patients may have low cortisols (usually high in depression). Exclude Addison’s disease.
Psychiatric changes
No convincing evidence to show that CFS is a purely psychiatric disorder.
Depression is usually secondary.
There is an increased risk of developing psychiatric disorder in CFS patients (2- to 7.5-fold compared with chronic disease controls).
There is overlap with somatization disorders.
Assessment
Assess the patient objectively (and try to ignore the long-standing patient’s interpretation of events).
Are criteria for CFS met?
What is the degree of disability?
What are the patient’s beliefs about his/her illness?
Are there any symptoms/signs of other medical problems?
Low-grade fever, muscle wasting, orthostatic hypotension, pallor, breathlessness, tremor allowable (deconditioning due to prolonged rest).
Marked weight loss, lymphadenopathy, and fever >38°C require further investigation and should not be accepted as part of CFS.
Investigations
There are no specific diagnostic tests.
Basic screen must include:
FBC, differential white count
acute-phase response (evidence for inflammatory disease—ESR/CRP)
LFTs, Cr&E, TFTs, blood sugar, CK
endomysial/tissue tranglutaminase antibody (tTG) antibody
urine (protein/sugar).
Other tests should only be carried out if there are suspicious findings on history or examination. These may include:
viral serology (EBV, HIV)
cortisol, short synacthen test
screening for connective tissue disease.
There is no role for routine viral serology, lymphocyte subsets, or autoantibody screens.
CFS 3: management, outcome, and children with CFS
Management
A holistic approach is required—‘mindfulness’ (Kabat-Zinn 2004).
Evaluate the contribution of life events and psychological background.
Identify significant secondary depression and deal with this.
Deal with bizarre beliefs: www.quackwatch.com is a useful website with robust rebuttals of bizarre beliefs; www.neurosymptoms.org/ is another useful sites for patients with non-organic neurological symptoms.
Reassurance early that no serious medical condition has been identified.
Detailed explanation of current theories of CFS.
Expected prognosis.
Limit investigation (and control multiple referrals!).
Management by the smallest possible team.
Physical reconditioning.
Graded exercise and pacing.
Sleep hygiene
Drug therapy is symptomatic (not curative).
Sodium valproate is well tolerated for pain.
Amitriptyline in very small doses may help sleep and FM pain.
Duloxetine is recommended for FM.
Melatonin is useful for teenagers with CFS and sleep disturbance (need to have a break every 4–6 weeks as effect wears off).
Antidepressants for reactive depression: citalopram is better tolerated than fluoxetine/paroxetine.
Psychological support.
Cognitive behaviour therapy (often resisted by patients).
Lightning therapy, an accelerated form of psychotherapy based on neurolinguistic programming (NLP) helps some patients significantly.
General support from a sympathetic medical team.
Fighting Fatigue (Pemberton and Berry 2009) is an excellent self-help guide for patients.
A recent study from Norway has suggested a response to rituximab—this finding needs replication in larger blinded trials.
There is NO place in management for:
immunoglobulin (intravenous or intramuscular)
antihistamines
interferons (usually make the symptoms worse)
antivirals (except where there is a proven persistent EBV infection)
antifungals
magnesium
colonic irrigation
anti-Candida diets
low-allergen diets
enzyme-potentiated desensitization.
Homeopathy, aromatherapy, reflexology, acupuncture may provide symptomatic relief.
Multiple medical referrals perpetuate illness.
Deal with need for support for benefits, occupational advice.
Outcome
The prognosis is variable.
Most patients show significant improvement over 2 years if identified early and entered into a management programme.
‘Cure’ rate is probably 6–13% (several different series).
If there is no improvement by 2 years, recovery is unlikely (assuming that no perpetuating features are identified).
It is important to discuss adaptation of the patient’s lifestyle to his/her illness early on.
There are no laboratory markers that predict outcome.
Progression of symptoms may mean that the original diagnosis is wrong—be prepared to re-evaluate.
Treat all new symptoms on their merits—just because a patient has a diagnosis of CFS/ME doesn’t mean that they will not develop other unrelated illnesses.
A poor outcome is associated with:
late presentation
unaddressed psychosocial factors
poor management (‘There is nothing wrong with you—it’s all in your mind’)
inadequate rehabilitation (failure to encourage exercise perpetuates deconditioning)
secondary gain
perpetuation of bizarre beliefs (Candida syndrome, total allergy syndrome).
Children with CFS
Syndrome is not as rare in children as previously thought!
Earlier assessment of a tired child is appropriate.
Beware of ‘Munchausen syndrome by proxy’.
Management is more complicated and must address family issues.
Depression is common (60–80% of childhood CFS cases).
The same principles as those identified above apply to investigation and management.
Psychosocial factors (bullying) and psychiatric problems must be dealt with.
Deal with peer-relationship problems and school avoidance.
Avoid home tuition, as this encourages social isolation.
Aim for a recovery programme including graded physical and intellectual exercise, with identification of recovery goals.
Idiopathic oedema
A syndrome of non-menstrually related swelling of face, hands, abdomen, and feet, with no identifiable causes.
Associated with affective, somatic, and functional symptoms, including debilitating fatigue.
Overlaps with CFS/ME, fibromyalgia and irritable bowel syndrome.
May respond to spironolactone or bromocriptine (dopaminergic mechanism?).
Macrophagic myofasciitis
Rare muscle disease, said to be triggered by aluminium salts in vaccines
Focal infiltration of vaccinated muscles with PAS+ macrophages.
Associated with systemic features:
Fatigue
Malaise
Generalised arthralgia and myalgia
Muscle weakness
Fever
Muscle biopsy & MRI may show abnormalities
No specific treatment – manage as for CFS/ME.
Burning mouth syndrome
Characterized by intraoral burning sensation without evidence of medical or dental disease.
Need to exclude xerostomia, aphthous ulceration, vitamin deficiencies, intra-oral infections including HSV.
Patch testing, particularly to nickel, amalgam components, and dental products (cinnamon, benzoates), may identify delayed hypersensitivity in a small number of patients.
It is one of a family of medically unexplained facial pain syndromes, which may have psychological elements.
May present as ‘oral allergy’—testing to prove to the patient that allergy is NOT the cause may be required.
Allergy does not cause continuous burning pain.
Treat with tricyclic antidepressants, gabapentin, clonazepam, or possibly pramipexole (non-ergot dopamine D2 receptor agonist, unlicensed indication).
Postural orthostatic tachycardia syndrome (POTS)
Condition seen predominantly in young women, often but not exclusively with CFS/ME. May be associated with vasovagal syncope.
Clinical features include postural dizziness, excessive thirst, and palpitations, as well as other CFS/ME symptoms.
Key clinical finding is inappropriate tachycardia on asking the patient to stand after resting horizontally. Pulse should rise to >120bpm.
Diagnosis requires formal tilt-table testing.
It is important to recognize this syndrome as it is amenable to treatment (and in the context of CFS this reduces overall fatigue). Treatment includes:
increase fluid and salt intake
avoid alcohol
fludrocortisone
midodrine
β-blockers (not well tolerated in CFS/ME)
ivabridine (experimental)
Sports immunology 1
The immunology of sport is interesting because of the increased susceptibility to infection that high-level sporting activity generates.
Changes may be due to acute effects of training/competition and longer-term adaptive changes.
Changes may be secondary to neurohumoral changes.
Chronic change is usually related to hard training (see ‘Sports immunology 2: over-training syndrome’, p.358).
Use of illicit drugs should be considered, as these may affect immune function.
Acute-phase response
Exercise increases acute-phase proteins (CRP, fibrinogen, haptoglobin), although considerable amounts of exercise (>2 hours) are required.
Levels of IL-1 (although this is contentious), IL-6, α- and γ-interferon, and TNFα in serum are increased (with caveats about serum measurements of cytokines).
LPS-stimulated release of cytokines by monocytes is also increased by adrenaline, which is present in high levels during exercise.
IL-2 levels are reduced.
Innate immune response
C3a increases significantly following exercise—the greater the duration of exercise, the greater the rise.
Damage to muscle fibres may be the trigger for alternate pathway activation.
After quite short bursts of exercise, a leucocytosis is present because of increased mobilization.
After marathons, a persistent marked neutrophil and monocyte leucocytosis is apparent.
Adrenaline may play a role in the mobilization, although it may still occur in the presence of β-blockade.
Neutrophils are also activated, and granule components may be detected in the circulation.
NK-cell numbers are increased in absolute and percentage terms, and NK activity is increased, except in high-intensity exercise (such as a marathon) when it is reduced.
Specific immunity
Many effects on the specific immune system have been described, although the relationship to clinical status is often obscure.
The following changes have been documented in B cells during and immediately after acute exercise:
no significant change in B-cell numbers
reduced salivary IgA after long-duration exercise
reduction of circulating antibody-producing cells
monocyte-induced suppression (indomethacin inhibitable, suggesting role for prostaglandins).
The following changes have been documented in T cells during and immediately after acute exercise:
increase in T cells (CD8+ > CD4+)
altered CD4:CD8 ratio
increased CD4+ CD45RO+ T cells (?activation or altered trafficking)
reduced proliferative response to PHA and ConA
increased proliferative responses to IL-2, LPS, PWM
increased soluble activation markers after long-duration exercise (sIL-2R, sCD8, sICAM-1, sCD23, sTNF-R, neopterin).
Many of the effects on the immune system are mediated by the combination of changes in circulating and local hormones:
catecholamines
growth hormone
endorphins
cortisol (which may be responsible for late effects).
Hypoxia and hyperthermia may also contribute.
Glutamine reduction due to increased muscle demand for glutamine as an energy source starves the immune system of an essential metabolic precursor, leading to impaired function.
Adaptive changes during training
Resting immunology of athletes during training does not normally show very dramatic changes.
During low-intensity training there is a decrease in total lymphocyte count, with a reduction of the CD4:CD8 ratio.
More intense training tends to have less effect.
NK-cell numbers increase slightly.
Most trained athletes show slightly higher neutrophil counts, although some long-distance runners may have a neutropenia.
Neutrophil (and monocyte) function is normal.
Acute changes in immunological parameters seen in trained athletes are less than in sedentary individuals undertaking a similar workload.
Exercise and infection
The acute changes noted above may give a window of opportunity to pathogens, accounting for increased susceptibility to infection post-exercise.
The window may last up to 2 weeks.
Risks seem to be mainly in long-distance (marathon) runners.
Sports immunology 2: over-training syndrome
There is a J-shaped curve relating overall immune function to exercise. Low and moderate levels of exercise improve immunological function; high levels lead to immunological impairment.
It is difficult to ascertain for any given individual what level of exercise will be compromising immune function.
Short-term fatigue is a normal consequence of exercise.
Prolonged fatigue is usually a marker of over-training.
This can usually be attributed to inappropriate training and/or competitive programmes that do not allow adequate recovery periods.
The nature of the over-training syndrome is uncertain, but might relate to chronic overproduction of acute-phase cytokines (e.g. TNF) and hormones (cortisol and thyroid hormones are increased while testosterone is decreased).
Interference with the neurohumoral axis may occur, and patients may have features of anxiety and depression.
Chronic glutamine deficiency may be a minor contributing factor.
Illicit drugs and inappropriate supplements may contribute (seek information by direct questioning).
High-intensity exercise may be a surrogate form of anorexia in young females in particular. Such athletes are at high risk of serious complication of exercise due to inadequate nutrition and over-exercising: stress fractures, premature osteoporosis, and iron-deficiency anaemia.
Immunology
Immunological changes of optimum training are difficult to analyse, but include:
increased NK-cell numbers and activity
minor changes in T- and B-cell numbers
little change in serum immunoglobulins
increased levels of soluble markers such as IL-2R, sCD8, sICAM-1, sCD23, and sTNF-R.
Very heavy training and/or competition tend to lead to a reduction in cell numbers and function and reductions in antibody levels.
Exercise itself tends to mobilize cells from storage pools (spleen, marginated cells) but this effect is transient.
In the over-training syndrome:
lymphocyte and NK-cell numbers are reduced
there is evidence of in vivo activation on the basis of expression of activation markers CD25, CD69, and HLA-DR (on T cells)
in vitro mitogen responses are reduced (a common finding where there is evidence of increased in vivo activation)
phagocytic cell function is impaired.
Investigation
Investigation should be geared towards excluding other contributors to fatigue:
full blood count including differential white count
acute phase (ESR/CRP)
glucose and thyroid and liver function test;
serological tests for chronic infection (EBV, Toxoplasma)
vitamin and mineral status (iron, especially in women, folate, B12)
serum immunoglobulins and lymphocyte surface markers if there is a history of significant infections.
Routine diagnostic use of lymphocyte subset analysis and in vitro tests of NK- and T-cell function are not normally required for management.
Treatment
Explain the cause of the problem.
Advise a period of reduction of training to base levels for a period of several months, followed by a gradual increase.
Emphasizing the need to have peaks and recovery troughs in the training programme is essential.
Attention to diet and vitamin and mineral supplementation may be required.
There is no good scientific evidence that high-dose vitamin C helps, but many sports people have empirically found that it reduces their susceptibility to infection. However, it may cause renal stones as it is metabolized to oxalate. This may be a particular problem in athletes who are prone to dehydration during competition, so it is important to emphasize the need for adequate hydration.
Refer to a sports medicine specialist (English Institute of Sport can advise: http://www.eis2win.co.uk/pages/Sport_Medicine.aspx).
Depression and immune function
There is a close link between mental state and immune function.
Lymphocytes have receptors for certain neurotransmitters (catecholamines) as well as neurohormones (endorphins).
Cytokines such as IL-1 affect cerebral function (fever, hormone release).
Chronic or severe acute stress may be both immunosuppressive and lead to an increased risk of infection, through multiple neurohumoral pathways.
Similar changes are seen in prolonged depressive illness.
Findings may include:
minor lymphopenia and reduced NK cells
poor NK function
reduced immunization responses.
Routine investigation of the immune system is not warranted unless there is evidence of a major susceptibility to bacterial or viral infection.
Recognition and treatment of underlying cause is essential.
Immunology of infection
Dealing with infection is the primary function of the immune system and the reader is referred to the standard immunology textbooks for details of this. However, there are certain clinically important points that need to be borne in mind when interpreting immunological tests taken in patients with active infection.
Neutrophils
A neutrophilia, often with a left shift (i.e. immature cells newly emigrating from the marrow) and toxic granulation, is a major early feature of bacterial infection.
Severe neutropenia may also result from overwhelming sepsis due to consumption exceeding the marrow capacity for production.
This must be distinguished from a primary neutropenia causing the infection. Bone marrow examination may help.
If severe, G-CSF may speed recovery.
Monocytes
Monocytosis is often seen in viral infections.
Compensatory monocytosis is also seen during infective episodes in neutropenic patients.
Eosinophils
Marked eosinophilia is a feature of parasitic infections.
In the UK marked eosinophilia with fever is more likely to be due to a hyper-eosinophilic syndrome with or without vasculitis than to an infection.
Eosinophilia >10×109/L will be due to hyper-eosinophilic syndromes, not parasites.
Hodgkin’s lymphoma may cause eosinophilia (and fever).
Levels of eosinophil cationic protein (ECP) may be significantly raised and are important in diseases like Churg–Strauss vasculitis, as high levels of ECP are neurotoxic.
Lymphocytes
Acute viral and bacterial infections often lead to a generalized proportional lymphopenia.
In viral infections this will be followed by a rise in the CD8+ cytotoxic T cells and a fall in CD4+ T cells, leading to a marked reversal of the CD4:CD8 ratio.
There is usually an increase in activation markers (CD25, HLA-DR).
For this reason, lymphocyte subset analysis is not suitable as surrogate testing for HIV.
EBV infection often leads to a marked lymphocytosis, with B cells followed by CD8+ T cells.
Very high B-cell counts may occur following EBV infection in bone marrow transplant patients where there are insufficient T cells to control the EBV-driven B-cell proliferation (B-lymphoproliferative disease).
Serum immunoglobulins
Acute bacterial infection may lead to severe panhypogammaglobulinaemia. This may lead to erroneous diagnosis of a primary antibody deficiency.
Repeat testing after infection has been treated.
Do not start IVIg until confirmatory tests have been carried out.
More commonly, there will be an initial rise in IgM followed by a polyclonal rise in IgG, which then returns to normal.
Chronic infection will lead to significant polyclonal increases in immunoglobulins and may be accompanied by the appearance of monoclonal bands in the serum (from anti-pathogen clones).
Bands are often multiple on a polyclonally increased background.
Excess free light chains may also be found in the urine.
Bands will disappear within a few months of satisfactory treatment.
Persistently raised IgM or IgA may be found in tuberculosis.
Complement
Viral infection tends to have little effect on complement.
Acute bacterial infection will often lead to reductions of C3 and C4 (as well as factor B if measured).
As complement components are acute-phase proteins, there may be normal levels despite significant consumption.
Complement breakdown products will be increased.
Haemolytic complement assays may show reduced activity related to critical reductions in one or more components (usually in the terminal lytic sequence).
Patients with bacterial endocarditis often show marked reductions of C3 and C4.
In patients with suspected post-streptococcal nephritis, persistence of a low C3 beyond 6 weeks should prompt a check for a C3-nephritic factor, an autoantibody which stabilizes the alternative pathway C3-convertase and leads to unregulated C3 cleavage.
In patients with meningococcal disease, assay of haemolytic complement to look for complement deficiency should be deferred for at least 4 weeks. Doing the tests early often leads to confusing results.
CRP
Highest levels of CRP (>300mg/L) are seen in bacterial infection.
Very highest levels (>400mg/L) are seen in Legionella infection.
Beware of elevated CRP in infection with herpesviruses, especially EBV (levels up to 100mg/L).
High levels may also be seen in certain malignancies, including lymphoma and hypernephroma (may present as PUO).
Immunological diseases of pregnancy 1
Pregnancy is a form of allograft and non-rejection is a complex multifactorial process. Readers are referred to major texts for detailed discussion.
Immunological changes can be documented during pregnancy:
reduction in T cells (mainly CD4+), which reaches a nadir around the seventh month
reduced NK-cell numbers
B-cell numbers and function remain static
antibody synthesis and serum immunoglobulin levels are essentially unchanged.
Despite the change from Th1 to Th2, there is no evidence for increased susceptibility to infection, with the exception of Listeria, which has a tropism for the placenta and requires macrophages and T cells for clearance (these are locally suppressed).
There are no changes in solid organ allograft tolerance during pregnancy.
Autoimmune diseases may behave unpredictably.
Lupus may become worse or better during pregnancy, but may relapse immediately after delivery because of the sudden hormonal changes.
Vaccine responses are normal.
Pre-eclampsia
See p.362.
Recurrent miscarriages
There are many immunological theories for recurrent miscarriages, but most have little in the way of supportive evidence.
Antibody-mediated theory.
Anti-phospholipid antibodies: well substantiated.
Anti-sperm antibodies: not substantiated.
Anti-trophoblast antibodies: not substantiated.
Blocking antibody deficiency (anti-paternal antibodies): these antibodies are well documented but appear to be irrelevant to pregnancy outcome (agammaglobulinaemic women and mice have normal pregnancies).
Absence of complement regulatory proteins CD55 and CD59 on trophoblast as a cause of recurrent miscarriage: no evidence so far.
Cell-mediated theory.
Excessive Th1 response: some evidence of increased Th1 cytokines (γ-IFN and TNF-α, both of which are abortifacient in mice) and Th1 responses to trophoblast antigens in recurrent aborters—this is a strong possibility.
Deficiency of Th2 cells/cytokines: no human evidence yet.
Deficiency of decidual ‘suppressor’ cells: uncertain whether this is cause or effect.
Inappropriate MHC class I and II expression: evidence in mice only; none from humans.
HLA homozygosity: no convincing evidence as inbred mouse strains reproduce normally.
Laboratory investigation
Screen for anti-phospholipid antibodies (cause microthrombi in placenta with placental failure):
anti-cardiolipin IgG and IgM antibodies—IgM anti-cardiolipin antibodies are significant if persistent
anti-β2 glycoprotein-1 antibodies (if available)
lupus anticoagulant: prolonged APTT—check dRVVT.
Platelet count (APS patients have moderate thrombocytopenia, 80–120×109/L).
Anti-thyroid peroxidase (microsomal) antibodies, anti-nuclear antibodies, antibodies to ENA (especially Ro and La).
C3 and C4.
These tests should identify otherwise ‘silent’ cases of SLE.
Management
Joint obstetric and medical management is required for such patients.
Low-dose aspirin or heparin may be required.
Treat anti-phospholipid syndrome (APS) patients with no previous history of thrombosis or pregnancy loss with low-dose aspirin alone.
Those with a prior history of thrombosis should go on to heparin.
Those with recurrent miscarriages and a previous history of thrombosis should go on to aspirin plus heparin.
Heparin is associated with occasional severe osteoporosis in pregnancy. It is not yet clear whether this effect is also seen with low molecular weight heparins.
Discuss the risks of these therapies fully with the patient.
If these treatments are unsuccessful, consider high-dose IVIg as an immunoregulatory agent. Counsel concerning potential infective risks (hepatitis, spongiform encephalopathies) and record information given in the notes.
The optimal treatment for recurrent miscarriages not associated with anti-phospholipid antibodies is unknown.
Many manipulations have been tried but there are few good clinical trials. In 58% of untreated patients successful pregnancy may ensue, and this figure rises to 85% with good supportive psychotherapy.
No convincing evidence that leucocyte transfusions, steroids, ciclosporin, progesterone (immunosuppressive in high doses), or other drugs make a significant difference.
Blood group incompatibility
Alloimmune thrombocytopenia
Immunological diseases of pregnancy 2: autoimmune diseases and immunodeficiency
Autoimmune diseases
Autoimmune diseases in the pregnant mother that are accompanied by IgG autoantibodies may occur in the fetus/neonate due to placental transmission of the antibody:
myasthenia gravis
thyroid disease.
This also confirms the pathogenicity of some antibodies.
Mothers with SLE who are anti-Ro or anti-La antibody positive are at increased risk of having babies affected with:
neonatal lupus: photosensitive rash (made worse if the baby is given phototherapy for jaundice)—self-limiting and disappears over first 6 months as maternal IgG is catabolized;
development of in utero complete heart block (Ro+ = 2%; Ro+/La+ = 5%).
Congenital complete heart block is caused by anti-Ro antibodies crossing the placenta between 8 and 12 weeks gestation and causing inflammation and subsequent fibrosis of fetal cardiac conduction system.
Death may occur in utero.
Survivors require immediate pacemaker insertion at birth (and require lifelong pacemakers).
Dexamethasone given during pregnancy crosses the placenta and may reduce inflammation. It must be given early to be effective. Prednisolone is metabolized by the placenta and is ineffective.
1 in 20 Ro+ mothers will be affected; if there has been an affected pregnancy, risk rises to 1 in 4.
Anti-La may also be associated with congenital complete heart block.
Children with neonatal lupus or congenital complete heart block are at increased risk of developing lupus in their own right.
Immunodeficiency
Primary antibody deficiency may be diagnosed during pregnancy when routine testing fails to identify isohaemagglutinins in the pregnant mother.
Replacement therapy should be started at once to ensure approximately normal levels of placental transfer.
Failure to treat means that the neonate will be at significant infective risk during the first 6–9 months of life.
If no maternal replacement has been undertaken, the infant should be given at least 6 months of IVIg in normal replacement doses, while continuing to receive the normal childhood immunizations.
Maternal infection (including rubella and the herpesviruses; see Chapter 2) during pregnancy, particularly peripartum, may also lead to neonatal immunodeficiency due to in utero or neonatal infection.
HIV infection poses particular risks of vertical transmission.
Schedules of prophylactic treatment with antiretroviral drugs are now used to reduce the risk of transmission.
Congenital HIV infection may cause hypogammaglobulinaemia and unsuspected cases may present with recurrent bacterial infections rather than the opportunist infections seen in adults.
Pre-eclampsia and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome
A syndrome of late pregnancy (5–7%) with severe hypertension and peripheral oedema, which if untreated causes fits and multi-organ failure.
Cause is unknown, but excessive IL-6 release and a placental tyrosine kinase may contribute to maternal endothelial activation.
Risk factors include:
anti-phospholipid antibody syndrome
nulliparous women
presence of anti-thyroid antibodies
extremes of maternal age
diabetes
pre-existing hypertension and/or renal disease.
Complement C4 is reduced.
HELLP syndrome is a form of severe pre-eclampsia with haemolysis, elevated liver enzymes, low platelets.
Urgent control of hypertension and rapid delivery are required for control of the syndrome.
References
Kabat-Zinn J (
Pemberton S, Berry C (
