Association between hypoparathyroidism and defective T cell immunity in 22q11.2 deletion syndrome.

AIMS: Although poor thymic function leading to viral and fungal infections can be a feature of chromosome 22q11.2 deletion syndrome, most patients have relatively normal immunity. The aim of this study was to investigate which clinical and laboratory parameters best predict the likelihood of serious or recurrent infections in patients with this syndrome. METHODS: Clinical and laboratory parameters from 64 patients with 22q11.2 deletion syndrome referred to two immunology centres in the north of England were studied retrospectively. RESULTS: 31 (48%) patients had no problems with infection, 21 (33%) had bacterial infections, and 12 (19%) had recurrent or persistent thrush and/or viral enteritis and bronchiolitis, the latter suggestive of a significant T cell immunodeficiency. Patients with a history of thrush/viral infections, but not those with bacterial infections, had significantly lower CD4+ and CD8+ T lymphocyte numbers (relative risk (95% CI) 0.3 (0.1 to 0.8)) and phytohaemagglutinin mitogen responses (0.4 (0.2 to 0.8)) adjusted for age at testing. Hypoparathyroidism was associated with low T lymphocyte numbers and function (p<0.05) as well as an increased risk of thrush/viral infections (p<0.0001) after adjusting for age at testing. CONCLUSIONS: 22q11.2 syndrome patients with hypoparathyroidism are more likely to have a clinically significant T cell immunodeficiency and lower laboratory parameters of T cell function, with a higher risk of thrush and viral bronchiolitis and enteritis. Measurement of absolute CD3 count is a simple and accurate predictor of fungal/viral infection risk, with phytohaemagglutinin mitogen responses providing little or no further value in most patients.

Clinical variability and characteristic autoantibody profile in primary C1q complement deficiency.

OBJECTIVES: C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. METHODS: A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. RESULTS: Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. CONCLUSIONS: Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.

Sarcoidosis and HTLV-1 infection.

An asymptomatic, homosexual, white man was found to have an abnormal chest x ray. A presumptive diagnosis of sarcoidosis was made, but pulmonary function tests and a transbronchial biopsy were normal. He then remained asymptomatic for 10 years until he developed a progressive spastic paraparesis. At this point, antibodies to human T cell lymphotropic virus type 1 (HTLV-1) were identified in the serum and cerebrospinal fluid, and the diagnosis of HTLV-1 associated myelopathy was made, the history suggesting sexual exposure to HTLV-1 many years previously. HTLV-1 is associated with a spectrum of immune related disorders, including a pulmonary sarcoid-like syndrome. Infection with this chronic proinflammatory retrovirus should be considered in the differential diagnosis of all immune disorders in at risk individuals.

Primary antibody deficiency and diagnostic delay.

AIMS: To assess the occurrence of diagnostic delay in primary antibody deficiency in the period 1989-2002, since a similar study in 1989, and to assess the impact of UK national guidelines communicated in 1995. METHODS: A retrospective case note review was performed of 89 consecutive patients with antibody deficiency referred to a regional referral centre for clinical immunology in north west England and north Wales. The delay in diagnosis and the estimated resulting morbidity in terms of infections were assessed. RESULTS: Fifty six of the 89 patients experienced delay in diagnosis. The overall median delay was 2 years (mean, 4.4), resulting in substantial morbidity (equivalent to two major infections and one minor infection). This shows a moderate improvement since the previous study in 1989 and since the introduction of UK national guidelines in 1995. Respiratory infections are the most frequent presenting infections, and respiratory physicians the most common source of referral. CONCLUSIONS: There is still considerable delay in the diagnosis of primary antibody deficiency, but the data suggest an improvement in practice since the previous study in 1989 and the distribution of national guidelines in 1995.

Clinical pathology accreditation: standards for the medical laboratory.

This article describes a new set of revised standards for the medical laboratory, which have been produced by Clinical Pathology Accreditation (UK) Ltd (CPA). The original standards have been in use since 1992 and it was recognised that extensive revision was required. A standards revision group was established by CPA and this group used several international standards as source references, so that the resulting new standards are compatible with the most recent international reference sources. The aim is to make the assessment of medical laboratories as objective as possible in the future. CPA plans to introduce these standards in the UK in 2003 following extensive consultation with professional bodies, piloting in selected laboratories, and training of assessors.

The role of fear of physical movement and activity in chronic fatigue syndrome.

OBJECTIVE: To examine beliefs in relation to avoidance of activity in chronic fatigue syndrome (CFS) patients. METHODS: The first phase consisted of modifying an existing chronic pain measure of kinesiophobia-fear of physical movement and activity-and validating it on the CFS population [Tampa Scale of Kinesiophobia-Fatigue (TSK-F); n=129; test-retest: r=.89, P<.001; alpha=.68]. Subscales of Illness Beliefs (alpha=.78) and Beliefs about Activity (alpha=.70) were identified. The second phase consisted of evaluating whether behavioural persistence was predicted by the TSK-F (n=33). Participants were asked to ride an exercise bike for as long as they felt able. RESULTS: Analyses indicated that behavioural persistence did not correlate with maximal heart rate or resting heart rate, level of tiredness, symptom severity, illness identity or emotional distress. However, the TSK-F did correlate highly with distance travelled and added a significant 15% of the variance in distance after adjustments for gender and physical functioning (PF). The TSK-F Beliefs about Activity subscale appears to be the predictive factor, explaining 12% of the variance in excise performance or rather 12% of the avoidance of exercise. CONCLUSION: Beliefs about Activity appear to be an important variable in predicting behaviour and avoidance of exercise. As avoidance has been suggested as a key to the maintenance of symptoms, disability and distress in CFS patients, this research has important theoretical, clinical and research implications.

Children with atopic dermatitis who carry toxin-positive Staphylococcus aureus strains have an expansion of blood CD5- B lymphocytes without an increase in disease severity.

Toxin-positive strains of Staphylococcus aureus (T + S. aureus) are present on the skin of some but not all patients with atopic dermatitis. Many staphylococcal toxins are superantigens, which can stimulate the immune response and thus may potentially lead to the very high levels of IgE characteristic of this condition, as well as exacerbating the clinical disease. The aim of this study was to determine whether the presence of T + S. aureus on the skin of children with atopic dermatitis was associated with in vivo evidence of a heightened humoral immune response, higher IgE levels and more severe clinical disease. Toxin gene expression in S. aureus isolated from the eczematous lesions of 28 children with atopic dermatitis was assessed by PCR. Clinical and immune data were also collected from this cohort. Thirteen of the 28 children (46%) were colonized with T + S. aureus strains. The presence of T + S. aureus was associated with a significant expansion in peripheral blood CD5- B cells (P = 0.01), and the more toxin types identified the greater the B-cell expansion (P = 0.002). However, in this cohort of children with atopic dermatitis, despite th in vivo expansion of B cells in children harbouring T + S. aureus, there was no associated increase in IgE levels or in clinical disease severity scores.

Setting standards for pathology service support to emergency services.

Quality standards have been established in two key areas of pathology directly relevant to standards for the provision of emergency medical services. First, there is a national scheme for accreditation of laboratory services--Clinical Pathology Accreditation (UK) Ltd (CPA)--which has been in formal operation since 1992 and currently covers about 80% of all UK laboratories. Secondly, guidelines have been issued by the Joint Working Group on Quality Assurance (JWGQA) on the support to any point-of-care (near patient) testing facilities. Point-of-care testing (POCT) is increasingly popular in emergency areas, where the availability of faster test results is expected to expedite diagnosis and treatment. When laboratory services are not accredited or POCT equipment and its usage are outside laboratory supervision, there should be concerns that quality standards for pathology service support of the emergency services are not being met.

Atopic eczema is associated with delayed maturation of the antibody response to pneumococcal vaccine.

The aim of this study was to investigate a previously undocumented observation, that children with atopic eczema under 9 years of age tended to have a poor antibody response to Pneumococcal vaccination. Thirty-five children (mean age 8.8 years, range 3-16 years) with moderate to severe atopic eczema but no history of systemic infection were studied retrospectively. Pneumococcal antibody responses after immunization with Pneumovax II were compared with a hospital control group consisting of 36 children (mean age 6.0 years, range 3-16 years) with recurrent upper respiratory tract infections. Only 17% of children with atopic eczema aged 3-8 years responded to Pneumovax. This response was significantly poorer than that of the controls (57%) (odds ratio 0.20, 95% confidence interval (CI) 0.05-0.84, P = 0.03). There were no significant differences in the levels of total IgG2, the component of IgG associated with protective antibody responses to Pneumococcus between the two groups. Delay in maturation of the total IgG and IgG2 antibody response to Pneumococcus is a feature in this group of children with moderately severe atopic eczema.

The application of near patient testing to microbiology.

Near patient testing (NPT) was the norm in days when urine was examined by smell and taste. More recently, general practitioners and physicians in genitourinary medicine began to use light microscopes in their consulting rooms to examine urine for pus cells and urethral and other swabs for pathogens. Increasing knowledge has led to specialisation, however, with clinicians obtaining specimens for examination by others. Improved technology has speeded up the practice of medicine, raising expectations of patients and doctors alike, and reductions in the size and expense of testing instruments have made a renaissance of NPT possible. Such a rebirth has already been seen in high dependency units and neonatal intensive care units, where arterial blood gases and serum bilirubin have to be tested in less time than it would take a sprinter to reach the laboratory. People with diabetes, rushing about in the community, stop and test their own blood glucose to determine the ideal dose of insulin, and patients with asthma measure peak expiratory flow rates to titrate doses of inhaled and oral corticosteroids. To what extent has NPT developed in microbiology? General practitioners have nitrite dipsticks and dipslides with which to identify urinary tract infections and elsewhere in this issue the prospect for testing for Helicobacter pylori infection is discussed. Do-it-yourself HIV testing kits can be bought in some countries. Are these desirable developments for communicable diseases, the results of whose investigation are used not only to benefit the individuals tested but also to monitor trends in populations and determine policies for the prevention and control of infection? If NPT is desirable, or inevitable, in microbiology, how can it be developed so as to ensure a high quality service both for patients and the population? This review considers the implications of NPT in the field of communicable diseases for microbiology laboratories, quality assurance, accreditation, and the legal framework in which medical devices are used.

Defective antibody production in patients with rheumatoid arthritis and bronchiectasis.

Bronchiectasis (BR) occurs in about 3% of patients with rheumatoid arthritis (RA). Defective antibody production is a rare but well-recognised cause of both BR and inflammatory arthritis. We examined the hypothesis that subtle specific antibody defects might play a role in the pathogenesis of BR associated with RA. Identification of defects in antibody production is important because substantial benefits may be gained from immunoglobulin replacement. Specific antibody production was assessed in 20 patients with RA and BR, 20 with BR alone, 20 with RA alone and 20 healthy controls (all groups matched for age and sex). All had normal total IgG. IgA and IgM and IgG subclass levels. Specific antibody production was assessed by assay of antibodies to representative polysaccharide and protein antigens. Subjects with subprotective titres were challenged with the appropriate vaccine. Defective antibody production was defined as a subprotective level despite immunisation. Three out of 20 patients with RA and BR had a defective IgG2 response to the polysaccharide antigen, but normal responses to the protein antigen. All of the subjects in the BR alone or healthy control group had normal antibody production. Two out of 20 patients with RA alone had defective production of antibodies against both protein and polysaccharide antigens; both were receiving gold therapy, a recognised cause of functional antibody defects. It was concluded that some patients with RA and BR have functional antibody defects and may benefit from antibody replacement. An unexpectedly high proportion of patients with RA alone also have functional antibody defects, possibly secondary to gold therapy.

Exacerbation of atopic dermatitis after bacillus Calmette-Guérin vaccination.

In two children with atopic dermatitis, routine vaccination with bacillus Calmette-Guérin (BCG) was followed by severe exacerbation of skin disease. If the sequence is cause and effect, a possible mechanism is stimulation of a Th2 lymphocyte cytokine profile by the vaccine, with migration of activated lymphocytes to inflamed skin. In children with active atopic dermatitis, BCG vaccination is best deferred until remission.

Raising standards in pathology: the accreditation process in the United Kingdom.

The accreditation scheme established by Clinical Pathology Accreditation (UK) Ltd has been in formal operation since 1992. So far, 933 laboratories have been inspected, nearly two-thirds of all laboratories in the UK. Of these, 73% are fully accredited, 24% have outstanding conditions requiring correction, and 3% have been referred. Inspectors have identified some regional and specialty differences, most notably in histopathology and cytology. The second cycle of inspection visits is underway. Most UK departments of pathology have embraced the concept of accreditation with relative enthusiasm and there has been strong support from professional bodies, specialist societies, health service managers, the independent sector and government departments.

The role of the complement cascade in sepsis.

Complement provides a critical and multifaceted defence system against infection. Following activation, complement can clear invading microorganisms by lysis or by opsonization, which promotes recognition by complement receptors on phagocytes. Complement activation products promote a local inflammatory response and are involved in the modulation of adaptive immune responses that lead to antibody production. The host has developed regulatory mechanisms for controlling complement activation and for protecting its own cells against complement attack. Some microorganisms have also evolved ways to avoid the opsonic and lytic action of complement.

Antipolysaccharide antibodies in 450 children with otitis media.

We have measured antibodies to pneumococcal and Haemophilus polysaccharides in a prospective study of 450 children aged 2-16 years with otitis media requiring grommets (ear tubes). Pneumococcal antibody levels were significantly higher in the 2-6 year (P < 0.004) and 7-10 year (P < 0.04) study groups in comparison with age-matched controls. There was no difference in Haemophilus antibody levels between the study and control group children for the age groups 2-6 years and 11-16 years. Haemophilus antibody levels were significantly lower in the 7-10 year (P < 0.003) group in comparison with age-matched controls. Eighty-eight out of 450 (19.6%) children had pneumococcal antibody levels below the 25th percentile. Nineteen out of 88 (21.6%) children with pneumococcal antibody levels below the 25th centile were test immunized with 23 valent Pneumococcal polysaccharide and unconjugated Haemophilus type b capsular polysaccharide. Of these 19 children (aged 4-11 years), five mounted suboptimal responses to both polysaccharide antigens, whilst one child failed to respond to Haemophilus polysaccharide alone. There was no significant difference in the prevalence of IgG subclass deficiency between the normal responders and poor responders to immunization (P = 0.12). We found no evidence of specific polysaccharide antibody deficiency in the vast majority of the 450 children studied. However, the significance of poor antibody responses to test immunization in a small minority of children with otitis media is unclear. Long-term follow up of these children is required to determine whether poor immunization responses herald the development of frank antibody deficiency.

Prolidase deficiency and systemic lupus erythematosus.

Two children with prolidase deficiency, an inborn error of proline metabolism, developed clinical and immunological abnormalities consistent with a diagnosis of systemic lupus erythematosus (SLE). The first child died from septicaemia, and SLE was only diagnosed during his terminal illness. As a result of this diagnosis his cousin, who was already known to have prolidase deficiency, was investigated further and a diagnosis of SLE confirmed. Following treatment with oral prednisolone her clinical condition has improved, although she has a persistently raised erythrocyte sedimentation rate (ESR) and florid facial rash. Both prolidase deficiency and SLE are associated with disturbances in immune function and have clinical features in common. It is likely that prolidase deficiency is a risk factor for the development of SLE. Additionally, patients with SLE should-where there is a family history or presentation in childhood-be specifically investigated for prolidase deficiency, since standard immunological or haematological investigations will not identify the characteristic biochemical abnormalities.

Effect of diagnostic delay on disease severity and outcome in glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies.

AIMS: To measure the time between onset of symptoms and intention to treat in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis; and to investigate the effect of any delay in diagnosis on disease severity at presentation and outcome. METHODS: All ANCA positive patients with biopsy proven glomerulonephritis presenting in the North West Region over a consecutive period of 57 months were identified from the North West Glomerular Disease Registry. Sixty nine patients were identified and notes from 61 were reviewed. RESULTS: The 61 patients had a median diagnostic delay of 92 days. In only 12 patients had an ANCA test been performed prior to the nephrology referral. Thirty three patients had renal failure requiring dialysis within one week of admission and had a shorter delay (median 72 days) than those not requiring dialysis (median 132 days). None of the 28 patients with independent renal function at presentation required dialysis subsequently. Eighteen (55%) of those who required dialysis recovered independent renal function at three months and 13 (39%) had long term recovery. Both for patients who did and did not undergo dialysis, a longer delay was correlated with an increased percentage of sclerotic glomeruli at presentation. Patients with end stage renal failure had a median delay of 92 days, compared with one of 42 days in those who were dialysis independent at final follow up. CONCLUSIONS: Prolonged delay in diagnosis of ANCA associated glomerulonephritis is associated with an increased risk of end stage renal failure.

Antibody deficiency associated with gold treatment: natural history and management in 22 patients.

OBJECTIVE: To perform a clinical and immunological study of patients with rheumatoid arthritis who develop subnormal serum immunoglobulins on gold treatment; to clarify the nature of the defect in antibody production and determine the natural history of this adverse reaction; to use this information to suggest guidelines for the detection, investigation, and management of this complication. METHODS: 22 patients who developed subnormal levels of one or more immunoglobulin isotypes while receiving gold treatment were recruited over a 10 year period from the practice of a single rheumatologist. Antibody production was assessed by measurement of total immunoglobulins and of specific antibody production against polysaccharide and protein antigens, with test immunisation if necessary. RESULTS: Two broad patterns of antibody deficiency were identified: (1) (n = 11) mild, affecting only one immunoglobulin isotype and with normal specific antibody production. These patients were in general able to continue gold without further deterioration in antibody production. (2) (n = 11) severe, affecting two or three immunoglobulin isotypes, with defective specific antibody production. Six patients developed significant infections and were treated with immunoglobulin. Gold was discontinued in all. Normal antibody production recovered in nine patients, and in all but one followed for more than one year. No relation was seen between duration/dose of gold and antibody deficiency. CONCLUSIONS: Gold-induced antibody deficiency may be more common than usually recognised. A spectrum of deficiency exists, with some patients developing infective complications. Antibody production should be monitored in patients on gold treatment.

The immunological background to transplantation.

Organs are transplanted clinically to rectify an irreversible functional deficit but, unless donor and recipient are genetically identical, graft antigens will trigger a rejection response by the recipient. In the early part of this century, experiments on transplantation of tumours showed that there were strict limitations on the ability of tumour grafts to survive. These 'laws of transplantation' were confirmed by the elegant work of Sir Peter Medawar and colleagues who also showed that rejection is a systemic process governed by lymphocytes. The study of skin graft rejection in mice led to the discovery of the major histocompatibility complex (MHC) antigens, the function of which is to bind processed antigens and present them to T lymphocytes. T lymphocytes are pivotal in transplant rejection. The sensitization phase of rejection is due mainly to passenger leucocytes in the graft being recognised as foreign by the recipient's CD4+ T cells. The effector phase of rejection involves these activated recipient T cells entering the graft and locally producing cytokines. The rate of rejection depends on the relative contribution of the underlying immunological effector mechanisms. Our understanding of the role of T cells in transplant rejection has contributed much to knowledge on T cell physiology and function. The need to prevent rejection has also led to the development and use of new immunomodulating agents, approaches which have implications in the treatment of many other immunological disorders.