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.

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.

An open study of interferon in HIV-antibody-positive men.

Alpha-2a-recombinant interferon (Roferon A) was given subcutaneously in a dose of 3 mega units twice weekly for 15-18 months to 14 HIV-antibody-positive, p24-antigen-negative men with minimal HIV-related disease. Interferon was well-tolerated and safe. Although there was either improvement or lack of deterioration initially in 22 out of 26 HIV disease markers, including lymphadenopathy, thrombocytopenic purpura and nail fungal infection, there were 11 instances of HIV disease indicators appearing during the study. At 15 months, six patients were withdrawn from the study because of clinical and immunological deterioration.

Erroneous values for the total white cell count and ESR in patients with cryoglobulinaemia.

Temperature dependent fluctuations in the erythrocyte sedimentation rate were noted during the assessment of one patient with symptomatic cryoglobulinaemia. Two patients with this condition were found to have erroneously high leucocyte counts when estimated by the Model S Coulter Counter. The artefact was directly related to the degree of exposure to cold before the estimation was performed and appeared to be due to the formation of microaggregates of cryoglobulin and fibrinogen.

Studies of intestinal lymphoid tissue. VI--Proliferative response of small intestinal epithelial lymphocytes distinguishes gluten- from non-gluten-induced enteropathy.

Several diseases of the small intestine, including gluten-sensitivity, present with malabsorption and a "flat" mucosa. Determination of the mitotic index of epithelial lymphocytes provides a simple, objective method of assessing, and thus of predicting, whether a flat mucosa is due to gluten-sensitivity (index greater than 0.2%), or not (index less than 0.2%). The use of this index in circumstances especially likely to cause diagnostic confusion--for example, intestinal lymphoma; Crohn's jejunitis of immunodeficiency--is illustrated in this paper. Of seven cases, five (two primary lymphoma, three immunodeficiency) had been treated with a gluten-free diet without benefit; a mitotic index performed on the initial biopsy in each of these patients could have predicted from the outset that none was gluten-sensitive. Of the remaining two cases, determination of the mitotic index on the biopsy initially obtained from a man with severe hypogammaglobulinaemia would have indicated that he was also gluten-sensitive. Empirical use of a gluten-free diet was avoided in the other patient (with flat small intestinal mucosa and low mitotic index) in whom the diagnosis was ultimately shown to be due to Crohn's disease of jejunum.

Detection of monoclonal immunoglobulins by immunoelectrophoresis: a possible source of error.

The technique of immunoelectrophoresis (IEP) is widely employed in the qualitative analysis of serum immunoglobulins. The most commonly used support media are agarose or agar gels, but the mobility of immunoglobulins is different in these two media. The presence of a small amount of a cathodal monoclonal immunoglobulin G may not be detected on IEP in agar if it is masked by larger amounts of polyclonal immunoglobulin of the same class. In these circumstances the use of agarose imparts to the monoclonal protein a different mobility from that of the bulk of the serum IgG and allows its positive identification.

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.

IgG myeloma presenting as ulcerative colitis.

Two patients who presented with ulcerative colitis are described. Both were found to have evidence of IgG monoclonal gammopathy and Bence-Jones proteinuria. This association has been reported previously only in the presence of myelomatous infiltration of the gastrointestinal tract or in amyloidosis, and hence the cases reported appear to be unique.

Waldenström's macroglobulinaemia secreting a paraprotein with lupus anticoagulant activity: possible association with gastrointestinal tract disease and malabsorption.

A 51 year old man with Waldenström's macroglobulinaemia presented with a malabsorptive syndrome related to extensive small bowel lymphangiectasia caused by immunoglobulin accumulation. The patient's plasma had strong lupus anticoagulant activity and the IgM lambda paraprotein displayed specificity for the negatively charged phospholipids phosphatidyl serine and phosphatidyl inositol, as well as the neutral phosphatidic acid. Despite treatment for the macroglobulinaemia the patient died and at necropsy was found to have myocardial ischaemia and segmental infarcts in the spleen and kidney. The coexistence of these relatively rare findings suggests a possible association between Waldenström's macroglobulinaemia with gastrointestinal manifestations and paraprotein specificity for phospholipid.

Influence of anticardiolipin antibodies on immediate patient outcome after myocardial infarction.

AIMS: To determine whether the presence of anticardiolipin antibodies in patients with suspected myocardial infarction is predictive of complications during hospital stay or after discharge. METHODS: Anticardiolipin antibodies were serially measured in a cohort of 111 patients, from the time of admission to the coronary care until till eight weeks after discharge. Associations with fatal and non-fatal cardiac complications were documented. RESULTS: The incidence of raised titres of IgG and IgM anticardiolipin antibodies (ACA) in patients with myocardial infarction was comparable with that in patients with ischaemic heart disease. ACA titres in patients with a previous myocardial infarct were not significantly different from those found in patients without a previous history of infarction. Over the period of the study, ACA titres in the myocardial infarct group did not change significantly from those recorded on admission, nor did those patients with raised ACA titres have a higher prevalence of complications in hospital or in the early period after discharge. CONCLUSIONS: There is no evidence that patients with an acute or previous myocardial infarct have higher ACA titres than those found in patients with ischaemic heart disease. Raised ACA titres soon after myocardial infarction do not influence immediate patient outcome.

Soya protein antibodies in man: their occurrence and possible relevance in coeliac disease.

Circulating antibodies to soya-derived protein antigens have been measured in patients with duodenitis, Crohn's disease, ulcerative colitis and coeliac disease. Significantly raised antibody titres were found frequently in the coeliac group, particularly those patients showing a suboptimal response to a gluten-free diet, but rarely in subjects with other gastrointestinal diseases. Antisoya activity was not necessarily accompanied by antibodies to other common dietary antigens. We suggest that some coeliacs may have an associated dietary soya sensitivity which could adversely influence their response to gluten withdrawal.

Reassessment of faecal alpha-1-antitrypsin excretion for use as screening test for intestinal protein loss.

Faecal alpha-1-antitrypsin and 51Cr-albumin losses in 42 patients with either gastrointestinal or hepatic disease were compared. The reference range was derived from measurements in 20 controls without gastrointestinal disease. Alpha-1-antitrypsin excretion was increased in patients with excessive 51Cr-albumin loss, and correlations were found between alpha-1-antitrypsin clearance and 51Cr-albumin excretion. Because of the considerable overlap of faecal alpha-1-antitrypsin excretion between controls and patients, sensitivity and specificity of the test were only 58% and 80%, respectively. This poor reliability could not be explained by sampling error or temporal variations in alpha-1-antitrypsin excretion. These results show that although faecal alpha-1-antitrypsin excretion correlates with 51Cr-albumin excretion when whole groups of patients are studied, its poor sensitivity makes it an unreliable measure of enteric protein loss.

Lymphocyte transformation responses to phytohaemagglutinin and pokeweed mitogen in patients at differing stages of HIV infection: are they worth measuring?

AIMS: To determine whether the routine measurement of lymphocyte transformation responses to mitogenic stimuli provide any information additional to that available from routine T cell CD4 and CD8 analysis in patients with HIV infection. METHODS: The case records of 197 immunologically investigated HIV seropositive patients were reviewed. The influence of disease stage on T lymphocyte subsets and lymphocyte transformation responses (LyTR) to phytohaemagglutinin (PHA) and Pokeweed mitogen was assessed. RESULTS: The median CD3 and CD4 counts and LyTR to PHA and Pokeweed mitogen were highest in patients with persistent generalised lymphadenopathy (PGL) and decreased progressively in the order: asymptomatic patients, those with ARC, those with AIDS. LyTR to PHA was preserved in over 70% of all patients, but the response to Pokeweed mitogen was depressed in 8% of patients with PGL, 34% of asymptomatic patients, 68% of those with ARC and 78% of those with AIDS. Subnormal values of both CD4 + T cells and LyTR to Pokeweed mitogen were more common in patients with ARC and AIDS (68%) than in those who were asymptomatic or had PGL (20%). CONCLUSIONS: CD4 T cell analysis and LyTR to Pokeweed mitogen, but not to PHA, both correlate with disease states in patients with HIV infection.

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.

Recurrent meningococcal septicaemia and properdin deficiency.

A 32-year-old male presented with two episodes of meningococcal septicaemia, each of which was caused by a different serogroup of Neisseria meningitidis. Examination of the alternative pathway of complement revealed the rare X-linked disorder properdin deficiency (PD). Meningococcal Infection in complement deficiency states is discussed and the unusual features of this case are highlighted.

Characteristics of monoclonal immunoglobulins that interfere with serum inorganic phosphate measurement.

The measurement of inorganic phosphate using an unmodified acid/molybdate assay is known to be subject to interference when paraproteinaemia exists. This phenomenon, due to precipitation in the reaction mixture, is not common to all paraproteins. We studied sera from 35 patients to determine whether interference in the assay was related to particular electrophysical characteristics of the paraproteins. There were spuriously elevated phosphate concentrations in 48.6% of the sera assayed. This could not be related to a direct effect of light chain type, electrical charge or IgG subclass. No IgA paraproteins were found to cause interference but there were immunoglobulin G (IgG) and immunoglobulin M (IgM) paraproteins in both the 'interfering' and 'non-interfering' groups. The median paraprotein concentration was similar in both groups but, where interference occurred, the degree increased in line with the paraprotein concentration. Although it does not seem possible to predict which samples will cause interference, it is important that the clinical implications of this problem are appreciated.

Chromosomal radiosensitivity in common variable immune deficiency.

From more than 500 tumours reported in human primary immune deficiencies a majority has been observed in two disorders: ataxia telangiectasia (A-T) and common variable immune deficiency (CVID). Since both diseases have an increased risk of lymphomas/leukaemias and gastrointestinal tumours, suggesting a common risk factor, and the cells derived from A-T patients exhibit an increased chromosomal radiosensitivity we analysed chromosome damage in the G2 lymphocytes of 24 CVID patients and 21 controls after X-irradiation in vitro. There was a significant difference in mean aberration yields between patients and controls. Three CVID patients had yields higher than the mean + 3SD of the controls. Six patients but only one control had yields higher than the mean + 2SD of controls. The patient with the highest chromosomal radiosensitivity subsequently developed a lymphoma. Repeat assays on the same blood sample, with a 24-h delay in setting up the second culture, showed as much variability for control donors as the variation between control donors although for CVID patients inter-individual variation was greater than the difference between results of repeat samples. There was a weak positive correlation between radiosensitivity and age of donor. Chromosomal radiosensitivity of five patients with X-linked hypogammaglobulinaemia was not different from healthy donors. The mean mitotic index (MI) for unirradiated samples from CVID patients was significantly lower than for controls and there was an inverse relationship between MI and aberration yields in the patients, but not in controls. We suggest that the defect in CVID patients that reduces response to mitogenic stimuli may have mechanism(s) in common with those involved in cellular repair processes.

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.

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.