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 At 15 months, six patients were withdrawn from the study because of clinical and immunological deterioration.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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.