Administering intravenous immunoglobulin during infection is associated with infusion reactions in selected patients.

BACKGROUND: Guidelines vary regarding the safety of administering intravenous immunoglobulin (IVIG) during infections, although evidence for this advice is lacking and is based on expert opinion. AIMS: We retrospectively studied patients with common variable immunodeficiency who reacted during IVIG therapy as to whether routinely obtained markers of infection such as C-reactive protein (CRP) were elevated. METHODS: 19 patients on replacement IVIG therapy in a hospital-based infusion unit were studied. CRP levels obtained were normalized to baseline levels without reactions (defined as 100). RESULTS: 8 of 19 patients had 16 reactions over a total of 107 infusions. Normalized CRP levels during reactions were higher [mean (±SD) of 258 (±215)] than during infusions with no reaction [mean 100 (±54.9), p = 0.017], and higher than in patients who did not react [mean 100 (±79.7), p = 0.017]. CONCLUSIONS: Some patients with IVIG reactions had elevated CRP levels suggesting that concurrent infection may have caused the reaction. Pre-emptive antibiotic therapy and delaying infusion could prevent unnecessary morbidity.

Do ribosomopathies explain some cases of common variable immunodeficiency?

The considerable clinical heterogeneity of patients with common variable immunodeficiency disorders (CVID) shares some similarity with bone-marrow failure disorders such as Diamond-Blackfan anaemia (DBA) and Shwachman-Diamond syndrome (SDS), now recognized as defects in ribosome biogenesis or ribosomopathies. The recognition of a patient with DBA who subsequently developed CVID lends support to our previous finding of a heterozygous mutation in the SBDS gene of SBDS in another CVID patient, suggesting that ribosome biogenesis defects are responsible for a subset of CVID. Genetic defects in the ribosomal translational machinery responsible for various bone marrow failure syndromes are recognized readily when they manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this perspective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other conditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future studies by testing for mutations in specific ribosomal genes. New knowledge might then be translated into novel therapeutic strategies for patients in this group of immunodeficiency disorders.

Limited value of testing for intrinsic factor antibodies with negative gastric parietal cell antibodies in pernicious anaemia.

BACKGROUND: The appropriate testing strategy for diagnosing pernicious anaemia using gastric parietal cell (GPC) and/or intrinsic factor antibodies (IFA) is controversial. Intrinsic factor antibodies are found in only about 70% of cases. Indirect immunofluorescence screening for gastric parietal cell antibodies is more sensitive, labour intensive, and less specific. METHODS: The frequency of antibody positivity (IFA and/or GPC) was retrospectively examined in patients tested for both autoantibodies over a three-year period. It was investigated whether B12 levels were related to antibody status. These findings were validated in a prospective study of IFA in 91 GPC negative patients with low B12 levels. RESULTS: Of 847 samples identified in the retrospective study, 4 (0.47%) were positive for only intrinsic factor antibodies, 731 (86.3%) positive for GPC alone, and 112 (13.2%) for both. Student t test on log-transformed data showed B12 levels had no bearing on autoantibody status. 91 consecutive patients with low B12 levels were tested for both autoantibodies; all were negative for gastric parietal cell antibodies. Only one sample was positive for intrinsic factor antibody using the porcine intrinsic factor assay, but was negative by a human recombinant intrinsic factor-based ELISA. CONCLUSIONS: This study provides evidence that testing for gastric parietal cell antibodies is an appropriate screening test for pernicious anaemia, with intrinsic factor antibodies reserved for confirmatory testing or in patients with other autoantibodies that mask the GPC pattern; B12 levels are not related to autoantibody status.

The clinical significance of antinucleolar antibodies.

BACKGROUND: The importance of antinucleolar antibodies seen by indirect immunofluorescence on HEp-2 cells, although associated with systemic sclerosis (SSc), in unselected patients is unknown. AIMS: To determine the true clinical significance of antinucleolar antibodies in an unselected patient population. METHODS: Antinucleolar antibody (ANoA) positive samples were identified in the immunology laboratory during routine autoimmune screening tests; case notes were reviewed using a standard proforma. RESULTS: 104 patients with ANoA were identified and ANoA+ samples were subclassified into homogeneous, clumpy and speckled antinucleolar types. SSc was evident in only two (1.8%) patients. Other connective tissue diseases were identified in 33 patients (32%); 22 patients (21%) had evidence of various malignancies. Both disordered liver function and anaemia were seen in 22 patients and were the commonest laboratory abnormalities. CONCLUSIONS: Neither the presence nor subtype of ANoA is specific for systemic sclerosis. Laboratory comments appended to results should reflect this fact.

Abnormal O-glycosylation of CD43 may account for some features of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder characterized by eczema, recurrent infections, thrombocytopenia and small platelets. There is an increased incidence of autoimmune phenomena particularly autoimmune haemolytic anaemias and vasculitic disorders. Mutations in the WASP gene encoding the cytoskeleton regulatory protein WASp (Wiskott-Aldrich syndrome protein) result in abnormal protein activity with defective cytoplasmic signaling and actin polymerization. This accounts for abnormal T cell responses to proliferation and susceptibility to infections, but does not fully explain the autoimmune phenomena nor the progressive lymphopenia seen in these patients. Wiskott Aldrich patients also demonstrate abnormal O-glycosylation of a highly conserved transmembrane glycoprotein CD43 that is expressed on most haemopoeitic cells. The altered glycosylation pattern on WAS lymphocytes is due to increased beta1-->6 GlcNACtransferase activity which leads to branched core 2 glycans or lower molecular forms of CD43 glycoprotein. The clinical hypothesis put forward is that abnormal O-glycosylation of CD43 may underlie the development of the autoimmune disorders and the progressive lymphopenia observed in WAS patients. Regulation of glycosylation of CD43 is important in the selection process of T cells within the thymus and abnormalities of glycosylation may cause many immune perturbations, such as the escape of self-reactive T cells into the periphery and subsequent development of autoimmune disease in these patients.

Best practice in primary care pathology: review 6.

This sixth best practice review examines four series of common primary care questions in laboratory medicine: (1) laboratory monitoring in hypertension and heart failure abnormalities; (2) markers of inflammatory joint disease; (3) laboratory investigation of chronic diarrhoea; and (4) mumps and chickenpox. The review is presented in question-answer format, referenced for each question series. The recommendations represent a precis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most are consensus based rather than evidence based. They will be updated periodically to take account of new information.

Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects.

Early recognition of primary immunodeficiency is essential to reduce morbidity and mortality, and yet failure to recognize these conditions is still a major problem for clinicians around the world. The problem is that general practitioners, physicians and paediatricians lack familiarity with these rare disorders, and lack guidance regarding the appropriate use of immunological investigations. A working party from the European Society for Immunodeficiencies (ESID) has published screening protocols for these rare disorders, which aim to help select which tests should be done in which patients. The success of these proposals will depend on all immunologists disseminating this information in a format that is suitable for the busy generalist, who may not be familiar with these immunological tests and concepts. Laboratories should expect increasing requests for these screening investigations, and should make themselves familiar with these protocols so that appropriate second-line investigations can be arranged in a timely fashion. Speedy and effective communication between the laboratory and clinician is essential, and clinically interpreted reports are mandatory. Although these protocols are part of a screening process, their effectiveness in practice remains to be established, and further refinement will be required over time. The early involvement of the clinical immunologist in cases of suspected immunodeficiency is key.

Changes in T cell subsets, interleukin-6 and C-reactive protein after laparoscopic and open colorectal resection for malignancy.

BACKGROUND: Attenuation of the immune response to surgery, as demonstrated with the laparoscopic approach to cholecystectomy, has potential benefits in patients undergoing laparoscopic colonic resection for malignancy. We aimed to study the perioperative immune response in patients undergoing laparoscopically assisted and open surgery for colorectal cancer. METHODS: This study involved 23 patients undergoing laparoscopically assisted (n = 13) and open surgery (n = 10). Interleukin-6 (IL-6) C-reactive protein (CRP), the total lymphocyte count, and the CD3, CD4, CD8, CD16, and CD19 lymphocyte subpopulations were assayed preoperatively and at 4, 8, 10, 24, 48, and 168 h postoperatively. RESULTS: Significant rises in IL-6 and CRP were demonstrated within 4 and 24 h, respectively (p < 0.001) in both groups. However, no significant difference between the groups was seen. Significant decreases in total lymphocyte count and all T cell subsets were demonstrated in both groups, beginning at 4 h (p < 0.01). However, no significant difference between the groups was seen. All parameters, excluding CRP, had returned to baseline by 7 days postoperatively in both groups. CONCLUSIONS: Patients with malignancy exhibit significant perioperative immune disturbance with laparoscopically assisted and open surgery. The current data do not provide justification for the laparoscopically assisted approach on grounds of immune preservation.