[Common variable immunodeficiency can present as a multisystemic disorder]. / Almindelig variabel immundefekt kan vise sig som en multisystemsygdom.

Common variable immunodeficiency is the second most common primary immunodeficiency with a prevalence of approx. 1/10.000-50.000. The clinical challenge is early diagnosis and efficient supportive treatment. The purpose of the present article is to focus on the complexity of the disease, including the risk of a long pre-diagnostic period and to focus on the sarcoidosis-like variant and the possible impact of immunoglobulin subclass deficiency.

Increased expression of CD69 on T cells as an early immune marker for human cytomegalovirus reactivation in chronic lymphocytic leukemia patients.

Reactivation of human cytomegalovirus (HCMV) remains a serious problem in immunosuppressed individuals. To investigate whether a change in the immune status can be used as an earlier marker for HCMV reactivation than the traditional PCR analysis, eight chronic lymphocytic leukemia (CLL) patients at risk for reactivation due to commencement of alemtuzumab (anti-CD52) treatment were longitudinally followed. Five series of consecutive weekly blood samples were immunophenotyped by flow cytometry to cover both the innate and adaptive immune responses. Concurrently, patients were monitored by PCR for HCMV reactivation. We found a minor upregulation of the early activation marker CD69 on NK cells immediately before HCMV was detected in circulation by PCR. Interestingly, for the specific immune response, CD69 was highly upregulated on CD3(+) T cells, especially for the CD8(+) subset, in the two patients experiencing an HCMV reactivation between 6 and 20 d before HCMV viremia was measured by PCR. Moreover, a CD4(+):CD8(+) ratio lower than 0.6 may indicate a trend toward an increased risk for viral reactivation. In conclusion, an increase in CD69 expression is a promising candidate as an early predictor of HCMV reactivation.

Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms.

Infections after chemotherapy often cause significant morbidity in patients with acute myeloid leukaemia (AML). Chitotriosidase (CHIT) and mannose-binding lectin (MBL) are part of the innate immune system. Polymorphism in the CHIT-coding gene (CHIT1) may be associated with Gram-negative sepsis in children with AML, and polymorphism in the MBL-coding gene (MBL2) seems to modify the risk of infections in several patient groups. The purpose of this study was to investigate the possible associations between polymorphisms in CHIT1, MBL2 and sepsis in adult patients treated with high-dose chemotherapy for AML. We included 190 patients treated with 526 cycles of chemotherapy. The follow-up period was 6 months from the diagnosis of AML. Prophylactic antibiotics were not used. We identified 604 febrile episodes with 246 episodes of sepsis. Thirty-two patients (17%) either died from infection or infection was a major concomitant factor for death. No significant associations between CHIT1 polymorphism and sepsis (P = 0.85) or death caused by sepsis (P = 0.14) were found. Furthermore, no significant associations between MBL2 polymorphism and sepsis (P = 0.76) or death caused by sepsis (P = 0.24) were observed. The severe and long-lasting neutropenia and mucositis after chemotherapy may explain why the MBL system does not protect against sepsis in patients with AML. Replacement therapy with recombinant MBL is not likely to decrease the risk of sepsis in patients with AML.

Chemotherapy-related infections in patients with multiple myeloma: associations with mannan-binding lectin genotypes.

OBJECTIVES: To study a possible association between mannan-binding lectin genotypes and severe infections in patients with multiple myeloma receiving moderate strength induction chemotherapy. METHODS: Chemotherapy-related infections were identified retrospectively using clinical records and database files. Mannan-binding lectin genotypes were identified with polymerase chain reaction on stored samples of stem cells or formalin-fixed paraffin-embedded bone marrow biopsies. RESULTS: We included 138 myeloma patients. In five patients, data were incomplete, and 133 patients were analysed. Eighty-eight patients were homozygous for wild-type MBL2 (AA) and forty-five patients were heterozygous or homozygous for variant genotypes (AO/OO). A total of 390 chemotherapy cycles were reviewed. Common Toxicity Criteria grades 3 and 4 infections in general were seen in relation to 104 cycles and were not more common in patient with variant MBL2 (P = 0.90). Septicaemia was seen after 10% of chemotherapy cycles in AA patients vs. 15% in AO/OO patients (P = 0.15). In multi-variate analyses, we found indication of a reduced risk of septicaemia in AA patients [OR 0.27 (0.08-0.90), P = 0.03], after first chemotherapy cycle, but reduction of the risk including all cycles was not significant. A similar trend was seen for grades 3 and 4 infections in general. CONCLUSIONS: During induction chemotherapy in patients with multiple myeloma, a general protective effect of wild-type MBL2 against chemotherapy-related infections was not apparent in this study. However, we found indications of a reduced occurrence of septicaemia in patients with wild-type compared with variant MBL2. Further studies in larger cohorts of patients are relevant.

Piperacillin-resistant Escherichia coli bacteraemia: relation to empiric therapy and clinical outcome.

Escherichia coli is a leading cause of bacteraemia. The aim of this study was to evaluate all E. coli positive blood cultures collected during a 4-y period in a haematological department using piperacillin plus netilmicin for empiric treatment of febrile episodes. We measured the incidence of piperacillin-resistant E. coli bacteraemia among haematological and non-haematological patients, described the importance of previous antibiotic treatment for resistance development in E. coli and evaluated the impact of piperacillin resistance on the clinical outcome of E. coli bacteraemia. 114 episodes of E. coli bacteraemia in 104 patients were recorded and 98 episodes in 88 patients (42 males and 46 females) with a median age of 64 y (range 19-85 y) were evaluated. In 81.6% of the episodes the patients had a haematological disorder, dominated by acute leukaemia (41.3%), chronic leukaemia (16.3%) and lymphoma (10%). The proportion of piperacillin-resistant E. coli was higher among haematological patients than non-haematological patients (25% vs 0%, p=0.02) and resistance was associated with piperacillin therapy during the previous month (p=0.05). No difference in clinical outcome was found between haematological patients infected with piperacillin-susceptible or -resistant E. coli (intensive care 12% vs 15%; mortality 22% vs 25%).

Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease which involves opsonization of platelets by autoantibodies directed against different surface glycoproteins, leading to their premature destruction by the reticuloendothelial system. Management of patients with refractory ITP is difficult. Recent studies have shown that rituximab, a chimeric anti-CD20 monoclonal antibody, is useful in the treatment of these patients, with overall response rates of about 50%. Most published reports have included a small number patients including case reports. The present study reports the results of a retrospective Danish multicenter study of rituximab in the treatment of adult patients with refractory ITP. Thirty-five patients (median age 52 years, range 17-82 years, 17 males) were included. One patient had immune thrombocytopenia and neutropenia. All patients had received prednisolone (Pred). Next to Pred, 25 patients had been treated with high-dose IgG, and in 16 patients a splenectomy had been performed. Sixteen patients had been treated with azathioprine. Other treatments included, e.g., cyclosporine, danazol, cyclophosphamide, vincristine, interferon, and dexamethasone. The patients were treated with a dose regimen of 375 mg/m2 i.v. approximately once weekly for 4 consecutive weeks. Six patients received a fixed dose of 500 mg disregarding their weight supplemented by 100 mg of methylprednisone i.v. or 50-100 mg of Pred given as premedication together with an antihistamine just before infusion of rituximab. The large majority of patients also received Pred and, in some cases, other concomitant immunosuppressive treatment during part of their rituximab treatment. A complete response (CR) was defined as a rise in the platelet count > 100 x 10(9)/L, a partial response (PR) as a rise in the platelet count > 50 x 10(9)/L, and a minor response (MR) as a rise in the platelet count < 50 x 10(9)/L. No response (NR) was defined as no increase in the platelet count. Because 4 patients were treated twice, a total of 39 outcomes of rituximab treatment were evaluated. Rituximab proved to be effective in 17 of 39 treatments [overall response 44% with 7 CR (18%) (1 patient showed a CR twice), 6 PR (15%), and 4 MR (10%)]. In 9/13 cases of CR or PR, the response (platelet level > 50 x 10(9)/L) was prompt, 1-2 weeks after the first infusion. The remaining patients responded 3-8 weeks later. Patients with CR and PR have been in remission for a median of 47 weeks. In general the side effects were few. In 2 cases, the treatment was stopped because of side effects either during or after the first infusion. Two fatal outcomes were recorded. A 71-year-old female with severe lung disease died 6 days after the first infusion of respiratory failure. The other patient, a 73-year-old man also with severe chronic obstructive lung disease, died of pneumonia approximately 13 weeks following the last rituximab treatment. It is concluded that rituximab may be a useful alternative therapy in patients with severe and symptomatic ITP refractory to conventional treatment.

Alemtuzumab-induced remission of both severe paraneoplastic pemphigus and leukaemic bone marrow infiltration in a case of treatment-resistant B-cell chronic lymphocytic leukaemia.

BACKGROUND: Alemtuzumab (MabCampath; ILEX Pharmaceuticals, Geneva, Switzerland) is a humanised monoclonal antibody directed against CD52. It belongs to a new group of monoclonal antibodies with anti-neoplastic effects used in chronic lymphocytic leukaemia (CLL) either as first-line treatment or in those cases resistant to alkylating drugs. Paraneoplastic pemphigus (PNP) is a severe mucocutaneus disease mostly associated with B-cell lymphoproliferative disorders. Independent of the course of the underlying malignancy, this disease is often resistant to conventional immunosuppressive treatment and may lead to death as a result of infectious complications. CASE PRESENTATION: We report a case where an ongoing long-term remission of PNP has been induced by alemtuzumab in a patient with an underlying B-CLL. A 68-yr-old male with a 4-yr history of B-CLL presented with a widespread blistering eruption on the extremities and trunk and a severe stomatitis. The diagnosis of PNP relied on the clinical, histological and direct immunofluorescence findings. Despite intensive treatment strategies with various immunosuppressive drugs and antibiotics, blisters continued to develop and the patient was deteriorating. When treated with alemtuzumab the mucocutaneous lesions healed almost completely within a few weeks and the patients' general condition improved significantly. After 12 wk of treatment with alemtuzumab, the CLL infiltration of the bone marrow previously quantified at 75-80% remitted completely. Twelve months later, the patient was still in remission with only a small residual ulceration on the lip and one on the penis. CONCLUSIONS: Based on this case report we recommend treatment with alemtuzumab to severe cases of PNP in CLL. However, further follow-up of this case is needed in order to assess the long-term effect of alemtuzumab treatment in PNP.

Identification of the hemoglobin scavenger receptor/CD163 as a natural soluble protein in plasma.

The hemoglobin scavenger receptor (HbSR/CD163) is an interleukin-6- and glucocorticoid-regulated macrophage/monocyte receptor for uptake of haptoglobin-hemoglobin complexes. Moreover, there are strong indications that HbSR serves an anti-inflammatory function. Immunoprecipitation and immunoblotting enabled identification of a soluble plasma form of HbSR (sHbSR) having an electrophoretic mobility equal to that of recombinant HbSR consisting of the extracellular domain (scavenger receptor cysteine-rich 1-9). A sandwich enzyme-linked immunosorbent assay was established and used to measure the sHbSR level in 130 healthy subjects (median, 1.87 mg/L; range, 0.73-4.69 mg/L). To evaluate the sHbSR levels in conditions with increased leukocyte stimulation and proliferation, 140 patients admitted to a hematological department were screened. Several patients, with a broad spectrum of diagnoses, had a level of sHbSR above the range of healthy persons. Patients with myelomonocytic leukemias and pneumonia/sepsis exhibited the highest levels (up to 67.3 mg/L). In conclusion, sHbSR is an abundant plasma protein potentially valuable in monitoring patients with infections and myelomonocytic leukemia.