David Boutboul

Late-Onset Combined Immune Deficiency: A Subset of Common Variable Immunodeficiency with Severe T Cell Defect

BACKGROUND Common variable immunodeficiency (CVID) is a primary immune deficiency defined by defective antibody production. In most series, a small proportion of patients present with opportunistic infections (OIs). METHODS The French DEFI study has enrolled patients with primary hypogammaglobulinemia and allows a detailed clinical and immunologic description of patients with previous OIs and/or at risk for OIs. RESULTS Among 313 patients with CVID, 28 patients (8.9%) presented with late-onset combined immune deficiency (LOCID), defined by the occurrence of an OI and/or a CD4(+) T cell count <200 x 10(6) cells/L, and were compared with the remaining 285 patients with CVID. The patients with LOCID more frequently belonged to consanguineous families (29% vs 8%; P = .004). They differed from patients with CVID with a higher prevalence of splenomegaly (64% vs 31%), granuloma (43% vs 10%), gastrointestinal disease (75% vs 42%), and lymphoma (29% vs 4%). Even on immunoglobulin substitution, they required more frequent antibiotics administration and hospitalization. Lymphocyte counts were lower, with a marked decrease in CD4(+) T cell counts (158 x 10(6) vs 604 x 10(6) cells/L; P < .001) and a severe defect in naive CD45RA(+)CCR7(+)CD4(+) T cell counts (<20% of total CD4(+) T cells in 71% of patients with LOCID vs 37% of patients with CVID; P = .001). The CD19(+) B cell compartment was also significantly decreased (20 x 10(6) vs 102 x 10(6) cells/L; P < .001). CONCLUSIONS LOCID differs from classic CVID in its clinical and immunologic characteristics. Systematic T cell phenotype may help to discriminate such patients from those with CVID. Identification of this phenotype should result in a more fitted diagnostic and therapeutic approach of infections and could provide insights for genetic diagnosis.

B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells

Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell-depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterized and compared to those of antibody-secreting cells from untreated ITP spleens and from healthy tissues. Antiplatelet-specific plasma cells (PC) were detected in the spleens of patients with ITP up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the single-cell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature, including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected in untreated ITP spleens. These results suggest that the milieu generated by B cell depletion promotes the differentiation and settlement of long-lived PC in the spleen.

A retrospective pilot evaluation of switching thrombopoietic receptor-agonists in immune thrombocytopenia

Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists with demonstrated efficacy against immune thrombocytopenia in prospective controlled studies, were recently authorized in most countries for adults with chronic immune thrombocytopenia. So far, no data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles were evaluated for 46 patients who sequentially received both drugs, switching from one to the other. The reasons for switching were: lack of efficacy for 23 patients, platelet-count fluctuations for 11, side effects for 4, and 8 patients’ preferences. For 50–80% of the patients, switching from romiplostim to eltrombopag or eltrombopag to romiplostim effectively impacted the platelet count, with fluctuations disappearing in 54% and side effects resolved in 100%. In 80% of the patients, the 2 thrombopoietic receptor-agonists achieved similar response patterns. Our results confirmed that switching from one thrombopoietic receptor-agonist to the other could be beneficial in clinical practice for patients with severe chronic immune thrombopenia who failed to respond or experienced adverse events to the first. (Clinical Trials.gov identifier: NCT01618734).

Defects in the CD19 complex predispose to glomerulonephritis, as well as IgG1 subclass deficiency

this article’s Fig E1, A and B in the Online Repository at www.jacionline.org). Control PBMCs, however, exhibited a characteristic aggregation of lymphocytes 24 hours after PHA stimulation that was not apparent in the patient’s PBMCs (Fig 2, A). The aggregation of normal lymphocytes after PHA stimulation can be blocked with CD18 antibodies, indicating an integrin-dependent event (Fig 2, B). Thus although the patient’s lymphocytes mobilized calcium and proliferated normally, they demonstrated abnormalities in integrin-dependent aggregation. Studies with Rac1 and Rac2 knockout mice have shown defects in T-cell development, proliferation, survival, adhesion, and migration. However, our patient did not demonstrate defects in T-cell proliferation or activation in vitro. Interestingly, mice that express a dominant-negative Rac1 mutation have abnormal T-cell development, despite nearly normal T-cell activation. Thus the phenotype of mice expressing the dominant-negative Rac1 mutation is similar to the phenotype found in our patient with a dominant-negative Rac2 mutation. Collectively, these observations suggest that abnormal T-cell development in our patient was a result of the cumulative effects of abolishing Rac1 and Rac2 function. We hypothesize that abnormal integrin-dependent functions of T cells lead to defective T-cell development in the thymus due to defects in migration, adhesion, and proper T-cell activation and selection. Furthermore, this report demonstrates that newborn screening by means of TREC analysis is a powerful tool that may detect rare mutations that affect the function of leukocytes apart from T cells. Deborah Accetta, MD Grant Syverson, MD Benedetta Bonacci, MS Sreelatha Reddy, PhD Christine Bengtson, BS Jill Surfus, BS Ronald Harbeck, PhD Anna Huttenlocher, MD William Grossman, MD John Routes, MD James Verbsky, MD, PhD

Coagulation Disorders and Bleedings in Critically Ill Patients With Hemophagocytic Lymphohistiocytosis.

AbstractReactive hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition related to a cytokine storm leading to multiorgan dysfunction. A better understanding of coagulation disorders, frequently reported in HLH patients, may improve outcomes.Critically ill HLH patients managed in a multidisciplinary national reference center were retrospectively included. Relationships between coagulation disorders, severe bleedings, and outcomes were assessed.One hundred and seventeen patients fulfilled the HLH 2004 criteria. The most common HLH etiology was hematologic conditions (73%), followed by infectious diseases (20%), systemic rheumatic diseases (5%), and undetermined HLH etiology (3%). All patients exerted thrombocytopenia. Coagulation disorders were diagnosed in 79 (68%) patients (61 had hypofibrinogenemia < 1.5 g/L, 51 had prothrombin time [PT] < 50%). The worst median value throughout ICU stay was 52% (38–65) for PT with a factor V level of 35% (27–43), 1.59 (1.30–2.09) for the activated partial thromboplastin time (APTT) ratio, and 2.33 g/L (1.13–3.86) for the fibrinogen level. Disseminated intravascular coagulation (DIC) was found in 50% of patients. Coagulation disorders were more frequent in immunocompromised patients, those with histological/cytological feature of hemophagocytosis, those with the highest ferritin concentrations, and in patients with HLH not related to infection. These patients were more prone to receive mechanical ventilation, vasopressors, or renal replacement therapy. Twenty-six (22%) patients presented severe bleeding complications, including 5 patients dying from hemorrhagic shock. Strikingly, the only coagulation parameter significantly associated with severe bleeding was low fibrinogen with a cutoff value of 2 g/L (P = 0.03). Overall, 33 (28%) patients died in the ICU and hospital mortality was 44%. Coagulation disorders were associated with higher mortality, especially fibrinogen < 2 g/L (P = 0.04) and PT value (P = 0.03). The occurrence of bleeding complications was not associated with higher risk of hospital death. Risk factors associated with mortality by multivariate analysis were fibrinogen level < 2 g/L (OR 2.42 [1.08–5.41]), SOFA score > 6 (OR 3.04 [1.32–6.98]), and age > 46 years (OR 2.26 [1.02–5.04]).Up to two-third of critically ill HLH patients present with coagulation disorders. Hypofibrinogenemia or DIC was found in half of the patients and low PT in 40%. These patients require more life support and have a higher mortality rate. Fibrinogen <2 g/L is associated with the occurrence of severe bleeding and mortality.

Metastatic cancer-related thrombotic microangiopathies: a cohort study

Thrombotic microangiopathies (TMAs) in patients with metastatic cancer are poorly characterized. We recorded 17 patients who had TMAs associated with disseminated solid cancer in our intensive care unit over an 11-year period. We compared them with a group of 20 patients with proven idiopathic thrombotic thrombocytopenic purpura hospitalized during the same period. We aimed to specify the clinical and biological features of cancer-related TMAs (CR-TMAs). CR-TMAs can either be inaugural of the underlying cancer or reflect worsening course. Clues to the presence of CR-TMA include respiratory symptoms, bone pain, myelemia or higher platelet count than in thrombotic thrombocytopenic purpura. In this context, bone marrow aspiration is a fast and gainful investigation to avoid plasmatherapy and immunosuppressive drugs. Indeed, this severe and poor-prognosis disease requires prompt diagnosis and rapid initiation of specific chemotherapy.

Outcomes after intensive care unit admission of patients with newly diagnosed lymphoma.

Abstract No data are available on outcomes of patients with lymphoma requiring intensive care unit (ICU) admission. We retrospectively studied 190 patients admitted to our ICU between 2000 and 2010, before or during the first chemotherapy course for lymphoma. Reasons for ICU admission were renal failure (36%), shock (28%), respiratory failure (26%), coma (22%) and monitoring (12%). Mechanical ventilation was needed in 45% of patients, dialysis in 41% and vasoactive drugs in 30%. ICU, hospital and 1-year mortality rates were 22%, 37% and 51%. By multivariate analysis, factors associated with higher hospital mortality were age > 50 years (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.02–4.9), poor performance status (OR, 3.36; 95% CI, 1.47–6.54), high Sequential Organ Failure Assessment (SOFA) score (OR, 1.15/point; 95% CI, 1.04–1.27), hemophagocytic syndrome (OR, 2.57; 95% CI, 1.03–6.40), Burkitt lymphoma (OR, 3.36; 95% CI, 1.38–8.19) and primary cerebral lymphoma (OR, 7.32; 95% CI, 1.06–50.54). Admission after 2004 was associated with better survival (OR, 0.35; 95% CI, 0.15–0.78).

Association of sarcoidosis and immune thrombocytopenia: presentation and outcome in a series of 20 patients.

The association of sarcoidosis and immune thrombocytopenia (ITP) has rarely been investigated. The aim of the current retrospective study was to investigate the clinical and biological phenotypes and outcome of this association in a large series of recent patients. Twenty patients (50% men) were included. Median age at sarcoidosis and ITP diagnosis was 36 (range, 10-83 yr) and 38 (range, 21-83 yr) years, respectively. In 11 of 20 (55%) patients, sarcoidosis onset preceded ITP (median interval, 48 mo; range, 6-216 mo). In 5 of 20 (25%) patients, the 2 conditions occurred concomitantly. In 4 of 20 (20%) patients, ITP onset preceded sarcoidosis (median interval, 68 mo; range, 15-153 mo). In 4 cases, sarcoidosis and ITP were not concomitant, since 1 condition was cured before the other was declared. In 12 of 20 (60%) patients there was a simultaneous onset or relapse of both ITP and sarcoidosis. Sarcoidosis phenotype was characterized by an acute onset in 40% of patients. The visceral involvement included thoracic sites in 19 of 20 (95%) patients and extrathoracic sites in 16 of 20 (80%) patients. At ITP onset, median platelet count was 11 × 109/L (range, 3-90); 17 (85%) patients had a platelet count <30 × 109/L. Seven (35%) patients had a bleeding score >8 without visceral bleeding. Nineteen of the 20 (95%) patients were treated specifically for ITP. After the first-line therapy (prednisone at 1 mg/kg per day for at least 3 consecutive weeks in all patients; with IVIg in addition for 10 patients with severe bleeding score), 12 of 19 (63%) patients achieved a complete response, 6 (31.5%) had a partial response, and only 1 patient failed to respond. At the end of ITP follow-up (median, 70 mo; range, 12-142 mo), 18 (90%) patients achieved a complete response, 1 achieved a partial response, and 1 had no response. After a median follow-up of 105 months, 13 of 20 (65%) patients had persistent sarcoidosis requiring prolonged therapy, and thus sarcoidosis represented the main long-term concern. Main conclusions were 1) ITP presentation was usually severe, but response to treatment was favorable in almost all cases, with no death and no severe bleeding, in contrast with older reports, 2) sarcoidosis was remarkable for the high proportion of cases with an acute onset, a chronic course, and the need for prolonged prednisone therapy, 3) sarcoidosis and ITP onset and evolution were not always synchronous. Abbreviations: ALPS = autoimmune lymphoproliferative syndrome, CR = complete response to treatment, HCQ = hydroxychloroquine, ITP = immune thrombocytopenia, IVIg = intravenous immunoglobulin, NR = no response to treatment, PR = partial response to treatment.

The full spectrum of Castleman disease: 273 patients studied over 20 years

The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman‐like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV‐8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV‐8 negative/idiopathic multicentric CD (iMCD). 2‐(18F)fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline‐vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV‐8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV‐8+ MCD, particularly in HIV‐infected patients.

Autoimmune cytopenias associated with inflammatory bowel diseases: Insights from a multicenter retrospective cohort

INTRODUCTION Autoimmune cytopenias (AIC) including autoimmune hemolytic anemia (AIHA) and immunologic thrombocytopenia (ITP) are rare immunologic disorders, scarcely reported in inflammatory bowel diseases (IBD). We conducted a multicentric retrospective study, including a case-control analysis, that aimed to describe the characteristics and outcomes of patients affected by AIC and IBD. METHOD Forty cases were recruited from 4 IBD centers and 2 AIC tertiary centers. Controls were recruited from the MICISTA registry. RESULTS From the MICISTA registry, incidences were estimated at 4.1/100,000 patient-years and 12.5/100,000 patient-years after IBD diagnosis for AIHA and ITP, respectively. All AIHA patients (n=14) had colonic involvement (13/14 with UC), whereas CD (52%) and UC (48%) diagnoses were evenly distributed among ITP patients. Compared to control IBD patients, cases were characterized by a higher frequency of extra-intestinal manifestations (37.5% vs 17%, p<0.001) and by the presence of IBD severitys hallmark. AIHA and IBD ran mainly in parallel, and 12 out of 14 AIHA were warm AIHA. In isolated cases, rituximab and infliximab were efficient to treat IBD and AIC, respectively. IBD surgery may induce AIC remission in some cases. CONCLUSION Although low, incidence of AIC appears higher in IBD patients compared to the general population. The association seems to be mainly non-fortuitous, especially for colitis-associated AIHA.