Cryoprecipitation of an anti-Pr2 monoclonal IgM cold agglutinin in the presence of GM3 ganglioside.

The mechanism of cryoprecipitation of a monoclonal IgM kappa cryoglobulin (Mou) with a cold agglutinin activity of Pr2 specificity has been studied. By immunodiffusion this cryoglobulin reacted (by its Fab' fragment) with micellar GM3, a ganglioside bearing the Pr2 antigenic determinant. In contrast to previous reports that indicated a possible temperature dependent self-association of IgM molecules via an immunological interaction leading to cold precipitation, we could not detect any affinity of this cryoglobulin for IgM when we used passive hemagglutination or an indirect enzyme-linked immunosorbent assay (ELISA). However, a GM3-like ganglioside could be extracted, by drastic methods, from the cryoglobulin studied at 22 degrees C, whereas no GM3 was extracted from two control cryoglobulins. Some minor gangliosides (representing less than 25% of total amount of bound gangliosides) were also extracted from Mou cryoglobulin and these gangliosides were shown to crossreact with GM3, as they specifically bind to Mou cryoglobulin by ELISA. After cryoprecipitation the serum still contained a monoclonal anti-Pr2 IgM kappa. A GM3-like ganglioside could be extracted from this purified IgM, and cryoprecipitability could be induced by the addition of a minute amount of micellar GM3. These results suggest that Mou cryoglobulin circulates as an immune complex and that cryoprecipitation may depend on unique IgM-GM3 (or IgM-GM3 cross-reacting gangliosides) complexes.

Activity of fludarabine in previously treated Waldenström's macroglobulinemia: a report of 71 cases. Groupe Coopératif Macroglobulinémie.

PURPOSE: There is no consensus on the treatment of patients with Waldenström's macroglobulinemia (WM) who develop primary or secondary resistance to frontline therapies. We report our experience on the activity and toxicity of fludarabine in 71 patients with WM resistant to prior chemotherapy regimens. PATIENTS AND METHODS: From January 1991 to June 1995, 71 patients were included in this retrospective study. The median age, median time from diagnosis to treatment, median immunoglobulin M (IgM) level, and median number of previous treatments were 68 years (range, 42 to 81), 5.9 years (range, 0.6 to 20), 35 g/L (range, 5 to 126), and two (range, one to four), respectively. RESULTS: Seventy-one patients received a median of six courses of fludarabine. Twenty-one (30%) responded with a partial response and 50 (70%) were considered as treatment failures. Forty-six patients died: 10 in the responder group and 36 in the failure group. Twenty-five patients were alive with a median follow-up time of 34 months. The overall median survival time of all treated patients was 23 months. The time to treatment failure was 32 months. The only factor that favorably influenced the response to fludarabine was a longer interval between the first treatment and the start of fludarabine. Pretreatment factors associated with shorter survival in the entire population were hemoglobin level less than 95 g/L (P = .02) and platelet count less than 75 x 10(9)/L (P = .02). CONCLUSION: The responses rate in this population with a poor prognosis is close to that reported in shorter series. Patients with WM who are resistant to alkylating agents should be identified early, so that salvage therapy with nucleoside analogs can be started without delay.

Sicca complex and infection with human immunodeficiency virus.

Five male patients with the persistent generalized lymphadenopathy syndrome also had a sicca complex. Salivary gland biopsy specimens showed diffuse lymphocytic infiltration of the glandular parenchyma. Serum autoantibodies and rheumatoid factor were not detected. All patients had IgG antibodies to human immunodeficiency virus and IgG to the viral capsid antigen of Epstein-Barr virus. These five patients had benign lymphocytic infiltrates in other organs (lung, liver, and kidneys). Sicca complex may be one of the various manifestations of the lymphoid hyperplasia noted in human immunodeficiency virus-infected patients. In these patients, the sicca complex showed specific features related to male predominance, lack of serum autoantibodies, and peripheral-blood T-lymphocyte subset distribution.

Pregnancy and paroxysmal nocturnal hemoglobinuria.

Our study concerns eight pregnancies, six of which were successful, in four patients with paroxysmal nocturnal hemoglobinuria (PNH). Several complications of PNH during pregnancy were prevented: chronic anemia, folate and iron deficiency, and deep-vein thrombosis. During puerperium, acute hemolytic crises, most probably triggered by delivery, were observed in two patients. Thrombotic complications could be prevented by early initiation of an anticoagulant therapy after delivery. The only neonatal complication, observed in two cases, was isoimmune hemolytic anemia related to the multiple blood transfusions received before and during pregnancy. These results show that successful pregnancies are possible in women with PNH provided that both the obstetricians and physicians in charge monitor the pregnancies closely.

Tumoral nasopharyngeal lymphoid hyperplasia in human immunodeficiency virus-infected patients.

Two patients presented with a large tumoral nasopharyngeal lesion with obstructive symptoms, which suggested a malignant tumor. They were black men of Caribbean origin who were infected with human immunodeficiency virus 1. In both cases, histologic examination revealed intense but benign lymphoid follicular hyperplasia, and immunohistochemical studies were consistent with its polyclonal nature. DNA studies performed on tumoral tissue failed to disclose immunoglobulin or T-cell receptor gene rearrangements. In one biopsy specimen, DNA hybridization using Epstein-Barr virus-specific probes showed no evidence of Epstein-Barr virus-DNA sequences. The nasopharynx can be involved in the diffuse extranodal lymphoid hyperplasia associated with human immunodeficiency virus infection.

AIDS-associated Kaposi's sarcoma in female patients.

Kaposi's sarcoma (KS) is very unusual in Caucasian women with AIDS. We conducted a retrospective survey of 12 female AIDS patients with KS, including 11 Caucasian women. HIV infection was thought to have been acquired after sexual contact, intravenous drug use (nine cases) or blood transfusion (three cases). In these patients KS was often the first manifestation of AIDS and showed an aggressive course. The disease was associated with a severe immunodeficiency (CD4 T lymphocyte count less than 100 x 10(6)/l in 50% of cases) and a poor prognosis. In four patients, lesions first developed on areas of sexual contact, supporting the hypothesis that KS is a sexually transmitted disease.

Impaired T-lymphocyte-dependent immune responses to microbial antigens in patients with HIV-1-associated persistent generalized lymphadenopathy.

T-cell mediated and humoral responses directed to microbial antigens were investigated, at the time of the initial visit, in a group of 139 patients with HIV-1-related persistent generalized lymphadenopathy (PGL) enrolled in a longitudinal study. In vivo and in vitro cell-mediated responses to tuberculin were lower in patients than in controls. Differences were not significant for candidin and streptococcal antigen in vitro, whereas higher responses were observed in the patient group for cytomegalovirus antigen. Following immunization, a subgroup of patients did not have a significantly raised serum antitetanus antibody level, whereas in vitro lymphocyte proliferative responses to tetanus toxoid were lower than in controls. No association was found between these abnormalities and other immunological parameters, including the blood level of CD4+ lymphocytes. Lower responses to most microbial antigens were observed in patients with HIV-1-related symptoms in addition to lymphadenopathy, or the patients who progressed to AIDS in the 2 years following the study. Moreover, intravenous drug users showed higher responses than homosexual patients, possibly because of the influence of previous infections on immunological responses to microbial antigens.

Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients.

OBJECTIVES: To describe, in a retrospective study, the clinical and pathological spectrum of multicentric Castleman's disease (MCD) in HIV infection. PATIENTS: The diagnosis of MCD was established by lymph node biopsy in 20 HIV-infected patients. All patients had been HIV-infected by sexual contact. At diagnosis, HIV infection was asymptomatic in eight patients and Kaposi's sarcoma was present in 12. Mean +/- SD CD4+ cell count was 156 +/- 99 x 10(6)/l. RESULTS: Patients were referred with a syndrome of fever and splenomegaly (100%), peripheral lymphadenopathy (90%), hepatomegaly (70%), severe weight loss (70%), respiratory symptoms (65%) and oedema (55%). Anaemia was a constant finding and seven (35%) patients presented with pancytopenia. Serum markers of inflammation were present in most patients: a high level of C reactive protein (90%), polyclonal hypergammaglobulinaemia (89%) and hypoalbuminaemia (56%). The histological pattern of the lymph nodes was characterized by small hyalinized germinal centres surrounded by concentric layers of small lymphocytes, vascular hyperplasia, hyalinized vessels and large interfollicular sheets of plasma cells. Five patients were classified as plasma cell type MCD and 15 as hyaline vascular/plasma cell (mixed) type. Immunophenotyping studies (n = 13) demonstrated a polyclonal B-cell process. No linkage with Epstein-Barr virus (EBV) could be demonstrated immunohistochemically using an anti-latent membrane protein-1 monoclonal antibody (n = 16) or by RNA in situ hybridization with an EBV-encoded RNA transcript-specific probe (n = 13). Remission was obtained with low-dose and usually single agent chemotherapy in 16 patients. During follow-up, non-Hodgkin's lymphoma developed in two patients and Kaposi's sarcoma in three. Fatal outcome occurred in 14 patients with a median survival of 14 months. CONCLUSION: MCD associated with HIV infection is a distinct clinico-pathological entity that can be differentiated from other types of HIV-associated systemic lymphoproliferative disorders. It is very similar to MCD observed in non-HIV-infected patients, except for the high prevalence of pulmonary symptoms and for the stronger association with Kaposi's sarcoma. Single-agent chemotherapy with vinblastine is effective and may prolong survival.

Antithyroid hormone antibodies induced by interferon-alpha.

A 40-yr-old woman known for a multinodular goiter had hyperthyroidism. Treatment with antithyroid drugs and iodine therapy was effective. One year later, she received interferon-alpha for treatment of essential cryoglobulinemia. At that time, the patient was euthyroid. Testing for antithyroglobulin, antimicrosome, anti-TSH receptor, and antithyroid hormone antibodies was negative. After a 1-yr course of interferon-alpha, goiter enlargement was noticed. Apparently elevated free T3 and T4 serum values were measured by RIA, contrasting with clinical euthyroidism and normal TSH values. High serum levels of antithyroid hormone antibodies were found in the patient's serum, using a radiolabeled hormone immunoprecipitation assay. Antithyroglobulin and antimicrosome antibodies titers were also elevated and paralleled antithyroid hormone antibodies. After cessation of interferon-alpha therapy, clinical status and TSH levels remained normal, while thyroid hormone values and antithyroid hormone antibody levels progressively normalized. To our knowledge, this is the first report of antithyroid hormone antibodies induced by interferon-alpha. Since thyroid dysfunction is described in 10-15% of treated patients, the fact that interferon-alpha can induce antithyroid hormone antibodies has important implications: 1) the prevalence or intensity of thyroid dysfunction could be overestimated; and 2) artifactually elevated free T3 and T4 serum values could lead to inappropriate therapy of thyroid disease or cessation of interferon treatment.

Clinical and pathologic features of Waldenström's macroglobulinemia in seven patients with serum monoclonal IgG or IgA.

The clinical, hematologic and pathologic findings in seven patients were similar to those of Waldenström's macroglobulinemia, but unexpectedly the serum monoclonal immunoglobulin belonged to the IgG class in five patients and to the IgA class in two. The bone marrow and lymph node lymphoid proliferation was pleomorphic, with the simultaneous presence of small lymphocytes, normal mature plasma cells and transitional lymphoplasmacytic cells. Immunofluorescence studies showed that a monoclonal immunoglobulin similar to that found in the serum was detectable on the membrane or in the cytoplasm of all the proliferating cells, which thus belonged to the same B cell clone. The study of these patients is in accordance with the concept that lymphoid disorders featured by a pleomorphic monoclonal B cell proliferation constitute a distinct clinicopathologic entity, which is not restricted to IgM-producing clones.

Toxoplasma gondii pneumonia in patients with the acquired immunodeficiency syndrome.

PURPOSE: To perform a retrospective and descriptive study of Toxoplasma gondii pneumonia in patients infected with the human immunodeficiency virus (HIV). Clinical presentation, diagnostic procedures, results of therapy, and hypotheses on pathophysiology are discussed. PATIENTS AND METHODS: The study consisted of 13 HIV-infected patients who had developed T. gondii pneumonia. Eight had acquired immunodeficiency syndrome (AIDS) prior to T. gondii pneumonia and three of them had non-Hodgkin's lymphoma. Mean CD4 cell count was 32 x 10(6)/L. Serum anti-toxoplasma antibody titers were measured by an indirect hemagglutination assay and/or by an indirect immunofluorescence assay. RESULTS: All patients had fever and bilateral pulmonary infiltrates; two of them presented with septic shock. Mean arterial oxygen tension was 47 +/- 12 mm Hg. The diagnosis was established by bronchoalveolar lavage in 10 of 11 cases, open lung biopsy in one case, and postmortem biopsy in two cases. Serologic evidence of past infection was observed in 11 of 12 cases, while one patient presented with acute disseminated disease and absence of serum anti-toxoplasma antibody response. Extrapulmonary involvement was present in seven patients: liver (four), brain (three), bone marrow (two), heart (two), stomach (one). Ten patients recovered from T. gondii pneumonia. CONCLUSION: T. gondii pneumonia must be considered in AIDS patients with severe diffuse bilateral pneumonia, especially when associated with a very low CD4 cell count or non-Hodgkin's lymphoma. In most of these cases, disseminated disease was associated with reactivation of prior latent infection.

Low CD83, but normal MHC class II and costimulatory molecule expression, on spleen dendritic cells from HIV+ patients.

Dendritic cells (DCs), which are the most potent antigen-presenting cells for T lymphocytes, are targets for HIV in vitro and in vivo. Antigen presentation by DCs has been suggested to be impaired during HIV infection; however, the extent to which DCs from HIV+ individuals are altered, particularly in lymphoid organs where T cell stimulation takes place, is not clear. To address this question, the levels of expression of functionally important molecules by spleen DCs from HIV+ patients (n = 6), and HIV- organ donors (n = 5) were compared. By rare event analysis of flow cytometry data, spleen DCs from HIV+ patients were not depleted, representing 0.6 +/- 0.4% of spleen mononuclear cells compared with 0.8 +/- 0.5% in HIV- spleens. Fresh HIV+ spleen DCs were MHC II+ and weakly CD86+CD40+, but negative for CD83 and CD80, and hence had a normal phenotype, showing no signs of in vivo activation. After 24 hr of culture, they upregulated the expression of MHC II, CD40, CD80, and CD86 to levels just as high as those on DCs from organ transplant donors. However, cultured DCs from HIV+ spleens showed lower expression of CD83, compared with DCs from HIV- spleens. The biological significance of this observation will be appreciated further when the function of this molecule is better known. These results suggest that putative defects in antigen presentation by DCs from HIV+ patients are not related to the surface expression of MHC II, CD40, CD80, or CD86.

HIV type 1-specific IgG2 antibodies: markers of helper T cell type 1 response and prognostic marker of long-term nonprogression.

The helper T type 1 (Th1) function of CD4(+) T lymphocytes is presumed to be of key importance in host defense against HIV-1. As the production of different antibody isotypes is dependent on this helper T function, we investigated whether HIV-1-specific responses of a particular IgG isotype could be a reliable marker of long-term HIV-1 control. Assessment of the IgG subclass distribution in the plasma of HIV-1-infected patients enrolled in the French prospective Asymptomatic Long-Term (ALT) cohort showed that IgG2 directed against HIV-1 Env gp41 and Gag proteins was associated with low viral load, high CD4(+) lymphocyte count, and weak neutralizing activity. By contrast, levels of anti-Env and anti-Pol IgG1 as well as the magnitude of neutralizing activity were correlated with the viral load and thus merely reflect the level of HIV replication. Furthermore, IgG2 directed against Gag proteins was significantly associated with HIV-1 p24-specific Th1 cell production of interferon gamma and interleukin 2. In multivariate analysis, only two variables, anti-gp41 IgG2 and plasma HIV-1 RNA, were found to be independent prognostic factors of remaining long-term nonprogressive over time. By providing new insight into the nature of an HIV-specific antibody response associated with the control of virus replication, these findings have implications for the design of HIV vaccines.

Chlorambucil-associated pneumonitis.

A patient developed an interstitial pneumonitis while receiving chlorambucil for a chronic lymphocytic leukemia (cumulative dose, 8,340 mg). Withdrawal of drug treatment was followed by rapid improvement in the clinical condition. Bronchoalveolar lavage showed a T-lymphocytic alveolitis, whereas blood lymphocytes were predominantly of the B phenotype. The T-lymphocytic alveolitis persisted 6 weeks after drug therapy cessation with a predominant CD8+ phenotype, as observed in some hypersensitivity pneumonitis induced by drugs.

B-cell pulmonary lymphoma: gene rearrangement analysis of bronchoalveolar lymphocytes by polymerase chain reaction.

STUDY OBJECTIVES: Non-Hodgkin's lymphomas (NHLs) are clonal proliferation of B or T lymphocytes. Assessment of clonality in lymphoid proliferations uses immunochemistry and, recently, molecular biology. The aim of our study is to assess the role of immunoglobulin gene rearrangement analysis on bronchoalveolar lymphocytes to aid in the diagnosis of B-cell pulmonary NHL. PATIENTS AND METHODS: The study took place in a university hospital. There were seven consecutive patients with B-cell-type pulmonary lymphoma and nine control subjects. Gene rearrangement analysis using polymerase chain reaction (PCR) technique was performed on alveolar lymphocytes recovered by BAL. RESULTS: Analysis of the immunoglobulin heavy chain gene rearrangement showed a predominant clonal alveolar lymphocyte population in six of seven patients while all control subjects showed germline pattern. CONCLUSIONS: Gene rearrangement analysis by PCR of alveolar lymphocytes would appear to be sensitive in patients with B-cell pulmonary NHL (six of seven patients) and specific (zero of nine in the control group). This simple test should be added only in the analysis of cells recovered by BAL in patients with suspected primary and secondary B-cell pulmonary NHL.

Pulmonary infections associated with systemic capillary leak syndrome attacks in a patient with hypogammaglobulinemia.

Systemic capillary leak syndrome (SCLS) is a rare disorder of unknown etiology, characterized by recurrent hypovolemic shock attacks associated in most cases with a serum monoclonal immunoglobulin. Prophylactic therapy is usually disappointing and the outcome is often fatal. We report on a patient with recurrent hypovolemic shocks consistent with the diagnosis of SCLS associated with severe serum panhypogammaglobulinemia but no detectable monoclonal immunoglobulin or B cell proliferation. Attacks were often preceded by severe respiratory infections. Both infections and attacks were successfully prevented by i.v. gammaglobulin replacement. Further evaluation is needed to assess the efficacy of i.v. gammaglobulins in patients with SCLS but without hypogammaglobulinemia.

Intensive chemotherapy (LNHIV-91 regimen) and G-CSF for HIV associated non-Hodgkin's lymphoma.

The purpose of the study was to evaluate the safety and long-term efficacy of an intensive chemotherapy regimen associated with G-CSF in HIV-associated non-Hodgkin's lymphoma (NHL). Fifty two consecutive patients with HIV infection, aggressive NHL and CD4+ cells > or = 100 x 10(6)/l were included. The median CD4 cell count was 276 x 10(6)/l. Nineteen tumors were of the Burkitt's type, 23 were large cells, 7 immunoblastic, and 3 anaplastic. Twenty-five patients had stage IV disease (bone marrow involvement in 7, and central nervous system in 9). Three cycles of ACVBP (doxorubicine, cyclophosphamide, vindesine, bleomycin, prednisolone) were given. A fourth cycle was delivered to patients in partial remission or with initial bulky disease. The induction was followed by three cycles of CVM (cyclophosphamide, etoposide, methotrexate). G-CSF 5 microg/kg was used at each cycle. Results showed that 37 patients (71%) achieved a complete remission. With a median follow-up of 74 months, 8 of them have relapsed. The median survival was 15 months and 34 patients have died (21 with NHL). The 4-year estimate survival was 33.9% (95% CI, 19.8%-47.4%). The Relative Dose-Intensity of the chemotherapy was 85% for doxorubicine and 87% for cyclophosphamide. In a multivariate analysis, homosexual men and patients with ECOG < 2 had a lower risk for death: RR = 0.32 (95% CI, 0.15-0.65) and RR = 0.36 (95% CI, 0.18-0.74), respectively. Achievement of complete remission was strongly associated with survival. In conclusion, it seems that in HIV-infected patients with NHL and a CD4 cell count above 100 x 10(6)/l, high complete remission rate and prolonged survival can be achieved with the intensive LNHIV-91 regimen.

[Adenoma of the liver in man]. / L'adénome du foie chez l'homme.

The authors report the case of a 28-year-old man with a solitary adenoma of the liver. The tumor was detected because of a raised erythrocyte sedimentation rate and serum fibrinogen. Review of the literature shows that adenoma of the liver is an uncommon tumor in man since only 30 other cases have been reported. The tumor is often multiple (55 p. 100) and the clinical manifestations are quite different from those observed in women: the adenoma is often asymptomatic (45 p. 100) and rupture is rare (10 p. 100). Androgens seem to be implicated in the development of adenoma in man since 8 out of 31 patients had received androgens for a long period of time; androgens also seem to favor the tumor's rupture.

[Reversible nephrotic syndrome in Crohn's disease complicated with renal amyloidosis]. / Syndrome néphrotique réversible au cours d'une maladie de Crohn compliquée d'amylose rénale.

A 24-year-old woman suffered from ano-rectal Crohn's disease and nephrotic syndrome due to glomerular amyloidosis AA. She received azathioprine and colchicine for two years. Both Crohn's disease and nephrotic syndrome resolved. However amyloid renal lesions were still present. This course is exceptional, and leads to a discussion of the treatment of amyloidosis associated with Crohn's disease.

[Hodgkin's disease and HIV infection. Study of 40 cases]. / Maladie de Hodgkin et infection HIV. Etude de 40 cas.

Hodgkin's disease seems to be more frequent in HIV infected patients than in general population with peculiar clinical and pathological aspects. We describe 40 cases of Hodgkin's disease in HIV infected patients followed between 1983 and 1993.