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Transient stress lymphocytosis: an immunophenotypic characterization of the most common cause of newly identified adult lymphocytosis in a tertiary hospital.

We prospectively evaluated 52 consecutive cases of newly identified absolute lymphocytosis to determine the hematologic and immunophenotypic features of transient stress lymphocytosis (TSL). The lymphocytosis in all cases was associated with an acute stressful event and ranged from 4,000 to 10,400/microL (4.0-10.4 x 10(9)/L). Compared with healthy individuals, patients with TSL showed an increase in the total WBC, absolute lymphocyte (ALC), absolute neutrophil (ANC), and platelet counts with no difference in hemoglobin levels. Immunophenotypic analyses of 38 cases revealed increases in absolute numbers of T B, and natural killer cells. Both CD4+ and CD8+ T cells were increased, predominantly accountedfor by an increase in memory cell subsets, with no change in gamma/delta T cells. Follow-up studies showed a significant reduction in the ALC with a concurrent increase in the ANC and reduction in hemoglobin values. The reduction in lymphocytes at resolution was accompanied by reduction in all broad Iymphocyte subsets. However, naive and memory subsets showed different patterns of alteration within the CD4+ and CD8+ populations, suggesting that acute stress differentially affects the in vivo distribution of these subsets.

Adolescent↗

Attempts at analysis of toxicity of pertussis vaccine. III. Effects of endotoxin on leukocytosis in mice due to lymphocytosis-promoting factor and reference preparations for determination of lymphocytosis-promoting factor.

The effect of bacterial endotoxin on the change in peripheral leukocyte population in mice due to the lymphocytosis-promoting factor (LPF) was investigated. Endotoxin affected not only the total leukocyte count but also the leukocyte proportions at any observation time. Both the coefficient and the intercept of regression of the leukocytic response on dose of LPF were modified by endotoxin. Therefore, in a valid biological assay for LPF using the peripheral leukocyte count as a response, a common reference preparation available for any test materials, irrespective of presence or absence of endotoxin, will be impracticable. Two reference preparations were tentatively established, one being a vaccine and the other an LPF preparation containing little endotoxin. A unitage of LP activity was assigned to each reference preparation. The results also showed that an LPF material to be tested for its possible effects on the lymphatic tissues or the reticuloendothelial system should be free from endotoxin.

Animals↗

Comparative immunophenotypic features of EBV-positive and EBV-negative atypical lymphocytosis.

BACKGROUND: Atypical lymphocytosis is a common peripheral blood abnormality seen not only in Epstein-Barr virus (EBV)-associated acute infectious mononucleosis but also in other conditions, including other viral infections, cancer, immune reactions, etc. Despite numerous reports of individual immunophenotypic alterations in EBV-positive infectious mononucleosis, a detailed comparative analysis of the immunophenotypic changes of peripheral blood lymphocyte subsets in infectious mononucleosis and other forms of atypical lymphocytosis is lacking. METHODS: Multiparametric flow immunocytometry with 26 monoclonal antibodies was performed on peripheral blood lymphocytes from 97 cases of atypical lymphocytosis and 37 normal controls. Atypical lymphocytosis was defined as absolute lymphocytosis with >10% atypical lymphocytes. Absolute or relative mean values of various lymphocyte subsets from EBV-positive cases, EBV-negative cases, and normal controls were compared with the Student's t-test. RESULTS: Highly significant abnormalities detected in atypical lymphocytosis include increases in CD3+/CD8+, CD3-/CD16/56+, CD3+/gammadelta+, CD8+/CD48-, CD8+/CD57-, CD8+/CD95+, CD4+/CCR5+ CD4+/CD7-, CD4+/CD43-, CD4+/CD48-, and CD4+/CD62L- subsets. In contrast, no change in absolute CD4+ T cell and CD19+ B cell counts is seen. When compared with EBV-negative cases, EBV-positive cases are characterized by younger age, and increased numbers of absolute lymphocytes, atypical lymphocytes, CD8+ cells, NK cells, gammadelta T cells, CD8+/CD45RO+ cells, CD8+/CD57- cells, and CD8+/CD28+ cells. CONCLUSIONS: All forms of atypical lymphocytosis are characterized by a marked increase in activated CD8-positive T cells, a moderate increase in NK cells, and no increase in CD4-positive T cells and B cells. Although morphologically indistinguishable, EBV-associated mononucleosis is characterized by several significant differences in peripheral blood lymphocyte subsets when compared with EBV-negative atypical lymphocytosis, most notably increased numbers of CD57-negative CD8 T cells and gammadelta T cells.

Animals↗

Alveolar lymphocytosis in patients with chronic uveitis: relationship to sarcoidosis.

Bronchoalveolar lavage (BAL) is frequently performed in patients with suspected ocular sarcoidosis. This study describes the immunogenetical, immunological, radiological, and functional features of a subclinical alveolar lymphocytosis unrelated to sarcoidosis in patients with chronic uveitis. Two hundred and ten patients with chronic uveitis of unknown origin, who underwent fiber-optic bronchoscopy with BAL as part of a prospective protocol over a three-year period, were evaluable for retrospective analysis. Sixty-five patients had alveolar lymphocytosis: Sarcoidosis was diagnosed in 13 (6%) patients, whereas alveolar lymphocytosis was considered unrelated to sarcoidosis in 52 (25%). Alveolar lymphocytosis unrelated to sarcoidosis was not associated with radiologically detectable interstitial lung disease or pulmonary function impairment. CD4/CD8 lymphocyte ratio was 3.7 +/- 3.0. Total cell count, total lymphocyte, and CD4 lymphocyte percentage were significantly lower when compared with sarcoidosis-related alveolitis (129,000 +/- 80,000 vs. 218,000 +/- 117,000, p <0.05; 33.1% +/- 13.2 vs. 39.7% +/- 13.2, p <0.05; and 54.3% +/- 18.2 vs. 65.4% +/- 10.1, p <0.05, respectively). Patients with alveolar lymphocytosis unrelated to sarcoidosis were older (47.8 +/- 17.7 years vs. 42.7 +/- 14.2 years, p <0.05) and more likely to carry the HLA-B51 allele (19.7% vs. 7.1%, p <0.01) than patients with chronic uveitis without alveolar lymphocytosis. They did not appear to be at risk of developing clinically apparent interstitial lung disease on followup. We conclude that alveolar lymphocytosis is frequently observed in patients with chronic uveitis. It is generally unrelated to sarcoidosis and may then be associated with a distinctive immunogenetic phenotype.

Bronchoalveolar Lavage Fluid↗

Characteristics of the CD8+ lymphocytosis during primary simian immunodeficiency virus infections.

OBJECTIVE: To investigate the source of the expanded blood CD8+ subsets during an acute primary simian immunodeficiency virus (SIV) infection of macaques and the potential role of these cells in disease progression. DESIGN AND METHODS: The primary CD8+ lymphocytosis, which occurs at 1-2 weeks following infection with SIVsmm/PBj-14, was examined in rhesus and cynomolgus macaques. Extensive subset analysis of the expanded blood CD8+ cell pool in a rhesus macaque was compared phenotypically with those in thymus, lymph nodes, spleen, ileum and lung washouts obtained at necropsy during blood lymphocytosis. The influence of the primary CD8+ cells expansion on disease progression was assessed at days 175-679 post-infection in long-term PBj-14 survivors staged according to immunological, virological and histopathological changes in their lymphoid organs. RESULT: The very rapid and transient blood lymphocytosis following infection consisted of two distinct CD45RA(low), CD8+ and CD28-, lymphocyte function-associated antigen (LFA)-1(high), CD45RA(high), CD8+ populations. These populations were present in low levels in thymus, lymph and spleen but were highly represented in mucosal tissues, such as long washout, in which CD28- LFA-1(high) CD45RA(high) CD8+ cells comprised 86% of CD8+ cells, and gut, which was predominantly CD45RA(low) CD28- CD8+ cells. A comparison of progressor and non-progressor PBj-14-infected rhesus and cynomolgus macaques also indicated that the existence or magnitude of a blood CD8+ lymphocytosis during the acute phase of infection did not by itself appear to influence or be predictive of disease progression. CONCLUSION: The marked blood CD8+ lymphocytosis observed during acute SIV infection did not result from expansion of virus-specific precursors in peripheral lymph node and did not appear to influence the rate of disease progression. The findings provide a novel explanation for the primary CD8+ cell lymphocytosis and invoke a mechanism whereby virus-induced cytokine/chemokine production in mucosal sites initiate the transient migration of a pre-existing CD8+ population into the blood from compartments such as lung and gut. Such results suggest that the magnitude of lymphocytosis may depend on the level of viral replication in mucosal tissues and the presence of other infections, for example, cytomegalovirus.

Animals↗

Acute lymphocytosis after trauma--early recognition of the high-risk patient?

An absolute lymphocyte count is included in the routine results provided by most automated blood cell counters, providing a prompt indication of peripheral blood lymphocytosis. Transient lymphocytosis is seen in many acutely ill patients, including those with multiple injuries. We have observed a significantly higher death rate among trauma patients with lymphocytosis at presentation; patients with lymphocytosis, on subsequent assessment of injury, proved to have higher Injury Severity Scores than those without lymphocytosis. Investigation of lymphocyte subsets in nine patients with lymphocytosis showed an increase in T cells, reversal of the CD4:CD8 ratio, and, in seven patients, an increase in "natural killer" cells. The presence of lymphocytosis and its early detection as part of a routine blood count may supply a readily available means of identifying a high-risk trauma patient.

Acute Disease↗

Clonal cell surface structures related to differentiation, activation and homing in B-cell chronic lymphocytic leukemia and monoclonal lymphocytosis of undetermined significance.

Cell surface structures related to differentiation, activation and "homing" were identified on the leukemic cell clone in blood of 64 patients with a monoclonal B-cell lymphoproliferative disorder. Patients were selected with regard to clinical signs and symptoms of the disease. 39 patients had progressive chronic lymphocytic leukemia of B-cell type (B-CLL): 16 with lymph node enlargement and 14 with progressive lymphocytosis as the most prominent symptom, respectively. 1 patient had an isolated splenomegaly and 8 had symptoms from enlarged lymph nodes, lymphocytosis and/or splenomegaly. 25 patients had an isolated monoclonal B-cell lymphocytosis in blood and bone-marrow but no other signs or symptoms of the disease. The lymphocytosis in these patients was considered to be of "undetermined significance" and the term B-cell lymphocytosis of undetermined significance (B-MLUS) was used. Patients with a prominent lymphadenopathy and/or splenomegaly had CD22+ leukemic cells while in patients with a progressive lymphocytosis the B-cell clone expressed Leu-8. Thus, CD22 might be related to the homing capacity of B lymphocytes for lymphnodes and spleen, while Leu-8 might define a circulating B-cell subset. In B-MLUS about 50% of the monoclonal B cells co-expressed Leu8 which is consistent with a more differentiated phenotype compared to B-CLL with progressive lymphocytosis. The CD22 expression was mostly low in B-MLUS although a few patients showed high values. The expression of receptors for growth factors (CD23, CD25, CD71) was higher in B-CLL compared to B-MLUS patients (p less than 0.001), which is consistent with a difference in lymphocyte activation stage and/or response to growth factors.

Aged↗

Serological response to filamentous hemagglutinin and lymphocytosis-promoting toxin of Bordetella pertussis.

Serum antibody responses to the filamentous hemagglutinin and the lymphocytosis-promoting toxin of Bordetella pertussis after vaccination with diphtheria and tetanus toxoids and pertussis vaccine, adsorbed, were assayed by using the enzyme-linked immunosorbent assay. The effect of early immunization, during the first week of life, on the antibody response also was determined. After vaccination, immunoglobulin G (IgG) and IgM directed against both the filamentous hemagglutinin and the lymphocytosis-promoting toxin were detected. Generally, antibody titers increased with subsequent injections and the age of the children. Maternal antibodies against filamentous hemagglutinin and lymphocytosis-promoting toxin were detected in cord blood. The ability of an infant to produce serum IgG anti-lymphocytosis-promoting toxin after vaccination with pertussis vaccine was inversely related to the cord blood serum IgG anti-lymphocytosis-promoting toxin titer at birth. A good antibody response was observed in infants with low cord blood titers, and a poor antibody response was seen in infants with high cord blood values. The IgM anti-lymphocytosis-promoting toxin response was good in groups with both low and high cord blood titer, with no significant difference observed between the two groups. No IgA anti-lymphocytosis-promoting toxin or IgA anti-filamentous hemagglutinin titers were observed in vaccines. IgA antibodies were observed in convalescent sera from two adults and may be presumptive evidence of infection with B. pertussis.

Antibodies, Bacterial↗

[Chronic granular T lymphocytosis of undetermined significance].

The clinical, morphologic, immunologic, functional, serologic and cytogenetic features of 4 cases of chronic granular T cell lymphocytosis with neutropenia were studied. The records of these patients were reviewed and an infectious event preceding the development of the disorder could be documented in 3 cases, suggesting a cause and effect relationship. A benign monoclonal gammopathy was detected in the remaining patient. The clinical picture was characterized by moderate blood and bone marrow lymphocytosis, neutropenia, hepatosplenomegaly, absence of lymphadenopathy, and a stable course, observed over a period of up to 11 years. Surface marker analysis in all the patients showed the common membrane phenotype of granular T cell lymphocytosis (CD3+, CD4-, CD8+, Leu7+). One patient treated with steroid therapy had reversal of lymphocytosis and severe neutropenia, which both recurred after steroids were withdrawn. The disorder again resolved after pulse steroid treatment. From these findings and a review of the literature, we suggest that granular T cell lymphocytosis with the immunologic phenotype exemplified by our cases is a distinct reactive or immunoregulatory disorder. In view of the similarities in character to benign monoclonal B cell lymphocytosis and idiopathic paraproteinaemia, we suggest that this disorder be termed chronic granular T cell lymphocytosis of undetermined significance.

Adult↗

Granulated T cell lymphocytosis with neutropenia: malignant or benign chronic lymphoproliferative disorder?

The clinical, morphological, immunologic, and cytogenetic features of seven cases of chronic granulated T cell lymphocytosis with neutropenia were studied. The disorder was characterized by moderate blood and bone marrow lymphocytosis, neutropenia, polyclonal hypergammaglobulinemia, splenomegaly, absence of lymphadenopathy, and a chronic, relatively stable clinical course. The proliferative lymphocytes manifested a cytotoxic/suppressor T lymphocyte phenotype. In two of four cases studied, blood lymphocytes showed clonal chromosome abnormalities. One patient treated with pulse steroid therapy had reversal of lymphocytosis and severe neutropenia with subsequent resolution of an intractable infection. The lymphocytosis and neutropenia recurred when steroids were withdrawn. Six of the seven patients were living three months to 17 years from diagnosis; one died at 4.3 years of an unrelated cause. Five of the patients, including the two with lymphocyte chromosome abnormalities, had persistent lymphocytosis and neutropenia from three months to 13 years from diagnosis. In two patients, the disease appears to have undergone spontaneous regression. No differences in clinical presentation or the morphological or immunologic characteristics of the proliferative lymphocytes were apparent between those patients with lymphocyte chromosome abnormalities and persistent disease and those who had a spontaneous regression. The finding of clonal chromosome abnormalities in the blood lymphocytes of two of the patients in this study suggests a neoplastic origin for chronic granulated T cell lymphocytosis with neutropenia. However, apparent spontaneous regression in two patients, one after 11 years, lends support to a chronic reactive or immunoregulatory disorder as the etiology. It is probable that cases of granulated T cell lymphocytosis with neutropenia, although morphologically and immunologically similar, are biologically heterogeneous.

Adult↗

Role of immunotyping in chronic lymphocytosis: review of the natural history of the condition in 145 adult patients.

We investigated the clinical value of immunotyping in 145 consecutive adult patients with absolute or relative lymphocytosis: 132 (91%) had B-cell lymphocytosis, 5 (4%) had T-cell lymphocytosis, 2 (1%) had hairy cell leukemia, and 6 (4%) had reactive lymphocytosis. Of the five patients with T-cell lymphocytosis, four were best categorized as having T gamma-chronic lymphoproliferative disease and had an indolent clinical course. Of the 132 patients with B-cell lymphocytosis, 121 (92%) had B-cell chronic lymphocytic leukemia (B-CLL), and 11 (8%) had small cleaved ("lymphosarcoma") cell leukemia. Patients with small cleaved cell leukemia had a worse clinical outcome than did those with B-CLL. We further analyzed the surface immunoglobulin (sIg) and CD20 (B-1) antigen expression patterns in B-CLL to determine whether any correlation existed with clinical outcome. A subset of patients with B-CLL in whom sIg was expressed in less than 20% of their lymphocytes had the best clinical outcome. HLA-DR (Ia-like) antigen typing helped identify B-CLL cases with minimal or no sIg expression. CD20 (B-1) antigen was weak or undetectable in most cases of B-CLL. Patients with B-CLL who had CD20 (B-1) in more than 20% of their lymphocytes did not have a different prognosis. Our data provide the incidence and natural history of the various subsets of CLL in a series of patients at a single institution. The type and extent of immunotyping necessary and practical in the clinical management of patients with CLL are explored.

Adult↗

Clinical, hematologic, and immunophenotypic characterization of canine large granular lymphocytosis.

Clinical, hematologic, and immunophenotypic data were studied in 25 dogs with large granular lymphocyte (LGL) lymphocytosis. Primarily large-breed dogs were affected, with an average age at initial diagnosis of 10 years (range 5-14 years). All dogs had persistent (>4 months) LGL lymphocytosis except for three that were euthanized with aggressive disease. Splenomegaly was reported in 12 of 20 dogs in which splenic size was evaluated. The clinical course was heterogeneous and dogs were divided into four groups based on similar clinical and hematologic findings: acute leukemia (3/25), persistent lymphocytosis with anemia (12/25), persistent lymphocytosis without anemia (8/25), and reactive lymphocytosis (2/25). Immunophenotypes varied within groups but were homogeneous among cells from the same patient except in the two dogs classified as reactive LGL lymphocytosis. Analysis of T-cell receptor (TCR) usage identified three main LGL lineages. TCRalphabeta was expressed in 15/25 (60%) cases. TCRgammadelta was expressed in 8/25 (32%) cases, and 2/25 (8%) cases were CD3-, compatible with NK cells. beta2 integrin expression was distinctive. CD11a was consistently expressed, while CD11b was absent. CD11c was expressed only weakly in 16/25 (64%) cases. The leukointegrin alphadbeta2 was highly prevalent on all LGL lineages, being expressed in 23/25 (92%) cases. Prominent involvement of the spleen, relative sparing of bone marrow, an unexpectedly large proportion of gammadelta T-cell LGLs, and the distinctive beta2 integrin expression pattern on diverse lineages of LGLs suggest the disease arises from unique populations of lymphocytes that preferentially localize in the splenic red pulp.

Age Factors↗

Colonic lymphocytosis in patients with celiac sprue.

We examined colonic biopsies from 39 patients with clinical and small bowel biopsy changes of celiac sprue. In 12 of 39 patients (31%), striking lymphocytic infiltration of the superficial colonic epithelium and chronic inflammation of the lamina propria were identified. These 12 cases had a mean of 30.4 lymphocytes per 100 superficial colonic epithelial cells, compared with means of 8.4 in sprue cases without colonic epithelial lymphocytosis, 4.8 in normal controls, and 32.4 in nine cases of lymphocytic colitis without concurrent celiac sprue. No case showed subepithelial collagen layer thickening. Four patients with celiac sprue and colonic lymphocytosis also had gastric biopsies; two showed gastric lymphocytosis. Intraepithelial lymphocytes at all sites were positive for the T-cell marker MT-1. These findings indicate that sprue-associated colonic lymphocytosis and lymphocytic colitis are histologically, quantitatively, and immunohistochemically indistinguishable, that the epithelial T-cell infiltration of celiac sprue occurs in glandular mucosa at all levels of the gastrointestinal tract, and that colonic subepithelial collagen deposition in patients with celiac sprue is an infrequent occurrence. These findings also suggest that gastrointestinal epithelial T-cell infiltration may be an immunologic response that is common in individuals sensitized to absorbed lumenal antigens, and that colonic lymphocytosis may occur as a response to a number of antigens, including gluten.

Celiac Disease↗

[Polyclonal B lymphocytosis and hyper-IgM: immunodeficiency and/or benign lymphoid proliferation associated with tobacco?].

PURPOSE: To study the association of polyclonal B-cell lymphocytosis with binucleated lymphocytes with clinical manifestations suggesting the existence of an immunodeficiency, to evaluate the effect of cigarette smoking on this 'benign lymphoid proliferation', to analyze the clonality of lymphocytes, to determine the levels of immunoglobulins (Ig) G, A, M. METHODS: Description and analysis of the results obtained in four patients and literature review. RESULTS: Polyclonal B-cell lymphocytosis is associated with both a decrease in IgA and IgG and an increase in IgM. Recurrent infectious episodes (bronchitis) were observed in two patients. Transient smoking cessation allowed a decrease in lymphocytosis and IgM levels in two patients. No hematological malignancy occurred during the follow-up, while biological abnormalities persisted. CONCLUSION: Persistent polyclonal B-cell lymphocytosis may be associated with minor clinical features of immunodeficiency. Smoking cessation may sometimes lead to a decrease in lymphocytosis and IgM.

Adult↗

Gamma delta T lymphocytosis associated with common variable immunodeficiency.

We present the case of a 28-year-old Caucasian female with common variable immunodeficiency (CVID) since age 5 who had a long history of hospitalizations for unexplained fevers and pulmonary infiltrates. The patient developed mild lymphocytosis 7 months prior to our evaluation. Flow cytometry of peripheral blood revealed an expansion of gamma delta T lymphocytes, mild CD4 T lymphocytopenia, and a reduced CD4/CD8 ratio (0.2). Two subpopulations of gamma delta T lymphocytes were found (CD3+/CD4-/CD8+, 47%; CD3+/CD4-/CD8-, 53%), the vast majority of which expressed V-delta 1. An infectious cause for the patient's gamma delta T lymphocytosis could not be found. The sputum was chronically colonized with Staphylococcus aureus, and the organism produced TSST-1 in vitro. A bronchoalveolar lavage (BAL) revealed marked lymphocytosis, but gamma delta T lymphocytes were not overrepresented in the BAL. Lymphocyte functional studies revealed poor proliferative responses to mitogens and staphylococcal superantigens and diminished cytokine production. V-delta 1 T lymphocytes from the patient's blood were not expanded in vitro in response to staphylococcal superantigens. TCR gene rearrangement studies confirmed the presence of J gamma and J beta 1 clonal rearrangements accounting for only a small subpopulation of the gamma delta T lymphocytes. These studies were repeated 5 months later and were unchanged. A bone marrow biopsy was negative for leukemia. Hence, the cause of the patient's gamma delta T lymphocytosis could not be determined despite evaluation for underlying malignancy, occult infection, or superantigen-driven stimulation. The patient ultimately died of progressive respiratory insufficiency. The state of current knowledge regarding gamma delta T lymphocytosis, decreased production of alpha beta T lymphocytes, and a low CD4/ CD8 ratio in association with CVID is discussed.

Adult↗