Impaired neutrophil function in patients with AIDS or AIDS-related complex: a comprehensive evaluation

We measured the neutrophil function of 6 patients with AIDS and Kaposi's sarcoma (KS); 22 patients with AIDS-related complex (ARC); and 28 healthy, heterosexual controls. Neutrophils from patients with ARC showed significantly less chemotaxis (P less than or equal to .025) than did those from patients with AIDS and KS or from controls. Serum from patients with AIDS and KS or with ARC significantly (P less than or equal to .05) inhibited chemotaxis of neutrophils from controls; heat treatment of the serum abolished this inhibitory effect. Bacterial killing by neutrophils from patients with AIDS and KS or with ARC was also significantly (P less than or equal to .05) less than for neutrophils from controls, as was neutrophil phagocytosis binding of Candida albicans (P less than or equal to .05). Expression of OKM1 antigen was increased in the patients studied. Enzyme degranulation, adherence, and aggregation were also examined. The defects found in neutrophil function are selective and may be important in the increased susceptibility of patients with human immunodeficiency virus infection to bacterial and fungal infections.     

Effects of passive immunization in patients with the acquired immunodeficiency syndrome-related complex and acquired immunodeficiency syndrome.

Infection with the human immunodeficiency virus type 1 (HIV-1) is usually followed by a vigorous immune response that temporarily protects against disease progression. After a variable asymptomatic period, acquired immunodeficiency syndrome (AIDS)-related complex (ARC) and AIDS develop in most infected individuals. We have demonstrated that healthy HIV-1-infected individuals have neutralizing antibodies and a high titer of antiviral antibodies. In contrast, AIDS patients have undetectable levels of neutralizing antibodies, low titers of antiviral antibodies, and, frequently, HIV p24 antigenemia. These observations prompted us to attempt passive immunization in ARC and AIDS patients. Ten consistently viral-antigen-positive patients (mean, greater than 6 months) were treated, resulting in sustained clearance of p24 antigen. Patients either maintained or increased their antiviral antibody titers. The raised titers result from increased antibody synthesis by the recipients. Circulating CD4+ cell counts were unchanged after 2 months. By the third month none of these patients remained in hospital. As this treatment was of minimal toxicity, it merits wider evaluation in ARC and AIDS patients.     

Serum thymidine kinase--a marker of bone marrow toxicity during treatment with zidovudine

Serum thymidine kinase (S-TK) was measured weekly in 16 randomly selected patients with AIDS or AIDS-related complex (ARC; Centers for Disease Control group IV A or group IV C-2) who participated in a controlled study of the efficacy of zidovudine therapy. S-TK increased significantly (P less than 0.01) in the zidovudine group, whereas it remained stable in the placebo (control) group. On the basis of this observation, the value of S-TK measurements as a predictor of bone marrow toxicity during zidovudine therapy was investigated in 42 patients with AIDS or ARC who received zidovudine as part of their usual treatment. There was a significant association between S-TK, haemoglobin and neutrophil counts measured after the first 4 weeks of therapy and the risk of developing bone marrow toxicity during the following 6 months. Combined, measurements of S-TK and neutrophil counts seem to be well suited for the identification of patients who have a high probability for developing bone marrow toxicity during zidovudine treatment.     

Treatment of aplastic anemia with KRN8601 (rhG-CSF)]

Thirty-nine patients with severe or moderate aplastic anemia received treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF). The first group of eight patients received rhG-CSF in doses of 100 to 400 micrograms/m2/d by a daily 30-minute intravenous infusion for one or two weeks. Doses up to 400 micrograms/m2/d were well tolerated and resulted in increases of neutrophil counts in 5 out of 8 patients. We gave rhG-CSF (400 micrograms/m2/d) to the second group of 26 patients by a daily 30-minute intravenous infusion for two weeks. The treatment resulted in an increase of neutrophil counts in 15 out of 26 patients (3.1 to 29.5 fold). Further, higher doses (800 or 1,200 micrograms/m2/d) were administered in 5 patients who did not respond to the dose of 400 micrograms/m2/d. The treatment increased the neutrophil counts in 3 out of 5 patients. The third group of five patients received rhG-CSF subcutaneously in doses of 20 to 400 micrograms/m2/d. An increase of neutrophil counts was noted in all five patients. Differential counts of bone marrow aspirate revealed an increase of myeloid: erythroid ratios. However, the responses were transient and neutrophil counts returned to basal levels within 1 approximately 2 weeks after discontinuing treatment. No severe toxicity due to rhG-CSF was observed. These results suggest that rhG-CSF is effective on stimulating granulopoiesis in patients with aplastic anemia. This treatment will be particularly useful for the patient with aplastic anemia suffering from bacterial or fungal infections.     

A phase II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes

We conducted a phase II study of the intravenous administration of a glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) for 7-14 d in 41 patients with the myelodysplastic syndromes (MDS). Administration of rhG-CSF elicited striking rises in both leucocyte and neutrophil counts in the majority of the patients irrespective of the FAB subtypes of MDS. The rises in neutrophil counts were dose dependent and 5 micrograms/kg/d of rhG-CSF yielded approximately an 8-fold increase in neutrophil counts. Leucocytes and neutrophil counts started to increase shortly after the first injection of 5 micrograms/kg, was maintained at significantly elevated levels during 14 d of treatment, and returned to the pretreatment levels within several days following discontinuation of rhG-CSF. The action of rhG-CSF was specific for neutrophils since leucocytosis was due exclusively to neutrophilic increase associated with an increased marrow myeloid maturation. There were no consistent changes in the monocyte, eosinophil, lymphocyte, platelet or reticulocyte counts. After treatment, the percentage of marrow blast cells was reduced in eight of 13 evaluable patients with refractory anaemia with an excess of blasts (RAEB) or RAEB in transformation (RAEB-t). No patients developed acute leukaemia during the treatment or in the immediate follow-up period. The treatment was well tolerated with only minimal toxicity. The results suggest that rhG-CSF is a safe and effective way to promptly improve neutropenia in MDS patients.     

Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor

Twenty children (aged 1 to 17 years) with severe or moderate aplastic anemia were treated with recombinant human granulocyte colony- stimulating factor (rhG-CSF) at a dose of 400 micrograms/m2 per day administered as a 30-minute intravenous (IV) infusion daily for 2 weeks. This treatment increased the neutrophil counts (2.7- to 28.0- fold) in 12 of the 20 patients. Increasing doses (800 or 1,200 micrograms/m2 per day) were administered to five patients who had not responded to the initial dose, and three showed an increase in neutrophil count. Differential counts of bone marrow (BM) aspirates showed an increase in the myeloid/erythroid ratio. The response was transient, however, and the neutrophil count returned to baseline within 2 to 10 days of discontinuing treatment. No severe toxicity attributable to rhG-CSF was observed. The results suggest that this agent is effective in stimulating granulopoiesis in children with aplastic anemia. Our study also indicates that rhG-CSF will be particularly useful in managing patients with aplastic anemia complicated by bacterial or fungal infection.     

Changes in neutrophil counts and functions after the administration of recombinant human granulocyte colony-stimulating factor in a patient with chronic idiopathic neutropenia]

The cause of chronic idiopathic neutropenia (CIN) is unknown. Recently recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been purified. Many studies of effects of rhG-CSF on the patients with neutropenia have been undertaken. We examined changes in neutrophil counts and functions after the administration of rhG-CSF in a patient with CIN. Six hours after the intravenous administration of 40 micrograms of rhG-CSF, neutrophil counts were raised from 90 to 1570/microliters, and the increased neutrophils functioned normally; chemotaxis, phagocytosis and O2(-) generation. It is suggested that rhG-CSF is beneficial for the treatment of infection in patients with CIN.     

Effects of recombinant human granulocyte colony-stimulating factor on leucopenia in zidovudine-treated patients with AIDS and AIDS related complex, a phase I/II study

Twelve male patients, eight with the acquired immunodeficiency syndrome (AIDS) and four with AIDS related complex (ARC), who had zidovudine associated neutropenia (less than 1 x 10(9) neutrophils/l) were treated with recombinant human granulocyte colony-stimulating factor (G-CSF) in a phase I/II study. Treatment consisted of daily subcutaneous injections with G-CSF in a weekly increasing dose of 0.4, 2, 5 or 10 micrograms/kg body weight until a neutrophil count of more than 3 x 10(9) neutrophils/l was observed. This effective dose was continued for up to 4 weeks, followed by 4 weeks observation period without G-CSF treatment. Two patients (both with ARC) reached target neutrophil counts at the lowest G-CSF dose, whereas nine patients needed 2 micrograms/kg. One patient discontinued treatment before he reached target neutrophil counts. Mean (+/- SD) neutrophil counts before and after 1 and 4 weeks of effective dose treatment were 0.65(+/- 0.188) x 10(9), 6.016(+/- 2.595) x 10(9) and 5.54(+/- 4.237) x 10(9)/l respectively (P less than 0.01). The number of monocytes increased from 0.171(+/- 0.113) to 0.501(+/- 0.274) and 0.474(+/- 0.374) x 10(9)/l after 1 and 4 weeks of treatment (P less than 0.01). Other haematologic parameters did not change significantly. Two weeks post-treatment the numbers of neutrophils and monocytes had returned to pre-treatment values. Mild side effects consisting of bone, joint or muscle pain were observed in three patients. Two patients (both with AIDS) did not complete the study. One patient stopped treatment because of fever and malaise, attributable to a generalized cytomegalovirus (CMV) infection and one patient had to stop zidovudine treatment because of severe thrombocytopenia. We conclude that G-CSF increases the number of circulating neutrophilic granulocytes in zidovudine-treated patients at relatively low doses and with few side-effects.     

Isotypes and IgG Subclasses of Anti-Fab Antibodies in Human Immunodeficiency Virus-Infected Hemophilia Patients

We reported recently that anti-Fab autoantibodies of the IgG isotype are associated with the decrease of helper/inducer (CD4+) lymphocytes in human immunodeficiency virus-infected (HIV+) hemophilia patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). In the present study we investigated the subclass distribution of IgG-anti-Fab autoantibodies, and whether anti-Fab antibodies of the IgA and IgM isotypes also are associated with the development of AIDS. Sera of HIV+ patients with AIDS had significantly higher IgA-anti-Fab activity than HIV+ patients with ARC (p<0.02), HIV+ patients without AIDS/ARC (p<0.0001), HIV-negative (HIV-) patients (p<0.001), or healthy controls (p<0.0001). An inverse association was found between IgA-anti-Fab activity and CD4+ cell counts (r = -0.396, p<10^-6). In contrast, no association of CD4+ cell counts was observed with IgM-anti-Fab. However, IgM-anti-Fab was significantly increased in patients with thrombocytopenia. We found a significant association between IgA-anti-Fab activity and serum neopterin concentrations (r = 0.310, p<10^-5). IgG-anti-Fab activity was detected mainly in the IgG3 fraction, although in HIV+ patients with AIDS/ARC various IgG subclasses were present. Affinity-purified anti-Fab antibodies isolated from sera of AIDS patients bound to rgp120-preincubated CD4+ cells of a healthy individual, supporting our hypothesis that anti-Fab antibodies and free circulating gp120 molecules are involved in the elimination of uninfected CD4+ cells. Removal of anti-Fab autoantibodies from the circulation by immune adsorbance might be a useful approach in the treatment of AIDS.     

A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia

Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0 or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0 micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was significantly increased at 24 hours after 10 micrograms/kg every 24-hour dose of rhG- CSF. The half-life of rhG-CSF was 4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF.     

Use of recombinant interferons and hematopoietic growth factors in patients infected with human immunodeficiency virus.

The recombinant cytokines are increasingly important therapeutic agents for patients with AIDS. Recombinant interferon-alpha has demonstrated antitumor and antiretroviral activities in patients with Kaposi's sarcoma. Limited studies with interferon-beta suggest that it also has antitumor effects in patients with Kaposi's sarcoma, but interferon-gamma appears to be ineffective in controlling this tumor. The hematopoietic growth factors, including erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been evaluated in several populations of human immunodeficiency virus (HIV)-infected individuals. The combination of G-CSF and recombinant human erythropoietin completely reversed the zidovudine-induced neutropenia of AIDS patients but was only partially effective in reversing anemia. In several clinical trials, GM-CSF induced marked increases in leukocyte counts and improved neutrophil function in some AIDS patients. In severely immunocompromised patients with disease caused by HIV who were receiving therapy with either G-CSF or GM-CSF, opportunistic infections continued to occur despite increases in circulating white blood cell counts. Recombinant cytokines may be used in the future in AIDS patients as adjunctive treatment with myelosuppressive antibiotics and chemotherapeutic drugs, as a possible means of enhancing host defense, or as agents of immune reconstitution.     

Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis in normal cats.

The objective of this study was to determine how recombinant human granulocyte colony-stimulating factor (rhG-CSF) affects hematopoiesis in normal cats. Recombinant human G-CSF was given at 3.0, 5.0, and 10.0 micrograms/kg to two cats each s.c. twice daily for 21 days. This resulted in significant (p less than 0.01) elevations of peripheral blood neutrophils from 3.0- to 9.2-fold above pretreatment levels and significantly (p less than 0.02) above levels of nontreated control cats (n = 4). A statistically significant dose-related response was not seen at these dosages in any parameter evaluated. The period of maximum neutrophilia occurred between days 10 and 14 of rhG-CSF treatment, with maximum neutrophil counts ranging from 20,370 cells/microliters to 61,400 cells/microliters (normal is less than 12,500). Lymphocytosis (greater than 7000 lymphocytes/microliters) and monocytosis (greater than 850 monocytes/microliters) were observed in 50% of the cats receiving rhG-CSF during the period of maximal neutrophil stimulation. Monocyte counts in treated cats were significantly (p less than 0.01) elevated over those of treatment controls on days 12-17. Lymphocyte numbers in rhG-CSF-treated cats were significantly elevated (p less than 0.05) over pretreatment controls on days 12 and 14 of rhG-CSF treatment. No significant changes were observed in reticulocyte counts, platelet counts, or hematocrit levels. By day 19, neutrophil levels had dropped significantly (p less than 0.01) from the maximum neutrophil levels, with one cat attaining a normal blood neutrophil count by day 21 of rhG-CSF treatment. Marrow aspirates revealed an overall increase in marrow cellularity through day 14 of treatment in rhG-CSF-treated cats, with increased myeloid:erythroid ratios (two- to ninefold) over those of nontreated controls. The erythroid and lymphoid component of the marrow decreased from day 0 to day 14, whereas the early myeloid progenitors (myeloblasts, progranulocytes, and myelocytes) increased significantly (p less than 0.05). No significant differences in the percentage of later myeloid forms in the marrow were observed over the treatment period. In vitro colony-forming assays of marrow obtained from treated cats revealed increases in granulocyte-macrophage colony-forming units (CFU-GM) through day 14, with subsequent decreases by day 21 of rhG-CSF treatment. Recombinant human G-CSF was also effective at in vitro stimulation of feline marrow cells from untreated cats in a dilution study, with maximal CFU-GM formation at 0.1 microgram rhG-CSF/ml assay.(ABSTRACT TRUNCATED AT 400 WORDS)     

A successful case of congenital agranulocytosis treated with recombinant human granulocyte colony-stimulating factor]

A 1-month-old girl was admitted because of staphylococcal cellulitis of the buttock and the shoulder, and peripheral agranulocytosis. CBC on admission showed 10,100/microliters of WBC with 1% mature neutrophils, 5% monocytes, 6% eosinophils, 2% basophils and 86% lymphocytes. Bone marrow aspiration revealed maturation arrest of neutrophil precursors at the level of myelocyte. We treated the patient with subcutaneous rhG-CSF (Kirin-Amgen, Tokyo) for sequential 7-day course at the starting dose of 3 micrograms/kg, and increased weekly. The dose was escalated at the level of 18 micrograms/kg for 2 weeks subcutaneously, 8 days after effective dose of 18 micrograms/kg, the absolute neutrophil counts more than 1,000/microliters was attained, and bone marrow aspiration showed an increase of neutrophil precursors beyond the myelocyte level with maturation. Our case proved that both WBC and absolute neutrophil counts were increased parallel with the dose escalation of rhG-CSF. Shortly after the cessation of rhG-CSF, WBC and absolute neutrophil counts were decreased. No side effect was detected except for mild splenomegaly which was resolved after cessation of rhG-CSF. In methylcellulose culture with PHA-LCM, marrow cell of patient produced normal number of CFU-GM, and myeloid precursors could proliferate and differentiate to normal polymorphonuclear neutrophils, but rhG-CSF produced only small number of CFU-GM. Our case confirms that rhG-CSF is a new approach to control the life-threatening infection of congenital agranulocytosis.     

Clinical effects of recombinant human granulocyte colony-stimulating factor in leukemia patients: a phase I/II study

A phase I/II study of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in 24 leukemia patients was conducted at our institute. Recombinant human G-CSF (50-200 micrograms/m2/day) was administered i.v. In seven allogeneic bone marrow transplantation (BMT) recipients, treatment with rhG-CSF was started 5 days after BMT. Neutrophils began to increase within 3 days after the start of rhG-CSF administration in five of seven patients. The mean duration necessary for recovery of neutrophils to greater than 500/microliters was 11.3 days after BMT with rhG-CSF; 26.8 days is the figure for recovery without rhG-CSF from Japanese historical data. In seven out of eight patients who received rhG-CSF administration after the first remission-induction chemotherapy, the neutrophil counts increased from less than 300/microliters to greater than 4000/microliters within 10 days. Blasts did not increase in all patients including four acute nonlymphocytic leukemia (ANLL) patients. Severe infections such as septicemia and pneumonia, which were unable to be controlled by antibiotics only, were successfully treated with rhG-CSF and antibiotics. rhG-CSF either stimulated or inhibited myeloid leukemic cells in some refractory cases. Mild bone pain occurred in one patient while receiving rhG-CSF i.v. rhG-CSF seems to have the ability to shorten the period of neutropenia, prevent infections after allogeneic BMT and remission-induction chemotherapy for acute leukemia, and support therapy for infections.     

Effects of granulocyte colony-stimulating factor on hyperoxia-induced lung injury in newborn piglets

Granulocyte colony-stimulating factor (G-CSF) increases the concentration and activation of neutrophils in the peripheral blood and has been used to prevent late-onset infection in premature infants. However, if G-CSF also augmented the inflammatory response in the lung, the incidence and severity of acute and chronic lung injury might be expected to increase. Using a newborn piglet model of acute lung injury, we examined the effects of rhG-CSF (recombinant-metHuG-CSF) on lung injury. Thirty-three newborn piglets were studied as follows: 1) Unventilated controls; 2) normally ventilated (PaCO2 = 35–45 torr) with room air(RA) for 48 h; 3) normally ventilated with RA for 48 h and received rhG-CSF (10 mg/kg/dose IV) at 0, 12, 24, and 36 h; 4) hyperventilated (PaCO2 = 15–25 torr) with 100% O2 for 48 h; 5) hyperventilated with 100% O2 for 48 h and received rhG-CSF (10 mg/kg/dose IV) at 0, 12, 24 and 36 h. Complete blood counts and and differentials were performed at 0, 24, and 48 h. Animals were sacrificed at 48 h, lungs were removed en bloc, and bronchoalveolar lavage (BAL) was performed. Total blood white blood cells and neutrophil counts increased significantly over 48 h in animals who received rhG-CSF either with normoventilation (p <0.0001) or hyperventilation with 100% O2 (p <0.003), and did not change significantly in the other experimental groups. However, there were no significant differences in BAL total cell counts, neutrophil chemotaxis activity, total protein, or albumin concentrations among the groups. Despite significantly increasing peripheral neutrophil counts, rhG-CSF did not potentiate acute lung injury or inflammation. This suggests that prophylactic administration strategies using rhG-CSF to prevent sepsis in premature infants should not increase the risk for developing acute and chronic lung disease.     

In vivo stimulation of granulopoiesis by recombinant human granulocyte colony-stimulating factor.

Osmotic pumps containing Escherichia coli-derived recombinant human granulocyte colony-stimulating factor (rhG-CSF) were attached to indwelling jugular vein catheters and implanted subcutaneously into Golden Syrian hamsters. Within 3 days, peripheral granulocyte counts had increased greater than 10-fold with a concomitant 4-fold increase in total leukocytes. Microscopic examination of Wright-Giemsa-stained blood smears from rhG-CSF hamsters showed that only the neutrophil subpopulation of granulocytes had increased. No significant changes in lymphocyte or monocyte counts were observed during the course of continuous rhG-CSF treatment. After subcutaneous injection at rhG-CSF doses of up to 10 micrograms X kg-1 X day-1 only granulocyte counts were affected. However, at higher dose levels, a transient thrombocytopenia was noted. Erythrocyte had lymphocyte/monocyte counts remained unaffected by rhG-CSF over the entire dose range (0.3-300 micrograms X kg-1 X day-1) studied. Total leukocyte counts increased 3-fold within 12 hr after a single s.c. injection of rhG-CSF. This early effect was associated with an increase in the total number of colony-forming cells and the percent of active cycling cells in the marrow. A sustained elevation of peripheral leukocyte and marrow progenitor counts was observed following seven daily s.c. injections of rhG-CSF. The ability of rhG-CSF to increase the production and release of granulocytes from the marrow may underlie the beneficial effect it produced on the restoration of peripheral leukocyte counts in hamsters made leukopenic by treatment with 5-fluorouracil.     

Autoimmunity against blood cells in human immunodeficiency-virus (HIV) infection

In persons with AIDS or at risk from AIDS, autoantibodies against platelets and granulocytes were frequently detected. Platelet-bound immunoglobulins were demonstrated by immunofluorescence in all 16 patients with AIDS, in five out of seven patients with AIDS-related complex/persistent generalized lymphadenopathy (ARC/PGL) and even in seven of 10 healthy sexually active homosexual men. Granulocyte-bound immunoglobulins were found by immunofluorescence in 12 of the 16 AIDS patients, five of the seven patients with ARC/PGL and two of the 10 symptomless men. Red cell bound immunoglobulins were not detected. All patients with AIDS and ARC/PGL and three of the symptomless men were seropositive for human immunodeficiency virus (HIV). The platelet- and granulocyte-bound immunoglobulins could be eluted in 93% and 67% of the cases, respectively. This indicates that specific autoantibodies, rather than circulating immune complexes, which were frequently increased, accounted for the findings. There was no relation between the serological findings and the platelet and granulocyte counts. We conclude that autoantibodies against platelets and granulocytes are common in patients with AIDS and those at risk.     

Striking inverse association of IgG-anti-Fab gamma antibodies and CD4 cell counts in patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex.

The contribution of autoimmune phenomena to the pathogenesis of acquired immunodeficiency syndrome (AIDS) is poorly understood. We investigated the relationship between IgG-anti-Fab gamma autoantibodies and the main immunologic feature of AIDS, the decrease of CD4+ helper lymphocytes. Sera of 33 human immunodeficiency virus (HIV) infected (HIV+) hemophilia patients with AIDS/AIDS-related complex (ARC), 57 HIV+ patients without AIDS/ARC, 23 HIV-negative (HIV-) patients, and 76 healthy controls were tested for antibody activity against the Fab region of IgG. Patients with AIDS/ARC had significantly higher IgG-anti-Fab gamma activity than HIV+ patients without AIDS/ARC, HIV- patients, or controls (P less than .0001). A striking inverse association was found between IgG-anti-Fab gamma and CD4+ cell counts (r = -.69; P less than 10(-6)). Sequential testing in 16 AIDS/ARC patients showed that an increase in the IgG-anti-Fab gamma activity was invariably accompanied by a decrease in the CD4+ cell count. IgG-anti-Fab gamma antibodies may play an important role in the immunopathogenesis of AIDS.     

Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b

The purpose of this study was to evaluate the efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of therapy on neutrophil numbers and in vitro neutrophil function and on bone marrow cellularity and morphology were studied. The clinical status of the patients and the occurrence of adverse events associated with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated with a significant increase in circulating neutrophil numbers (P <. 01) and an improvement in neutrophil function as assessed in vitro. In addition, rhG-CSF therapy produced a significant increase in marrow cellularity and an increase in myeloid:erythroid (M:E) ratio, indicating stimulation of granulopoeisis. No adverse effects on marrow function were noted; in particular, no myelodysplasia or marrow exhaustion was seen. Use of rhG-CSF therapy was associated with objective and subjective improvements in infection-related morbidity. The therapy was well tolerated, although all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF therapy is efficacious in the management of neutropenia and neutrophil dysfunction associated with GSD type 1b. Patients on this therapy need to be monitored for hypersplenism. Continued follow-up will be necessary to confirm long-term safety; however, no significant short-term toxicity was noted.     

Quantitative histological study of enteropathy associated with HIV infection.

A quantitative histological study was performed on small intestinal biopsies from eight ambulatory patients with HIV infection (AIDS/AIDS-related complex, ARC) and compared with those from 16 normal subjects. Enteropathy was assessed by measurement of villus area, crypt length and mitotic count, as well as duodenal counts of intraepithelial lymphocytes, mucosal mast cells and goblet cells. Enteropathy in subjects with AIDS/ARC was shown by reduced mean villus area of 0.363 (SD 0.081) compared with 0.500 (SD 0.064) mm2 in control subjects (p less than 0.0001), while intestinal crypts were of similar length with 239 (SD 36) compared with 225 (SD 28 microns, but mitotic count was increased to 3.8 (SD 1.2) compared with 2.4 (SD 0.8) (p = 0.01) in the same control subjects. These results indicate villous atrophy with impaired crypt hyperplasia. Duodenal cell counts showed similar numbers of mucosal mast cells, intraepithelial lymphocytes and goblet cells in AIDS/ARC patients and fifteen control subjects.