Granulocyte colony-stimulating factor (rh G-CSF) as an adjunct to interferon alpha therapy of neutropenic patients with hairy cell leukemia

Summary Six patients with hairy cell leukemia (HCL) and neutropenia (median neutrophil count 563/l, range 30–1200) were treated with recombinant human granulocyte colony-stimulating factor (G-CSF) at a dose of 5g/kg by daily subcutaneous injection as an adjunct to interferon-alpha (IFN-a) therapy, in order to ameliorate neutropenia. Five of six patients responded to G-CSF with normalization of neutrophil counts (>1800/l) within 2–11 days and a median neutrophil count of 5211/l (range 4312–10160) at the end of G-CSF therapy. In three of these patients, infections resolved when neutropoiesis recovered. In one patient with very severe neutropenia (30/l), in whom myeloid progenitors were not detectable, G-CSF therapy failed to restore granulopoiesis. Cessation or interruption of G-CSF after 2–5 weeks of therapy resulted in a rapid decline of neutrophil counts to lower or subnormal levels (median value 1478/l, range 770–2739) within 1 week, suggesting that the improvement of granulopoiesis was dependent on G-CSF and not due to IFN-a therapy. G-CSF may be a useful adjunct to IFN-a therapy in patients with HCL in order to manage or prevent neutropenic complications in the early phase of treatment.     

Characterization of the bone marrow immunofluorescence test in childhood autoimmune neutropenia

The bone marrow immunofluorescenece test (BMIFT) demonstrates autoantibodies to granulocytes and their precursors on fresh-frozen bone marrow slides. It may be used to differentiate childhood autoimmune neutropenia (AIN) from other causes of childhood neutropenia, even when circulating neutrophil counts are low. We sought to characterize the diagnostic utility of the BMIFT in childhood AIN. All BMIFT requests for investigation of children with neutropenia between January 1998 and May 2007 were reviewed. Patients were classified as AIN or nonautoimmune causes. Baseline demographic data, results of BMIFT, granulocyte immunofluorescence testing and bone marrow findings were collected from clinical records and the institutional laboratory database. Seventy-six children had BMIFT performed for investigation of neutropenia. There were 45 patients diagnosed with AIN, 28 with nonimmune neutropenia and three failed tests. The median age of children with AIN was 1.2 years (range 0.3-15.3), compared with 3.6 years (range 0.1-15.7) in the nonautoimmune group. The median neutrophil count in AIN was 0.3 x 10(9)/l (0.9 x 10(9)/l in nonautoimmune). BMIFT was positive in 24 of 45 patients with AIN and 0 of 28 with nonautoimmune neutropenia (sensitivity 53%, specificity 100%, positive predictive value (PPV) 100%, negative predictive value 57%). Ten patients had other autoimmune diatheses at diagnosis. The BMIFT is a simple, highly specific test with excellent PPV and thus is a clinically useful test to confirm AIN in children.     

Neutrophil antibody specificity in different types of childhood autoimmune neutropenia.

Autoimmune neutropenia (AIN) in children can be divided into 2 forms. In primary AIN, neutropenia is the sole abnormality, and although neutrophil counts are generally below 500 microL(-1), mild bacterial infections occur. Primary AIN is mostly seen in young children and shows a self-limited course. AIN occurring in association with autoimmune diseases (secondary AIN) often shows more severe infectious complications. We analyzed clinical and serological data from 28 pediatric patients with AIN to evaluate whether there is a possible relationship between specificity of the neutrophil autoantibodies and the clinical course of the disease. Specificity of the circulating antibodies was determined with the indirect granulocyte immunofluorescence test (GIFT) and a panel of phenotyped donor neutrophils. The samples were further analyzed in the monoclonal antibody immobilization of granulocyte antigens assay (MAIGA) for neutrophil antigen (NA)1, NA2, CD11a, and CD11b specificity. With the indirect GIFT, an antibody specificity was deduced in 26 of the 28 analyzed samples. In all but 3 sera from patients with primary AIN, NA1-(76%) or NA2-(10%) specific antibodies were detected with the indirect GIFT. In 2 samples, the reactivity in the indirect GIFT was too weak to draw conclusions, but the MAIGA showed NA1 and/or NA2 specificity of the antibodies. One serum, from a patient with primary AIN with a persistent neutropenia for more than 6 years, contained NA1, possibly pan-FcgammaRIIIb, and CD11a antibodies. In 4 sera from patients with primary AIN, weak antibodies with CD11a or CD11b specificity were detected with the MAIGA. Sera from 7 patients with secondary AIN contained in all cases antibodies with pan-FcgammaRIIIb specificity, as deduced from the indirect GIFT results and absorbance/elution experiments performed with 2 sera. The MAIGA confirmed this for only 1 of the 5 tested sera. Furthermore, CD11a antibodies were detected in 1 of the 5 tested sera. In conclusion, our results indicate that primary AIN is usually associated with NA-specific antibodies, whereas secondary AIN seems to be associated with pan-FcgammaRIIIb antibodies. Thus, characterization of the antibodies in sera from children with AIN discriminates patients with primary AIN from those with secondary AIN.     

Clinical experience with the use of rhG‐CSF in secondary autoimmune neutropenia

This paper outlines the impact of granulocyte‐colony stimulating factor (G‐CSF) used as a single modality therapy in 17 patients with secondary autoimmune neutropenia (S‐AIN) who had been treated a multiple number of times previously. Fifteen of these patients had demonstrable antineutrophil antibodies and two had cellular S‐AIN with haemopoietic inhibitory T‐cells present in the marrow. Prior to treatment, all had had problems with infection. All patients responded within 7 days of commencement of treatment. Provided G‐CSF neutrophil counts were maintained above 1 × 10⁹/l, no further infections occurred. This was achievable by using G‐CSF administered as infrequently as once every 8 days. Eight of the 17 patients remained on G‐CSF, although five switched to the glycosylated form because of side‐effects. None have developed osteoporosis despite 47.29 patient years of total experience with G‐CSF. In conclusion both glycosylated and nonglycosylated G‐CSF can be used effectively in treating AIN on a long‐term basis.     

Autoimmune neutropenia due to antineutrophil antibodies in a patient with primary sclerosing cholangitis

Autoimmune neutropenia (AIN) is defined as a decrease in the circulating absolute neutrophil count (ANC) to less than 1500/μl caused by serum antineutrophil antibodies. Secondary AIN is associated with various autoimmune diseases. Herein we present the case of a patient with primary sclerosing cholangitis (PSC) who developed secondary AIN. A 19-year-old man was admitted due to liver injury, and a diagnosis of PSC was established by cholangiogram and liver biopsy. Severe neutropenia, with the ANC down to 130/μl, developed during his hospital course. No medications had been given at that time and bone marrow aspiration revealed no abnormality. Therefore we suspected secondary AIN as a causative etiology and examined whether antineutrophil antibodies were detectable in the patient’s sera by flow cytometric analysis of the granulocyte indirect immunofluorescence test. We found that antineutrophil antibody was strongly positive on admission, and the titer decreased along with recovery from neutropenia. This is the first reported case of a patient with PSC who developed AIN, with detection of serum antineutrophil antibodies.     

Hematopoietic recovery following high-dose combined alkylating-agent chemotherapy and autologous bone marrow support in patients in phase-I clinical trials of colony-stimulating factors: G-CSF,GM-CSF,IL-1, IL-2, M-CSF

Summary Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8–16 g/kg/ day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GMCSF day + 21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24–32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm³) at day +11 and ANC greater than 500/mm³ at day +16. Optimal dose of GCSF and GM-CSF to stimulate neutrophil recovery post transplant was 4–8 g/kg/day and 8–16 g/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.This work has been supported in part by The National Heart, Lung, and Blood Institute, grant P01CA47741. Joanne Kurtzberg, MD is a scholar of the Leukemia Society of America     

Granulocyte colony-stimulating factor (G-CSF) treatment in a neutropenic leukemia patient with diffuse interstitial pulmonary infiltrates

Summary Adult respiratory distress syndrome (ARDS) in patients suffering from acute leukemia usually occurs during chemotherapy-induced neutropenia. In addition, intensified chemotherapy with high-dose cytosine arabinoside and mediastinal irradiation may contribute to the development of ARDS. This complication is usually refractory to conservative treatement with antibiotics, steroids, and mechanical ventilation. In this report, we describe a 25-year-old patient with acute lymphoblastic leukemia who developed ARDS during the phase of chemotherapy-induced neutropenia. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) at doses of 300–600 g/day led to a prompt increase of peripheral granulocyte counts. With resolution of neutropenia, respiratory function gradually improved, and mechanical ventilatory support was stopped after 2 weeks. From this observation we surmise that the application of G-CSF may be an effective therapeutic approach for preventing the fatal outcome of ARDS in leukemia patients with bone marrow aplasia.     

Ganciclovir-related neutropenia after preemptive therapy for cytomegalovirus infection: comparison between cord blood and bone marrow transplantation

We studied ganciclovir (GCV)-related neutropenia after preemptive therapy for cytomegalovirus infection: 9 of 17 (53%) cord blood transplantation (CBT) patients and 18 of 20 (90%) bone marrow transplantation (BMT) patients developed GCV-related neutropenia with an absolute neutrophil count (ANC) of less than 1000/l. Among the patients who did not receive granulocyte colony-stimulating factor, 2 (13%) and 1 (7%) CBT patients, and 10 (56%) and 8 (44%) BMT patients, developed neutropenia with an ANC of less than 500 and 250/l, respectively. The incidences of neutropenia in patients with an ANC of less than 1000, 500, and 250/l were significantly lower after CBT in comparison with BMT. Two BMT patients, but no CBT patients, developed neutropenic fever, and both patients recovered after antibiotic therapy. In CBT patients, a creatinine clearance rate of less than 50 ml/min and an absence of steroid therapy were associated with a greater incidence of GCV-related neutropenia. No risk factors for GCV-related neutropenia were found in BMT patients. These results suggest that GCV may be less toxic to myeloid progenitor cells from cord blood than those from bone marrow.     

Treatment of acute myeloblastic leukemia in adults. The GOELAM experience

The GOELAM group conducted 2 consecutive trials on the treatment of de novo acute myeloblastic leukemia (AML) in adults. In the GOELAM1 protocol 786 patients aged 15–65 were randomized between two induction treatments (ARA-C 200 mg/m²/day for 7 days plus either Idarubicin 8 mg/m²/day for 5 days or Rubidazone 200 mg/m²/day for 4 days). Out of 731 evaluable patients, 521 (71%) achieved complete remission (CR) without significant difference between the 2 anthracyclines. For patients aged 51–65, the CR rate was significantly higher with Idarubicin (75%) than with Rubidazone (61%) (p=0,03). In this group of patients the post-remission therapy consisted in only one course of high dose ARA-C plus m-Amsa and the 6 year disease free survival (DFS) was 24% (intention to treat analysis). For patients aged 15–50 years, the post remission therapy was either allogeneic bone marrow transplantation (BMT) (patients up to 40 years of age with an HLA identical sibling) or a first course of intensive consolidation chemotherapy (ICC) followed by a randomization between autologous unpurged bone marrow transplantation (ABMT) and a second course of ICC. There was no significant difference in the 4 year DFS between allogeneic BMT (42%) and the other types of intensive post remission-therapy (40%). The 4 year DFS was 42% for ABMT and 38% for ICC (p=0.46) (intention to treat analysis). However the median duration of thrombocytopenia was much longer after ABMT (109.5 days versus 18.5 days p=0.0001). The GOELAM SA3 randomized placebo-controlled protocol tested the impact of GM-CSF given during and after induction treatment for elderly patients (55–75 years). In this study, 232 evaluable patients received induction chemotherapy (Idarubicin 8 mg/m²/day for 5 days plus ARA-C 100 mg/m²/day for 7 days) plus placebo or GM-CSF 5g/kg/day from day 1 until the end of neutropenia. The CR rate was 61.5%. The median duration of neutropenia was shorter in the GM-CSF arm (22 days versus 27 days p=0.0001). There was no overall significant advantage for the GM-CSF arm, in terms of CR rate and survival. However for patients age 55–64 the 2 year DFS was significantly higher in the GM-CSF arm (43% vs 17% p=0.0013).This work was supported by a major grant from Programme Hospitalier de Recherche Clinique     

Clinical experience with the use of rhG-CSF in secondary autoimmune neutropenia

This paper outlines the impact of granulocyte-colony stimulating factor (G-CSF) used as a single modality therapy in 17 patients with secondary autoimmune neutropenia (S-AIN) who had been treated a multiple number of times previously. Fifteen of these patients had demonstrable antineutrophil antibodies and two had cellular S-AIN with haemopoietic inhibitory T-cells present in the marrow. Prior to treatment, all had had problems with infection. All patients responded within 7 days of commencement of treatment. Provided G-CSF neutrophil counts were maintained above 1 x 109/l, no further infections occurred. This was achievable by using G-CSF administered as infrequently as once every 8 days. Eight of the 17 patients remained on G-CSF, although five switched to the glycosylated form because of side-effects. None have developed osteoporosis despite 47.29 patient years of total experience with G-CSF. In conclusion both glycosylated and nonglycosylated G-CSF can be used effectively in treating AIN on a long-term basis.     

Treatment results of tonsillar lymphoma: a 10-year experience

Primary extranodal non-Hodgkins lymphomas of the head and neck account for 10–20% of all non-Hodgkins lymphomas. Primary tonsillar lymphoma accounts for less than 1% of head and neck malignancies, although the tonsil is the most common primary extranodal site of head and neck non-Hodgkins lymphomas. In this study we analyzed our cases of tonsillar lymphoma treated in our institution during the last 10 years to compare the finding of this study with those of previous studies. We reviewed the cases of tonsillar lymphoma treated in the Radiation Oncology Department of Shiraz University from 1992 to 2002. Clinical data were obtained from patients files. The patients were treated by combined chemotherapy [a median of six cycles of a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone)] and radiation therapy (40–50 Gy to the primary site and neck). Chemotherapy mainly preceded radiotherapy, although the sequence of radiotherapy and chemotherapy was determined by individual physicians and patients choice. Surgery was used mainly to establish the diagnosis, and tonsillectomy was performed for localized small lesions. Between 1992 and 2002, 19 patients with stage IE (10), IIE (7), and IIIE (2) disease were treated. Median and mean age was 48 and 44 years (range: 22–76 years), respectively, at the time of diagnosis, with a male to female ratio of 1.2:1. The vast majority of patients presented in early stages with aggressive histology. High-grade tumors seemed to affect mainly young people (p=0.226). Diffuse large B-cell lymphomas were the most prevalent. Male patients were significantly younger than females (p=0.021). The patients were treated by combined chemotherapy and radiation therapy. All patients achieved and maintained complete remission with a median of 60 months relapse-free survival and a 5-year cause-specific survival rate of 100%. All patients developed some degree of oropharyngeal mucositis. Three patients (16%) experienced grade 3 or 4 neutropenia. Mild (grade I) xerostomia remained persistently in four patients (21%). A late fatal side effect was observed in one patient who developed radiation-induced sarcoma 7 years after initial diagnosis and died 8 months later without evidence of recurrent lymphoma. Complete follow-up was obtained in all patients. The follow-up period ranged from 18 to 141 months with a median of 60 and a mean of 60.4 months. At the time of last follow-up, all patients but one were alive. Age, sex, stage, bulk of disease, performance status, number of chemotherapy cycles, number of involved sites, histologic subtypes, and radiation dose were analyzed as prognostically significant for disease-specific survival in our cases. Significant prognostic factors were not identified by multivariate analysis. Combined chemotherapy and radiation therapy is safe, highly effective, and probably curative for most patients with primary tonsillar lymphoma.An erratum to this article can be found at     

Bone marrow myeloid cell kinetics during treatment of small cell carcinoma of the lung with chemotherapy not associated and associated with granulocyte-macrophage colony-stimulating factor

Summary Information on the kinetics of bone marrow (BM) myeloid precursors (BMMP) is required for integrating cancer chemotherapy with granulocyte-macrophage colony-stimulating factor (rhGM-CSF), with the aim of reducing neutropenia. Using bivariate flow-cytometric analysis of the in vivo incorporation of bromodeoxyuridine (BUDR) vs DNA content we have studied the kinetics of BMMP in 21 patients with SCLC during the first of six chemotherapy courses (etoposide, epirubicin, andcis-platinum, days 1–3, every 21 days), given alone (eight patients) or followed by rhGM-CSF (10g/kg/day s.c, days 4–14) as BM rescue (eight patients) or both preceded (days -17 to -7, as BM priming) and followed by rhGM-CSF (five patients). At 11–14 days after the start of these therapies there was an increase in the baseline proliferative activity of proliferating BMMP and a shortening in the time needed by the metamyelocyte to mature and to leave the marrow. Both effects were greater and were maintained to a significantly greater degree a week later in patients who received chemotherapy plus rhGM-CSF rescue than in those who received chemotherapy alone or rhGM-CSF priming alone. At day 11–14 the pretreatment median cell production rate of pBMMP was increased by 340%, 150%, and 183% and the maturation time was reduced by 80%, 45%, and 57%, respectively, in the three groups. A week later, the corresponding figures were 206%, 111%, and 157% and 50%, 18%, and 45%. Hence, an identical rhGM-CSF schedule is more effective in increasing the neutrophil production by BMMP when given following chemotherapy as BM rescue than before it as BM priming. In both the rescue and the priming schedule, the increase in proliferative activity of BMMP just at the end of rhGM-CSF stimulation was linked to both an increase in the labeling index and a reduction in duration of S-phase (TS), while a week later it was linked solely to reduction in TS. This could actually reduce one of the two kinetic targets of subsequently administered cytostatics, i.e., a high LI and a long time spent in S phase. From this study, accurate kinetic data can be obtained with the in vivo BUDR technique that are useful in scheduling rhGM-CSF.     

Relation between leukocyte counts and cortisol secretion in CML patients undergoing combined TNF α/IFN α therapy

Summary During long-term interferon -2b (IFN) therapy of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) patients, short-term effects of tumor necrosis factor (TNF) on peripheral leukocyte counts, as well as cortisol and corticotropin (ACTH) release were studied. TNF (40–160g/m²) was given as a 2-h infusion on 5 consecutive days every 3 weeks, in addition to s.c. daily IFN injections (4 mio U/m²), to four (two male/two female) patients, who had been treated for more than 8 months with IFN and additionally for 0–7 months with TNF. Leukocyte counts, cortisol, and ACTH were determined at 30-min intervals between 4 p.m. and midnight. Profiles were determined the day before and on day 1 of TNF therapy. Leukocyte numbers decreased 30 min after start of TNF administration and increased 30–60 min later with a rebound until the next TNF application. The increase of leukocyte counts was due mostly to neutrophil granulocytes. ACTH levels increased 30 min, cortisol 60 min, and leukocyte counts 90 min after start of TNF infusion. Metopirone, an inhibitor of cortisol synthesis given to one patient, suppressed the TNF-induced stimulation of cortisol secretion and subsequent increase of leukocyte counts, while ACTH blood levels were enhanced. It was concluded that leukocyte count increases after TNF/IFN administration might be related to TNF-evoked cortisol secretion.     

Impaired alveolar gas exchange in acute pancreatitis

We evaluated the alveolar–arterial oxygen difference (A-a) and the ratio between P_ao₂ and the fractional concentration of inspired oxygen (P/F) in acute pancreatitis. Eleven patients had mild uncomplicated disease, six showed acute abdominal fluid collections, six had acute abdominal collections and asymptomatic x-ray lung involvement, three presented transient dyspneic episodes, and four had severe acute pancreatitis requiring prolonged oxygen therapy. In the uncomplicated disease, respiratory function was normal; in the six patients with abdominal collections only, A-a increased by 50% and P/F decreased by 20–30%; in the six patients with abdominal collections and asymptomatic x-ray lung involvement, A-a increased by 50–70% and P/F decreased by 40%; the three patients with dyspneic episodes showed a twofold increase in A-a and a 40% decrease in P/F; the four patients with severe pancreatitis had a two- to threefold increase in A-a and a 40–50% decrease in P/F. Hence respiratory function is normal only in uncomplicated pancreatitis; in the presence of complications, disturbance of gas exchange always occurs, requiring careful control and treatment.     

Cell cycle kinetics of hematopoiesis before and after in vivo administration of GM-CSF in refractory anemia: Evidence for a shortening of the granulocyte release time

Summary GM-CSF administration to patients with refractory anemia (RA) induces an increase in neutrophils and eosinophils. We studied cell kinetic mechanisms underlying this observation using clonogenic assays and in vivo iododeoxyuridine labeling of bone marrow cells. Cell cycle kinetics were studied in three patients before and during GM-CSF administration (two daily subcutaneous injections of 54 or 108 g). No consistent effect on the relative number of bone marrow CFU-GM was noticed. The DNA synthesis time and potential doubling time of low-density bone marrow cells remained essentially the same. A slight decrease (1.5–3.7%) in labeling index was found, originating from the myelo(-mono)cytic lineage. In all three patients the release time of labeled granulocytes from the bone marrow into the peripheral blood was shortened (before GM-CSF treatment 5–7 days and during GM-CSF 3–4 days). Cell cycle kinetics of CD34⁺ cells were studied in order to obtain kinetic information on immature precursor and progenitor cells. The DNA synthesis time of the CD34⁺ cells was shortened during GM-CSF therapy, resulting in a shorter potential doubling time. GM-CSF administration to patients with RA results in a rise in granulocytes that might be due partly to an accelerated release of granulocytes from the bone marrow compartment into the circulating blood and partly to an increased proliferative activity of the immature precursor and progenitor cells.     

Successful treatment of autoimmune neutropenia with recombinant human granulocyte-colony stimulating factor (R-metHuG-CSF)

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG-CSF at 5–8 μg/kg body weight (300–480 μg) daily; the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0×10⁹/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can be maintained on a low dose administered twice or thrice weekly.     

Sustained Viral Response Is Rarely Achieved in Patients with High Viral Load of HCV RNA by Excessive Interferon Therapy

Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50–94% of patients with 2 × 10⁴ copies/ml (competitive RT-PCR) or <100 × 10³ copies/ml (Amplicor monitor) of HCV RNA by 468–1206 MU of IFN, but response was only 0–25% of the patients with 2 × 10^5.5 copies/ml (competitive RT-PCR) or >200 × 10³ copies/ml (Amplicor monitor), even with 468–1206 MU of IFN. A high sustained rate was demonstrated in patients with 100–200 × 10³ copies/ml of HCV RNA by 901–1206 MU of IFN, in comparison to that with 900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100–200 × 10³ copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000–227,000 for one person-viral eradication in the patients with <100, 100–200, and >200 × 10³ copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with <200 × 10³ copies/ml of HCV RNA.     

Differential cell count and lymphocyte subsets in bronchoalveolar lavage during pneumonia with and without peripheral neutropenia

One hundred immunocompromised HIV negative patients with microbiologically positive pneumonia underwent bronchoalveolar lavage (BAL) studies. Thirty cases showed peripheral neutropenia (<1000 neutrophils/L), 70 did not. The total cell number in BAL, the differential cell counts, and the lymphocyte subsets (CD4, CD8, CD19, CD57) were measured. Patients with pneumonia and normal or elevated peripheral neutrophils had a significantly increased total number of cells in BAL compared to patients with peripheral neutropenia (3,2 ± 2 vs 1,3 ± 0,6 × 105 cells/ml lavage fluid, p < 0.01). Ninety percent of the BAL differential cell counts obtained in patients exceeding 1000 neutrophils/L showed a lymphocytic and/or neutrophilic alveolitis, whereas only 54% of patients with peripheral neutropenia displayed abnormal counts (p < 0.01). Yet the typical pattern of neutrophilic alveolitis was found more often for peripheral neutrophil counts over 1000/L with high significance (p < 0.0001). Abnormal BAL cell patterns for neutropenic patients uniformly showed a lymphocytic alveolitis, only 10% additionally conformed with the pattern of neutrophilic alveolitis. Patients with pneumonia with and without peripheral neutropenia had similar findings in BAL lymphocyte subsets and exhibited a reduced CD4/CD8 ratio compared to controls (p < 0.05). The high susceptibility of severe neutropenic patients to pulmonary, especially fungal infections may be explained by the local lack of neutrophils.

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Effectiveness of phosphodiesterase-5 inhibitor therapy for portopulmonary hypertension

BACKGROUND:

Portopulmonary hypertension is associated with significant morbidity and mortality. Phosphodiesterase-5 inhibitor therapy is efficacious in other causes of WHO group I pulmonary arterial hypertension.

OBJECTIVE:

To evaluate the efficacy and safety of phosphodiesterase-5 inhibitor therapy in patients with portopulmonary hypertension.

METHODS:

A single-centre retrospective cohort study that included patients with a diagnosis of portopulmonary hypertension was performed. The primary outcome was change in pulmonary vascular resistance after six months of phosphodiesterase-5 inhibitor therapy. A secondary evaluation investigated the effect on other hemodynamic measurements, 6 min walk distance, functional class, safety outcomes and survival.

RESULTS:

Of 1385 patients screened, 25 patients with portopulmonary hypertension were identified, of whom 20 received a phosphodiesterase-5 inhibitor. After six months, there was a significant decrease in pulmonary vascular resistance (−236 dyn·s·cm⁻⁵ [95% CI −343 dyn·s·cm⁻⁵ to −130 dyn·s·cm⁻⁵]; P<0.001), mean pulmonary artery pressure (−8.9 mmHg [95% CI −13.7 mmHg to −4.2 mmHg]; P=0.001) and an increase in Fick cardiac output (0.9 L/min [95% CI 0.1 L/min to 1.6 L/min]; P=0.02). There was no change in 6 min walk distance. The proportion of subjects with a WHO functional class III or IV was significantly reduced at six months compared with baseline (18% versus 61%; P=0.002). Safety outcomes did not reveal any adverse events.

CONCLUSIONS:

Phosphodiesterase-5 inhibitor therapy improved hemodynamics and functional class at six months in a cohort of patients with portopulmonary hypertension.     

Prevalence of aspirin resistance in patients with type 2 diabetes

Abstract Aspirin resistance has been recognised to occur in patients with cardiovascular disease and is associated with poor clinical prognosis. The purpose of the present study was to evaluate the prevalence of aspirin resistance in 172 patients with diabetes mellitus type 2 (DM-2). Platelet function of 172 consecutive patients with type 2 diabetes on chronic aspirin therapy was evaluated. The effect of aspirin was assessed using the platelet function analyser (PFA-100) system, reporting platelet-dependent thrombus formation as the time required to close a small aperture in a biologically active membrane. Resistance to aspirin was defined as a normal collagen/epinephrine-induced closure time (82–165 s). Aspirin responders were defined when closure time was 300 s. Thirty-seven (21.5%) of the type 2 diabetic patients were found to be resistant to chronic aspirin therapy, 29 (16.9%) were semi-responders and 106 (61.6%) were responders. Univariate analysis revealed that aspirin non-responders were significantly younger (p<0.05) compared to aspirin responders. A significant number of type 2 diabetic patients are resistant to aspirin therapy. Aspirin resistance can be evaluated by point-of-care testing and should be recognised in diabetic patients that are treated for primary or secondary prevention.