Granulocyte transfusion: revisited

Neutrophils are the immune system's main cellular defense against bacterial and fungal infections. Transfusion of granulocytes has been considered a therapeutic modality for severe bacterial and fungal infections in patients with prolonged neutropenia and with functional neutrophil disorders. Good theoretic and experimental evidence demonstrating granulocyte transfusion efficacy exists in preventing and treating severe infection. However, clinical evidence has been more difficult to interpret, with efficacy equivocal in many studies and further trials hindered by limitations in collecting adequate doses of leukocytes from healthy steroid-mobilized donors. The development and use of granulocyte colony-stimulating factor to stimulate normal donors has generated renewed interest in granulocyte transfusions. In clinical studies, granulocyte colony-stimulating factor has markedly enhanced the yield of leukocytes collected from normal donors, which may improve clinical outcomes in patients with severe infections and neutropenia who receive granulocyte transfusions. Preliminary clinical evidence, when correct granulocyte dose per patient body weight is optimized, suggests efficacy. However, well-designed randomized clinical trials are necessary to definitively establish granulocyte transfusions as a viable therapeutic modality in the treatment of severe bacterial and fungal infections in patients with functional neutrophil disorders or neutropenia.     

Granulocyte transfusion

PURPOSE OF REVIEW: Granulocyte transfusions have been used for more than four decades. Several issues have complicated the analysis of previous studies, including the utilization of improved antimicrobials, the effects of recipient alloimmunization and variable cell dose. The use of granulocyte colony-stimulating factor for donor stimulation has revived interest in granulocyte transfusion. The aim of this review is to evaluate the most recent studies in granulocyte transfusion therapy and their clinical applicability. RECENT FINDINGS: Granulocyte colony-stimulating factor use has increased the granulocyte yield by approximately fourfold. Multiple recent studies have shown that granulocyte transfusions can be helpful in controlling severe infections progressing despite the use of appropriate antibiotics, with a response rate of 40-80% with variability in results depending on patient characteristics. This benefit is limited to a small patient population as the incidence of prolonged reversible neutropenia is relatively small. Severe side effects have been rare in those studies. SUMMARY: Granulocyte transfusions are beneficial in neutropenic patients with severe uncontrolled infection. The underlying disease process is the major determinant of outcome in these patients. Because granulocyte transfusions are not commonly used, centers are not currently able to provide transfusions in a timely fashion. Nonalloimmunized patients can receive cells from nonmatched ABO compatible donors, while alloimmunized patients should receive granulocytes from either HLA-matched donors or donors selected by leukoagglutination or lymphocytotoxicity crossmatching. Further studies are needed to clarify the optimal starting time and frequency of transfusions, and the best method for identifying donor-recipient compatibility.     

Granulocyte transfusion therapy and amphotericin B: Adverse reactions?

One hundred twenty-five granulocyte transfusions were given concurrently with amphotericin B to 31 granulocytopenic patients with acute leukemia during a four year period. Twenty-six patients had culture-documented, and 5 had presumed fungal infections; pulmonary infiltrates were present in 26 patient courses. Eight patients developed pulmonary deterioration temporally related to therapy with amphotericin, granulocyte transfusions, or both. One event occurred following amphotericin alone. Three additional reactions occurred in alloimmunized patients with antibodies to human leukocyte antigens (HLA) who received random donor granulocytes, which may indicate a potential mechanism for the pulmonary reactions. Two reactions potentially represent an adverse interaction between amphotericin and granulocytes, but these were reversible and were not unlike reactions expected with each modality alone. Our data fail to document a specific detrimental interaction between granulocyte transfusions and amphotericin beyond the reactions associated with each modality, and the data suggest that other clinical factors, particularly infection and alloimmunization, also contribute to pulmonary decompensation. We nevertheless recommend great care and attention be given to administering these modalities in the setting of severely ill patients.     

Granulocyte transfusion: a review

Neutrophils are the body's main defence against invasion by bacteria and fungi and, below a level of 1 x 10(9)/l, there is a direct relationship between their circulating number and the risk of systemic infection. Despite advances in supportive care, such as improved broad-spectrum antibiotics and the haemopoietic growth factors, neutropenia following myelosuppressive chemotherapy for malignant disease remains the most important cause of treatment-related morbidity and mortality and its most important dose-limiting toxicity. Although there is clear theoretical, experimental and anecdotal clinical evidence supporting the use of transfused granulocytes to prevent and treat infection in neutropenia, early attempts at exploiting this clinically were unsuccessful, mainly because of difficulties in collecting a sufficient number of cells. Improvements in the technology of collection, including the use of red cell sedimenting agents, glucocorticoids and, more recently, granulocyte-colony-stimulating factor, now allow granulocyte doses within the therapeutic range to be routinely collected. Preliminary evidence suggests clinical efficacy. However, well-designed trials with clinically relevant end-points will be required before granulocyte transfusion can become part of routine clinical practice.     

Granulocyte transfusion: current status

Infection associated with therapy-related neutropenia continues to be a major cause of morbidity and mortality. Renewed interest in granulocyte transfusion therapy as treatment for this condition has been generated by the observation that large doses of granulocytes can be obtained from donors who have been stimulated with granulocyte colony-stimulating factor (G-CSF). Granulocytes collected from these donors have been shown to effectively raise the patient's neutrophil count and appear to function normally as judged both by in vitro and in vivo measures. The evidence for clinical efficacy is limited to that of case reports and small series, and the results are not uniform. Randomized controlled clinical trials are needed to determine whether this therapy is useful in either clearing infections or prolonging survival.     

Laser balloon angioplasty: potential clinical applications

Coronary laser balloon angioplasty (LBA) is a new technique which permits application of heat (generated by the laser source) and pressure (by balloon inflation) to thermally weld tissue during coronary angioplasty (PTCA). The goal of LBA is to achieve a large, smooth arterial lumen, by thermal welding of dissection flaps, elimination of elastic recoil, elimination of vasospasm, reduction in platelet activation, desiccation of thrombus, and inhibition of smooth muscle cell proliferation (Table 1). The LBA system consists of a 50 watt continuous wave Nd:YAG laser with a wavelength of 1060 nm, and a modified coronary balloon angioplasty catheter with a 4.3 French shaft and a PET balloon measuring 20 mm in length and 2.5, 3.0 and 3.5 mm in diameter. For clinical use, laser doses ranging from 250 to 450 joules each are delivered over 20 seconds, to achieve adventitial tissue temperatures of 90 to 110 degrees C. The LBA technique is quite similar to that of conventional PTCA. The LBA catheter is usually positioned over a 0.014" guidewire through an 8 French guiding catheter. Once the laser balloon is in position, the balloon is inflated to a pressure of 4 atmospheres and the programmed laser dose is delivered over 20 seconds, followed by continued balloon inflation for an additional 20 to 40 seconds while the temperature of the arterial wall returns to normal. Conventional PTCA is virtually never necessary to improve lumen appearance and dimensions after LBA. LBA has been shown to be effective in the management of acute failure of PTCA, due to abrupt closure or severe dissection with impaired flow ("impending closure").(ABSTRACT TRUNCATED AT 250 WORDS)     

Thalidomide: current and potential clinical applications

More than three decades after its withdrawal from the world marketplace, thalidomide is attracting growing interest because of its reported immunomodulatory and anti-inflammatory properties. Current evidence indicates that thalidomide reduces the activity of the inflammatory cytokine tumor necrosis factor (TNF)-alpha by accelerating the degradation of its messenger RNA. Thalidomide also inhibits angiogenesis. Recently, the drug was approved for sale in the United States for the treatment of erythema nodosum leprosum, an inflammatory complication of Hansen's disease. However, it has long been used successfully in several other dermatologic disorders, including aphthous stomatitis, Beh?et's syndrome, chronic cutaneous systemic lupus erythematosus, and graft-versus-host disease, the apparent shared characteristic of which is immune dysregulation. Many recent studies have evaluated thalidomide in patients with human immunodeficiency virus (HIV) infection; the drug is efficacious against oral aphthous ulcers, HIV-associated wasting syndrome, HIV-related diarrhea, and Kaposi's sarcoma. To prevent teratogenicity, a comprehensive program has been established to control access to the drug, including registration of prescribing physicians, dispensing pharmacies, and patients; mandatory informed consent and education procedures; and limitation of the quantity of drug dispensed. Clinical and, in some patients, electrophysiologic monitoring for peripheral neuropathy is indicated with thalidomide therapy. Other adverse effects include sedation and constipation. With appropriate safeguards, thalidomide may benefit patients with a broad variety of disorders for which existing treatments are inadequate.     

Granulocyte transfusion in the G-CSF era

Granulocyte transfusions have been used since the 1960s with varying degrees of clinical success in the treatment of infection in patients with neutropenia or inherited granulocyte disorders. A number of studies have indicated that efficacy may well be associated with the dose of granulocytes delivered. Collection of granulocytes using modern apheresis machines and corticosteroid administration yields approximately 20～30×10⁹ neutrophils, unlikely to be adequate for treating an established infection. The administration of G-CSF to healthy donors has resulted in average granulocyte yields up to 8×10¹⁰ cells. Normal or near normal blood neutrophil counts are often attained when these concentrates are transfused to neutropenic recipients, and these levels are sustained for up to 24 h. G-CSF-primed granulocytes appear to be functionally normal by both in vitro and in vivo measurements. Adverse effects experienced by recipients are similar to those seen with traditional doses of granulocytes. G-CSF administration to donors is well tolerated. Controlled clinical trials are needed to determine the therapeutic efficacy of G-CSF-primed granulocyte transfusions.     

Granulocyte transfusion in the G-CSF era

Granulocyte transfusions have been used since the 1960s with varying degrees of clinical success in the treatment of infection in patients with neutropenia or inherited granulocyte disorders. A number of studies have indicated that efficacy may well be associated with the dose of granulocytes delivered. Collection of granulocytes using modern apheresis machines and corticosteroid administration yields approximately 20 to approximately 30 x 10(9) neutrophils, unlikely to be adequate for treating an established infection. The administration of G-CSF to healthy donors has resulted in average granulocyte yields up to 8 x 10(10) cells. Normal or near normal blood neutrophil counts are often attained when these concentrates are transfused to neutropenic recipients, and these levels are sustained for up to 24 h. G-CSF-primed granulocytes appear to be functionally normal by both in vitro and in vivo measurements. Adverse effects experienced by recipients are similar to those seen with traditional doses of granulocytes. G-CSF administration to donors is well tolerated. Controlled clinical trials are needed to determine the therapeutic efficacy of G-CSF-primed granulocyte transfusions.     

2021 clinical trials update: Innovations in hemophilia therapy

Therapies engineered to prolong clotting factor protein circulation time, manipulate the balance of pro‐coagulant and anti‐coagulant proteins, or introduce new genetic material to enable endogenous factor protein production dominate the clinical trial landscape of hemophilia. The availability of clotting factor concentrates and the establishment of primary prophylaxis have dramatically improved health outcomes for hemophilia patients. But, the burden of hemostatic therapy remains significant, and many barriers to consistent longitudinal use of prophylaxis exist. Several types of emerging therapeutics including engineered factor concentrates, substitutive therapies, rebalancing therapies, and gene transfer/editing all aim to reduce the challenges of current hemophilia treatment. Emerging treatment options may reduce treatment frequency or need for intravenous administration. They may also introduce new challenges in laboratory assessment of hemostasis. These novel therapies must not introduce significant new health risks and continue to support similar or improved outcomes. The potential ramifications of rebalancing the coagulation cascade, particularly in a stress or inflammatory state, or introduction of new genetic material are not trivial. The focus of this review is to provide an overview of active and recently completed clinical trials as well as emerging preclinical data investigating new therapeutic possibilities for hemophilia patients and potentially other rare bleeding disorders.     

Coccidioidomycosis: clinical update

Over the last decade coccidioidomycosis, a fungal infection endemic to the desert Southwest of the United States, has gained national prominence. This review summarizes recent advances in the clinical understanding of this disease. Immunosuppressive therapy and infection with the human immunodeficiency virus are recognized risk factors for the development of severe, progressive disease. Although relatively uncommon, extrapulmonary dissemination of Coccidioides immitis can lead to chronic infection of the skin, bones, and meninges. Culture and histologic examination are important in establishment of the diagnosis, but serologic tests remain both diagnostically and prognostically useful. Treatment is problematic. Coccidioidomycosis is an unpredictable disease, and assessments of drug efficacy are difficult. Ketoconazole is challenging amphotericin B as the preferred treatment for some manifestations. However, many of the adverse effects of ketoconazole have only recently been recognized. Newer antifungal agents, such as fluconazole and itraconazole, hold promise for the future.     

Gastroparesis: clinical update

Gastroparesis refers to chronically abnormal gastric motility characterized by symptoms suggestive of mechanical obstruction and delayed gastric emptying in the absence of mechanical obstruction. It may be idiopathic or attributable to neuropathic or myopathic abnormalities, such as diabetes mellitus, postvagotomy, postviral infection, and scleroderma. Dietary and behavioral modification, prokinetic drugs, and surgical interventions have been used in managing patients with gastroparesis. Although mild gastroparesis is usually well managed with these treatment options, severe gastroparesis may be very difficult to control and may require referral to a specialist center if symptoms are intractable despite pharmacological therapy and dietetic support. New advances in drug therapy, botulinum toxin injection, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. This article critically reviews the advances in the field from the perspective of the clinician.