7th International Immunoglobulin Conference: Immunoglobulin in clinical practice.

Immunoglobulin (Ig) replacement therapy has been the mainstay of primary immunodeficiencies (PID) treatment for more than 30 years and has substantially changed the lives of patients. This review focuses on aspects of Ig use in clinical practice in addition to discussing prioritizing future Ig use. Despite Ig therapy, PID patients continue to be predisposed to recurrent, subclinical respiratory tract infections, which may lead to chronic lung disease. Research has shown that one of the underlying reasons for this deterioration in lung function is the differential distribution and concentration of Ig isotypes in the airway lumen. Further to this, the relationship between Ig dose and infection outcome is explored, expanding on end-of-cycle loss of efficacy (wear-off) particularly with intravenous immunoglobulin (IVIg), how this can confound the determination of optimal IgG dose and how our aim of treatment should be to improve clinical outcome. This review goes on to discuss the safety of Ig replacement therapy, which is generally well tolerated by most patients, compares the rates of systemic adverse reactions between IVIg and SCIg and highlights the advantages of SCIg administration in this respect, including the use of pre-infused subcutaneous recombinant human hyaluronidase to aid subcutaneous infusion volumes. The growing demand for Ig replacement therapy is challenging physicians; here we show the development of prioritization algorithms to assist in identifying those who will benefit most from this clinically valuable therapy.

7th International Immunoglobulin Conference: Immunoglobulin in clinical practice.

Intravenous and subcutaneous immunoglobulins (IVIg and SCIg, respectively) are increasingly used in clinical practice, not only as replacement therapy but also for immunomodulation. Physicians have learned that primary immunodeficiency (PID) patients are susceptible to recurrent respiratory tract infections even when appropriately treated with immunoglobulin (Ig) therapy. Further investigation will establish whether a combined therapeutic approach including Ig dose optimization will prevent progressive lung disease in PID. The wear-off effects observed with IVIg can be minimized by adjusting the dosing regimen. It is also possible to avoid the cyclic wear-off following transition to SCIg administration. Consideration of benefit versus risk with Ig therapy includes evaluating the potential occurrence of thromboembolic and haemolytic events, which may be more frequent when Ig is administered in high doses and in the presence of pre-existing risk factors. The ability to select an administration method from IVIg, SCIg or hyaluronidase-facilitated SCIg infusions provides patient choice and alternatives if one or other administration route is not suitable for a patient. The evolution in indications, applications, and understanding of Ig therapy described here has reinforced the need for robust methods to prioritize Ig use.

Subcutaneous immunoglobulin: opportunities and outlook.

Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.

Small cis-acting sequences that specify secondary structures in a chloroplast mRNA are essential for RNA stability and translation.

Nucleus-encoded proteins interact with cis-acting elements in chloroplast transcripts to promote RNA stability and translation. We have analyzed the structure and function of three such elements within the Chlamydomonas petD 5' untranslated region; petD encodes subunit IV of the cytochrome b(6)/f complex. These elements were delineated by linker-scanning mutagenesis, and RNA secondary structures were investigated by mapping nuclease-sensitive sites in vitro and by in vivo dimethyl sulfate RNA modification. Element I spans a maximum of 8 nucleotides (nt) at the 5' end of the mRNA; it is essential for RNA stability and plays a role in translation. This element appears to form a small stem-loop that may interact with a previously described nucleus-encoded factor to block 5'-->3' exoribonucleolytic degradation. Elements II and III, located in the center and near the 3' end of the 5' untranslated region, respectively, are essential for translation, but mutations in these elements do not affect mRNA stability. Element II is a maximum of 16 nt in length, does not form an obvious secondary structure, and appears to bind proteins that protect it from dimethyl sulfate modification. Element III spans a maximum of 14 nt and appears to form a stem-loop in vivo, based on dimethyl sulfate modification and the sequences of intragenic suppressors of element III mutations. Furthermore, mutations in element II result in changes in the RNA structure near element III, consistent with a long-range interaction that may promote translation.

Primary immunodeficiencies: genetic risk factors for lymphoma.

It has been estimated that up to 25% of patients with certain genetically determined immunodeficiencies will develop tumors, primarily B-cell lymphomas, during their lifetime. Epstein-Barr virus appears to be an important cofactor in the development of lymphoproliferative disorders in patients with primary immunodeficiencies, as well as acquired immunodeficiencies. Additionally, host defects in immunoregulation and/or gene rearrangement, which are features of certain primary immunodeficiencies, probably contribute to the risk of lymphomagenesis in patients at risk.

Willingness to perform euthanasia. A survey of physician attitudes.

BACKGROUND: In the United States, few studies have examined important variables in physician attitudes toward the practice of euthanasia, such as the patient's underlying disease, mental capacity, and age, and the physician's specialty and religion. We administered a case-based survey to analyze the impact of such specific variables on physician attitudes toward the practice. METHODS: A four-section survey solicited (1) physician responses to three hypothetical cases in which patients requested euthanasia; (2) physicians' general opinions about euthanasia and how its legalization might affect them personally and professionally; and (3) demographic information. Analysis focused on physicians' characteristics as they related to their responses to the various aspects of euthanasia elicited in the survey. Univariate and multivariate analyses, using logistic regression, were performed. RESULTS: Completed and analyzable surveys were returned by 740 physicians. We found that physicians felt more comfortable with euthanasia requests from nondecisional, nonterminal patients who had left advance directives than they did with requests from decisional patients suffering from grave illnesses or injuries, or from decisional patients who had early signs of a progressive but nonlethal neurologic disease. We also found that physicians' specialties and religions correlated with their responses to the hypothetical cases and with their generalized attitudes toward euthanasia. CONCLUSIONS: Given the disparity in responding physicians' attitudes toward euthanasia, along with the fact that values based on religious affiliation or profession may underlie many physicians' opposition to the practice, we conclude that if euthanasia is to be legalized, safeguards protective of patients and physicians must be incorporated.

A survey of sued and nonsued physicians and suing patients.

To systematically assess the impact of malpractice litigation on the doctor-patient relationship and to collect data that might suggest effective tort reform, we surveyed 642 sued physicians, nonsued physicians, and suing patients in Wisconsin. Parallel forms of survey instruments obtained information regarding changes in physicians' practices, changes in attitudes toward patients or physicians, and changes in physical and emotional well-being as a result of malpractice litigation or the threat of the same. In addition, opinions regarding causes and deterrents of malpractice litigation were obtained. Results suggested that claims or threats of malpractice suits had a negative impact on physicians' practices and emotional well-being; that this negative impact was more pronounced when the sued physician had been more personally involved with his patient prior to the malpractice claim; and that suing patients' and sued physicians' understanding of their relationship before the malpractice claim significantly differed. All respondents viewed improved physician-patient communication as the most effective method of preventing malpractice claims. Informal, alternative dispute resolution mechanisms in hospitals and clinics and improved peer review may decrease litigation and its deleterious effects.

Hematite-coated microfossils: primary ecological fingerprint or taphonomic oddity of the Paleoproterozoic?

Microfossils belonging to the 1.88-billion-year-old 'Gunflint-biota' are preserved as carbonaceous and hematitic filaments and spheres that are believed to represent ancient chemolithoautotrophic Fe(II) oxidizing bacteria that grew above a chemocline where ferruginous seawater upwelled into shallow, oxygenated waters. This 'biological' model posits that hematite formed during burial from dewatering of the precursor ferric oxyhydroxides that encrusted Fe(II)-oxidizing bacteria. Here, we present an alternate 'taphonomic' model in which iron-rich groundwaters discharged into buried stromatolites; thus, the mineralization reactions are more informative of diagenetic processes than they are for primary marine conditions. We sampled centimeter-scale columnar stromatolites from both the lower and upper stromatolite horizons of the Biwabik and Gunflint formations, across a range of metamorphic gradients including unaltered to prehnite-pumpellyite taconite, supergene altered ore, and amphibolite-pyroxene grade contact-metamorphic zones. Fossils are rare to very rare and comprise curved filaments that exist in clusters with similar orientations. The filaments from throughout the Biwabik are similar to well-preserved carbonaceous Gunflintia from Ontario. Spheres of Huroniospora are also found in both formations. Microfossils from the least altered sections are preserved as carbon. Prehnite-pumpellyite samples are composed of either carbon or hematite (Fe2 O3 ). Within the contact aureole, filaments are densely coated by magnetite (Fe3 O4 ); the highest grade samples are secondarily oxidized to martite. The consistency in stromatolite microstructure and lithofacies throughout the metamorphic grades suggests they formed under similar environmental conditions. Post-depositional alteration led to replacement of the carbon by iron oxide. The facies association, filament distribution, and lack of branching and attached spherical cells argue against Gunflintia being a direct analogue to common marine, chemolithoautotrophic Fe(II)-oxidizing bacteria. Instead, we propose that the presence of hematite-coated microfossils is a reflection of taphonomic processes and does not necessarily reflect the byproduct of an original microbial ecosystem.

Unidirectional absorption of gentamicin from the peritoneum during continuous ambulatory peritoneal dialysis.

Gentamicin kinetics were determined after intravenous or intraperitoneal injection in five patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Our objective was to determine rate of absorption of gentamicin from the peritoneum into the systemic circulation and vice versa. After intraperitoneal instillation of 1 mg/kg in the CAPD fluid during a 6-hr dwell time, the antibiotic appeared in the serum within 15 min in four of five patients. Peak serum concentrations ranged between 1.6 and 7.2 mg/l(mean +/- SD = 3.52 +/- 2.22) in all five patients and the time to reach peak concentration was 3.8 +/- 1.5 hr. Peritoneal gentamicin clearance was 13 ml/min. Percent extraction of gentamicin from the PD fluid within the 6 hr of intraperitoneal exposure ranged from 65% to 100% (mean +/- SD = 86.8 +/- 13.2). The fraction of the intraperitoneal dose absorbed into systemic circulation was found to be 0.84 independently by calculating the ratio of AUCip and AUCiv. When the same dose of gentamicin was injected intravenously (1 mg/kg), no gentamicin could be detected in the peritoneal fluid in three of five patients and only a very small amount of the drug was present for a brief period of time in the remaining two. The kinetic parameters of intravenous gentamicin were: volume of distribution, 0.3 l/kg; elimination rate constant, 0.028 hr(-1), plasma clearance 0.009 l/kg . min(-1), and half-life 27.4 hr. In two patients with acute peritonitis treated with intraperitoneal gentamicin, peak serum concentrations were found to range between 3.5 and 4.5 mg/l. These data suggest that gentamicin is rapidly absorbed from the peritoneal fluid into the blood compartment, but that occurrence of the reverse exchange is negligible. Thus, CAPD would not be expected to alter the elimination characteristics of intravenous gentamicin. Instillation of gentamicin in CAPD fluid may allow rapid absorption to reach therapeutic serum concentrations.

Renal aspergilloma: an unusual cause of infection in a patient with the acquired immunodeficiency syndrome.

The case of a 36-year-old man with the acquired immunodeficiency syndrome (AIDS) and a renal aspergilloma is reported. Aspergillus infections are uncommon in patients with AIDS. Isolated renal aspergillomas have rarely been reported in the non-AIDS population (14 cases) and have never been reported in a patient with AIDS. The patient we describe was clinically symptomatic and initially treated medically, but he did not respond to intravenous amphotericin and oral itraconazole. He eventually required nephrectomy; however, there was local recurrence of the aspergilloma postoperatively. We comment on some issues in the spectrum of Aspergillus infections in AIDS and review the literature on the manifestations and treatment of renal aspergillomas.

Massive post-transplant proteinuria. Biopsy proven nil disease.

A case of massive proteinuria following an A-match living donor transplantation is described. All attempts to define the cause of the proteinuria failed. The proteinuria resolved while the patient was on triple-drug therapy. Presently, the patient remains well with minimal proteinuria and excellent renal function.

Massive post-transplant proteinuria with minimal histological changes.

Three patients developed massive proteinuria, hypoalbuminemia, and edema after transplantation. These findings occurred in the immediate post-transplant period in two patients, and renal failure developed. The third patient developed proteinuria 4 months post-transplantation. There was complete remission of proteinuria in two patients and recovery of renal function in one. Renal histology was similar in all. Light microscopy demonstrated that the glomeruli contained a mild increase in mesangial matrix, but were otherwise normal. No significant interstitial cellular infiltration or fibrosis was present. Immunofluorescence microscopy revealed no staining for immunoglobulins or complement. Electron microscopy demonstrated fusion of foot processes, but the glomerular basement membrane was normal. No electron-dense deposits were found. The usual causes of post-transplant nephrotic syndrome were ruled out. We believe these three patients represent a unique disorder of the transplanted kidney.

Immunoregulatory abnormalities in patients with Epstein-Barr virus-associated B cell lymphoproliferative disorders.

EBVirus-associated B cell lymphoproliferative disorder (BLPD) is a recognized complication of primary immunodeficiency and organ as well as bone marrow transplantation. Although the nature of the immune defects that predispose to the development of BLPD are unknown, it is postulated that aberrant T cell responses are involved. It is our hypothesis that unbalanced lymphokine production is a major contributory factor to abnormal B cell growth in response to EBV, resulting in BLPD. Since IFN-alpha and IL-4 are important regulators of B cell proliferation and also regulate the synthesis of IgE, we determined serum levels of IFN-alpha, IL-4, and IgE in 8 patients with newly diagnosed BLPD. Comparison was made to healthy recipients of organ transplants on immunosuppressive therapy without BLPD, and normal EBV seropositive controls. Levels of serum IL-4 were significantly elevated in both patients with BLPD as well as in healthy immunosuppressed organ transplant recipients as compared with normal healthy individuals. Patients with BLPD exhibited a combination of significantly lower levels of serum IFN-alpha, and significantly higher levels of serum IgE than either healthy EBV seropositive individuals or healthy recipients of organ transplants on immunosuppressive therapy. These results suggest that imbalance in the proportions of circulating cytokines favoring B cell proliferation may be contributing to the development of EBV-associated BLPD. The potential significance of the finding of low IFN-alpha in patients who develop BLPD is exemplified by our recent success in the treatment of BLPD with IFN-alpha and intravenous IgG.

Relationship of immunodeficiency to lymphoid malignancy.

Individuals with either primary or secondary immunodeficiencies are at high risk to develop not only infections but also malignancy (especially of the lymphoid system). The major focus of this paper is on malignancies that develop in immunodeficiency syndromes, particularly malignancies in naturally occurring immunodeficiencies and following bone marrow transplantation (BMT). As of August, 1986, 514 cases of naturally occurring immunodeficiencies have been registered at the Immunodeficiency Cancer Registry. Overall non-Hodgkin's lymphomas predominate in these patients, accounting for 48.6% of all cases. Non-Hodgkin's lymphoma is the predominant malignancy in ataxia-telangiectasia, common variable immunodeficiency, Wiskott-Aldrich syndrome (WAS) and severe combined immunodeficiency (SCID). The histopathology of the lymphomas differs somewhat in each of the disorders. In WAS, large cell "histiocytic" lymphoma predominates, with most cases having the features of B lymphocytes, including pleomorphic immunocytoma and immunoblastic lymphoma. Non-Hodgkin's lymphoma in SCID also generally has B cell features and in some cases multiple copies of Epstein-Barr virus (EBV) genomic DNA have been found in tumor tissue. In contrast to ataxia-telangiectasia, in which non-Hodgkin's lymphoma is also the predominant neoplasm, the morphology and cell marker characteristics are more similar to those seen in nonimmunodeficient children. The lymphomas in ataxia-telangiectasia are very heterogeneous with representation from all the major histologic subtypes. We have found no relationship between the degree of immunodeficiency and the development of malignancy. Immunodeficiency following BMT, as in naturally occurring immunodeficiencies, appears to predispose patients to the development of lymphoid malignancy, especially for recipients of partially mismatched bone marrow. In Minnesota 8 patients have developed B cell lympho-proliferative disorders (BLPD) following BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Mismatched bone marrow transplantation for Omenn syndrome: a variant of severe combined immunodeficiency.

Omenn syndrome is a variant of SCID, inherited as an autosomal recessive disorder, and characterized by severe eczematoid dermatitis, eosinophilia, elevated serum IgE and a distinctive histology in enlarged lymph nodes. The etiology of Omenn syndrome is unknown, however, unlike other forms of SCID; patients with Omenn syndrome have activated T lymphocytes in their circulation capable of non-MHC restricted cytotoxic function. Recently, it has been observed that the use of immunosuppressive therapy, particularly cyclosporine, can modify the clinical manifestations of the disorder. Prior to the use of bone marrow transplantation this disease was universally fatal. Death typically occurred in infancy as the result of opportunistic infections and/or malignancies, most notably lymphomas. While bone marrow transplantation has become quite successful for many phenotypes of SCID, even with the use of alternative donors other than histocompatible siblings, in Omenn syndrome it remains a challenge. In our experience, patients with Omenn syndrome exhibit a higher incidence of Gram negative sepsis, before and during transplantation, and carry a significant risk of post-transplant rejection when compared with patients with other phenotypes of SCID. We report the results of six patients treated with bone marrow transplantation from alternative donors, three had unrelated donors (URD) and three had haplo-identical parental donors. Five of the six patients achieved complete and/or durable donor cell engraftment and only one patient experienced acute GVHD. Three patients died of transplant-related complications (infection or EBV-associated B cell lymphoma) between day +22 and day +95 post-transplant. Three patients survived more than 1 year post-transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: risk factors, treatment and outcome.

Twenty-six cases of B cell lymphoproliferative disorder (BLPD) were identified among 2395 patients following hematopoietic stem cell transplants (HSCT) for which an overall incidence of BLPD was 1.2%. The true incidence was probably higher, since 9/26 of the diagnoses were made at autopsy. No BLPD was observed following autologous HSCT, so risk factor analyses were confined to the 1542 allogeneic HSCT. Factors assessed were HLA-mismatching (> or = 1 antigen), T cell depletion (TCD), presence of acute GvHD (grades II-IV), donor type (related vs unrelated), age of recipient and donor, and underlying disease. Factors found to be statistically significant included patients transplanted for immune deficiency and CML, donor age > or = 18 years, TCD, and HLA-mismatching, with recipients of combined TCD and HLA-mismatched grafts having the highest incidence. Factors found to be statistically significant in a multiple regression analysis were TCD, donor age and immune deficiency, although 7/8 of the patients with immunodeficiencies and BLPD received a TCD graft from a haploidentical parent. The overall mortality was 92% (24/26). One patient had a spontaneous remission, but subsequently died >1 year later of chronic GVHD. Thirteen patients received therapy for BLPD. Three patients received lymphocyte infusions without response. The only patients with responses and longterm survival received alpha interferon (alphaIFN). Of seven patients treated with alphaIFN there were four responses (one partial and three complete). These data demonstrate that alphaIFN can be an effective agent against BLPD following HSCT, if a timely diagnosis is made.

Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients.

Thyroid function was evaluated in children surviving disease-free for 2 years or more following bone marrow transplantation (BMT) for severe aplastic anemia (27 patients), acute non-lymphoblastic leukemia (28 patients), and acute lymphoblastic leukemia (25 patients). Pre-BMT conditioning consisted of high dose chemotherapy and total lymphoid irradiation with 750 cGy for patients with severe aplastic anemia, and for patients with leukemia, high dose chemotherapy and single dose total body irradiation with 750-850 cGy (33 patients) or fractionated total body irradiation with 1320 cGy (20 patients). Compensated hypothyroidism (elevated thyroid stimulating hormone (TSH) with a normal thyroxine index) occurred in 20/80 patients with a median time of onset of 12.3 months post-BMT (range 4-30). No patients developed primary hypothyroidism (elevated thyroid stimulating hormone with low thyroxine index). In seven patients, compensated hypothyroidism was transient with TSH returning to normal at a median of 60 months post-BMT (range 11-75). Six patients with compensated hypothyroidism received thyroid hormone replacement therapy. Time to development of compensated hypothyroidism was associated (p = 0.03) with underlying disease and radiation (11 of 27 patients with severe aplastic anemia + total lymphoid irradiation versus nine of 53 patients with leukemia + total body irradiation). In aplastic anemia patients, but not patients with leukemia, the incidence of thyroid hypofunction 5 years post-transplant was significantly higher (p less than 0.001) in those receiving methotrexate alone (82%) as prophylaxis for graft-versus-host disease compared with those receiving a regimen of methotrexate, antithymocyte globulin and prednisone (16%).

Role of renal biopsy in end stage renal failure.

The role of renal biopsy in 46 patients with end stage renal failure was assessed. Renal tissue was obtained by open renal biopsy in 24 patients, by needle biopsy in 5, and at bilateral nephrectomy in 17. In 4 patients the renal biopsy specimens showed advanced changes that could only be diagnosed as "end stage kidney". In 42 patients (91 per cent), a precise renal diagnosis was made. In 20 patients (43 per cent) the prebiopsy clinical impression differed from the histologic diagnosis. In the 29 patients undergoing renal biopsy, minor postoperative morbidity occurred in 5. We conclude that a renal biopsy in patients with end stage renal failure will result in a change in clinical diagnosis in a significant number of patients and can be performed with low morbidity.

Renovascular hypertension.

In current clinical practice, angiographic evaluation of patients with suspected renovascular hypertension usually follows clinical suspicion and positive captopril scintigraphy. Early digital angiography and percutaneous renal artery angioplasty have evolved as the accepted treatment pattern. Doppler sonography and MR angiography continue to be evaluated as potential methods of noninvasive screening.

Legal bases for the control of analgesic drugs.

Governments throughout the world have struggled for decades to ensure the availability of narcotic analgesics for legitimate medical and scientific purposes while controlling the abuse and illegal diversion of such substances. While the international drug-control system has effectively limited illicit trafficking of opioids, concerns remain about its effectiveness in ensuring the availability of these drugs for legitimate purposes. In the United States, federal legislation accommodates the use of controlled substances for medical and scientific purposes more effectively than does state law. Many states' controlled substance laws hinder appropriate opioid prescribing through (a) the use of ill-defined terms, (b) restriction of pain prescriptions to a specific number of dosage units; and/or (c) utilization of multiple-copy prescription programs. A more efficient state approach to monitoring inappropriate schedule II prescribing and dispensing may be through an electronic, computer-based pharmacy point-of-sale system, through which pharmacists can be alerted instantaneously to patients receiving the same drug from multiple pharmacies. In addition, states should consider modifying their approaches to drug abuse by adopting the revised Uniform Controlled Substances Act and/or establishing state pain initiatives.