Fred Gill

Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia

Abstract Since early diagnosis of even a disseminated fungal infection is difficult and treatment often ineffective in a patient with persistent granulocytopenia, we have prospectively evaluated continued antibiotic therapy and early empiric antifungal therapy in patients with prolonged fever and granulocytopenia. Between November 1975 and December 1979, all patients with fever (oral temperature >38 °C three times per 24 hours or >38.5 °C once) plus granulocytopenia (polymorphonuclear leukocytes 3 ), were evaluated and began an empiric antibiotic regimen consisting of Keflin ® , gentamicin and carbenicillin (KGC). Of the 652 episodes of fever and granulocytopenia (in 271 patients), initial evaluation failed to define an infectious etiology in 323 (49.5 percent). In 50 of the patients in whom initial evaluation did not demonstrate an infectious etiology, fever and granulocytopenia continued after seven days of therapy with KGC, without evidence for the etiology of their persistent fever. These patients were randomized to either discontinue receiving KGC (Group 1); continue receiving KGC (Group 2); continue receiving KGC with the addition of empiric amphotericin B (Group 3). The duration of granulocytopenia was comparable in the three groups (median 24 days, range 8 to 51 days). Clinically or microbiologically demonstrable infections occurred in nine of 16 patients who discontinued the KGC regimen (Group 1) (six also experienced shock, p Empiric amphotericin B therapy was also evaluated for its effectiveness in patients whose initial evaluation revealed an infectious etiology with fungal colonization throughout their alimentary tract but in whom fever and granulocytopenia remained despite at least seven days of therapy with appropriate antibiotics. In addition, the postmortem records of all patients dying between 1970 and 1979 were reviewed to ascertain the cause of death and the type of antimicrobial therapy received prior to death. Only one death due to fungal invasion occurred, when therapy with amphotericin B was instituted after one week of broad-spectrum antibiotic therapy. Collectively, these data suggest that continuing antibiotic therapy reduces early bacterial infections in patients with persistent fever and granulocytopenia and that empiric antifungal therapy also appears necessary to prevent fungal superinfections and to control clinically undetected fungal invasion.

Duration of empiric antibiotic therapy in granulocytopenic patients with cancer

Abstract Early initiation of empiric antibiotic therapy in febrile cancer patients has become established practice, but the appropriate duration of antibiotic therapy when no infectious source can be identified is unknown. The complications of broad-spectrum antibiotics argue for brief treatment, but the risk of an inadequately treated infection in the granulocytopenic patient favors longer therapy. We prospectively studied 306 episodes of fever and granulocytopenia in 143 patients with leukemia or solid tumor (age one to 33 years) with respect to the duration of empiric antibiotic treatment. Eligible patients (fever > 38 °C three times/24 hours or > 38.5 °C once, plus polymorphonuclear leukocytes 3 ) had an extensive diagnostic evaluation, including at least two preantibiotic blood cultures, and therapy was then started with a broad-spectrum antibiotic regimen— Keflin ® , gentamicin and carbenicillin (KGC). Initial evaluation failed to identify an infectious etiology for the fever in 142 of 306 (46 per cent) episodes. Fifty-six of 142 (39 per cent) of these fevers of unknown origin were associated with persistent granulocytopenia for more than seven days; in 33 of these, defervescence occurred while the patients received KGC. After seven days of empiric KGC therapy, the 33 patients with fevers of unknown origin who had become afebrile with empiric antibiotics but whose polymorphonuclear leukocytes remained less than 500/mm 3 were randomized to either continue or discontinue (dc) to receive KGC. The patients who continued to receive KGC until their polymorphonuclear leukocytes were more than 500/mm 3 had no infectious sequelae. However, in seven of 17 (41 per cent) of the patients randomized to dc KGC infectious sequelae developed (p = 0.007) within a median of two days of discontinuing KGC (two with fever which again responded to KGC therapy, and five with a documented infection [two ultimately fatal]). In none of the patients did a resistant microbial flora or superinfection develop. These data suggest that the patient with a fever of unknown origin who becomes afebrile during empiric antibiotic therapy may profit from continued therapy while granulocytopenia persists.

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

Purpose:This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program’s application of genomic technology to establish diagnoses, and details the Program’s success rate during its first 2 years.Methods:Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.Results:Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.Conclusion:The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.Genet Med 2012:14(1):51–59

A RANDOMIZED PILOT STUDY OF SYSTEMIC IMMUNOSUPPRESSION IN THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION WITH CHOROIDAL NEOVASCULARIZATION

Background: Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. Methods: This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion: These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated.

Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS).

ALPS is a disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to marked lymphadenopathy, hepatosplenomegaly, and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in 12 patients, 9 children, and 3 adults, out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health.

The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience.

Purpose:Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants.Methods:Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data.Results:We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable.Conclusion:Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family.Genet Med 16 10, 741–750.

The relationship of fever, granulocytopenia and antimicrobial therapy to bacteremia in cancer patients

The relationship of fever, granulocytopenia, and antimicrobial thereapy to bacteremia was studied retrospectively in 53 cancer patients. Severe granulocytopenia was present at the time blood cultures were positive in 27 of 31 episodes of bacteremia. Twenty‐five episodes of bacteremia were documented before the initiation of antimicrobial therapy in patients who were granulocytopenic and febrile. No bacteremia occurred in the absence of fever. Only two bacteremias occurred while patients were receiving parenteral antimicrobials. Antimicrobial therapy was terminated 30 times in the presence of granulocytopenia and fever, and subsequent bacteremia occurred in 14 patients within 4 days. Patients who died with fungal disease did not receive more antibiotics than patients who died without fungal disease. These data suggest a rationale for long‐term use of antimicrobial therapy in patients with persistent granulocytopenia and fever.

IgG4-related disease presenting as recurrent mastoiditis

IgG4-related disease (IgG4-RD) is a recently recognized disorder characterized by an overabundance of IgG4-positive plasma cells in affected tissues and, frequently, elevated serum IgG4 levels. First recognized in the context of autoimmune pancreatitisi, IgG4-RD presents as either a localized area of involvement within a single organ or as a multicentric disease, affecting several organs. Those organs include the pancreas, gallbladder, salivary glands, retroperitoneum, kidneys, lungs, prostate, ocular adnexaii, maxillary sinus, ethmoid sinusiii, lacrimal glands, breast, liver, large blood vessels, mediastinum, lymph nodesiv, pituitaryv, esophagusvi, and dura matervii. The histopathology of IgG4-RD involves a lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. The disease process generally destroys the normal tissue architecture and replaces it with fibrotic tissue, creating a variety of histologic patterns. The appearance can be pseudolymphomatous (characterized by a dense infiltrate of small lymphocytes), sclerosing (characterized by fibrosis with some areas of lymphocyte aggregates), or mixed (characterized by fibrosis, plasma cells, and lymphocytic infiltrates)viii. IgG4-RD lesions can progress by infiltrating the surrounding tissues or by expanding as a space-occupying mass. The lesions are often exquisitely sensitive to glucocorticoids, but long-term, prospective therapeutic trials are lacking. We hereby describe a patient with IgG4-RD manifesting as recurrent inflammatory disease of the middle ear and mastoid, complicated by bone erosion.

Scleritis and multiple systemic autoimmune manifestations in chronic natural killer cell lymphocytosis associated with elevated TCRalpha/beta+CD3+CD4-CD8- double-negative T cells.

Background/aims Chronic natural killer lymphocytosis (CNKL) has been associated with systemic autoimmunity; however, its association with scleritis or ocular autoimmunity has not been characterised. The natural killer (NK) cell function and immunophenotype of a patient with CNKL who developed bilateral scleritis and multiple systemic autoimmune findings were evaluated. Methods The ophthalmic records of a patient with CNKL and scleritis were reviewed over a 6-year period. Flow cytometry was performed to evaluate T cell, NK and B cell populations. NK cellular functions (ie, NK cytotoxicity and cytokine/chemokine production following interleukin 2 (IL2) stimulation) were evaluated. Results A 56-year-old woman with vitiligo, psoriatic arthritis, thyroiditis, erythema nodosum, bilateral anterior scleritis and Sjogren syndrome was managed with multiple immunosuppressive medications, including prednisone, mycophenolate mofetil and methotrexate. Flow cytometry showed a persistent elevation of CD56+CD3− NK cells greater than 40%, which was consistent with CNKL. NK cell cytotoxicity assay identified a deficiency of K562 cell lysis in the patient (1.46 mean-fold greater in control vs patient). NK cytokine/chemokine production following IL2 stimulation was also deficient (2.5–32.5-fold greater in control). Cytokines/chemokines assessed included pro-inflammatory (interferon γ, tumor necrosis factor α, IL1, monocyte chemotactic protein 1) and immunoregulatory cytokines (IL4, IL5 and IL10). An abnormal elevation of TCRα/β+ CD3+CD4−CD8− T cells suggestive of autoimmune lymphoproliferative syndrome was observed; however, apoptosis dysfunction was not found. Conclusion The association of increased but dysfunctional NK cells in the context of multiple systemic and ocular manifestations suggests a role of NK cells in the pathogenesis of our patients disease. Further studies regarding NK cell dysfunction and ocular autoimmunity are needed.