Publications by authors named "Juan C Gea-Banacloche"

20 Publications

  • Page 1 of 1

Mild to moderate COVID-19 illness in adult outpatients: Characteristics, symptoms, and outcomes in the first 4 weeks of illness.

Medicine (Baltimore) 2021 Jun;100(24):e26371

Division of Infectious Diseases.

Abstract: Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness.At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness.We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms.Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.
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http://dx.doi.org/10.1097/MD.0000000000026371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213280PMC
June 2021

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections.

Blood Rev 2018 09 16;32(5):387-399. Epub 2018 Mar 16.

Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, United States.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies.
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http://dx.doi.org/10.1016/j.blre.2018.03.004DOI Listing
September 2018

Allogeneic T Cells That Express an Anti-CD19 Chimeric Antigen Receptor Induce Remissions of B-Cell Malignancies That Progress After Allogeneic Hematopoietic Stem-Cell Transplantation Without Causing Graft-Versus-Host Disease.

J Clin Oncol 2016 Apr 25;34(10):1112-21. Epub 2016 Jan 25.

Jennifer N. Brudno, Robert P.T. Somerville, Victoria Shi, Jeremy J. Rose, David C. Halverson, Daniel H. Fowler, Juan C. Gea-Banacloche, Steven Z. Pavletic, Dennis D. Hickstein, Tangying L. Lu, Steven A. Feldman, Alexander T. Iwamoto, Brenna G. Hansen, Bazetta Blacklock-Schuver, Frances T. Hakim, Steven A. Rosenberg, Ronald E. Gress, and James N. Kochenderfer, National Cancer Institute; Roger Kurlander and Irina Maric, National Institutes of Health, Bethesda; Jennifer S. Wilder, Frederick National Laboratory for Cancer Research, Frederick, MD; and Andre Goy, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ.

Purpose: Progressive malignancy is the leading cause of death after allogeneic hematopoietic stem-cell transplantation (alloHSCT). After alloHSCT, B-cell malignancies often are treated with unmanipulated donor lymphocyte infusions (DLIs) from the transplant donor. DLIs frequently are not effective at eradicating malignancy and often cause graft-versus-host disease, a potentially lethal immune response against normal recipient tissues.

Methods: We conducted a clinical trial of allogeneic T cells genetically engineered to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Patients with B-cell malignancies that had progressed after alloHSCT received a single infusion of CAR T cells. No chemotherapy or other therapies were administered. The T cells were obtained from each recipient's alloHSCT donor.

Results: Eight of 20 treated patients obtained remission, which included six complete remissions (CRs) and two partial remissions. The response rate was highest for acute lymphoblastic leukemia, with four of five patients obtaining minimal residual disease-negative CR. Responses also occurred in chronic lymphocytic leukemia and lymphoma. The longest ongoing CR was more than 30 months in a patient with chronic lymphocytic leukemia. New-onset acute graft-versus-host disease after CAR T-cell infusion developed in none of the patients. Toxicities included fever, tachycardia, and hypotension. Peak blood CAR T-cell levels were higher in patients who obtained remissions than in those who did not. Programmed cell death protein-1 expression was significantly elevated on CAR T cells after infusion. Presence of blood B cells before CAR T-cell infusion was associated with higher postinfusion CAR T-cell levels.

Conclusion: Allogeneic anti-CD19 CAR T cells can effectively treat B-cell malignancies that progress after alloHSCT. The findings point toward a future when antigen-specific T-cell therapies will play a central role in alloHSCT.
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http://dx.doi.org/10.1200/JCO.2015.64.5929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872017PMC
April 2016

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report.

Biol Blood Marrow Transplant 2015 Jul 31;21(7):1167-87. Epub 2015 Mar 31.

Blood and Marrow Transplantation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.

The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence.
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http://dx.doi.org/10.1016/j.bbmt.2015.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821166PMC
July 2015

The utility of bronchoalveolar lavage beta-D-glucan testing for the diagnosis of invasive fungal infections.

J Infect 2014 Sep 4;69(3):278-83. Epub 2014 May 4.

Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 9000 Rockville Pike, Building 10 CRC, Room 11C 102, Bethesda, MD 20892, USA. Electronic address:

Objectives: To investigate the utility of beta-D-glucan (BDG) testing in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive fungal infection (IFI), as compared to BAL galactomannan (GM).

Methods: We retrospectively reviewed medical records of 132 consecutive patients at the National Institutes of Health (NIH) in whom BAL BDG testing was performed for diagnosis of pneumonia. Using the European Organization for Research and Treatment of Cancer/Mycoses Study Group guidelines, we determined which patients had proven or probable IFI, and assessed the diagnostic performance of BAL BDG testing, relative to BAL GM. We also determined the reproducibility of the BDG assay in BAL via repeat testing of patient samples.

Results: Ten patients had Pneumocystis pneumonia, and 34 patients had proven/probable IFI, including 14 with invasive aspergillosis (IA). BAL BDG was 100% sensitive for Pneumocystis. Although BAL BDG had similar sensitivity to BAL GM for the diagnosis of IA and IFI, it exhibited inferior specificity. Repeat testing demonstrated poor reproducibility of the BDG assay in BAL but not in serum.

Conclusions: BDG testing exhibits poor specificity and reproducibility in BAL. Identification of the BAL-specific factors that may interfere with the performance of the assay could improve the clinical usefulness of BAL BDG testing.
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http://dx.doi.org/10.1016/j.jinf.2014.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127351PMC
September 2014

Clostridium difficile: deleterious impact on hematopoietic stem cell transplantation.

Curr Hematol Malig Rep 2014 Mar;9(1):85-90

Servicio de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain.

C. difficile infection (CDI), the most common cause of hospital-acquired diarrhea, is very frequent after hematopoietic stem cell transplantation (HSCT). Recent publications suggest it affects between 6 % and 20 % of HSCT recipients during the first year and is more common following allogeneic transplant (allo-HSCT). The best diagnostic strategy remains to be defined, but molecular testing for the toxin genes by polymerase chain reaction (PCR) seems to be replacing the traditional enzyme immunoassays (EIA). The higher sensitivity of the PCR may result in increased measured incidence of disease. C. difficile infection typically occurs during the first month after HSCT. Although the course of CDI after HSCT does not seem to be different than in other hospitalized patients, it may result in worsening of bowel graft versus host disease (GVHD) after allo-HSCT. Current evidence suggests a reciprocal effect by which GVHD may increase the risk of CDI and C. difficile disease may increase the risk of GVHD. Metronidazole was the treatment most commonly used in all recent series, followed by the combination metronidazole and oral vancomycin. There is minimal information on the use of fidaxomicin in HSCT recipients. Regarding stool transplant, there is one case report of successful use of this modality in an HSCT recipient. These two newer approaches will certainly be investigated in the future.
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http://dx.doi.org/10.1007/s11899-013-0193-yDOI Listing
March 2014

Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation.

Blood 2013 Dec 20;122(25):4129-39. Epub 2013 Sep 20.

Experimental Transplantation and Immunology Branch and.

New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation (alloHSCT). We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. T cells for genetic modification were obtained from each patient's alloHSCT donor. All patients had malignancy that persisted after alloHSCT and standard donor lymphocyte infusions (DLIs). Patients did not receive chemotherapy prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions. The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells. Three patients had regressions of their malignancies. One patient with chronic lymphocytic leukemia (CLL) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells, another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed, and a patient with mantle cell lymphoma obtained an ongoing partial remission. None of the 10 patients developed graft-versus-host disease (GVHD). Toxicities included transient hypotension and fever. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to standard DLIs without causing GVHD.
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http://dx.doi.org/10.1182/blood-2013-08-519413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862276PMC
December 2013

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation.

Neurology 2013 Apr 20;80(16):1494-500. Epub 2013 Mar 20.

National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USA.

Objective: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review.

Methods: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT.

Results: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT.

Conclusion: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research.
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http://dx.doi.org/10.1212/WNL.0b013e31828cf8a2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662358PMC
April 2013

Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation.

Blood 2013 Apr 20;121(15):2864-74. Epub 2013 Feb 20.

Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4(+) T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4(+) Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4(+) Th2 and Th1 cells relative to regulatory T cells and CD8(+) T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens.
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http://dx.doi.org/10.1182/blood-2012-08-446872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624934PMC
April 2013

National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis.

Biol Blood Marrow Transplant 2013 Apr 20;19(4):632-9. Epub 2013 Jan 20.

Pediatric Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA.

Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated (r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus ≤49 months, hazard ratio [HR] = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/μL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors.
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http://dx.doi.org/10.1016/j.bbmt.2013.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619213PMC
April 2013

Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome.

Blood 2011 Sep 13;118(10):2653-5. Epub 2011 Jun 13.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892-1684, USA.

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.
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http://dx.doi.org/10.1182/blood-2011-05-356352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172785PMC
September 2011

Rituximab-associated infections.

Semin Hematol 2010 Apr;47(2):187-98

Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.

After more than 10 years of use, rituximab has proven to be remarkably safe. However, accumulated evidence now suggests that under some circumstances it may significantly increase the risk of infections. This risk is difficult to quantify because of confounding factors (namely, concomitant use of immunosuppressive or chemotherapeutic agents and underlying conditions), as well as under-reporting. Increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by human immunodeficiency virus (HIV) infection or immunosuppressive agents like fludarabine. From the practical standpoint, the most important infection is hepatitis B reactivation, which may be delayed and result in fulminant liver failure and death. Special care should be placed on screening for hepatitis B virus (HBV) and preemptive antiviral treatment. Some investigators have reported an increase in Pneumocystis pneumonia. Finally, there is increasing evidence of a possible association with progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by the polyomavirus JC. This review enumerates the described infectious complications, summarizes the possible underlying mechanisms of the increased risk, and makes recommendations regarding prevention, diagnosis and management.
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http://dx.doi.org/10.1053/j.seminhematol.2010.01.002DOI Listing
April 2010

Improvements in the prevention and management of infectious complications after hematopoietic stem cell transplantation.

Cancer Treat Res 2009 ;144:539-73

Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1007/978-0-387-78580-6_21DOI Listing
September 2010

Sepsis caused by Elizabethkingia miricola successfully treated with tigecycline and levofloxacin.

Diagn Microbiol Infect Dis 2008 Dec 7;62(4):430-2. Epub 2008 Oct 7.

Department of Internal Medicine, New York Hospital Queens/Weill-Cornell Medical College, Flushing, NY 11355, USA.

Elizabethkingia miricola is a Gram-negative rod that was initially isolated from condensation water of the space station Mir. This is the 1st reported case of human disease caused by this organism.
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http://dx.doi.org/10.1016/j.diagmicrobio.2008.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650818PMC
December 2008

Monoclonal antibody therapeutics and risk for infection.

Pediatr Infect Dis J 2007 Nov;26(11):1049-52

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1097/INF.0b013e31815a044fDOI Listing
November 2007

Antibacterial prophylaxis reduced the incidence of fever in patients receiving chemotherapy for solid tumors or lymphoma.

ACP J Club 2006 Mar-Apr;144(2):42

National Institutes of Health, Bethesda, Maryland, USA.

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March 2006

Sepsis associated with immunosuppressive medications: an evidence-based review.

Crit Care Med 2004 Nov;32(11 Suppl):S578-90

National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Objective: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for sepsis associated with immunosuppressive medications that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.

Design: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee.

Methods: The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591.

Conclusion: Immunosuppressed patients, by definition, are susceptible to a wider spectrum of infectious agents than immunologically normal patients and, thus, require a broader spectrum antimicrobial regimen when they present with sepsis or septic shock. Special expertise managing immunosuppressed patient populations is needed to predict and establish the correct diagnosis and to choose appropriate empiric and specific agents and maximize the likelihood that patients will survive these microbial challenges.
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http://dx.doi.org/10.1097/01.ccm.0000143020.27340.ffDOI Listing
November 2004

Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer.

J Clin Oncol 2004 Oct 16;22(19):3886-92. Epub 2004 Aug 16.

Experimental Transplantation and Immunology Branch, Center for Cancer Research/National Cancer Institute/National Institutes of Health, Building 10, Room 12N226, Bethesda, MD 20892, USA.

Purpose: Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen-matched siblings.

Patients And Methods: Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 x 10(6), 5 x 10(6), and 10 x 10(6) CD3(+) cells/kg were infused on days +42, +70, and +98 post-allogeneic HSCT, respectively.

Results: Objective tumor regressions occurred after day +28 post-allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post-allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD.

Conclusion: Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease.
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http://dx.doi.org/10.1200/JCO.2004.01.127DOI Listing
October 2004

Clinical pharmacology of antifungal compounds.

Infect Dis Clin North Am 2003 Mar;17(1):159-91, ix

Infectious Disease Research Program, Center for Bone Marrow Transplantation, Department of Pediatric Hematology/Oncology, Wilhelms-University Medical Center, Domagkstrasse 9a, 48149 Muenster, Germany.

Prompted by the worldwide surge in fungal infections, the past decade has witnessed a considerable expansion in antifungal drug research. New compounds have entered the clinical arena, and major progress has been made in defining paradigms of antifungal therapies. This article provides an up-to-date review on the clinical pharmacology, indications, and dosage recommendations of approved and currently investigational therapeutics for treatment of invasive fungal infections in adult and pediatric patients.
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http://dx.doi.org/10.1016/s0891-5520(02)00068-5DOI Listing
March 2003