Fatal cytomegalovirus pneumonia in patients with haematological malignancies: an autopsy-based case-control study.

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2008 Dec;14(12):1160-6.

Abstract

Cytomegalovirus (CMV) pneumonia is a life-threatening infection in patients with haematological malignancies (HMs) or in haematopoietic stem cell transplant (HSCT) recipients. To assess the incidence and risk factors for developing fatal CMV pneumonia in these patients, a case-control study based on 999 autopsies was performed at The University of Texas M. D. Anderson Cancer Center, Houston, Texas (January 1990 to December 2004). Twenty-five cases (patients who died with CMV pneumonia) were matched with 34 controls (patients who died without CMV pneumonia) by type of HM or HSCT, year of autopsy, age and gender. The incidence of CMV pneumonia declined between January 1990 to June /1997 and July 1997 to December 2004 (CMV pneumonia rates were 22/620 and 3/379 autopsies, respectively; p 0.006). Logistic regression analysis identified complete remission and sustained lymphopenia as independent predictors of CMV pneumonia (all p <0.05). The incidence of fatal CMV pneumonia has decreased over the last 15 years, which might reflect earlier diagnosis or the use of pre-emptive therapy or more effective preventive strategies. Complete remission of an HM does not preclude the development of CMV pneumonia among patients with prolonged lymphopenia.

Herpes simplex virus lower respiratory tract infection in patients with solid tumors.

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Aisenberg GM, Torres HA, Tarrand J, Safdar A, Bodey G, Chemaly RF.

2009 Jan 1;115(1):199-206.
Abstract

BACKGROUND:

The clinical significance of herpes simplex virus (HSV) isolated in lower respiratory tract specimens (LRTS) of patients with solid tumors (ST) is unknown. In the current study, the authors attempted to determine the clinical relevance of this finding among ST patients.

METHODS:

The authors reviewed records of ST patients admitted to the study institution between April 2000 and April 2004 with clinical and radiologic evidence of pneumonia, and HSV identified in LRTS by culture alone or culture and cytology. Patients were categorized as having proven (HSV identified by culture and cytology from the LRTS), probable (HSV as the sole pathogen by culture alone), and possible (HSV along with copathogens identified by culture) HSV pneumonia.

RESULTS:

Forty-five ST patients with either proven (6 patients), probable (25 patients), or possible (14 patients) HSV pneumonia were identified. When compared with patients with probable or possible HSV pneumonia, more patients with proven infection were on mechanical ventilation (40% vs 50% vs 100%, respectively; P=.03), and had longer length of stay in the intensive care unit (12 days vs 13 days vs 26 days, respectively; P=.05). The overall mortality rate was 22% (10 patients). Four of 25 (16%) patients who received HSV-directed antiviral therapy died during their hospital stay versus 6 of 20 (30%) who were not treated (P=.3). None of the 6 patients with proven HSV pneumonia who were treated with acyclovir died. On univariate analysis, risk factors for mortality included underlying breast cancer, an Acute Physiology and Chronic Health Evaluation (APACHE) II score>15, admission to the intensive care unit, and use of mechanical ventilation and vasopressors (all P<or=.05), with underlying breast cancer and APACHE II score>15 being found to be independent predictors of death by multiple logistic regression analysis (all P<or=.05).

CONCLUSIONS:

Having a proven HSV pneumonia appears to be associated with high morbidity and with no increase in mortality in ST patients. This subset of patients appears to benefit from acyclovir therapy.

Copyright (c) 2008 American Cancer Society.

De novo T-lymphocyte responses against baculovirus-derived recombinant influenzavirus hemagglutinin generated by a naive umbilical cord blood model of dendritic cell vaccination.

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2009 Mar 4;27(10):1479-84.
Abstract

Cancer patients and recipients of hematopoietic stem cell transplantation exhibit a negligible response to influenza vaccine. Toward the goal of addressing this issue, we developed an in vitro model of dendritic cell (DC) immunotherapy utilizing DCs generated from naïve umbilical cord blood (UCB). UCB DCs were loaded with purified rHA protein and used to stimulate autologous T-lymphocytes. Upon recall with HA-loaded autologous DC, a 4-10-fold increase in the number of IFN-gamma producing T-lymphocytes was observed in comparison to T-cells stimulated with control DCs. Antigen-specific T-cell functionality was determined by (51)Cr lytic assay. Using a peptide library of predicted HA binding epitopes, we mapped an HA-specific, DR15-restricted CD4 T-cell epitope and observed tetramer positive cells. This model demonstrates that HA-specific immune responses might possibly be generated in a de novo fashion and suggests that dendritic cell immunotherapy for the prevention of influenza in populations of immunosuppressed individuals could be feasible.

Fungal cytoskeleton dysfunction or immune activation triggered by beta-glucan synthase inhibitors: potential mechanisms for the prolonged antifungal activity of echinocandins.

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2009 Jul 1;115(13):2812-5.

Inhaled therapeutics for prevention and treatment of pneumonia.

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Safdar A, Shelburne SA, Evans SE, Dickey BF.

Expert Opin Drug Saf. 2009 Jul;8(4):435-49.

 

The lungs are the most common site of serious infection owing to their large
surface area exposed to the external environment and minimum barrier defense.
However, this architecture makes the lungs readily available for topical therapy.
Therapeutic aerosols include those directed towards improving mucociliary
clearance of pathogens, stimulation of innate resistance to microbial infection,
cytokine stimulation of immune function and delivery of antibiotics. In our
opinion inhaled antimicrobials are underused, especially in patients with
difficult-to-treat lung infections. The use of inhaled antimicrobial therapy has
become an important part of the treatment of airway infection with Pseudomonas
aeruginosa in cystic fibrosis and the prevention of invasive fungal infection in
patients undergoing heart and lung transplantation. Cytokine inhaled therapy has
also been explored in the treatment of neoplastic and infectious disease. The
choice of pulmonary drug delivery systems remains critical as air-jet and
ultrasonic nebulizer may deliver sub-optimum drug concentration if not used
properly. In future development of this field, we recommend an emphasis on the
study of the use of aerosolized hypertonic saline solution to reduce pathogen
burden in the airways of subjects infected with microbes of low virulence,
stimulation of innate resistance to prevent pneumonia in immunocompromised
subjects using cytokines or synthetic pathogen-associated molecular pattern
analogues and more opportunities for the use of inhaled antimicrobials. These
therapeutics are still in their infancy but show great promise.

Infections in non-myeloablative hematopoietic stem cell transplantation patients with lymphoid malignancies: spectrum of infections, predictors of outcome and proposed guidelines for fungal infection prevention.

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Safdar A, Rodriguez GH, Mihu CN, Mora-Ramos L, Mulanovich V, Chemaly RF, Champlin RE, Khouri I.

Bone Marrow Transplant. 2010 Feb;45(2):339-47.

The overall risk of infections is lower in patients undergoing non-myeloablative allogeneic stem cell transplantation (NST) than in conventional stem cell transplant recipients. We sought to evaluate conditions associated with increased
risk of infections after NST. In 81 patients, 187 infection episodes were noted; chronic lymphocytic leukemia (138 episodes/100 person-years) and recipients of matched unrelated donor graft (128 episodes/100 person-years) had higher risk of
infection. Only half of the cytomegalovirus (CMV) infections occurred 31-100 days after transplantation. Most patients with CMV infection were non-neutropenic (100%), had lymphoma (76%), were younger (<55 years; 72%) and had received matched related donor (MRD) graft (72%). However, graft-versus-host disease (GVHD) was present in only 15% of these patients. Seven (78%) of nine invasive fungal infections (IFI) were diagnosed >100 days after NST and were associated
with high mortality (78%). Most patients with IFI were also not neutropenic (100%), had received MRD graft (100%), had lymphoma (78%) and were given systemic steroids (78%); unlike CMV infection, 67% of these patients also had GVHD. On the
basis of our results, we propose that NST recipients with lymphoma treated with high-dose corticosteroids for GVHD be considered for antifungal prophylaxis or pre-emptive antifungal therapy.

Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley’s legacy revisited.

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Decker WK, Safdar A.

Cytokine Growth Factor Rev. 2009 Aug;20(4):271-81.

 

In the nineteenth century, William B. Coley induced durable remission of inoperable metastatic sarcoma by repeatedly injecting live streptococcus bacilli  and, subsequently, heat-killed bacterial extracts into the primary tumor. While Coley’s contemporaries debated the veracity of his results, this bold treatment protocol established the new scientific field of immunology. In Coley’s era, the scientific and medical communities lacked the prerequisite knowledge to validate  and understand his treatment protocols. Today, a more comprehensive understanding of the human immune system, anchored by the discovery of the mammalian Toll-like  receptor gene family in the 1990s, permits a mechanistic understanding of his results. Coley’s cocktail of TLR agonists likely stimulated a complex cascade of  cytokines, each of which plays a unique and vital role in the orchestration of the immune response. Here we explore Coley’s legacy: a dissection of those cytokines which possess the immunostimulatory properties necessary to modulate the immune system and ameliorate human disease. The discussion is limited to molecules that have been able to show therapeutic promise in the clinical setting.

Recent favorable outcomes in critically ill patients with cancer may mitigate historic acquiescent optimism in critical care unit therapy.

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2010 Jan;38(1):293-4. doi: 10.1097/CCM.0b013e3181bfeabc.
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Immunomodulation Therapy for Invasive Aspergillosis: Discussion on Myeloid Growth Factors, Recombinant Cytokines, and Antifungal Drug Immune Modulation.

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Safdar A.

Curr Fungal Infect Rep. 2010 Mar;4(1):1-7.

Understanding fungal pathogenesis and host-pathogen immune interaction at various stages of infection is critical to examine strategies for bolstering antifungal immune defenses. Recombinant myeloid growth factors, especially granulocyte-macrophage colony-stimulating factor and the protagonist T helper (Th) 1 cytokine, interferon-γ, are most frequently used in patients with refractory invasive aspergillosis. These cytokines are given alone or in combination and have also been used together in neutropenic patients receiving donor granulocyte transfusions. Recently, a number of investigators have presented provoking data regarding auxiliary effect of conventional antifungal drugs on hosts’ immune response and pathogen’s susceptibility for antifungal immune defenses. Antifungal immunotherapy and its ameliorative role in treatment for Aspergillus disease will need clinical trials that 1) consider well-characterized fungal disease; 2) illustrate underlying immune defect(s) (such as Th1 vs Th2, vs Th17 and functional status of natural killer and effector scavenger cells); 3) include a more specific patient population; 4) include standardized antifungal drug therapy; and importantly 5) consider its impact on
hosts’ immune response and changes in pathogen’s susceptibility and virulence. At present, immunotherapy is reserved for patients with life-threatening invasive fungal disease in whom conventional antifungal drug therapy has failed, or for patients with advanced fungal disease and with factors associated with high probability of failure of conventional therapy alone.

 

Feasibility of aerosolized colistin in the era of escalating drug-resistant Pseudomonas pneumonia: pressing need for validation clinical trials.

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2010 Jul;36(7):1110-1. doi: 10.1007/s00134-010-1883-8. Epub 2010 Apr 16.

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