Granulocyte macrophage colony-stimulating factor in 66 patients with myeloid or lymphoid neoplasms and recipients of hematopoietic stem cell transplantation with invasive fungal disease.

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Safdar A, Rodriguez G, Zuniga J, Al Akhrass F, Georgescu G, Pande A.

Acta Haematol. 2013;129(1):26-34.

ABSTRACT

BACKGROUND/AIMS: Adding granulocyte macrophage colony-stimulating factor (GM-CSF) may improve the response to antifungal therapy in immunosuppressed patients with invasive fungal disease (IFD).

METHODS: We retrospectively assessed 66 patients in whom GM-CSF was given during antifungal therapy.

RESULTS: Severe neutropenia (77%) and refractory/relapsed cancer (65%) were common in the group. Prior to GM-CSF therapy, 15% of patients received high-dose corticosteroids for a median of 30 ± 16 days [median cumulative dose (c.d.) 1,184 ± 1,019 mg], and 9 received steroids during GM-CSF therapy for a median of 16 ± 12 days (median c.d. 230 ± 1,314 mg). Mild toxic effects were noted in 9% of patients; there were no cases of cardiopulmonary toxicity. All-cause deaths were observed in 68% of patients and 48% died of progressive IFD. High-dose corticosteroids prior to GM-CSF (OR 24; 95% CI 2.21-264.9; p ≤ 0.009), GM-CSF started in the intensive care unit (OR 10; 95% CI 1.66-63.8; p ≤ 0.01), concurrent granulocyte transfusions (OR 5; 95% CI 1.27-16.8; p ≤ 0.02) and proven/probable IFD (OR 4; 95% CI 1-16.2; p ≤ 0.05) predicted antifungal treatment failure.

CONCLUSIONS: GM-CSF adjuvant therapy was tolerated without serous toxicity and antifungal treatment failure remained a challenge in patients treated with high-dose systemic corticosteroids.

Copyright © 2012 S. Karger AG, Basel.

 

Baculovirus-expressed influenza vaccine. A novel technology for safe and expeditious vaccine production for human use.

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Safdar A, Cox MM.

Expert Opin Investig Drugs. 2007 Jul;16(7):927-34. Review.

Abstract

Effectiveness of the influenza vaccine in persons with high-risk conditions needs to be improved. In this paper, the authors review various vaccination strategies, including repeated doses of the vaccine or the use of higher hemagglutinin (HA) content vaccines that have been shown to result in improved immunogenicity. A recombinant HA vaccine produced in insect cells using the baculovirus vectors system presents the possibility for safe and expeditious vaccine production. The high purity of the antigen enables administration at much higher doses without a significant increase in side effects in human subjects. An overview of the use of this production system for the development of alternative influenza vaccine targets is also provided, such as neuraminidase and possibly M2. However, the role of M2 may be more appropriate as an adjuvant vaccine in combination with standard HA vaccine supplement and needs further evaluation. The conclusion that the insect cell-baculovirus production technology is a modern solution for rapid viral or parasitic antigen production is made and that this technology is particularly suitable for influenza where annual adjustment of the vaccine is required. In addition, a highly purified recombinant protein vaccine results in an improved influenza vaccine response in those with high-risk medical conditions.

Antifungal immunity and adjuvant cytokine immune enhancement in cancer patients with invasive fungal infections.

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Safdar A.

Clin Microbiol Infect. 2007 Jan;13(1):1-4. Review.

Abstract

Invasive fungal infections are common in severely immunosuppressed patients with cancer and in recipients of haematopoietic transplants. Response to antifungal therapy alone is often inadequate. Pro-inflammatory cytokines are critical for promoting innate and adaptive cellular antifungal immune responses. Recombinant cytokines, including granulocyte-macrophage-colony stimulating factor and interferon-gamma, have been studied as adjuvant therapies for severely immunosuppressed cancer patients with difficult-to-treat invasive mycoses. The limited clinical experience to date shows a possible benefit of these cytokines, and further controlled clinical trials are needed to validate their routine use in cancer patients and stem-cell transplant recipients with invasive fungal infections who are likely to have a poor response to antifungal drug therapy.

Polymicrobial infection in patients with cancer: an underappreciated and underreported entity.

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Rolston KV, Bodey GP, Safdar A.

Clin Infect Dis. 2007 Jul 15;45(2):228-33. Epub 2007 Jun 4. Review.

Abstract

Polymicrobial infections account for ~15% of infections in immunocompromised patients with cancer. However, limited information exists regarding the spectrum and microbiology of these infections, even in severely neutropenic patients. Most studies describe only monomicrobial bloodstream infections in detail, and information regarding polymicrobial infections and nonbacteremic infections is often incomplete or not provided at all. The current lack of well-established definitions for various infections in the immunocompromised host, including pneumonia, neutropenic enterocolitis, and polymicrobial infections, probably plays an important role in the paucity of published information. In this review, we briefly describe the limited information available regarding polymicrobial infections in patients with cancer and address the need for establishing consensus definitions for site-specific polymicrobial infections in neutropenic and nonneutropenic patients. We anticipate that, as factual information regarding such infections becomes available, a more comprehensive understanding of the true scope and impact of these infections will emerge, leading to appropriate modifications in the diagnostic work-up and in the therapeutic approaches used in treating these patients.

 

Stenotrophomonas maltophilia pneumonia in cancer patients without traditional risk factors for infection, 1997-2004.

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Aisenberg G, Rolston KV, Dickey BF, Kontoyiannis DP, Raad II, Safdar A.

Eur J Clin Microbiol Infect Dis. 2007 Jan;26(1):13-20.

Abstract

In order to elucidate the spectrum of Stenotrophomonas maltophilia pneumonia in cancer patients without traditional risk factors, 44 cancer patients (cases) with S. maltophilia pneumonia in whom S. maltophilia pneumonia risk factors were not present were compared with two S. maltophilia pneumonia risk groups (controls) including 43 neutropenic non-intensive care unit (ICU) and 21 non-neutropenic ICU patients. The case and control patients had similar demographic and underlying clinical characteristics. Compared with case patients with S. maltophilia pneumonia, neutropenic patients had higher exposure to carbapenem antibiotics (58 vs. 41%; p < 0.03), more frequent hematologic malignancy (95 vs. 64%; p < 0.0003), and they presented with concurrent bacteremia more often (23 vs. 0%; p < 0.0005). Patients with S. maltophilia pneumonia in the ICU needed vasopressor therapy more frequently than cases (62 vs. 5%; p < 0.0001). Hospital-acquired S. maltophilia pneumonia was more common among controls than cases (98 vs. 61%; p < 0.000002). Among the cases, 15 (34%) received outpatient oral antimicrobial therapy, while 29 were hospitalized and eight (28%) were subsequently admitted to the ICU. The mean duration of ICU stay, even among these eight patients (19 +/- 40 days), was comparable to that of patients with neutropenia (23 +/- 26 days) and those who developed S. maltophilia pneumonia during their ICU stay (34 +/- 22 days; p = 0.46). The overall infection-associated mortality in the 108 patients with S. maltophilia pneumonia was 25%. Twenty percent of patients without traditional risk factors for S. maltophilia pneumonia died due to progressive infection. In a multivariate logistic regression analysis, only admission to the ICU predicted death (odds ratio 33; 95% confidence interval, 4.51-241.2; p < 0.0006). The results of this study indicate S. maltophilia pneumonia is a serious infection even in non-neutropenic, non-ICU patients with cancer.

High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation.

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Safdar A, Rodriguez G, Rolston KV, O’Brien S, Khouri IF, Shpall EJ, Keating MJ, Kantarjian HM, Champlin RE, Raad II, Kontoyiannis DP.

Bone Marrow Transplant. 2007 Feb;39(3):157-64.

Abstract

Pneumocandins have concentration-dependent antifungal activity and higher dose of caspofungin (HD-CAP) in combination with other licensed antifungal therapy (OLAT) may improve response. Thirty-four patients who received HD-CAP were compared with 63 patients who received standard dose (SD)-CAP. There were no differences between the groups in either patient or disease characteristics. Significantly more patients in the HD-CAP arm had extrapulmonary infections (29 vs 8% in SD group; P=0.0053), and non-Aspergillus species infection (21 vs 6%; P=0.05) and had received prior antifungal therapy (71 vs 33%; P=0.0004). No serious adverse reactions were noted in patients receiving HD- or SD-CAP therapy. Twelve weeks after treatment commenced 44% had a complete or partial response compared with 29% in SD-CAP group (P=0.1). Logistic regression analysis showed a significant probability of a favorable outcome at 12 weeks in patients who received HD-CAP (OR 3.066, 95% CI, 1.092-8.61; P=0.033). This may in part reflect higher number of patients in HD group had received granulocyte-macrophage colony-stimulating factor (41 vs 14% in SD group; P=0.04) and/or interferon gamma (26 vs 5% in SD group; P=0.003) immune enhancement. Further studies are needed to evaluate efficacy of HD-CAP in severely immunosuppressed cancer patients with invasive fungal infections.

Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine-breakthrough infections, 1989-2005.

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Youssef S, Rodriguez G, Rolston KV, Champlin RE, Raad II, Safdar A.

Medicine (Baltimore). 2007 Mar;86(2):69-77.

Abstract

Streptococcus pneumoniae infections can cause serious systemic disease in patients following hematopoietic stem cell transplantation (HSCT), and the response to pneumococcal vaccine is inadequate in most HSCT recipients. We evaluated the clinical spectrum of pneumococcal disease and vaccine-breakthrough infections in HSCT recipients at our cancer center in a retrospective analysis of all consecutive episodes of S. pneumoniae infection from 1989 through 2005. During the study period, 7888 patients underwent HSCT at our center; we identified 47 HSCT recipients with 54 S. pneumoniae infections. The overall incidence of S. pneumoniae infection was 7 per 1000 HSCTs. The incidence was higher in recipients of allogeneic grafts than in recipients of autologous grafts (9 vs. 5 per 1000 HSCTs, respectively; p <or= 0.012). Thirty-two of the 47 patients (68%) had leukemia or lymphoma; 24 patients (51%) had a malignancy that was in complete remission. Seventeen patients (36%) had graft-versus-host disease, which was chronic in 16. The 54 episodes of S. pneumoniae infection occurred 433 +/- 669 days after HSCT; 5 patients (11%) had multiple episodes. Four episodes of S. pneumoniae infection occurred within 100 days following transplantation (45 +/- 49 d); 2 of these were during the pre-engraftment period and 3 were nosocomial infections. All 50 late post-transplant episodes (93%), which occurred 473 +/- 671 days following transplantation, were community-acquired infections (p < 0.00016). Thirty-three episodes (61%) presented as bacteremic pneumonia, 10 (19%) as pneumonia, and 8 (15%) as uncomplicated S. pneumoniae bacteremia alone. Logistic regression analysis showed that patients receiving systemic corticosteroids had increased risk for bacteremic pneumonia (odds ratio [OR], 11.7; 95% confidence intervals [CI], 1.371-99.280; p <or= 0.025). Patients with lymphoma (OR, 6.101; 95% CI, 1.106-33.640; p <or= 0.04) were more likely to develop pneumonia alone. In 27 episodes (93%) among 29 in which S. pneumoniae susceptibility testing was performed, the patients received concordant antimicrobials. Among the 6 patients (13%) who died of S. pneumoniae infection, 4 had S. pneumoniae bacteremic pneumonia and only 1 had chronic GVHD. Admission to a critical care unit at the onset of infection (OR, 15.5; 95% CI, 2.116-113.541; p <or= 0.007) and each unit increase in APACHE II score increase the probability of death (OR, 1.9; 95% CI, 1.181-3.054; p <or= 0.008). All 5 (11%) patients who developed vaccine-breakthrough S. pneumoniae infection (546 +/- 732 d following vaccination) had pneumonia, and in 4 patients concurrent bacteremia also occurred. A serious S. pneumoniae infection in HSCT recipients occurred more commonly in patients with lymphoma and patients receiving high-dose systemic corticosteroid therapy. It is noteworthy that there were no cases of extrapulmonary organ infection in HSCT recipients who presented with S. pneumoniae infection at our institution.

Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study.

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Chemaly RF, Torres HA, Aguilera EA, Mattiuzzi G, Cabanillas M, Kantarjian H, Gonzalez V, Safdar A, Raad II.

Clin Infect Dis. 2007 Apr 1;44(7):964-7. Epub 2007 Feb 14.

Abstract

We reviewed the records of 33 patients with leukemia who experienced influenza during the period from October 2000 to March 2004. Three (38%) of the 8 patients who did not receive neuraminidase inhibitor therapy and none of the 25 patients who received it died of influenza pneumonia (P=.001). The use of neuraminidase inhibitor therapy seems to improve the outcome of influenza in patients with leukemia.

Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006.

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Lamaris GA, Chamilos G, Lewis RE, Safdar A, Raad II, Kontoyiannis DP.

Clin Infect Dis. 2006 Dec 15;43(12):1580-4. Epub 2006 Nov 9.

Abstract

We reviewed the records of patients with cancer who had Scedosporium infection (due to Scedosporium apiospermum and Scedosporium prolificans in 21 and 4 patients, respectively). The incidence of Scedosporium infection increased from 0.82 cases per 100,000 patient-inpatient days (in 1993-1998) to 1.33 cases per 100,000 patient-inpatient days (in 1999-2005). Cases of S. prolificans infection occurred only after 2000. Dissemination occurred in 16 patients (64%). The 12-week mortality rates were 70% and 100% for S. apiospermum and S. prolificans infection, respectively.

Oral topical cidofovir: novel route of drug delivery in a severely immunosuppressed patient with refractory multidrug-resistant herpes simplex virus infection.

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Sims CR, Thompson K, Chemaly RF, Shpall EJ, Champlin RE, Safdar A.

Transpl Infect Dis. 2007 Sep;9(3):256-9. Epub 2007 Jul 1.

Abstract

We present a case of serious treatment-refractory acyclovir- and foscarnet-resistant herpes simplex virus (HSV) type-1 orolingual infection that responded to oral cidofovir rinses after failure of acyclovir and foscarnet therapy. The use of 3% cidofovir in a saline rinse for refractory mucosal HSV infection appears promising but needs prospective evaluation.