Use In Immunocompromised Patients Research Articles

Clinical outcomes of immunomodulation therapy in immunocompromised patients with severe Covid-19 and high oxygen requirement

Covid-19 disease is implicated in increased mortality among immunocompromised patients. The JAK inhibitor, baricitinib (bar), or the IL-6 inhibitor, tocilizumab (toc), demonstrated a survival benefit in patients with severe disease.However, evidence supporting their use in immunocompromised patients with severe Covid-19 is scarce.We aimed to assess clinical outcomes of bar/toc treatment in immunocompromised patients. A multi-center registry of consecutive immunocompromised patients hospitalized due to severe Covid-19 during the Omicron variant dominance period. After excluding patients who did not require high oxygen supply, patients treated with bar/toc were compared to patients treated by standard of care (SOC). Primary outcome was in hospital mortality. Secondary outcomes were 30 and 60 day mortality, super-infection and thromboembolic events. Among an overall 228 immunocompromised patients hospitalized in six Israeli hospitals with severe Covid-19, 112 patients required high oxygen support, of whom 48 (43%) were treated with bar/toc. In-hospital mortality rates were exceptionally high and did not significantly differ between bar/toc and SOC treated patients (62.5% vs. 64.1%, p = 1.0). A logistic regression analysis revealed that advanced age and incomplete vaccination were predictors of in-hospital mortality. Patients treated with bar/toc had no excess of suspected super-infection (62.8% vs. 60.7%, p = 0.84) or thromboembolic events (8.3% vs 3.1%, p = 0.39). In immunocompromised patients with severe Covid-19 and a high oxygen demand, bar/toc therapy was not associated with reduced mortality or with a higher rate of associated complications, compared to SOC. Larger prospective studies should better address efficacy and safety.

AZD7442 utilization for Pre-Exposure Prophylaxis Against COVID-19 in a French Early Access Program

Abstract Background AZD7442, a combination of 2 neutralizing antibodies, has been shown to reduce symptomatic COVID-19 risk by 83% at 6 months among high-risk individuals in a Phase 3 trial (PROVENT). The French Health Authorities authorized AZD7442 use in immunocompromised patients through Early Access Program (EAP). Eligibility for EAP was serological anti-spike levels of < 260 BAU/ml and very high risk of severe COVID. This abstract aims to describe the AZD7442 eligible population in France and characterize AZD7442 uptake in the EAP. Methods This is a retrospective observational database analysis of the EAP data. Demographics, and clinical characteristics of participants are described. Results 27,782 patients were included in the EAP between 12/15/2021 and 11/30/2022. AZD7442 was mostly prescribed by onco-hematologists (24.2%), followed by nephrologists (19.9%), internal medicine specialists (15.6%), and rheumatologists (6.5%). 50% of participants were over 65 years, 54.7% were male. The majority (96.7%) had received at least three vaccine doses at inclusion. Most common comorbidities were cancer (34.9%), chronic kidney disease (23.7%), hypertension (23.2%), cardiovascular disease (19.4% >2CV factors), and diabetes (9.2%). 6 months follow-up data were available for 2106 patients. Conclusions In the EAP, health care professionals prioritized IC patients at the highest risk of severe COVID-19, consistent with the authorization granted in France. However, based on the approved criteria, HCP have the potential to broaden the use of AZD7442 among different IC groups which can lead to more equitable access. The large size of the EAP presents an opportunity to generate evidence regarding the effectiveness of AZD7442. Lack of follow up data highlights the need to enrich the EAP data to study relevant effectiveness endpoints as COVID-19 hospitalizations and mortality. An innovative observational comparative study is planned by combining EAP data and French National Claims database SNDS. Key messages • These findings could guide future efforts to implement COVID-19 prophylaxis measures. • The large size of the EAP presents an opportunity to generate evidence regarding the effectiveness of AZD7442.

In-vivo and human evidence for potential efficacy of therapeutic polyclonal RSV neutralizing antibodies for palivizumab-resistant RSV infections

BackgroundMonoclonal antibody (palivizumab), intravenous immune globulin (IGIV), or respiratory syncytial virus (RSV)-polyclonal-hyperimmune-globulin (RSV-IG as Respigam®, RI-001, RI-002) are used with ribavirin in RSV-infected immunocompromised patients, with debated efficacy. Palivizumab-resistance (PR) can arise during treatment of persistent infections in this population. RSV-IG may confer benefit in PR-RSV infection. MethodsRSV-IG [RI-001] was provided for an immunocompromised infant with RSV-pneumonitis refractory to ribavirin and palivizumab. RSV-neutralizing antibody, respiratory RSV load (qPCR), and F-gene-sequence-detection of PR was determined. Prophylactic RSV-IG [RI-002] or palivizumab was administered in a cotton-rat model infected with wild-type and PR-RSV. Lung RSV load and neutralizing antibody were measured. ResultsAs protective RI-001-neutralizing antibody titers waned in the infant, a subpopulation of PR-escape mutants were detected with a fatal RSV-burden in the lungs. In PR-RSV-infected cotton rats, prophylactic RI-002 reduced RSV-load in the lungs (2.45 vs 0.28 log10 PFU/g lung-tissue reduction, respectively, p < 0.05) and provided protective RSV-neutralizing antibody. ConclusionsRSV-IG and ribavirin use in immunocompromised patients requires further study.

Role of Polymerase Chain Reaction-Based Diagnosis of Respiratory Viruses in Febrile Neutropenic Patients.

Background Neutropenic patients are commonly affected by respiratory infections, whereas respiratory viral infections causing high morbidity and mortality are routinely diagnosed in developing countries like India. Our study aimed to investigate the prevalence of respiratory viral infections in pediatric cancer patients with febrile neutropenia. Methods This prospective study was performed on 45 neutropenia patients with hematological malignancies. Nasal swabs were collected and analyzed by real-time multiplex polymerase chain reaction (PCR), covering the following viruses: influenza A virus, influenza B virus, human parainfluenza virus (subtypes 1-4), human respiratory syncytial virus A and B, enterovirus, human-coronavirus (HCoV: HKU1, NL63, 229E, and OC43), human bocavirus, adenovirus, human rhinovirus, human-metapneumovirus A and B, human paraechovirus, and a bacteriumMycoplasma pneumoniae. Patients enrolled in the study since the COVID-19 pandemic was also detected for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results Of the 45 cases included in our study, 26 cases showed the presence of at least one positivity by PCR (57.7%): 23 patients had monoinfection with only one virus, two patients were found positive for coinfection with two viruses, and one patient was found positive for three viruses. The most detected viruses were human rhinovirus (26.9%, n=7) and coronavirus 19 (19.2%, n=5). A total of 11.5% of the patients had multiple viral infections. About 19 (42.2%) of the patients enrolled in our study had no viral pathogen detected. Conclusion We found that respiratory viruses contribute significantly to the development of neutropenic fever, as evidenced by the results of our prospective study. Individualizing infection treatment can reduce antibiotic use in immunocompromised patients. Thus, routine screening for viremia may be warranted in this clinical setting.

633. Eravacycline Use in Immunocompromised Patients: Multicenter Evaluation of Clinical and Safety Endpoints

Abstract Background Infections caused by multidrug-resistant (MDR) bacteria are an increasingly common public health threat associated with worse outcomes in immunocompromised patients. Eravacycline (ERV) has potent in-vitro activity against MDR Gram-negative and Gram-positive bacteria and has demonstrated non-inferiority to meropenem in the phase III IGNITE4 trial; however, the trial excluded immunocompromised patients. We aimed to evaluate clinical and safety endpoints of immunocompromised patients receiving ERV as definitive therapy. Methods Multicenter, retrospective, observational study conducted from October 2018 to April 2022. Adult hospitalized immunocompromised patients treated with ERV for ≥72 hours were included. Immunocompromised patients were defined as having any of the following: chemo or radiation therapy &amp;lt; 30 days of hospital admission, HIV/AIDS with CD4 &amp;lt; 200, chronic steroids ( &amp;gt;40 mg prednisone or equivalent. The primary outcome was 30-day survival. Secondary outcomes were lack of 30-day infection recurrence and drug-related safety events. Results Overall, 75 immunocompromised patients treated with ERV were included from 17 United States medical centers. Median (IQR) age was 62 (53-70) and 61.6% were male. Hospital length of stay was 28 (13-42) days and 67% were admitted to the intensive care unit. SOFA and APACHE II scores were 3.5 (1-7) and 16 (11-20), respectively. Common infection sources were intra-abdominal (26%) and lower respiratory tract (18%); 24% were bacteremic. Most patients had cultured Enterobacterales (58.7%) and Enterococci (37%) spp. infections. Of those, 21.3% were CRE and 19% were VRE. Infectious diseases consult was obtained in 91.8% of cases. Time elapsed from index culture collection to ERV initiation was 4 (2-8) days and duration of ERV therapy was 7 (4-12) days. In total, 81.3% of immunocompromised patients achieved 30-day survival and 90.7% did not have 30-day infection recurrence. Probable drug-related adverse events occurred in 5.3% of patients (GI 4%, rash 1%). Conclusion A majority of immunocompromised patients receiving ERV as definitive therapy achieved 30-day survival and did not experience infection recurrence. ERV use in immunocompromised subpopulations will benefit from studies tailored to their specific characteristics. Disclosures Kimberly C. Claeys, PharmD, BioFire Diagnostics: Honoraria Bruce M. Jones, Pharm.D., FIDSA, BCPS, AbbVie: Advisor/Consultant|AbbVie: Honoraria|La Jolla: Honoraria|Melinta: Advisor/Consultant|Paratek: Honoraria|Regeneron: Honoraria.

A pharmacokinetic-pharmacodynamic (PKPD) model-based analysis of tedizolid against enterococci using the hollow-fibre infection model

Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients. In this study, we assessed the 'pure' pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus in the hollow-fibre infection model (HFIM). Unbound plasma concentration time profiles (200-5000 mg/day IV) were simulated in the HFIM over 120 h against an Enterococcus faecalis strain and two clinical isolates of Enterococcus faecium (VRE-vanB and VRE-vanA). Next, a PKPD model describing tedizolid efficacy against bacterial isolates was developed. A population PK model was linked to the developed PKPD model and utilized to predict the bacterial kinetics in plasma and in target tissues [adipose, muscle, epithelial lining fluid (ELF) and sputum] over 120 h of therapy. The PKPD model adequately described the bacterial kill kinetics for all bacterial populations. At the human recommended dose of 200 mg/day, bacterial growth was predicted in plasma and all tissues, except for ELF. Bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h. An fAUC/MIC of 80 related to stasis over 120 h. Subpopulations resistant to 3 × MIC were amplified in plasma and target tissues, except for ELF, at doses of 200-800 mg/day. The human dose of 200 mg/day was insufficient to suppress bacterial growth in the HFIM, indicating that further components contribute to the clinical effect of tedizolid. This study supports the warning/precaution for tedizolid to limit its use in immunocompromised patients.

Lactobacillus bloodstream infections genetically related to probiotic use in pediatric hematopoietic cell transplant patients.

We describe a cluster of 6 pediatric hematopoietic cell transplant recipients with Lactobacillus bacteremia attributed to probiotic use. Lactobacillus isolates cultured from probiotics and patients' blood were proven to be related using whole-genome sequencing. Clinical studies are needed to evaluate the safety of probiotic use in immunocompromised patients.

1034. FebriDx use in Immunocompromised Patients in a Real-World Hospital Setting during the second (COVID-19) wave in Italy

BackgroundThe diagnosis of acute respiratory infection (ARI) in patients with immunosuppression secondary to disease or medications is often unclear. Symptoms may be absent or blunted, and acute phase reactants, like procalcitonin (PCT) and C-reactive protein (CRP) may not elevate. For these patients, minor signs or symptoms could lead to hospitalization and antibiotic prescriptions to prevent complications or death. FebriDx® is a rapid, qualitative immunoassay test designed to distinguish between viral or bacterial respiratory infection through simultaneous detection of both CRP and Myxovirus resistance protein A (MxA) from a fingerstick blood sample. MethodsFebriDx was evaluated as part of a real-world prospective, observational study in hospitalized patients with symptoms of ARI and suspected COVID-19 in a single tertiary care center in Italy (August, 2020 - January, 2021). A sub analysis of patients with expected reduced host immune responses secondary to immunosuppression by disease or medication was performed. (Classified by treating clinician; patient on high dose steroids/ immunosuppressive therapy, or underlying condition like cancer or autoimmune disease). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were calculated for FebriDx with respect to the final diagnosis.ResultsWe included 28 patients from 200 in the study, 16 patients had a final diagnosis of bacterial infection and 12 had viral infection. FebriDx showed a sensitivity of 91.7% to accurately diagnose viral infection and 93.8% for bacterial infection (see tables). Serum CRP was not available for 4 of the patients included (14%) and elevated in the remaining patients. PCT was not available for one patient with viral infection and was elevated in 50.0%. FebriDx Performance when compared to Clinical DiagnosisConclusionFebriDx demonstrated a higher accuracy for differentiating bacterial vs. viral infection in an immunocompromised cohort than single biomarkers CRP and PCT. FebriDx demonstrated a high diagnostic accuracy to differentiate viral from bacterial infection in patients with chronic immunosuppressive conditions in a real-world setting and had better performance than standalone CRP and PCT to distinguish viral and bacterial ARI in immunocompromised patients. Disclosures Catalina Suarez-Cuervo, MD, Lumos Diagnostics (Employee)

COVID-19 vaccine use in immunocompromised patients: A commentary on evidence and recommendations.

PurposeWhile COVID-19 vaccine emergency use authorization (EUA) deemed the vaccines to be effective and safe for public use, the phase 3 trials leading to EUA predominantly excluded patients with immunocompromising conditions. Immunocompromised patients make up a significant proportion of the population, and in light of recent mass vaccination efforts, we aim to review current evidence and recommendations of COVID-19 vaccines in 4 patient populations with immunocompromising disorders or conditions: human immunodeficiency virus (HIV) infection, solid organ transplantation, rheumatoid arthritis, and inflammatory bowel disease.SummaryGiven the evolving data on the safety and efficacy of the approved COVID-19 vaccines in the immunocompromised population, it is vital that pharmacists and other immunizing providers understand the current data and recommendations and provide the public with accurate information. To date, the only immunocompromised subgroup included in phase 3 COVID-19 vaccine trials have been those with HIV infection. However, recent retrospective trials have provided reassuring data on the safety of the COVID-19 vaccine in immunocompromised patients, and the interim analysis of the Moderna phase 3 trial produced promising data on efficacy in HIV-infected patients. Presently, the US Centers for Disease Control and Prevention, British Society for Immunology, and various other governmental and professional societies and organizations endorse COVID-19 vaccination in the immunocompromised population.ConclusionWhile additional data is needed to determine the effects of immunocompromising medical conditions and immunosuppressing medications on the efficacy of the vaccine, the benefits of vaccination is anticipated to outweigh theoretical risks. Thus, COVID-19 vaccination is recommended for immunocompromised patients at this time, and providers should make efforts to decrease vaccine hesitancy in this population through education and reassurance.

The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response.

Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.

Association Between Prescribed Opioids and Infections in Patients With Neutropenia and Cancer

This nested case-control study examines the association of risk of infection with opioid use in immunocompromised patients.

Discovery of Novel Anti-cryptosporidial Activities From Natural Products by in vitro High-Throughput Phenotypic Screening.

Cryptosporidium parvum is a globally distributed zoonotic protozoan parasite of both medical and veterinary importance. Nitazoxanide is the only FDA-approved drug to treat cryptosporidiosis in immunocompetent people, but it is not fully effective. There is no drug approved by FDA for use in immunocompromised patients or in animals. In the present study, we conducted phenotypic screening of 800 nature products with defined chemical structures for potential novel activity against the growth of C. parvum in vitro. We identified a large number of compounds showing low to sub-micromolar anti-cryptosporidial activity, and fully characterized 16 top hits for anti-parasitic efficacies in vitro [EC50 values from 0.122 to 3.940 μM, cytotoxicity (TC50) values from 6.31 to >100 μm] and their safety margins. Among them, 11 compounds were derived from plants with EC50 values from 0.267 to 3.940 μM [i.e., cedrelone, deoxysappanone B 7,4′-dimethyl ether (Deox B 7,4), tanshinone IIA, baicalein, deoxysappanone B 7,3′-dimethyl ether acetate, daunorubicin, dihydrogambogic acid, deacetylgedunin, deacetoxy-7-oxogedunin, dihydrotanshinone I, 2,3,4′-trihydroxy-4-methoxybenzophenone, and 3-deoxo-3beta-hydroxy-mexicanolide 16-enol ether]. Three compounds with sub-micromolar EC50 values (i.e., cedrelone, Deox B 7,4, and baicalein) were further investigated for their effectiveness on various parasite developmental stages in vitro. Cedrelone and baicalein were more effective than Dexo B 7,4 when treating parasite for shorter periods of time, but all three compounds could kill the parasite irreversibly. These findings provide us a large selection of new structures derived from natural products to be explored for developing anti-cryptosporidial therapeutics.

Incidence and Risk Factors for Developing Herpes Zoster Among a Cohort of Patients Diagnosed with Lymphoma at a Community Cancer Center

IntroductionLymphoid neoplasms are among the most common hematologic malignancies. Viral infections are important causes of mortality and morbidity in patients with lymphoma. The majority of viral infectious complications in these patients result from the reactivation of various viruses such as Herpes Zoster (HZ). Most cases of HZ are self-limited; however, immunocompromised patients have a higher mortality rate from HZ and are at greater risk for recurrences and more serious and atypical complications.The most important established risk factors for developing HZ in cancer patients include neutropenia, duration and intensity of treatment, type of chemotherapy received, comorbid conditions such as Diabetes Mellitus, being recipient of a stem cell transplant, among others. However, the impact of baseline laboratory characteristics such as absolute lymphocyte count (ALC) and lactate dehydrogenase (LDH) as well as the cell type and stage of lymphoma at diagnosis on the risk of developing HZ remains unclear.Anecdotal data suggest that prophylaxis with acyclovir might be beneficial to decrease the incidence of HZ among patients with lymphoma receiving chemotherapy. Although it is well known that the two FDA-approved HZ vaccines decrease the incidence of this condition in immunocompetent hosts, the Advisory Committee on Immunization Practices has not made recommendations regarding its use in immunocompromised patients. In view of the debilitating condition of lymphoma patients and the unclear effectiveness of anti-HZ vaccine in this disorder, it seems urgent to find better preventive and treatment strategies.Materials and methodsWe conducted a retrospective cohort study of patients diagnosed with lymphoma registered in the database of Auxilio Mutuo Cancer Center (AMCC). Our study analyzed the incidence of HZ in patients diagnosed with lymphoma at any time during the course of illness. The duration of this study was from 1997-2017. The variables were the following: gender, age >50 at diagnosis, type of chemotherapy, having diabetes mellitus, having received an autologous stem cell transplant (ASCT), multiple courses of chemotherapy, radiotherapy, rituximab, or what we labeled as “highly immunosuppressive chemotherapy (HIC)”, date of relapse or death, stage at diagnosis, indolent or aggressive presentation, baseline LDH, baseline ALC<1000, and date of HZ. The frequencies of each categorical variable were compared with chi-square tests (χ2 test) or Fisher's exact tests. All statistical analyses were based on two-sided hypothesis tests with a significance level of P< 0.05.ResultsFrom 1997-2017 there were 414 lymphoma patients with median age at diagnosis of 53 years. There were 90 patients with HD, 6 patients with NK/T-cell lymphoma, and 319 with NHL. During a median follow up of 10 years a total of 46 HZ cases were identified for an overall incidence density of 11.2%. Higher rates of HZ were associated with the following factors: multiple courses of chemotherapy (p=0.035), indolent lymphoma (p=0.012), advanced stage at diagnosis (p=0.034), having received HIC (p<0.001), and having lymphopenia at the time of diagnosis (p=0.038). The other variables studied did not exhibit higher rates of HZ.DiscussionOur study is one of the first to estimate incidence rates of HZ and examine risk factors and complications of HZ in lymphoma patients according to specific histologic subtype and presentation. The overall incidence among all groups was significantly higher than in the general population. We have documented that HZ incidence varies with treatment regimens and stage of disease at diagnosis as well as presentation of indolent vs aggressive. Lymphocytopenia was not described previously in the literature as a risk factor for developing HZ but in our cohort patients having ALC<1000 at diagnosis displayed a significantly higher incidence of HZ. The patients who received multiple courses of chemotherapy and HIC also exhibited significantly elevated risks for HZ. Because the overall incidence of HZ was higher among the patients with lymphoma during chemotherapy, prophylaxes against HZmight be considered, particularly for patients with the risk factors. However, optimal duration and preferred regimen for prophylaxis remain to be elucidated. DisclosuresNo relevant conflicts of interest to declare.

The Exonuclease Activity of Herpes Simplex Virus 1 UL12 Is Required for Production of Viral DNA That Can Be Packaged To Produce Infectious Virus.

The herpes simplex virus (HSV) type I alkaline nuclease, UL12, has 5'-to-3' exonuclease activity and shares homology with nucleases from other members of the Herpesviridae family. We previously reported that a UL12-null virus exhibits a severe defect in viral growth. To determine whether the growth defect was a result of loss of nuclease activity or another function of UL12, we introduced an exonuclease-inactivating mutation into the viral genome. The recombinant virus, UL12 D340E (the D340E mutant), behaved identically to the null virus (AN-1) in virus yield experiments, exhibiting a 4-log decrease in the production of infectious virus. Furthermore, both viruses were severely defective in cell-to-cell spread and produced fewer DNA-containing capsids and more empty capsids than wild-type virus. In addition, DNA packaged by the viral mutants was aberrant, as determined by infectivity assays and pulsed-field gel electrophoresis. We conclude that UL12 exonuclease activity is essential for the production of viral DNA that can be packaged to produce infectious virus. This conclusion was bolstered by experiments showing that a series of natural and synthetic α-hydroxytropolones recently reported to inhibit HSV replication also inhibit the nuclease activity of UL12. Taken together, our results demonstrate that the exonuclease activity of UL12 is essential for the production of infectious virus and may be considered a target for development of antiviral agents.IMPORTANCE Herpes simplex virus is a major pathogen, and although nucleoside analogs such as acyclovir are highly effective in controlling HSV-1 or -2 infections in immunocompetent individuals, their use in immunocompromised patients is complicated by the development of resistance. Identification of additional proteins essential for viral replication is necessary to develop improved therapies. In this communication, we confirm that the exonuclease activity of UL12 is essential for viral replication through the analysis of a nuclease-deficient viral mutant. We demonstrate that the exonuclease activity of UL12 is essential for the production of viral progeny and thus provides an attractive, druggable enzymatic target.

ACIP votes to recommend PCV13 for adults aged 65 years and older

At an interim meeting on August 13, 2014, just in time for the upcoming respiratory season, CDC's Advisory Committee on Immunization Practices (ACIP) voted 13 to 2 to recommend the pneumococcal conjugate vaccine PCV13 (Prevnar 13 - Pfizer) for adults aged 65 years and older. The committee had delayed discussion and a vote at its June meeting to gather more information on the use of PCV13 in this patient population (for details, see page 21 of the August issue).

Tuberculosis Vaccines: Review of Current Development Trends and Future Challenges

Despite plaguing humans for thousands of years, tuberculosis remains a widespread and lethal public health problem throughout the world today. The recent rise of multi-drug-resistant tuberculosis (MDR-TB) perpetuates the public health threat while presenting a potential bioterrorism agent. The BCG vaccine is the only available prevention against TB, yet it elicits inconsistent protection when given to infants, fails to provide consistent protection in adults against pulmonary disease, and is unsafe for use in immunocompromised patients. A new crop of TB vaccine candidates has entered into clinical trials, with a second generation following shortly. These new TB vaccines are hoped to provide a safe, efficacious replacement, or addition to, the nearly century-old BCG and provide protection against TB disease beyond childhood. This review details the status of the most promising TB vaccine candidates in development, as one of these candidates may play a key role in defending against an ominous health threat.

Immune Evasion by B-cell Lymphoma

Immune Evasion by B-cell Lymphoma

Zoster Vaccine: Current Status and Future Prospects

Live, attenuated Oka/Merck varicella-zoster virus (VZV) vaccine (zoster vaccine) protects immunocompetent adults from herpes zoster and its complications. Success of zoster vaccine in preventing the clinical manifestations of latent VZV reactivation contrasts with the failure to achieve similar results with vaccination to prevent recurrent herpes simplex. This reflects major differences in the pathophysiology of latency and reactivation of these 2 alphaherpesviruses. The Shingles Prevention Study and many others have demonstrated that VZV-specific cell-mediated immunity, but not VZV antibody, plays a critical role in limiting reactivation and replication of latent VZV and, thus, in preventing herpes zoster and its complications. Consequently, induction of VZV-specific cell-mediated immunity and not antibody should be used as a proxy for the clinical efficacy of new formulations and uses of zoster vaccine. Prospects for improved zoster vaccines and their use in immunocompromised patients are discussed, and questions related to zoster vaccine use are addressed.

Diagnostic Usefulness of a T-cell-based Assay for Extrapulmonary Tuberculosis in Immunocompromised Patients

Background The low reactivity of the tuberculin skin test limits its clinical use in immunocompromised patients with extrapulmonary tuberculosis. A recently developed T-cell-based assay for diagnosing tuberculosis infection gave promising results. However, there were few data on the usefulness of this assay for diagnosing extrapulmonary tuberculosis in immunocompromised patients. Methods All adult patients with suspected extrapulmonary tuberculosis were prospectively enrolled at 2 university-affiliated hospitals over an 18-month period. In addition to the conventional tests for diagnosing extrapulmonary tuberculosis, enzyme-linked immunospot (ELISPOT) assay for the interferon-γ-producing T-cell response to early secretory antigenic target-6 and culture filtrate protein-10 was performed. The final diagnoses in patients with suspected extrapulmonary tuberculosis were classified by clinical category. Results There were 179 patients with suspected extrapulmonary tuberculosis enrolled: 59 (33%) were classified as immunocompromised. Of the 179 patients, 75 (42%) were classified as extrapulmonary tuberculosis, including 56 confirmed tuberculosis plus 19 probable tuberculosis, and 97 (54%) were classified as not tuberculosis. The remaining 7 (4%) had possible tuberculosis and were excluded from the final analysis. The tuberculin skin test (induration size ≥10 mm) was less sensitive in immunocompromised patients (38%; 95% confidence interval [CI], 19%-59%) than in immunocompetent patients (69%; 95% CI, 54%-81%, P = .01). In contrast, the ELISPOT assay retained a high sensitivity: (88%; 95% CI, 68%-97%) in immunocompromised patients compared with 96% (95% CI, 87%-100%) in immunocompetent patients ( P = .32). Conclusion The immunosuppressive condition does not affect the diagnostic sensitivity of the ELISPOT assay for extrapulmonary tuberculosis.

Curcumin as a promising antifungal of clinical interest

The antifungal activity of curcumin was evaluated against 23 fungi strains and its in vitro inhibitory effect on the adhesion of Candida species to human buccal epithelial cells (BEC) was also investigated. The antifungal susceptibility was evaluated by broth microdilution assay following the CLSI (formerly the NCCLS) guidelines. The inhibitory effect of curcumin on the cell adhesion was performed with Candida species and BEC. Paracoccidioides brasiliensis isolates were the most susceptible to curcumin while the growth of Aspergillus isolates was not affected. Curcumin was much more efficient than fluconazole in inhibiting the adhesion of Candida species to BEC, particularly those strains isolated from the buccal mucosa of AIDS patients. The lack of antifungal compounds with reduced side effects highlights the importance of studying natural products for this purpose. Curcumin was a more potent antifungal than fluconazole against P. brasiliensis, the causal agent of the neglected disease paracoccidioidomycosis. Curcumin dramatically inhibited the adhesion of Candida species isolated from AIDS patients to BEC, demonstrating that curcumin is a promising lead compound that warrants further investigation into its therapeutical use in immunocompromised patients.