Pilar Pérez-Romero

Therapeutic effect of the acquisition of cytomegalovirus-specific immune response during preemptive treatment.

Background. It has been suggested that preemptive therapy against cytomegalovirus (CMV) infection after transplantation promotes a CMV-specific immune response. Our objective was to determine whether solid-organ transplant patients at high risk for CMV infection treated preemptively acquire a CMV-specific immune response and whether the acquired immune response confers immunity by controlling subsequent CMV replication episodes and by protecting from late-onset CMV disease. Methods. Patients were followed up for 18 months after transplantation. CMV viral load was determined using real-time polymerase chain reaction assays, and the T-cell immune response was characterized by intracellular cytokine staining. Results. The 21 patients studied developed CMV replication episodes at a median of 4 weeks (range 2–8 weeks) after transplantation and a CMV-specific T-cell response within a median of 12 weeks (range 10–20 weeks). The decline in the incidence of CMV replication episodes is inversely correlated with the acquisition of the CMV-specific T-cell response (linear regression r2=0.781, Pearson correlation=−0.883; P=0.001). There were no CMV replication episodes after week 47 of transplantation. In addition, after acquisition of the immune response, 42 replication episodes were cleared without treatment. The time taken for immune clearance of replication correlated with the peak viral load (P=0.01). No incidence of CMV early or late-onset disease was detected. Conclusions. Our results demonstrate that preemptive therapy is a safe and an effective strategy for the control of CMV infection in solid-organ transplant recipients at high risk for CMV infection. This is the first study that reports a therapeutic effect of the acquisition of CMV-specific immune response during preemptive treatment.

Unexpected severity of cases of influenza B infection in patients that required hospitalization during the first postpandemic wave

OBJECTIVES After the last pandemic the knowledge regarding influenza A infection has improved however, the outcomes of influenza B infection remain poorly studied. The aim of this study was to compare the features of influenza B versus influenza A(H1N1)pdm09 infections during the 2010-2011 epidemic-season. METHODS A prospective, observational-cohort of adults with laboratory-confirmed influenza infection during the 2010-2011 epidemic-season was studied RESULTS Fifty cases of influenza B and 80 of influenza A(H1N1)pdm09 infection were enrolled. Among patients with influenza B, the median age was 34 years-old (23-64), 30% pregnant, 24% obese, 34% transplant recipients and 14% with bacterial co-infection. Twenty-eight percent of patients had pneumonia with alveolar localized pattern and five (10%) died. Pneumonia was associated with delayed antiviral therapy, older age, higher Charlson score, invasive mechanical ventilation and bacterial co-infection. Obesity and pregnancy were not associated with complicated influenza B infection. The proportion of pneumonia, admission to the ICU and mortality did not differ between cases of influenza A(H1N1)pdm09 and influenza B infection. CONCLUSIONS Influenza B infection causes severe infection and it is associated with pneumonia or death, similar to influenza A(H1N1)pdm09 infection. Rapid diagnosis and early antiviral therapy are necessary for managing influenza pneumonia during epidemic periods.

Pandemic influenza A(H1N1) virus infection in solid organ transplant recipients: impact of viral and non-viral co-infection

Abstract Solid organ transplant recipients (SOTR) are at risk of serious influenza-related complications. The impact of respiratory co-infection in SOTR with 2009 pandemic influenza A(H1N1) is unknown. A multicentre prospective study of consecutive cases of pandemic influenza A(H1N1) in SOTR was carried out to assess the clinical characteristics and outcome and the risk factors for co-infection. Overall, 51 patients were included. Median time from transplant was 3.7 years, 5.9% of the cases occurred perioperatively and 7.8% were hospitalacquired. Pneumonia was diagnosed in 15 (29.4%) patients. Ten cases were severe (19.6%): 13.7% were admitted to intensive care units, 5.9% suffered septic shock, 5.9% developed acute graft rejection and 7.8% died. Co-infection was detected in 15 patients (29.4%): eight viral, six bacterial and one fungal. Viral co-infection did not affect the outcome. Patients with non-viral co-infection had a worse outcome: longer hospital stay (26.2 ± 20.7 vs. 5.5 ± 10.2) and higher rate of severe diseases (85.7% vs. 2.3%) and mortality (42.8% vs. 2.3%). Independent risk factors for non-viral co-infection were: diabetes mellitus and septic shock. Other factors associated with severe influenza were: delayed antiviral therapy, diabetes mellitus, time since transplantation <90 days and pneumonia. In conclusion, pandemic influenza A can cause significant direct and indirect effects in SOTR, especially in the early post-transplant period, and should be treated early. Clinicians should be aware of the possibility of non-viral co-infection, mainly in diabetic patients and severe cases. An effort should be made to prevent influenza with immunization of the patient and the environment.

Therapy With m-TOR Inhibitors Decreases the Response to the Pandemic Influenza A H1N1 Vaccine in Solid Organ Transplant Recipients

Concern has been raised regarding the response to vaccination in solid organ transplant recipients (SOTR) undergoing immunosuppressant regimens and the possibility of rejection related to the immune response associated with pandemic influenza H1N1–2009 vaccination. The goal of this study was to assess the immunogenicity, efficacy and safety of the pandemic vaccine in SOTR. We performed a multicenter prospective study in SOTR receiving the pandemic vaccine. Immunological response was determined in serum 5 weeks after vaccination by microneutralization assays, and immunoglobulins were measured by ELISA. Three hundred and forty‐six SOTR were included. Preexisting seroprotection was detected in 13.6% of cases and rates of seroconversion and seroprotection after vaccination were 73.1% and 82.9%, respectively. Patients with baseline antibody titers had better geometric mean titers (GMT)‐post after pandemic vaccination (339.4 vs. 121.4, p < 0.001). Younger age, liver disease and m‐TOR inhibitor therapy were independently associated with lower seroprotection and GMT‐post. There were no major adverse effects or rejection episodes. Pandemic vaccine was safe in SOTR and elicited an adequate response, although lower than in healthy individuals. This is the first study describing a decreased response after vaccination in patients receiving mTOR inhibitors who presented lower seroprotection rates and lower GMT‐post.

Comparison of the new Abbott Real Time CMV assay and the Abbott CMV PCR Kit for the quantitation of plasma cytomegalovirus DNAemia

CMV DNA loads measured by the new Abbott RealTime CMV PCR were significantly higher than those quantitated by the Abbott CMV PCR kit (approximately 1 log(10)), and provided a better estimate of the actual CMV load present in plasma specimens as inferred by the use of the WHO standard.

Deficient long-term response to pandemic vaccine results in an insufficient antibody response to seasonal influenza vaccination in solid organ transplant recipients.

Background. Little is known about the long-term antibody response to the 2009-H1N1 vaccine in solid organ transplant recipients (SOTR) and its clinical repercussion on the efficacy of following 2010–2011 influenza vaccine. Methods. We performed a multicenter prospective study in SOTR receiving one dose of the nonadjuvant 2010–2011 seasonal influenza vaccine and determined the immunological response at 5 weeks after vaccination. Results. One hundred SOTR were included. Long-term antibody titers to the previous vaccine were only detected in one third of the patients. Patients with baseline titers had significantly higher seroprotection for the 2009-H1N1 strain (100% vs. 73%, relative risks [RR] 1.37, 95% confidence intervals [CI] 1.19–1.57; P=0.006), for H3N2 strain (100% vs. 62.2%, RR 1.61, 95% CI 1.36–1.90; P=0.005), and for B strain (100% vs. 69%; P=0.02). The seroconversion rate in patients with baseline titers was 90.9% vs. 73% (RR 2.97, 95% CI 0.75–11.74; P=0.07) for the 2009-H1N1 strain, 92.2% vs. 62.2% (RR 5.29, 95% CI 0.8–35.7; P=0.02) for the H3N2 strain, and 58.3% vs. 69% (P=0.45) for the B strain. Conclusions. SOTR response to the 2010–2011 influenza vaccine was not optimal. The response was related to baseline titers; however, most of the patients did not exhibit detectable antibodies at vaccination lacking long-term response. New strategies are necessary to improve vaccination efficacy.

Reduced incidence of pneumonia in influenza-vaccinated solid organ transplant recipients with influenza disease

Abstract Whether influenza vaccination influences the severity of illness in cases of clinical failure in solid organ transplant (SOT) recipients receiving influenza vaccine has not been extensively studied. Our goal was to evaluate the frequency of influenza vaccination among SOT recipients with influenza disease and its impact on the illness severity during the 2010–2011 season. Adult SOT recipients with confirmed influenza infection were included from December 2010 to April 2011. Follow-up data were recorded and antibody titres were determined using a microneutralization assay. Sixty-four SOT recipients were included in the study, ten (15.6%) with severe disease, requiring admission to intensive care units, of whom four (6.3%) died. In all, 34 (53.1%) received the 2010–2011 seasonal influenza vaccine and 32 (50.0%) received the 2009-H1N1 pandemic vaccine, and none had detectable antibodies against influenza at the time of diagnosis of influenza infection. Twenty-three (67.6%) of the patients that received the vaccine required hospital admission and presented less dyspnoea (10, 29.4% versus 14 (50.0%), p 0.09) and pneumonia (8, 23.8% versus 15, 50.0%, p 0.03, relative risk 0.3, 95% CI 0.1-0.9) than unvaccinated patients, with relative risk reductions of 60% and 70%, respectively. Although influenza vaccination confers protection on SOT recipients against developing influenza pneumonia, the rate of clinical failure is still high. New strategies to improve influenza immunization are needed for this group of patients.

Two Doses of Inactivated Influenza Vaccine Improve Immune Response in Solid Organ Transplant Recipients: Results of TRANSGRIPE 1–2, a Randomized Controlled Clinical Trial

Background Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. Methods TRANSGRIPE 1-2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. Results A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups. Conclusions In SOTR, a booster strategy 5 weeks after standard influenza vaccination is safe and effective and induces an increased antibody response compared with standard influenza vaccination consisting of a single dose. Clinical Trials Registration EudraCT (2011-003243-21).

Quantitative Real-Time PCR for Detection of Acinetobacter baumannii Colonization in the Hospital Environment

ABSTRACT A real-time PCR assay was developed for detecting the presence of Acinetobacter baumannii on hospital equipment and compared to conventional bacterial culture using 100 hospital environmental samples. The real-time PCR detected contaminated surfaces in 4 h with high sensitivity (100%) compared to conventional culture. Thirty-eight percent of samples were positive by real-time PCR and negative by bacterial culture (false positives), possibly indicating the widespread presence of bacterial DNA that is not associated with viable bacteria.

Prevalence and resistance mutations of non-B HIV-1 subtypes among immigrants in Southern Spain along the decade 2000-2010

BackgroundMost of the non-B HIV-1 subtypes are predominant in Sub-Saharan Africa and India although they have been found worldwide. In the last decade, immigration from these areas has increased considerably in Spain. The objective of this study was to evaluate the prevalence of non-B subtypes circulating in a cohort of HIV-1-infected immigrants in Seville, Southern Spain and to identify drug resistance-associated mutations.MethodsComplete protease and first 220 codons of the reverse transcriptase coding regions were amplified and sequenced by population sequencing. HIV-1 subtypes were determined using Stanford University Drug Resistance Database, and phylogenetic analysis was performed comparing multiple reported sequences. Drug resistance mutations were defined according to the International AIDS Society-USA.ResultsFrom 2000 to 2010 a total of 1,089 newly diagnosed HIV-1-infected patients were enrolled in our cohort. Of these, 121 were immigrants, of which 98 had ethical approval and informed consent to include in our study. Twenty-nine immigrants (29/98, 29.6%) were infected with non-B subtypes, of which 15/29 (51.7%) were CRF02-AG, mostly from Sub-Saharan Africa, and 2/29 (6.9%) were CRF01-AE from Eastern Europe. A, C, F, J and G subtypes from Eastern Europe, Central-South America and Sub-Saharan Africa were also present. Some others harboured recombinant forms CRF02-AG/CRF01-AE, CRF2-AG/G and F/B, B/C, and K/G, in PR and RT-coding regions. Patients infected with non-B subtypes showed a high frequency of minor protease inhibitor resistance mutations, M36I, L63P, and K20R/I. Only one patient, CRF02_AG, showed major resistance mutation L90M. Major RT inhibitor resistance mutations K70R and A98G were present in one patient with subtype G, L100I in one patient with CRF01_AE, and K103N in another patient with CRF01_AE. Three patients had other mutations such as V118I, E138A and V90I.ConclusionsThe circulation of non-B subtypes has significantly increased in Southern Spain during the last decade, with 29.6% prevalence, in association with demographic changes among immigrants. This could be an issue in the treatment and management of these patients. Resistance mutations have been detected in these patients with a prevalence of 7% among treatment-naïve patients compared with the 21% detected among patients under HAART or during treatment interruption.