Introduction: Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. Methods: We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. Results: Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. Conclusions: While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

This study addresses the dynamic of viral load rebound and immune system changes in a cohort of eight consecutive HIV-1-infected patients in very early stages [all the patients were taking highly active antiretroviral therapy (HAART} and were recruited in the coordinating center from a larger study] who decided to discontinue HAART after 1 year of treatment and effective virologic response. The safety of this procedure and the outcome with reintroduction of the same treatment was also investigated. Plasma, cerebrospinal fluid (CSF), and lymphatic tissue viral loads were measured at baseline; lymphocyte immunophenotyping and CD4 lymphocyte proliferative responses to mitogens and specific antigens were assessed. The same antiretroviral therapy was reintroduced as soon as plasma viral load became detectable (above 200copies/ml). At day 0, plasma viral load was below 20copies/ml in all eight patients (and below 5copies/ml in five of eight patients). A rebound in plasma viral load was detected in all patients from day 3 to day 31 with a mean doubling time of 2.01 (SE 0.29) days. Three out of eight patients achieved a peak plasma viral load at least 0.5log10 above baseline, pretreatment values. Mutations associated with resistance to reverse transcriptase or protease inhibitors were not detected. After 31 days off therapy, CD4 lymphocytes decreased [mean 45% (SE 4) to 37% (SE 3); P=0.04], CD8+CD28+ lymphocytes decreased [mean 59% (SE 5) to 43% (SE 4); P=0.03], and CD8+CD38+ lymphocytes increased [mean 55% (SE 3) to 66% (SE 4); P=0.009]. Mean stimulation indices of lymphocytes treated with phytohemagglutinin (PHA) and CD3 decreased from day 0 to day 31 from 34% (SE 8) to 17% (SE 9) (P=0.06) and from 24% (SE 8) to 5% (SE 2) (P=0.02), respectively. These changes were mainly contributed by the group of five patients with plasma viral load below 5copies/ml at day 0. Viral load dropped below 20copies/ml in all patients after 1 month of restarting the same antiretroviral regimen. Discontinuation of HAART after 1 year of successful treatment is followed by a rapid rebound of viral load; this rapidly returns to undetectable levels following reintroduction of the same treatment. In patients with more effective control of virus replication (viremia below 5copies/ml), discontinuation of treatment was associated with more severe impairment of immunologic parameters.

Introduction: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. Methods: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. Results: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. Conclusions: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

SUMMARY: In recent years, the increasing number of donors from different regions of the world is providing a new challenge for the management and selection of suitable donors. This is a worldwide problem in most countries with transplantation programs, especially due to the increase in immigration and international travel. This paper elaborates recommendations regarding the selection criteria for donors from foreign countries who could potentially transmit tropical or geographically restricted infections to solid-organ transplant recipients. For this purpose, an extensive review of the medical literature focusing on viral, fungal, and parasitic infections that could be transmitted during transplantation from donors who have lived or traveled in countries where these infections are endemic has been performed, with special emphasis on tropical and imported infections. The review also includes cases described in the literature as well as risks of transmission during transplantation, microbiological tests available, and recommendations for each infection. A table listing different infectious agents with their geographic distributions and specific recommendations is included.

Current treatment guidelines for HIV infection recommend a relatively late initiation of highly active antiretroviral therapy (HAART). Nevertheless, there is still a concern that immune recovery may not be as complete once CD4⁺ T cells have decreased below a certain threshold. This study addressed the long-term response of CD4⁺ T-cell counts in patients on HAART and analyzed the influence of baseline CD4⁺ T-cell counts, baseline viral load, and age. An observational analysis of evolution of CD4⁺ T cells in 861 antiretroviral therapy–naive chronic HIV-1–infected patients who started treatment consisting of at least 3 drugs in or after 1996 was performed. Patients were classified in 4 groups according to baseline CD4⁺ T cells: <200 cells/mm³, 200–349 cells/mm³, 350–499 cells/mm³, and ≥500 cells/mm³. The main outcome measures were proportion of patients with CD4⁺ T cells 500/mm³ at last determination and rate of CD4⁺ T-cell recovery. Patients were followed-up for a median of 173 weeks (interquartile range [IQR], 100–234). There were no differences in follow-up between the 4 groups. CD4⁺ T cells increased in the whole cohort from a median of 214 cells/mm³ (IQR, 90–355) to 499 cells/mm³ (IQR, 312–733) (P < 0.001). Compared with the group with a baseline CD4⁺ T-cell count of ≥500/mm³, the relative risk of having a last determination of CD4⁺ T-cell counts >200 cells/mm³ was 0.79 (95% CI, 0.75–0.83), 0.92 (95% CI, 0.89–0.96) and 1 for baseline CD4⁺ T cells 500 cells/mm³ was 0.32 (95% CI, 0.27–0.39, P < 0.001), 0.69 (95% CI, 0.60–0.79, P < 0.001), and 0.94 (95% CI, 0.83–1.06, P = 0.38) for baseline CD4⁺ T-cell counts <200 cells/mm³, 200–349 cells/mm³, and 350–499 cells/mm³, respectively, compared with a baseline CD4⁺ T-cell count of ≥500 cells/mm³. The increase in CD4⁺ T cells from baseline was statistically significant and was maintained for up to 4 years of follow-up. This increase seemed to slow down after approximately 3 years and reached a plateau after 4–5 years of follow-up even in patients who achieved and maintained viral suppression in plasma. Long-term immune recovery is possible regardless of baseline CD4⁺ T-cell count. However, patients who start therapy with a CD4⁺ T-cell count <200 cells/mm³ have poorer immunologic outcome as measured by the proportion of patients with CD4⁺ T cells 500/mm³ at last determination. It seems that the immune recovery slows down after approximately 3 years of HAART and reaches a plateau after 4–5 years of HAART.