Dysfunctional peripheral T follicular helper cells dominate in people with impaired influenza vaccine responses: Results from the FLORAH study.

Antigen-primed cluster of differentiation (CD) 4+ T follicular helper (Tfh) cells interact with B cells in the germinal centers (GCs) of lymph nodes to generate vaccine-induced antibody (Ab) responses. In the circulation, peripheral Tfh (pTfh) cells, a subset of memory CD4 T cells, serve as surrogates for GC Tfh because of several functional and phenotypic similarities between them. We investigated features of H1N1 influenza antigen-specific pTfh (Ag.pTfh) in virologically controlled HIV+ volunteers on antiretroviral therapy (ART) and healthy control (HC) participants selected from a seasonal influenza vaccine responsiveness study. Selection of the participants was made based on age, defined as young (18-40 y) and old (>60 y) and on their classification as a vaccine responder (VR) or vaccine nonresponder (VNR). VRs demonstrated expansion of CD40L+ and CD69+ Ag.pTfh, with induction of intracellular interleukin 21 (IL-21) and inducible costimulator (ICOS) post vaccination; these responses were strongest in young HC VRs and were less prominent in HIV+ individuals of all ages. Ag.pTfh in VNRs exhibited dramatically different characteristics from VRs, displaying an altered phenotype and a cytokine profile dominated by cytokines IL-2, tumor necrosis factor alpha (TNF-α), or IL-17 but lacking in IL-21. In coculture experiments, sorted pTfh did not support the B cell IgG production in VNRs and were predominantly an inflammatory T helper 1 (Th1)/T helper 17 (Th17) phenotype with lower ICOS and higher programmed cell death protein 1 (PD1) expression. Induction of IL-21 and ICOS on Ag.pTfh cells are negatively affected by both aging and HIV infection. Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in healthy aging and those aging with HIV infection.

HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine.

BACKGROUND: Antibody responses to seasonal influenza vaccines are defective during older age and human immunodeficiency virus (HIV) infection. The effect of HIV on immune function in aging is relatively unknown. METHODS: HIV-infected and HIV-uninfected young women (age, 19-54 years) and older women (age, >55 years) were evaluated for B-cell and T-cell responses before and 4 weeks after influenza vaccination. RESULTS: Frequencies of seroprotection pre-vaccination and vaccine responsiveness (≥4-fold increase in antibody titer) were lower in HIV-infected participants than in age-matched HIV-uninfected participants. A subgroup of vaccine nonresponders were compared to responders and found to have reduced frequencies of memory B cells and antigen-specific antibody-secreting cells after vaccination. Frequencies of peripheral T-follicular helper (pTfh) cells correlated with memory B-cell function and influenza A(H1N1) antibody titers. Serologic and immunologic deficits were most frequent in older HIV-infected participants. Underlying CD4(+) T-cell immune activation and inflammation correlated negatively with antibody titers and B-cell function, which was not enhanced by exogenous interleukin 21 supplementation in HIV-infected, older vaccine nonresponders. CONCLUSIONS: Immune activation associated with HIV infection and impaired pTfh function heighten deficiencies in antibody responses to influenza vaccine in older individuals. Strategies to reduce immune activation or augment pTfh function may enhance antibody responses in the aging HIV-infected population.

Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine.

The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5(+) CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.

Fungal endophthalmitis: fourteen years' experience from a center in India.

BACKGROUND: As fungal endophthalmitis is an emerging challenge, the study was carried out to determine the prevalence and the spectrum of fungal agents causing endophthalmitis from a single center, to identify the risk factors, and to correlate clinical course of illness with the agents involved. METHODS: The microbiological and clinical records of all fungal endophthalmitis diagnosed during January 1992 through December 2005 at a tertiary center in India were reviewed retrospectively. During this period, treatment protocol of the patients with fungal endophthalmitis was pars plana vitrectomy, instillation of intravitreal amphotericin B (5 microg) and dexamethasone (400 microg). Additionally, oral fluconazole (27 patients) or itraconazole (78 patients) was given in 105 patients. RESULTS: Fungal endophthalmitis was diagnosed in 113 patients and they were categorized into: postcataract surgery (53 patients), posttrauma (48), and endogenous (12) groups. Aspergillus species was the most common (54.4%) agent isolated, followed by yeasts (24.6%), and melanized fungi (10.5%). Among Aspergilli, Aspergillus flavus was the most common (24.6%) species whereas Candida tropicalis (8.8%) was in the yeast. Other rare agents isolated include Fonsecaea pedrosoi, Fusarium solani, Paecilomyces lilacinus, Pseudallescheria boydii, Colletotrichum dematium, Cryptococcus neoformans, and Trichosporon cutaneum. Visual acuity after therapy remained <20/400 in 77.4%, 64.3%, 50.0%, and 16.7% patients infected with Aspergillus species, yeasts, melanized fungi and other mycelial fungi, respectively. The outcome was unfavorable in 52.8%, 66.7%, and 33.3% patients with postoperative, posttrauma, and endogenous groups, respectively. CONCLUSIONS: This study is the largest series of fungal endophthalmitis from a single center and highlights the fact that a vast array of fungi can cause endophthalmitis though Aspergilli are the common agents. The combination of pars plana vitrectomy and intravitreal amphotericin B with or without fluconazole/itraconazole was the common mode of therapy in such patients. However, the main challenge is suspecting fungal etiology at the time of presentation and accurately diagnosing those patients.

Circulating inflammatory monocytes contribute to impaired influenza vaccine responses in HIV-infected participants.

OBJECTIVE: Antibody responses are often impaired in old age and in HIV-positive (HIV+) infection despite virologic control with antiretroviral therapy but innate immunologic determinants are not well understood. DESIGN: Monocytes and natural killer cells were examined for relationships to age, HIV infection and influenza vaccine responses. METHODS: Virologically suppressed HIV+ (n = 139) and HIV-negative (HIV-) (n = 137) participants classified by age as young (18-39 years), middle-aged (40-59 years) and old (≥60 years) were evaluated preinfluenza and postinfluenza vaccination. RESULTS: Prevaccination frequencies of inflammatory monocytes were highest in old HIV+ and HIV-, with old HIV+ exhibiting higher frequency of integrin CD11b on inflammatory monocytes that was correlated with age, expression of C-C chemokine receptor-2 (CCR2) and plasma soluble tumor necrosis factor receptor-1 (sTNFR1), with inverse correlation with postvaccination influenza H1N1 antibody titers. Higher frequencies of CD11b+ inflammatory monocytes (CD11b(hi), >48.4%) compared with low frequencies of CD11b+ inflammatory monocytes (<15.8%) was associated with higher prevaccination frequencies of total and inflammatory monocytes and higher CCR2 MFI, higher plasma sTNFR1 and CXCL-10 with higher lipopolysaccharide stimulated expression of TNFα and IL-6, concomitant with lower postvaccination influenza antibody titers. In HIV+ CD11b(hi) expressers, the depletion of inflammatory monocytes from peripheral blood mononuclear cells resulted in enhanced antigen-specific CD4+ T-cell proliferation. Immature CD56(hi) natural killer cells were lower in young HIV+ compared with young HIV- participants. CONCLUSION: Perturbations of innate immunity and inflammation signified by high CD11b on inflammatory monocytes are exacerbated with aging in HIV+ and negatively impact immune function involved in Ab response to influenza vaccination.

Impact of aging and HIV infection on serologic response to seasonal influenza vaccination.

OBJECTIVE: To determine influence of age and HIV infection on influenza vaccine responses. DESIGN: Evaluate serologic response to seasonal trivalent influenza vaccine (TIV) as the immunologic outcome in HIV-infected (HIV⁺) and age-matched HIV negative (HIV⁻) adults. METHODS: During 2013-2016, 151 virologically controlled HIV⁺ individuals on antiretroviral therapy and 164 HIV⁻ volunteers grouped by age as young (<40 years), middle aged (40-59 years) and old (≥60 years) were administered TIV and investigated for serum antibody response to vaccine antigens. RESULTS: At prevaccination (T0) titers were in seroprotective range in more than 90% of participants. Antibody titers increased in all participants postvaccination but frequency of classified vaccine responders to individual or all three vaccine antigens at 3-4 weeks was higher in HIV⁻ than HIV⁺ adults with the greatest differences manifesting in the young age group. Of the three vaccine strains in TIV, antibody responses at T2 were weakest against H3N2 with those to H1N1 and B antigens dominating. Among the age groups, the titers for H1N1 and B were lowest in old age, with evidence of an age-associated interaction in HIV⁺ persons with antibody to B antigen. CONCLUSION: Greater frequencies of vaccine nonresponders are seen in HIV⁺ young compared with HIV⁻ adults and the observed age-associated interaction for B antigen in HIV⁺ persons are supportive of the concept of premature immune senescence in controlled HIV infection. High-potency influenza vaccination recommended for healthy aging could be considered for HIV⁺ adults of all ages.

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age.

Combination antiretroviral therapies (cART)can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative "healthy controls" (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old (>60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Minimizing Relapse in Mandibular Asymmetry Correction by BSSRO with Intentional Osteotomy of Distal Segment: A Prospective Study.

INTRODUCTION: Surgical correction of the patients with mandibular asymmetry by bilateral sagittal split ramus osteotomy (BSSRO) creats remarkable results in the immediate post operative period, but it carries a high risk of relapse by powerful muscle forces and the osteotomized segments. To minimize this risk, literatures highlight the procedure of an intentional osteotomy and stripping of muscles. A prospective study was conducted in Government Dental College, Kottayam, Kerala, to assess the effect of intentional osteotomy of posterior part of distal segment and stripping of medial pterygoid muscle on the proximal segment on affected side in mandibular asymmetry patients treated with BSSRO. MATERIALS AND METHODS: 20 patients above 18 years with mandibular asymmetry underwent surgical correction by BSSRO setback and rotation. Clinical evaluation and postero anterior cephalogram (PA Ceph) were used to assess relapse. PA cephalogram taken post operatively at 2 weeks, 6 months and 1year were compared using cephalometric parameters by Grummons analysis to assess relapse. Paired t test and Chi-square test was used to analyse quantitative and qualitative parameters respectively with statistical significance of p < 0.05. RESULTS: Barring Methodological errors which is inevitable, the amount of relapse was not statistically significant with respect to dental midline, chin midline and frontal photograph. CONCLUSION: Intentional osteotomy of posterior part of distal segment and stripping of medial pterygoid muscle on the affected side can prevent relapse in patients who underwent surgical correction of mandibular asymmetry by BSSRO set back and rotation.

The rising trend of invasive zygomycosis in patients with uncontrolled diabetes mellitus.

Zygomycosis is an emerging infection worldwide. A study was conducted to understand its spectrum in the Indian scenario. All patients diagnosed for invasive zygomycosis at a tertiary care center in north India from 2000-2004, were retrospectively analyzed. A total of 178 cases (mean average of 35.6 cases/year) of zygomycosis were diagnosed. Rhino-orbito-cerebral type (54.5%) was the commonest presentation followed by cutaneous (14.6%), disseminated (9.0%), and gastrointestinal (8.4%) zygomycosis. Renal and pulmonary zygomycosis were seen in 6.7% patients each. Uncontrolled diabetes mellitus (in 73.6% of cases) was the significant risk factor in all types (Odds Ratio 1.5-8.0) except renal zygomycosis. Breach of skin was the risk factor in 46.2% patients with cutaneous zygomycosis. However, no risk factor could be detected in 11.8% patients. Antemortem diagnosis was possible in 83.7% cases. The commonest (61.5%) isolate was Rhizopus oryzae followed by Apophysomyces elegans in 27% patients. Combination of debridement surgery and amphotericin B therapy was significantly better in survival of the patients (P<0.005) than amphotericin B alone (79.6% vs. 51.7% survival). Thus, a rising trend of invasive zygomycosis was observed in patients with uncontrolled diabetes mellitus in India. Consistent diagnosis of renal zygomycosis in apparently healthy hosts and the emergence of A. elegans in India demand further study.