Shireesha Dhanireddy

2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia

Mechanical ventilation (MV) is frequently employed for the management of critically ill patients with respiratory failure. A major complication of mechanical ventilation (MV) is the development of ventilator-associated pneumonia (VAP), in which Staphylococcus aureus is a prominent pathogen. Moreover, previous studies suggest that MV may be an important cofactor in the development of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). S. aureus pulmonary infection was induced in spontaneously breathing mice (C57Bl/6) or mechanically ventilated mice to determine whether MV contributes to the development of ALI and/or systemic inflammation. The combination of MV and bacteria significantly increased the influx of neutrophils into bronchoalveolar lavage fluid (BALF), augmented pulmonary production of the proinflammatory cytokines KC, MIP-2, TNF-α, and IL-6, and increased alveolar-capillary permeability to proteins. MV also induced proinflammatory cytokine expression in peripheral blood, associated with extrapulmonary hepatic and renal dysfunction. Surprisingly, bacterial clearance in the lungs and extrapulmonary bacterial dissemination was not affected by MV. These data indicate that MV exacerbates both pulmonary and systemic inflammation in response to bacteria and contributes to the pathogenesis of both ALI and the multiple organ dysfunction syndrome, without necessarily affecting bacterial clearance or extra-pulmonary bacterial dissemination.

Paradoxical Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Treated With Combination Antiretroviral Therapy After AIDS-Defining Opportunistic Infection

BACKGROUND The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs. METHODS We examined patients in the University of Washington Human Immunodeficiency Virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics, and immunologic changes in patients with and without IRIS. RESULTS Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7%-16%) developed paradoxical IRIS in the first year on ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs 7% [1/15], P < .01). Patients with mucocutaneous KS and tuberculosis-IRIS experienced greater median increase in CD4(+) cell count during the first 6 months of ART compared with those without IRIS (+158 vs +53 cells/μL, P = .04, mucocutaneous KS; +261 vs +113, P = .04, tuberculosis). CONCLUSIONS Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in >10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality.

Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction

IntroductionMultiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury.MethodsWe administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 μg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS).ResultsMyeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-α.ConclusionNon-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.

Hepatitis B vaccination in HIV-infected adults: current evidence, recommendations and practical considerations

Immunization with hepatitis B (HBV) vaccine is recommended for all HIV-infected individuals without immunity to HBV. This patient population, however, has relatively poor HBV vaccine responses. Factors associated with this impaired HBV vaccine response in HIV-infected individuals may include older age, uncontrolled HIV replication, and low nadir CD4 cell count. Postvaccination testing for HBV surface antibody is recommended and vaccine non-responders should undergo repeat immunization with a full series. The benefit of double dosage, the appropriate strategy for HIV-infected patients with isolated HBV core antibody and the timing and number of vaccinations in persons with advanced immunosuppression on highly active antiretroviral therapy remain controversial areas.

Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen

BACKGROUND The Fas/FasL system is both proapoptotic and proinflammatory. FasL is inhibited by decoy receptor-3 (DcR3), a naturally occurring decoy receptor. We determined the effects of systemic blockade of the Fas/FasL system by a DcR3 analog (DcR3-a) in mice with pneumococcal pneumonia. METHODS Streptococcus pneumoniae (7.2 x 105 or 1.9 x 107 cfu/mL) was instilled intratracheally into untreated C57Bl/6 mice, C57Bl/6 mice treated with DcR3-a, or Fas-deficient lpr mice, and the mice were studied 48 h later. RESULTS After instillation of the lower bacterial dose, disruption of the Fas/FasL system by either DcR3-a or the lpr mutation resulted in improved clearance of bacteria in the lungs (mean +/- SE, 4.6+/-2.1 x 10(6) and 3.5 +/- 1.6 x 10(6) cfu/lung, respectively, vs. 21.9+/-9.3 x 10(6) cfu/lung in untreated C57Bl/6 mice; P<.05) and decreased percentage of polymorphonuclear neutrophils in bronchoalveolar lavage fluid (mean +/- SE, 19.3%+/-9.5% and 20.2%+/-7.8%, respectively, vs. 55.0%+/-12.2% in untreated C57Bl/6 mice; P<.05). These changes were associated with decreased lung concentrations of the proinflammatory cytokines tumor necrosis factor- alpha and macrophage inflammatory protein-2 and with a decrease in apoptotic cells in the alveolar walls. CONCLUSION Blockade of the Fas/FasL system by DcR3-a in the lungs improves clearance of bacteria in mice with pneumococcal pneumonia.

Integrating a web-based, patient-administered assessment into primary care for HIV-infected adults.

Providers routinely under diagnose at risk behaviors and outcomes, including depression, suicidal ideation, substance abuse, and poor medication adherence. To address this, we developed a web-based, self-administered patient-reported assessment tool and integrated it into routine primary care for HIV-infected adults. Printed results were delivered to providers and social workers immediately prior to patient appointments. The assessment included brief, validated instruments measuring clinically relevant domains including depression, substance use, medication adherence, and HIV transmission risk behaviors. Utilizing the Institute for Healthcare Improvements Plan-Do-Study-Act (PDSA) approach to quality improvement, we addressed issues with clinic flow, technology, scheduling, and delivery of assessment results with the support of all levels of clinic staff. We found web-based patient-reported assessments to be a feasible tool that can be integrated into a busy multi-provider HIV primary care clinic. These assessments may improve provider recognition of key patient behaviors and outcomes. Critical factors for successful integration of such assessments into clinical care include: strong top-level /ort from clinic management, provider understanding of patient-reported assessments as a valuable clinical tool, tailoring the assessment to meet provider needs, communication among clinic staff to address flow issues, timeliness of delivery, and sound technological resources.

Outcomes of a Clinic-Based Surveillance-Informed Intervention to Relink Patients to HIV Care

Background:Improving patient retention in HIV care is crucial to improving the HIV care continuum. We instituted and evaluated a relinkage program that uses clinical data to identify potentially out-of-care patients, matches those data to public health surveillance, and employs a linkage specialist (LS) to coordinate care relinkage. Methods:The intervention began November 1, 2012, in the largest HIV clinic in Washington State. We evaluated program outcomes and compared patient outcomes in the year after initiation of the intervention to a historical control cohort of patients. Cox proportional hazard ratios were used to compare time to relinkage to care between cohorts, and regression models using generalized estimated equations were preformed to examine secondary outcomes of relinkage to care, engagement in care, and viral suppression. Results:A total of 753 patients were identified as “out of care” on November 1, 2012. Matching with surveillance data and initial LS investigations found that 596 (79%) of these patients had moved, transferred care, or were incarcerated. Of the 157 remaining patients, 40 (25%) relinked to care before LS contact, and the LS successfully contacted 38 (24%). A total of 116 (15%) patients in the intervention cohort relinked to care and 24 (20%) were contacted by the LS. Compared with the historical cohort, the time to relinkage was shorter among patients in the intervention cohort [adjusted hazard ratio = 1.7 (1.2–2.3)] and a greater proportion relinked (15% vs. 10%). Conclusions:This clinic-based surveillance-informed relinkage intervention showed statistically significant but modest effectiveness in returning out-of-care patients to HIV care compared with historical controls.

Immune Response to Hepatitis B Virus Vaccination Among HIV-1 Infected and Uninfected Adults in Kenya

BACKGROUND In studies from high-income countries, human immunodeficiency virus type 1 (HIV-1)-infected persons have diminished responses to hepatitis B virus (HBV) vaccination, compared with HIV-1-uninfected persons, but data from other settings are limited. METHODS We compared the immune response to HBV vaccination among HIV-1-infected and HIV-1-uninfected Kenyan adults and assessed the response of HIV-1-infected initial nonresponders to revaccination with a standard HBV vaccine series. RESULTS Of 603 participants, 310 (51.4%) were HIV-1-infected, for whom the median CD4(+) T-cell count was 557 cells/μL (interquartile range, 428-725 cells/μL); none were receiving antiretroviral therapy. Nonresponse to HBV vaccine was higher among HIV-1-infected participants, compared with HIV-1-uninfected participants (35.8% vs 14.3%; odds ratio, 3.33; P < .001). Of 102 HIV-1-infected initial nonresponders, 88 (86.3%) responded to revaccination, for an overall response, including to revaccination, of 94.9%. Among HIV-1-infected individuals, lower CD4(+) T-cell counts and male sex were independent predictors of nonresponse to initial vaccination, and lower body mass index, higher plasma HIV-1 RNA levels, and longer time to revaccination predicted nonresponse to revaccination. CONCLUSIONS Kenyan adults had similar HBV vaccination responses as persons from high-income countries. Timely revaccination of HIV-1-infected nonresponders increased response to the vaccine to 95%.