Asthma, Airflow Obstruction, and Eosinophilic Airway Inflammation Prevalence in Western Kenya: A Population-Based Cross-Sectional Study.

Objectives: Determine the prevalence of airway disease (e.g., asthma, airflow obstruction, and eosinophilic airway inflammation) in Kenya, as well as related correlates of airway disease and health-related quality of life. Methods: A three-stage, cluster-randomized cross-sectional study in Uasin Gishu County, Kenya was conducted. Individuals 12 years and older completed questionnaires (including St. George's Respiratory Questionnaire for COPD, SGRQ-C), spirometry, and fractional exhaled nitric oxide (FeNO) testing. Prevalence ratios with 95% confidence intervals (CIs) were calculated. Multivariable models were used to assess correlates of airflow obstruction and high FeNO. Results: Three hundred ninety-two participants completed questionnaires, 369 completed FeNO testing, and 305 completed spirometry. Mean age was 37.5 years; 64% were women. The prevalence of asthma, airflow obstruction on spirometry, and eosinophilic airway inflammation was 21.7%, 12.3% and 15.7% respectively in the population. Women had significantly higher SGRQ-C scores compared to men (15.0 vs. 7.7). Wheezing or whistling in the last year and SGRQ-C scores were strongly associated with FeNO levels >50 ppb after adjusting for age, gender, BMI, and tobacco use. Conclusion: Airway disease is a significant health problem in Kenya affecting a young population who lack a significant tobacco use history.

Neuroimaging and immunological features of neurocognitive function related to substance use in people with HIV.

This study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms.

Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study.

Animal models suggest postoperative cognitive dysfunction may be caused by brain monocyte influx. To study this in humans, we developed a flow cytometry panel to profile cerebrospinal fluid (CSF) samples collected before and after major noncardiac surgery in 5 patients ≥60 years of age who developed postoperative cognitive dysfunction and 5 matched controls who did not. We detected 12,654 ± 4895 cells/10 mL of CSF sample (mean ± SD). Patients who developed postoperative cognitive dysfunction showed an increased CSF monocyte/lymphocyte ratio and monocyte chemoattractant protein 1 receptor downregulation on CSF monocytes 24 hours after surgery. These pilot data demonstrate that CSF flow cytometry can be used to study mechanisms of postoperative neurocognitive dysfunction.

The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.

BACKGROUND/OBJECTIVES: Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN: Observational prospective cohort. SETTING: Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS: Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS: Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION: INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae. J Am Geriatr Soc 67:794-798, 2019.

Causes of death on antiretroviral therapy: a post-mortem study from South Africa.

BACKGROUND: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. METHODS: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. RESULTS: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. CONCLUSIONS: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge.

Acute HIV infection among pregnant women in Malawi.

There are limited data on acute HIV infection (AHI) prevalence during pregnancy. Malawian pregnant women admitted in the third trimester and meeting eligibility criteria underwent dual HIV rapid antibody testing. AHI prevalence was retrospectively detected through HIV RNA pooling of seronegative plasma. Among 3,825 pregnant women screened, dual HIV rapid testing indicated that 30.2% were HIV positive, 69.7% were HIV negative, and 0.1% were indeterminate. Sensitivity and specificity of dual rapid testing was 99.0% and 98.7%, respectively. Of 2,666 seronegative specimens, 2,327 had samples available for HIV RNA pooling; 5 women (0.21%) (95% confidence interval, 0.03-0.40%) had AHI with a median peripartum viral load of 1,324,766 copies/mL. Pregnant women are at risk for AHI, warranting counseling of all women and their sexual partners about incident HIV during pregnancy. Dual HIV rapid tests have high sensitivity and specificity. HIV testing should be repeated in the third trimester and/or at delivery.

Immune restoration diseases reflect diverse immunopathological mechanisms.

Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study.

OBJECTIVE: To determine the incidence, clinical manifestations, risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. DESIGN: Prospective surveillance cohort and nested case-control study in a large, University hospital-based antiretroviral therapy (ART) clinic. METHODS: A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case-control study with controls matched to IRIS cases on ART duration. RESULTS: During the first 6 months of ART, 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44, 41%), abscess formation and suppurative folliculitis (8/44, 18.2%), varicella zoster (6/44, 13.6%), herpes simplex (4/44, 9.1%), cryptococcal meningitis (3/44, 6.8%), molluscum contagiosum (3/44, 6.8%), and Kaposi's sarcoma (2/44, 4.5%). Median IRIS onset was 48 days (interquartile range, 29-99) from ART initiation. In comparison with controls, IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/microl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/microl; P = 0.05), but similar virological and immunological response to ART. In multivariable analyses, higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/microl increase). Most IRIS cases were mild, with ART discontinued in three (6.8%) patients, corticosteroids administered to four (9.1%) patients, and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. CONCLUSIONS: IRIS may affect 10% of patients initiating ART in Africa, particularly those with advanced immunosuppression, but severe, life-threatening IRIS is uncommon.

Smoking and predictors of pneumonia among HIV-infected patients receiving care in the HAART era.

BACKGROUND: Smoking tobacco is disproportionably common among HIV-infected patients in the highly active antiretroviral therapy (HAART) era. METHODS: An observational cohort study of 300 HIV-positive patients receiving care between 1996 and 2005 examined the effect of smoking on pneumonia risk. Multivariable analyses assessed the association between smoking and pneumonia risk and identified independent predictors of pneumonia during the HAART era. RESULTS: Current smoking was common (67%). Eighty-two patients (27%) experienced 119 pneumonia episodes during 2151 patient-years of follow-up, with 7.2 episodes/100 person-years among smokers and 2.9 episodes/100 person-years among non-smokers (unadjusted incidence rate ratio (IRR): 2.50 (95% CI: 1.58, 4.09). Adjustment for age and HIV RNA level resulted in an IRR of 1.77 (95% CI: 0.98, 3.21). No prior antiretroviral therapy use (P-value <0.001), higher HIV RNA level (P-value = 0.01), lower CD4 count (P-value = 0.01), younger age (P-value = 0.01), and alcohol use (P-value = 0.04) were independent predictors of pneumonia. HAART use decreased pneumonia risk (IRR 0.28, 95% CI: 0.18, 0.44). CONCLUSIONS: While HIV-positive smokers had over a 2-fold increase in the rate of pneumonia, the trend did not reach statistical significance in multivariable models. Clinical factors such as HAART, alcohol use and immunological status are important in pneumonia risk.

Mycobacterium avium-intracellulare cellulitis occurring with septic arthritis after joint injection: a case report.

BACKGROUND: Cellulitis caused by Mycobacterium avium-intracellulare has rarely been described. Mycobacterium avium-intracellulare is a rare cause of septic arthritis after intra-articular injection, though the causative role of injection is difficult to ascertain in such cases. CASE PRESENTATION: A 57-year-old with rheumatoid arthritis treated with prednisone and azathioprine developed bilateral painful degenerative shoulder arthritis. After corticosteroid injections into both acromioclavicular joints, he developed bilateral cellulitis centered over the injection sites. Skin biopsy showed non-caseating granulomas, and culture grew Mycobacterium avium-intracellulare. Joint aspiration also revealed Mycobacterium avium-intracellulare infection. CONCLUSION: Although rare, skin and joint infections caused by Mycobacterium avium-intracellulare should be considered in any immunocompromised host, particularly after intra-articular injection. Stains for acid-fast bacilli may be negative in pathologic samples even in the presence of infection; cultures of tissue specimens should always be obtained.