Alveolar T-helper 17 responses to streptococcus pneumoniae are preserved in ART-untreated and treated HIV-infected Malawian adults.

OBJECTIVE: We explored if HIV infection is associated with impaired T-Helper 17 responses against Streptococcus pneumoniae in the lung. METHODS: We recruited 30 HIV-uninfected healthy controls, 23 asymptomatic HIV-infected adults not on ART, and 40 asymptomatic HIV-infected adults on ART (Median time 3.5yrs), in whom we collected bronchoalveolar lavage fluid. We measured alveolar CD4+ T cell immune responses following stimulation with pneumococcal cell culture supernatant using flow cytometry-based intracellular cytokine staining. RESULTS: We found that the proportion of alveolar CD4+ T cells producing IL-17A following stimulation with pneumococcal cell culture supernatant (CCS) was similar between HIV-uninfected controls and ART-naïve HIV-infected adults (0.10% vs. 0.14%; p = 0.9273). In contrast, the proportion and relative absolute counts of CD4+ T cells producing IL-17A in response to pneumococcal CCS were higher in ART-treated HIV-infected adults compared HIV-uninfected controls (0.22% vs. 0.10%, p = 0.0166; 5420 vs. 1902 cells/100 ml BAL fluid; p = 0.0519). The increase in relative absolute numbers of IL-17A-producing alveolar CD4+ T cells in ART-treated individuals was not correlated with the peripheral blood CD4+ T cell count (r=-0.1876, p = 0.1785). CONCLUSION: Alveolar Th17 responses against S. pneumoniae are preserved in HIV-infected adults. This suggests that there are other alternative mechanisms that are altered in HIV-infected individuals that render them more susceptible to pneumococcal pneumonia.

HIV-associated disruption of lung cytokine networks is incompletely restored in asymptomatic HIV-infected Malawian adults on antiretroviral therapy.

Disruption of lung cytokine networks during chronic HIV infection is incompletely restored in individuals on antiretroviral therapy.

Asymptomatic HIV-infected individuals on antiretroviral therapy exhibit impaired lung CD4(+) T-cell responses to mycobacteria.

RATIONALE: HIV-infected persons on antiretroviral therapy (ART) remain at higher risk of pulmonary tuberculosis (TB) than HIV-uninfected individuals. This increased susceptibility may be caused by impairment of alveolar macrophage (AM) function and/or mycobacteria-specific alveolar CD4(+) T-cell responses observed in HIV-infected ART-naive adults. OBJECTIVES: To determine whether ART was associated with improvement in both AM function, assessed by phagosomal proteolysis, and alveolar CD4(+) T-cell responses to Mycobacterium in HIV-infected individuals. METHODS: Peripheral blood was drawn and bronchoalveolar lavage (BAL) performed on healthy, 35 HIV-uninfected, 25 HIV-infected ART-naive, and 50 HIV-infected ART-treated asymptomatic adults. Phagosomal proteolysis of AM was assessed with fluorogenic beads. Mycobacteria-specific CD4(+) T-cell responses were measured by intracellular cytokine staining. MEASUREMENTS AND MAIN RESULTS: HIV-infected adults on ART exhibited lower plasma HIV viral load and higher blood CD4(+) T-cell count than ART-naive adults. AM proteolysis and total mycobacteria-specific Th1 CD4(+) T-cell responses in individuals on ART for greater than or equal to 4 years were similar to HIV-uninfected control subjects but those on ART for less than 4 years had impaired responses. Total influenza-specific alveolar Th1 CD4(+) T-cell responses were intact in all individuals receiving ART. In contrast, BAL and blood mycobacteria-specific polyfunctional CD4(+) T-cell responses were impaired in adults on ART irrespective of duration. CONCLUSIONS: AM and mycobacteria-specific alveolar CD4(+) T-cell responses in HIV-infected adults on ART for less than 4 years are impaired and may partly explain the high risk of TB in HIV-infected individuals on ART. Strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB in HIV-infected adults who initiate ART should be investigated.

High-resolution single nucleotide polymorphism analysis distinguishes recrudescence and reinfection in recurrent invasive nontyphoidal Salmonella typhimurium disease.

BACKGROUND: Bloodstream infection with invasive nontyphoidal Salmonella (iNTS) is common and severe among human immunodeficiency virus (HIV)-infected adults throughout sub-Saharan Africa. The epidemiology of iNTS is poorly understood. Survivors frequently experience multiply recurrent iNTS disease, despite appropriate antimicrobial therapy, but recrudescence and reinfection have previously been difficult to distinguish. METHODS: We used high-resolution single nucleotide polymorphism (SNP) typing and whole-genome phylogenetics to investigate 47 iNTS isolates from 14 patients with multiple recurrences following an index presentation with iNTS disease in Blantyre, Malawi. We isolated nontyphoidal salmonellae organisms from blood (n = 35), bone marrow (n = 8), stool (n = 2), urine (n = 1), and throat (n = 1) samples; these isolates comprised serotypes Typhimurium (n = 43) and Enteritidis (n = 4). RESULTS: Recrudescence with identical or highly phylogenetically related isolates accounted for 78% of recurrences, and reinfection with phylogenetically distinct isolates accounted for 22% of recurrences. Both recrudescence and reinfection could occur in the same individual, and reinfection could either precede or follow recrudescence. The number of days to recurrence (23-486 d) was not different for recrudescence or reinfection. The number of days to recrudescence was unrelated to the number of SNPs accumulated by recrudescent organisms, suggesting that there was little genetic change during persistence in the host, despite exposure to multiple courses of antibiotics. Of Salmonella Typhimurium isolates, 42 of 43 were pathovar ST313. CONCLUSIONS: High-resolution whole-genome phylogenetics successfully discriminated recrudescent iNTS from reinfection, despite a high level of clonality within and among individuals, giving insights into pathogenesis and management. These methods also have adequate resolution to investigate the epidemiology and transmission of this important African pathogen.

Invasive non-typhoid salmonellae establish systemic intracellular infection in HIV-infected adults: an emerging disease pathogenesis.

BACKGROUND: Salmonellae are facultative intracellular pathogens. Non-typhoid salmonellae (NTS) cause self-limiting mucosal disease in immunocompetent adults but invasive, recurrent disease among human immunodeficiency virus (HIV)-infected adults in Africa. The importance of intracellular NTS infection in HIV is unknown. METHODS: We performed quantitative pour-plate culture of blood samples obtained during febrile events among 495 Malawian adults on 871 occasions, and NTS were isolated at 158 events. Ninety-eight percent were HIV infected, with a median CD4 count of 67 cells/microL. Lysis of pour plates and gentamicin exclusion testing were used to investigate the presence of intracellular NTS in blood and bone marrow. RESULTS: Total viable NTS counts in blood were low (1 colony-forming unit [CFU]/mL) but correlated independently with lower CD4 count and with IL-10 and IL-6 levels, especially at recurrence, suggesting failure to clear intracellular infection. Viable NTS load in blood and bone marrow were closely correlated at index events, but NTS were significantly concentrated in bone marrow, compared with blood samples, at recurrences (6 vs 1 CFU/mL), suggesting systemic tissue replication. Both lysis-pour-plating and gentamicin exclusion testing demonstrated intracellular infection with >1 CFU/cell in both blood and bone marrow specimens. Intracellular bacteria were demonstrated in bone marrow at both index and recurrent events, showing that this is an early and enduring feature of pathogenesis, but intracellular NTS were detected in blood only at index events, particularly in patients with a CD4 count <50 cells/microL. Intravascular NTS at recurrence may therefore reflect extracellular "overspill" from an intracellular sanctuary site, following failure of immunological control. CONCLUSIONS: Invasive NTS have established a new and emerging pathogenesis in the context of HIV infection in Africa.

Non-typhoidal salmonella bacteraemia--an under-recognized feature of AIDS in African adults.

Non-typhoidal salmonella (NTS) infections are severe, invasive and recurrent in the HIV-infected adult, and NTS are the commonest cause of hospital admission with bacteraemia in sub-Saharan Africa. NTS bacteraemia typically presents in patients with HIV/AIDS once the CD4 count falls below 200 cells/microL. In-patient mortality is 35%-60%, and is highest in patients with confusion or severe anaemia. Among survivors, 25%-45% may have single or multiple recurrences of NTS bacteraemia 1-6 months after the first illness, requiring retreatment. Diagnosis relies on blood culture, so in many areas this disease cannot be definitively diagnosed, and must be empirically treated. Treatment is guided by local antibiotic sensitivities; fluoroquinolones are particularly useful for initial treatment if there is multidrug reistance to other agents, and may result in lower recurrence rates than other agents. Where possible, long-term secondary chemoprophylaxis to prevent recurrence is advisable. Successful ARV treatment also prevents recurrence. There is inadequate knowledge about the epidemiology of carriage and transmission among at-risk populations.

Susceptibility of pseudomonas aeruginosa to cefepime versus ceftazidime in patients with cystic fibrosis.

STUDY OBJECTIVES: To compare the susceptibility of respiratory cultures of Pseudomonas aeruginosa obtained from patients with cystic fibrosis to cefepime versus ceftazidime. The pattern of cumulative resistance of P aeruginosa to cefepime in patients who had received at least one treatment course of cefepime between two sputum cultures was also characterized. DESIGN: Prospective consecutive data collection. SETTING: University-affiliated cystic fibrosis clinic and medical center. PATIENTS: Eighty patients with cystic fibrosis who had at least one sputum culture positive for P aeruginosa with reported microbiologic susceptibilities to cefepime and ceftazidime. INTERVENTION: Patient data was collected and analyzed. Measurements and Main Results. Two hundred and thirty-one P aeruginosa isolates were collected over 6 months. A total of 16.4% and 8.7% of the isolates were nonsusceptible to cefepime and ceftazidime, respectively (p=0.01). In eight patients who had not received cefepime before the study period, nonsusceptibility was 11.8% and 27.2% before and after exposure to cefepime, respectively. CONCLUSIONS: Susceptibility of P. aeruginosa isolates in patients with cystic fibrosis was lower with cefepime than with ceftazidime. Follow-up surveillance to determine changes in susceptibility of P aeruginosa isolates to cefepime is warranted.

Effects of therapeutic doses of albuterol on beta2-adrenergic receptor density and metabolic changes.

Beta2-agonist drugs at inhaled supratherapeutic doses or when given orally or parenterally alter peripheral lymphocyte beta2-adrenoceptor density (betaAR) and have demonstrable metabolic effects. However, it is not known whether these changes occur at therapeutic inhaled doses. We therefore studied the effects of therapeutic doses of inhaled albuterol in five asthmatic subjects (mean age 23.0+/-2.4 years) and six normal subjects (mean age 28.3+/-3.3 years). Subjects were studied in a randomized, double-blind protocol in which each subject received either inhaled albuterol (270 microg four times daily) for 2 weeks followed by placebo or vice versa in two sequential 2-week periods separated by a 2-week washout period. In the asthmatics, baseline FEV1 increased significantly (p < 0.05) after 2 weeks of inhaled albuterol treatment compared to the initial visit and after 2 weeks of placebo (mean FEV1: 3.2 L+/-0.7 L, 2.9 L+/-0.5 L, and 3.0 L+/-0. 7 L, respectively). Baseline peripheral lymphocyte betaAR was not significantly different (p > 0.05) between the asthmatic (mean: 757+/-176) and normal subjects (mean: 732+/-251). However, in neither group was there any significant change (p > 0.05) in betaAR or plasma potassium, insulin, or glucose, either acutely or after 2 weeks of albuterol therapy. The present study confirms that there is no difference in peripheral lymphocyte betaAR between asthmatic and normal subjects and also shows that at therapeutic doses of inhaled albuterol, there are no significant changes in betaAR or metabolic effects.

Pediatric sleep disorders: new developments and evolving understanding.

Disorders of sleep in children are distinctly different from sleep disorders in adults. Since children are forced to constantly learn and adapt, the effects of disordered sleep may be more profound. This paper reviews the disorders of sleep that are most significant in each of the stages of development from infancy to adulthood. Recent literature pertaining to advances in the diagnosis and treatment of sudden infant death syndrome and obstructive sleep apnea syndrome in children are highlighted. In addition, recent literature on the relationship of behavior and learning problems to sleep disorders is examined.

The spectrum of sleep-disordered breathing.

The term sleep-disordered breathing has been used synonymously with the term obstructive sleep apnea syndrome (OSAS). In a broader sense, however, the disorders of breathing during sleep exist along a spectrum of severity. The mildest form of sleep-related breathing disorder is intermittent snoring, which is primarily a nuisance without significant health sequelae. The most severe form of disordered breathing is the obesity-hypoventilation syndrome, which is associated with severe morbidity and very high mortality. In between these two extremes are disorders of gradually increasing impact on morbidity and mortality: persistent snoring, upper airway resistance syndrome, and OSAS.

Monitoring sleep and breathing: methodology. Part I: Monitoring breathing.

There is considerable variation in monitoring techniques and definitions of sleep-disordered breathing. Work underway in the Sleep Heart Health Study may help to clarify these issues. Home and portable monitoring have the potential to improve cost and convenience of diagnosis and treatment of sleep disorders but are currently indicated only in specific instances. Detection and monitoring of pediatric sleep-disoriented breathing varies considerably from that of adults.

Variability of peripheral blood lymphocyte beta-2-adrenergic receptor density in humans.

Beta2-adrenergic receptor (betaAR) density on peripheral blood lymphocytes has been used as an index to reflect the betaAR state of the body. Lymphocytes betaARs are unequally distributed among lymphocyte subpopulations, with the highest density on CD8+ cells and the lowest on CD4+ cells. Thus, the measurement of peripheral blood lymphocyte betaAR density could vary with changes in CD4+ and CD8+ cell concentrations. We examined the individual and intersubject variance of betaAR density and lymphocyte subpopulations over time in 10 normal subjects, studied on 3 to 5 different d always at approximately 9:00 A.M. over a 4- to 12-wk period. Peripheral blood lymphocytes were isolated and beta2-adrenergic receptor density was determined by specific binding of [125I]-(-)iodopindolol, and lymphocyte subpopulations were measured by flow cytometry. Average receptors per lymphocyte were 776 +/- 183. Whereas the absolute values of CD4+% and CD8+% cell concentrations varied little in individual subjects (coefficient of variation 9.5% and 11.1%, respectively), the individual betaAR variance was greater (coefficient of variation 22.4%). However there was a significant correlation between betaAR and CD4+% and CD8+% cell concentration (correlation coefficients: -0.58, p < 0.001; +0.51, p < 0.001, respectively). This information is relevant to interpretations of changes in peripheral betaAR in humans.

Tolerance and intolerance to continuous positive airway pressure.

Nasal continuous positive airway pressure (CPAP) is the most effective and widely used therapy for obstructive sleep apnea. As with any chronic therapy, long-term compliance has a significant impact on its effectiveness. Only about half of patients use CPAP for more than half the night on five or more nights per week. Approximately 4 hours of CPAP therapy per night appears to significantly improve daytime alertness and performance. Four hours of therapy also seems to improve sleep-disordered breathing for the remainder of the night. Patient education and close follow-up and intervention appear to improve long-term tolerance. Autotitration CPAP or bilevel positive airway pressure systems are no more effective or better tolerated than conventional CPAP therapy. They may be useful options if patients have been unable to tolerate conventional CPAP therapy.

Tetralogy of Fallot with absent pulmonary valve and bronchial compression: treatment with endobronchial stents.

Absent pulmonary valve syndrome (APVS) is a rare congenital cardiac lesion. The lesion includes ventricular septal defect, overriding aorta, and absence of the pulmonary valve, with resultant pulmonary incompetence. It has been suggested that the pulmonary incompetence induces intrauterine dilatation of the pulmonary artery, which leads to tracheobronchial compression. One of the presenting features in infants with APVS is severe airway obstruction, which may be difficult to manage. We report an infant who benefited from bilateral endobronchial endoscopic stent placement.

Pralidoxime continuous infusion in the treatment of organophosphate poisoning.

OBJECTIVE: To report a case of organophosphate poisoning treated with a continuous infusion of pralidoxime chloride. CASE SUMMARY: A 27-year-old white man presented with extreme agitation, muscle weakness and fasciculations, and respiratory failure after ingesting an organophosphate pesticide (Dursban, active ingredients chlorpyrifos and xylene) as a suicide attempt. Atropine sulfate and pralidoxime chloride were administered intermittently, but the patient continued to be extremely agitated and have muscle fasciculations. Subsequently, a continuous intravenous infusion of pralidoxime (8 mg/mL concentration) at 500 mg/h was initiated to help control breakthrough nicotinic symptoms. Therapy with atropine and pralidoxime was continued for approximately 72 hours. Therapy was discontinued due to the predominance of anticholinergic symptoms and the patient's increased awareness. DISCUSSION: Severe organophosphate poisoning with nicotinic and/or central manifestations should be treated with pralidoxime in addition to atropine. The rationale supporting the use of pralidoxime as a continuous infusion in this case includes: (1) slow absorption of organophosphate compounds following exposure to large quantities, (2) unknown quantity ingested, (3) delayed nicotinic effects from redistribution of lipid-soluble organophosphate and metabolic activation of phosphorothioates such as chlorpyrifos, and (4) intensive care monitoring. There is limited documentation in the literature of continuous infusions of pralidoxime used to treat organophosphate poisoning and the stability of the admixture is unknown. CONCLUSIONS: A continuous pralidoxime infusion successfully managed the prolonged nicotinic symptoms seen after ingestion of an organophosphate. A continuous infusion of pralidoxime may be particularly useful in cases of organophosphate poisoning when the extent of chemical exposure or quantity of chemical ingested is unknown but potentially toxic and the therapy must be symptomatically managed.