Prevalence of non-tuberculous mycobacteria in HIV-infected patients admitted to hospital with pneumonia.

People living with the human immunodeficiency virus (PLWH) may be particularly vulnerable to the consequences of non-tuberculous mycobacteria (NTM) given their defective T cell-mediated immunity and high rates of structural lung disease. To determine the prevalence of NTM in PLWH hospitalized with pneumonia and to assess the potential predictors of NTM isolation. Secondary data analysis of a prospective cohort study (2007-2011) of early bronchoscopy in PLWH presenting with suspected pneumonia was undertaken. Subjects with any species of NTM, henceforth described as 'NTM of undetermined significance' (NTM-US), isolated from sputum or bronchoalveolar lavage fluid (BALF), were included in the analysis. Potential predictors were chosen a priori. Among 196 HIV-infected subjects hospitalized with pneumonia, 96 had respiratory samples positive for NTM-US, with 91% of all NTM-US isolated from sputum compared with BALF. The overall prevalence of NTM-US was 49% (96/196). More NTM subjects were smokers (P = 0.08), with a history of chronic obstructive pulmonary disease (P = 0.08). Among those with pathogenic NTM, 39% (34/88) would have met American Thoracic Society microbiologic criteria for NTM pulmonary disease (17% of total cohort). Respiratory cultures, predominantly sputum samples, were positive for NTM-US in 45% of HIV-infected subjects admitted to hospital for pneumonia. Further research is needed to characterize the prevalence of NTM in PLWH and help establish specific diagnostic criteria in this population. .

Serum and bal beta-D-glucan for the diagnosis of Pneumocystis pneumonia in HIV positive patients.

BACKGROUND/PURPOSE: The diagnosis of patients with pulmonary infiltrates and human immunodeficiency virus (HIV) infection remains a challenge. In current clinical practice the gold standard for Pneumocystis jirovecii pneumonia (PCP) diagnosis remains the identification of the organism in bronco alveolar lavage (BAL) using microscopy (e.g., silver stain). (1->3)-ß -d-glucan (BG) is a polysaccharide that is present within the cell wall of Pneumocystis and other fungi. METHODS: We analyzed serum and BAL lavage fluid from a cohort of 119 patients that did have HIV, a diagnosis of pneumonia and underwent bronchoscopy (FOB) for diagnosis of PCP. RESULTS: The discriminative power of serum BG for the diagnosis of PCP in this group of patients was very high. Using a cutoff of 300 pg/mL, the sensitivity, specificity, positive predictive value(PPV) and negative predictive value (NPV) were 91%, 92%, 89% and 93% respectively. A model for ROC with just serum BG (N = 108) had an AUC of 0.95. Serum procalcitonin (PCT) and BAL BG were not as accurate for the diagnosis of PCP. For BAL BG using a cutoff of 783 pg/mL, the sensitivity,specificity, positive predictive value (PPV) and negative predictive value (NPV) were 72%, 79%,72% and 79% respectively. The differences between the medians for serum PCT between the group with a without PCP did not reach statistical significance (p = 0.6137). CONCLUSION: The measurement of serum BG should be incorporated in the diagnostic work up of HIV positive patients with dyspnea and infiltrates on chest X X-ray. Our study confirms the diagnostic value of serum BG previously reported by others but we add a cutoff value that we believe is more accurate for patients with AIDS and suspicion of PCP.

Pneumocystis colonisation is common among hospitalised HIV infected patients with non-Pneumocystis pneumonia.

BACKGROUND: When Pneumocystis DNA is recovered from respiratory specimens of patients without Pneumocystis pneumonia (PCP), patients are said to be colonised with Pneumocystis, although the significance of this state is unknown. Understanding risk factors for and outcomes of colonisation may provide insights into the life cycle and transmission dynamics of Pneumocystis jirovecii. METHODS: We performed a cross sectional study of the prevalence and clinical predictors of Pneumocystis colonisation in 172 HIV infected, PCP negative inpatients undergoing diagnostic evaluation of 183 episodes of pneumonia at either the Medical Center of Louisiana at New Orleans between 2003 and 2005 or San Francisco General Hospital between 2000 and 2005. DNA was extracted from sputum and bronchoalveolar lavage specimens and amplified using a nested PCR assay at the mitochondrial large subunit (18S) ribosomal RNA locus. Colonisation was deemed present if Pneumocystis DNA was identified by both gel electrophoresis and direct DNA sequencing. RESULTS: 68% (117/172) of all patients were colonised with Pneumocystis. No strong associations with colonisation were identified for any demographic factors. Among clinical factors, having a CD4+ T cell count

Host defense in respiratory infections.

Respiratory defenses against infection involve a diverse and complex system. Mechanical barriers limit exposure of the respiratory tract to potential pathogenic organisms, whereas the mucociliary apparatus and cough reflexes work to expel any microbes that may bypass the initial defenses. When microorganisms have gained entry to the lower respiratory tract, the alveolar macrophage and recruited phagocytes may eliminate the culprits before active infection can be established. Only after the failure of the innate immune defenses is a specific immune response mounted. Examination of clinical defects in host defense allows one to understand the importance of the multitude of components of the lung's immune defense system.

Development and characterization of a molecular viability assay for Pneumocystis carinii f sp hominis.

Pneumocystis carinii pneumonia (PCP) remains the most common opportunistic infection among human immunodeficiency virus-infected persons. Despite this, little is known concerning the transmission dynamics of this infection. In the absence of a reliable method to isolate and culture P. carinii from environmental samples, it has not been possible to assess the importance of person-to-person transmission in the epidemiology of PCP. A molecular viability assay was developed for the human form of P. carinii (P. carinii f sp hominis) that is applicable to both clinical specimens and environmental samples. This assay will enable the evaluation of the spread and persistence of viable human P. carinii in the environment.

Keratinocyte growth factor attenuates hydrostatic pulmonary edema in an isolated, perfused rat lung model.

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.

The effects of granulocyte colony-stimulating factor and neutrophil recruitment on the pulmonary chemokine response to intratracheal endotoxin.

Although G-CSF has been shown to increase neutrophil (polymorphonuclear leukocyte, PMN) recruitment into the lung during pulmonary infection, relatively little is known about the local chemokine profiles associated with this enhanced PMN delivery. We investigated the effects of G-CSF and PMN recruitment on the pulmonary chemokine response to intratracheal LPS. Rats pretreated twice daily for 2 days with an s.c. injection of G-CSF (50 microg/kg) were sacrificed at either 90 min or 4 h after intratracheal LPS (100 microg) challenge. Pulmonary recruitment of PMNs was not observed at 90 min post LPS challenge. Macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) concentrations in bronchoalveolar lavage (BAL) fluid were similar in animals pretreated with or without G-CSF at this time. G-CSF pretreatment enhanced pulmonary recruitment of PMNs (5-fold) and greatly reduced MIP-2 and CINC levels in BAL fluid at 4 h after LPS challenge. In vitro, the presence of MIP-2 and CINC after LPS stimulation of alveolar macrophages was decreased by coculturing with circulating PMNs but not G-CSF. G-CSF had no direct effect on LPS-induced MIP-2 and CINC mRNA expression by alveolar macrophages. Pulmonary recruited PMNs showed a significant increase in cell-associated MIP-2 and CINC. Cell-associated MIP-2 and CINC of circulating PMNs were markedly increased after exposure of these cells to the BAL fluid of LPS-challenged lungs. These data suggest that recruited PMNs are important cells in modulating the local chemokine response. G-CSF augments PMN recruitment and, thereby, lowers local chemokine levels, which may be one mechanism resulting in the subsidence of the host proinflammatory response.

Keratinocyte growth factor prevents ventilator-induced lung injury in an ex vivo rat model.

Mechanical ventilation has been shown to produce lung injury characterized by noncardiogenic pulmonary edema. Keratinocyte growth factor (KGF) is a heparin-binding growth factor that causes alveolar type II pneumocyte hyperplasia. KGF pretreatment and the resultant pneumocyte hyperplasia reduce fluid flux in models of lung injury. We utilized the isolated perfused rat lung model to produce lung injury by varying tidal volume and the level of positive end-expiratory pressure during mechanical ventilation. Pretreatment with KGF attenuated ventilator-induced lung injury (VILI). This was demonstrated by lower wet-to-dry lung weight ratios and less lung water accumulation in the KGF group. Further, KGF prevented the decline in dynamic compliance and alveolar protein accumulation in VILI. KGF pretreatment reduced alveolar accumulation of intravascularly administered fluorescein isothiocyanate-labeled high-molecular-weight dextran. Thus, pretreatment with KFG attenuates injury in this ex vivo model of VILI via mechanisms that prevent increases in permeability.

Gender differences in toxicokinetics, liver metabolism, and plasma esterase activity: observations from a chronic (27-week) toxicity study of enalapril/diltiazem combinations in rats.

Diltiazem (DTZ), a calcium channel blocker, and enalapril (EN), an angiotensin-converting enzyme inhibitor, are being developed as combination therapy for cardiovascular disease. A toxicokinetic evaluation of EN and DTZ drug levels during a 27-week toxicity study used an enzyme assay to measure EN and an HPLC assay to measure DTZ, deacetylated DTZ (DAD), and desmethyl DTZ (DMD). EN exposure during drug week 7 was proportional to dose and without dispositional gender differences. However, gender differences in DTZ and metabolite plasma profiles were dramatic. For example, female DTZ Cmax values were roughly 15-20% of males; DAD plasma Cmax values were roughly 3- to 10-fold greater; and the desmethyl metabolite, DMD, was roughly 2- to 10-fold lower. Sodium fluoride added to samples taken during drug week 26 to inhibit plasma esterase activity did not alter DTZ plasma profiles, suggesting that gender differences in DTZ and metabolite plasma levels were not caused by sample degradation. Liver esterase activity in treated rats was significantly greater (p > 0.05) than controls, whereas plasma activity was not affected. Female plasma and liver esterase activities were roughly 3- and 5-fold greater than males (p < 0.002), respectively, which may explain the low DTZ and high DAD plasma levels we measured. These results indicate that liver and plasma esterase activity is much greater in female rats and may be responsible for the differences in drug and metabolite plasma profiles relative to males. In addition, chronic coadministration of EN/DTZ may modestly increase liver esterase activity.

Elevated parathyroid hormone-related protein and hypercalcemia in a patient with cutaneous squamous cell carcinoma complicating hidradenitis suppurativa.

We have described the case of a patient with long-standing hidradenitis suppurativa in whom associated cutaneous squamous cell carcinoma developed; this was complicated by hypercalcemia. Serum PTH-RP levels were elevated to 14.8 pmol/L. This is the third case report of hypercalcemia associated with squamous cell carcinoma complicating hidradenitis suppurativa and the first in which an elevated serum PTH-RP level has been documented in cutaneous squamous cell carcinoma.