Characterization of aerosol output from various nebulizer/compressor combinations.

OBJECTIVES: Different commercially available nebulizers and compressors are available. However, the optimal combination for drug delivery is unknown. METHODS: Flow rates of five different compressors (n = 3/compressor) tested alone and in combination with five different commercial nebulizers (n = 9 of each brand of nebulizer) were evaluated. Thereafter, the performances of the different nebulizers were evaluated using 2.5 mg albuterol solution (0.5 mL) added to 2.5 mL saline at flow rates of 2, 3, 4, and 5 L/minute using a laser particle analyzer. Volume median diameter and percentage of particles in the respirable range (1-5 microm) were calculated from this data. Time for nebulization (in seconds) and residual volume (in milliliters) were also recorded. RESULTS: The mean flow rates for the compressors evaluated without a nebulizer attached ranged from 6.6 L/minute (LifeCare Freedom-neb; LifeCare International, Lafayette, CO) to 12.2 L/minute (DeVilbiss Pulmo-Aide; DeVilbiss Health Care, Somerset, PA). Flow rates for the nebulizer/compressor combinations ranged from 2.08 L/minute (Pari LC Jet Proneb; Pari Respiratory Equipment, Richmond, VA) to 5.42 L/minute (Puritan Bennett Raindrop; Puritan Bennett, Lenexa, KS/Omron Compare; Omron, Health Care,Vernon Hills, IL). Using the repeated measure ANOVA model, the interaction between flow rate and device was significant (P < 0.001) for both percentage of particles in the respirable range and log volume median diameter. It was observed that the percentage of particles in the respirable range for the Pari LC Jet did not increase across flow rates in contrast to the other 4 nebulizers. All comparisons to the Pari LC Jet at 2 L/minute were significant. CONCLUSIONS: Marked variability exists in the flow rates among different commercially available compressors used for home nebulization of inhaled pulmonary medications. Different nebulizer/compressor combinations have markedly different performance characteristics which could result in different efficacy and safety profiles of the medications being administered via these devices. We recommend that this type of information be used as a starting point for selecting different nebulizer/compressor combinations. Further clinical evaluation is warranted.

Cell-mediated immune response to tuberculosis antigens: comparison of skin testing and measurement of in vitro gamma interferon production in whole-blood culture.

Although delayed-type hypersensitivity skin testing with tuberculin purified protein derivative (PPD) is the standard for tuberculosis screening, its variability suggests the need for a more sensitive, noninvasive test. An in vitro whole-blood assay has been proposed as an alternative. Using health care worker volunteers, we confirmed the correlation between PPD skin test (PPD-ST) results (positive, induration of >15 mm) and a standardized gamma interferon (IFN-gamma) assay, QuantiFERON-TB (Q-IFN), manufactured by CSL Biosciences in Australia, and we evaluated Mycobacterium tuberculosis culture subfractions as potential substitutes for PPD. Twenty healthy volunteers with positive PPD-ST results and 20 PPD-ST-negative controls were enrolled. Whole blood was cultured with human PPD antigens (HuPPD), Mycobacterium avium complex (MAC) PPD, phytohemagglutinin (PHA), and four M. tuberculosis culture subfractions: low-molecular-weight culture, filtrate, culture filtrate without lipoarabinomannan, soluble cell wall proteins, and cytosolic proteins, all developed from M. tuberculosis strain H(37)RV. Secretion of IFN-gamma (expressed as international units per milliliter) was measured by an enzyme immunoassay. The PPD or subculture fraction response as a percentage of the PHA response was used to determine positivity. Sixteen of 20 PPD-ST-positive individuals were classified as M. tuberculosis positive by Q-IFN, and 1 was classified as MAC positive. Sixteen of 20 PPD-ST-negative individuals were M. tuberculosis negative by Q-IFN, 2 were MAC positive, and 2 were M. tuberculosis positive. The tuberculosis culture subfractions stimulated IFN-gamma production in PPD-ST-positive volunteers, and significant differences could be seen between the two PPD-ST groups with all subfractions except soluble cell wall protein; however, the response was variable and no better than the Q-IFN PPD. The agreement between the Q-IFN test and the PPD-ST was good (Cohen's kappa = 0.73). The Q-IFN assay can be a useful tool in further studies of immune responses to M. tuberculosis antigens.

Comparison of three commercial ultrasonic nebulizers.

BACKGROUND: The clinical acceptance of the initial ultrasonic nebulizers was impeded by their production of significant quantities of droplets larger than the respirable range that could have resulted in poor pulmonary deposition of nebulized medications. Subsequent modifications in the design of ultrasonic nebulizers have occurred. Overall nebulizer performance characteristics of the newer ultrasonic devices have not been evaluated. OBJECTIVE: Three commercially available ultrasonic nebulizers (DeVilbiss-Pulmosonic, Omron-Microair, Rhône Poulenc-Rorer-Fisoneb) were studied to compare the aerosol output characteristics. METHODS: The parameters studied were total volume output (TVO), time to nebulize total output (TTO), percent of droplets with volume diameters in the respirable range (PDVRR, 1 to 5 microm), albuterol concentration during nebulization, and the total drug delivered. All nebulizers were filled with 2.5 mL of saline and 0.5 mL of albuterol nebulizer solution. Three units from each manufacturer, each from a different lot, were evaluated in duplicate. RESULTS: The nebulizer with the largest volume output was the Omron (mean 2.94 mL), which also demonstrated the longest nebulization time (mean 10.3 min). The DeVilbiss and Rhône Poulenc-Rorer units delivered smaller volumes (mean 2.5 mL, 2.4 mL, respectively) but nebulized more rapidly (mean 2.21 min, 3.54 min, respectively). The Omron nebulizer generated the highest PDVRR with a mean of 38%. The DeVilbiss had a mean PDVRR of 16% and the Rhône Poulenc-Rorer a mean PDVRR of 21%. The majority of droplets from all three machines had a volume diameter smaller than the respirable range, ie, in the 0.5 to 1.0 microm range (Omron-60%, DeVilbiss-83%, Rhône Poulenc-Rorer-79%). For all three nebulizers there appeared to be no concentrating or diluting effect during nebulization implying that equal quantities of albuterol and diluent were delivered. The Rhône Poulenc-Rorer units demonstrated the greatest unit-to-unit variability with respect to TVO while the Omron units demonstrated the greatest unit to unit variability with respect to TTO. CONCLUSION: We conclude that several improvements in the design of ultrasonic nebulizers have resulted in the reduction of the size of the droplets generated. Our evaluation of the three commercially available ultrasonic nebulizers revealed that the majority of droplets generated were within or below the respirable range. There was no concentrating or diluting effect during nebulization for all three nebulizers. The output characteristics of the three devices differ and this will effect the delivery time as well as amount of drug delivered to the lungs.

Varicella immunity: persistent serologic non-response to immunization.

OBJECTIVE: Varicella-zoster (VZV) infection is an occupational hazard for health care workers. The "gold standard" for assessing protection is a positive antibody titer. We present a case of persistent serologic non-responsiveness following VZV immunization and discuss a management strategy. METHODS: A 29-year-old woman, immunocompetent pediatric resident was repeatedly removed from her clinical duties because of a negative history of chicken pox and the absence of a VZV antibody titer. She received a total of three doses of the VZV vaccine and continued to have a negative antibody titer as measured by a commercial ELISA assay (Wampole). Subsequently, she had three direct contacts with infectious children and did not develop clinical chicken pox. RESULTS: A lymphocyte proliferation assay was performed using inactivated varicella vaccine and tetanus antigens. The patient's varicella and tetanus stimulation index (SI) were 46.5 and 42, respectively. The SI for the positive control (a patient recently recovered from a wild type infection) were 144 (varicella specific), and 114 (tetanus). The SI secondary to VZV antigens reported in the literature is 30.5 +/- 9.1. We reassessed the varicella antibody titer using more sensitive assays: fluorescent antibody to membrane antigen and latex agglutination. Both tests verified the presence of VZV specific IgG at a titer of 1:8 in our patient. CONCLUSION: This case illustrates that in a subgroup of individuals the antibody response to VZV vaccine may be low despite an adequate cell-mediated response. Commercial VZV ELISA assays were designed to measure higher titers associated with natural infection rather than the lower titer induced by the vaccine. Repeated immunizations plus more sensitive measures of VZV-specific IgG should be used to validate protection rather than the current commonly utilized ELISA screening. Clinicians should be aware of the variability in VZV-specific antibody assays when assessing post VZV vaccine titers prior to determining protection in health care workers.

A drug interaction between zafirlukast and theophylline.

The apparent low adverse effect profile of the new drug zafirlukast has made it an attractive choice in the treatment of asthma. We present the first case (to our knowledge) of a potentially serious drug-drug interaction between zafirlukast and theophylline. A 15-year-old white girl with asthma had been taking theophylline (Slo-bid, Rhone-Poulenc Rorer Pharmaceuticals Inc, Collegeville, Pa) (300 mg twice daily), with drug levels of approximately 61 micromol/L (11.0 microg/mL) for several years. Recently, her serum theophylline levels had increased to the toxic range (133.2 micromol/L [24 microg/mL]) shortly after the addition of zafirlukast (Accolate, Zeneca Pharmaceuticals, Wilmington, Del) to her regimen. Attempts were made to stop and then restart the theophylline therapy at progressively lower doses; however, with each attempt, the patient's reaction to the drug became more toxic, with serum theophylline levels ranging between 99.9 and 149.9 micromol/L (18 and 27 microg/mL). So this potential drug-drug interaction could be investigated, the patient stopped taking both drugs for 1 week. Then, she again started taking theophylline (75 mg twice daily), and over 2 days reached a steady state serum theophylline level of 12.8 to 14.4 micromol/L (2.3-2.6 microg/mL). On the third day, zafirlukast (20 mg twice daily) was reintroduced to the regimen, and the theophylline therapy was continued. By the fifth day, a dramatic 7-fold increase was seen in the serum theophylline level (101.6 micromol/L [18.3 microg/mL]). The areas under the curve for theophylline alone and theophylline with zafirlukast were 29.3 and 197 (mg x h)/L, respectively. One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high concentrations of zafirlukast. Although the current metabolism of the 2 drugs in combination is poorly understood, the potential for serious interactions seems to exist in the rapidly growing population of persons with asthma, for whom they may be prescribed. The noted increase in the theophylline level after zafirlukast administration is in contrast to the original reports by the manufacturer. Therefore, we recommend that physicians evaluate serum theophylline levels closely when prescribing the 2 drugs in combination.

Probenecid hypersensitivity in AIDS: a case report.

BACKGROUND: Cidofovir plus probenecid is a new therapeutic alternative for refractory cytomegalovirus and acyclovir-resistant herpes infections in AIDS patients. Probenecid is used in conjunction with the antiherpetic medication (cidofovir) in order to reduce the incidence of nephrotoxicity by cidofovir. OBJECTIVE: To present therapeutic alternatives for successful administration of probenecid to AIDS patients who develop a hypersensitivity reaction to the medication. METHODS AND RESULTS: We describe a patient with AIDS who was being treated with the cidofovir/probenecid combination for a peri-anal acyclovir-resistant herpetic infection. The patient subsequently developed a cutaneous hypersensitivity reaction to probenecid alone. A pretreatment regimen consisting of prednisone, H1 and H2 blockers was administered before the dosing of probenecid in order for the patient to continue with the antiviral therapy. CONCLUSION: Cutaneous hypersensitivity reactions to probenecid may be seen more frequently with the increasing use of cidofovir in AIDS patients. Our pre-treatment protocol is one therapeutic alternative to be considered in order to continue with probenecid.

Cytokine production in cell culture by peripheral blood mononuclear cells from immunocompetent hosts.

The production of interleukin 2 (IL-2) gamma interferon, IL-4, tumor necrosis factor alpha (TNF-alpha), TNF-beta, IL-5, and IL-10 in vitro by peripheral blood mononuclear cells cultured from healthy immunocompetent subjects after mitogen stimulation was determined. The mitogens used were concanavalin A, phytohemagglutinin, pokeweed mitogen, and Staphylococcus aureus Cowen. The results obtained provide a normal range for the production of these cytokines under specified conditions in vitro.

Mugwort and sage (Artemisia) pollen cross-reactivity: ELISA inhibition and immunoblot evaluation.

BACKGROUND: Plants of the genus Artemisia are a source of fall allergic symptoms, particularly in the western United States. Studies have characterized the allergens in one of the major species (A. vulgaris) but currently there are no cross-reactivity data on the major United States species. OBJECTIVE: The purpose of this study was to investigate the in vitro cross-reactivity among nine Artemisia species: A. frigida, A. annua, A. biennis, A. filifolia, A. tridentata, A. californica, A. gnaphalodes, A. ludoviciana, and A. vulgaris. METHODS: The cross-reactivity was demonstrated with the use of enzyme-linked immunosorbent assay (ELISA) inhibitions and immunoblotting techniques utilizing a serum pool from patients allergic to Artemisia species. RESULTS: The enzyme-linked immunosorbent assay inhibitions revealed strong cross-reactivity among all nine species with A. biennis and A. tridentata being two of the strongest inhibitors. The polyacrylamide gel electrophoresis showed a great deal of similarity in the bands among the nine species. The nitrocellulose blots showed similar IgE binding patterns among the Artemisia species with strong inhibition among all nine extracts. CONCLUSIONS: These data all demonstrate very strong in vitro cross-reactivity among the nine Artemisia species studied. Such data have significant clinical relevance, suggesting that a single Artemisia species may be sufficient for allergy skin testing and formulation of immunotherapy extracts.

Atmospheric mold spore counts in relation to meteorological parameters.

Fungal spore counts of Cladosporium, Alternaria, and Epicoccum were studied during 8 years in Denver, Colorado. Fungal spore counts were obtained daily during the pollinating season by a Rotorod sampler. Weather data were obtained from the National Climatic Data Center. Daily averages of temperature, relative humidity, daily precipitation, barometric pressure, and wind speed were studied. A time series analysis was performed on the data to mathematically model the spore counts in relation to weather parameters. Using SAS PROC ARIMA software, a regression analysis was performed, regressing the spore counts on the weather variables assuming an autoregressive moving average (ARMA) error structure. Cladosporium was found to be positively correlated (P < 0.02) with average daily temperature, relative humidity, and negatively correlated with precipitation. Alternaria and Epicoccum did not show increased predictability with weather variables. A mathematical model was derived for Cladosporium spore counts using the annual seasonal cycle and significant weather variables. The model for Alternaria and Epicoccum incorporated the annual seasonal cycle. Fungal spore counts can be modeled by time series analysis and related to meteorological parameters controlling for seasonallity; this modeling can provide estimates of exposure to fungal aeroallergens.

Gamma delta T lymphocytosis associated with common variable immunodeficiency.

We present the case of a 28-year-old Caucasian female with common variable immunodeficiency (CVID) since age 5 who had a long history of hospitalizations for unexplained fevers and pulmonary infiltrates. The patient developed mild lymphocytosis 7 months prior to our evaluation. Flow cytometry of peripheral blood revealed an expansion of gamma delta T lymphocytes, mild CD4 T lymphocytopenia, and a reduced CD4/CD8 ratio (0.2). Two subpopulations of gamma delta T lymphocytes were found (CD3+/CD4-/CD8+, 47%; CD3+/CD4-/CD8-, 53%), the vast majority of which expressed V-delta 1. An infectious cause for the patient's gamma delta T lymphocytosis could not be found. The sputum was chronically colonized with Staphylococcus aureus, and the organism produced TSST-1 in vitro. A bronchoalveolar lavage (BAL) revealed marked lymphocytosis, but gamma delta T lymphocytes were not overrepresented in the BAL. Lymphocyte functional studies revealed poor proliferative responses to mitogens and staphylococcal superantigens and diminished cytokine production. V-delta 1 T lymphocytes from the patient's blood were not expanded in vitro in response to staphylococcal superantigens. TCR gene rearrangement studies confirmed the presence of J gamma and J beta 1 clonal rearrangements accounting for only a small subpopulation of the gamma delta T lymphocytes. These studies were repeated 5 months later and were unchanged. A bone marrow biopsy was negative for leukemia. Hence, the cause of the patient's gamma delta T lymphocytosis could not be determined despite evaluation for underlying malignancy, occult infection, or superantigen-driven stimulation. The patient ultimately died of progressive respiratory insufficiency. The state of current knowledge regarding gamma delta T lymphocytosis, decreased production of alpha beta T lymphocytes, and a low CD4/ CD8 ratio in association with CVID is discussed.

Cardiac tamponade and recurrent upper respiratory tract infections in a 22-year-old woman.

The association of IgA deficiency with SLE is clearly established but occurs in only a small percentage of patients. Several hypotheses address the relationship between the two disease processes but the common link remains undetermined. It is important to investigate the diagnosis of IgA deficiency in patients presenting with SLE in order to provide the most appropriate treatment. This patient not only represents a rare presentation of SLE but highlights the uncommon occurrence with IgA deficiency and brings forth valuable teaching points of both diseases.

Human papilloma virus associated with solitary squamous papilloma complicated by bronchiectasis and bronchial stenosis.

A 28-year-old man presented with recurrent pneumonias for 6 years. Chest radiograph and computed tomography showed localized bronchiectasis of the anterior segment of the left upper lobe. Bronchoscopy showed bronchial stenosis without an endobronchial lesion. After 6 weeks of antibiotic treatment, the patient had a recurrent pneumonia and underwent left upper lobectomy that showed a solitary squamous papilloma. In situ hybridization studies of the papilloma were reactive for human papilloma virus subtypes 6/11.