The many faces of Pulmonary Langerhans Cell Histiocytosis.

Langerhans Cell Histiocytosis is a rare disease with variable presentation and prognosis in adults and in children. Histiocytosis of the ocular choroidal tissue has never been reported before in adults. We present two cases, one with choroidal involvement with asymptomatic nodulo-cystic changes in the lungs and another case with advanced single organ pulmonary involvement. We discuss the various treatment modalities and highlight the lack of adequate guidelines to treat adults. Most of the current guidelines are based on evidence derived from pediatric literature. We would also like to draw attention to the asymptomatic nature of the lung involvement and suggest that imaging of the lung be obtained in all cases of Langerhans Cell Histiocytosis.

Systemic delivery of atropine sulfate by the MicroDose Dry-Powder Inhaler.

BACKGROUND: Inhaled atropine is being developed as a systemic and pulmonary treatment for the extended recovery period after chemical weapons exposure. We performed a pharmacokinetics study comparing inhaled atropine delivery using the MicroDose Therapeutx Dry Powder Inhaler (DPIA) with intramuscular (IM) atropine delivery via auto-injector (AUTO). METHODS: The MicroDose DPIA utilizes a novel piezoelectric system to aerosolize drug and excipient from a foil dosing blister. Subjects inhaled a 1.95-mg atropine sulfate dose from the dry powder inhaler on one study day [5 doses × 0.4 mg per dose (nominal) delivered over 12 min] and received a 2-mg IM injection via the AtroPen® auto-injector on another. Pharmacokinetics, pharmacodynamic response, and safety were studied for 12 hr. RESULTS: A total of 17 subjects were enrolled. All subjects completed IM dosing. One subject did not perform inhaled delivery due to a skin reaction from the IM dose. Pharmacokinetic results were as follows: area under the curve concentration, DPIA=20.1±5.8, AUTO=23.7±4.9 ng hr/mL (means±SD); maximum concentration reached, DPIA=7.7±3.5, AUTO=11.0±3.8 ng/mL; time to reach maximum concentration, DPIA=0.25±0.47, AUTO=0.19±0.23 hr. Pharmacodynamic results were as follows: maximum increase in heart rate, DPIA=18±12, AUTO=23±13 beats/min; average change in 1-sec forced expiratory volume at 30 min, DPIA=0.16±0.22 L, AUTO=0.11±0.29 L. The relative bioavailability for DPIA was 87% (based on output dose). Two subjects demonstrated allergic responses: one to the first dose (AUTO), which was mild and transient, and one to the second dose (DPIA), which was moderate in severity, required treatment with oral and intravenous (IV) diphenhydramine and IV steroids, and lasted more than 7 days. CONCLUSIONS: Dry powder inhalation is a highly bioavailable route for attaining rapid and consistent systemic concentrations of atropine.

Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells.

Actin released from damaged cells after a variety of tissue injuries appears to be involved in multiple organ dysfunction syndrome. Under experimental conditions, when the quantity of actin present in plasma is made to exceed the protective capacity of the actin-scavenging mechanism, microembolism and pulmonary vascular angiopathy have been noted in rats. It remains to be determined whether this injury is a result of a direct toxic effect or occurs indirectly via platelet activation or fibrin interactions. We examined the effect of sera from patients with adult respiratory distress syndrome (ARDS), as well as G-actin added to normal serum, on the viability, morphology, and function of cultured sheep pulmonary artery endothelial cells (SPAEC). Both patient sera and normal sera to which actin was added were toxic in the cell culture model; this toxicity could be abrogated, at least partially, by preincubation with gelsolin, which is known to complex with actin. A significant portion of the toxicity of sera from patients with ARDS was sensitive to heat (56 degrees C), suggesting an important role of complement. Sera from patients with ARDS were shown to contain filaments of F-actin by immunoblot and rhodamine phalloidin staining after ultracentrifugation. Thus, saturation of the actin-scavenging system by addition of exogenous G-actin to plasma produces direct pulmonary endothelial cell injury. Furthermore, plasma from patients with ARDS secondary to bacterial pneumonia is toxic to SPAEC, and a small but significant contributory role of actin is apparent in these studies.

Analysis of antibody response to Cryptococcus neoformans in five patients with AIDS and cryptococcosis by immunoblotting.

OBJECTIVES: The serological response of five patients with AIDS and cryptococcosis to non capsular antigens from Cryptococcus neoformans var. neoformans has been investigated. METHODS: Pressates of different isolates of C. neoformans were used as antigenic preparation for immunoblotting of patient samples. RESULTS: Multiple sera and cerebrospinal fluids sequentially collected from five AIDS patients with cryptococcosis showed a wide heterogeneity in antibody response with bands at 48. 43, 38 and 26 kD being present in all clinical samples of all five patients. The variation in banding patterns of the sequential samples from three patients was correlated with a decrease of the antigen titre and with an amelioration of the cryptococcal infection. CONCLUSIONS: We identified antibodies to four immunodominant non-capsular antigens, which might represent major target molecules of the humoral response of patients with cryptococcosis.

A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure.

We compared noninvasive positive-pressure ventilation (NPPV), using bilevel positive airway pressure, with usual medical care (UMC) in the therapy of patients with acute respiratory failure (ARF) in a prospective, randomized trial. Patients were subgrouped according to the disease leading to ARF (chronic obstructive pulmonary disease [COPD], a non-COPD-related pulmonary process, neuromuscular disease, and status postextubation), and were then randomized to NPPV or UMC. Thirty-two patients were evaluated in the NPPV group and 29 in the UMC group. The rate of endotracheal intubation (ETI) was significantly lower in the NPPV than in the UMC group (6.38 intubations versus 21.25 intubations per 100 ICU days, p = 0.002). Mortality rates in the intensive care unit (ICU) were similar for the two treatment groups (2.39 deaths versus 4.27 deaths per 100 ICU days, p = 0.21, NPPV versus UMC, respectively). Patients with hypoxemic ARF in the NPPV group had a significantly lower ETI rate than those in the UMC group (7.46 intubations versus 22.64 intubations per 100 ICU days, p = 0.026); a similar trend was noted for patients with hypercapnic ARF (5.41 intubations versus 18.52 intubations per 100 ICU days, p = 0.064, NPPV versus UMC, respectively). Patients with ARF in the non-COPD category had a lower rate of ETI with NPPV than with UMC (8.45 intubations versus 30.30 intubations per 100 ICU days, p = 0.01). Although the rate of ETI was lower among COPD patients receiving NPPV, this trend did not reach statistical significance (5.26 intubations versus 15.63 intubations per 100 ICU days, p = 0.12, NPPV versus UMC, respectively). In conclusion, NPPV with bilevel positive airway pressure reduces the rate of ETI in patients with ARF of various etiologies.

Growth hormone improves body mass recovery with refeeding after chronic undernutrition-induced muscle atrophy in aging male rats.

The effects of growth hormone (GH) administration and refeeding after chronic undernutrition (UN) were investigated in Fischer 344 male rats aging into senescence (24.5 mo of age) during UN initiated at 12.5 mo of age that produced muscle atrophy and a 50% decrease in body mass. Muscle mass, protein, myosin heavy-chain (MHC) composition and circulating testosterone levels were measured and compared to controls with free access to food. Within 9 wk, refeeding + GH restored body mass to control levels, whereas it was still decreased with refeeding alone. By 24.5 mo of age, refeeding alone restored body mass, while addition of GH resulted in overshoot. UN uniformly decreased mass of the gastrocnemius, extensor digitorum longus, soleus and diaphragm muscles to 50-60% of controls. Refeeding and refeeding + GH restored these losses with some overshoot of gastrocnemius muscle suggesting hypertrophy. UN more than doubled slow Type I MHC composition and approximately halved fast Type IIB and IIX MHC in the deep gastrocnemius muscle while it increased Type IIA MHC in the diaphragm. Refeeding and refeeding + GH reversed these shifts. MHC shifts in the extensor digitorum longus and soleus muscles were not statistically significant, whereas UN increased fast Type IIA MHC followed by decrease with refeeding + GH. UN decreased testosterone levels to nearly zero followed by restoration with refeeding and refeeding + GH. We conclude that the phenotype of mixed-MHC muscles such as the gastrocnemius and diaphragm are most affected by chronic UN, which is reversible with refeeding and refeeding + GH. These alterations were associated with changes in circulating testosterone, which may be a key regulatory element in these processes.

Growth hormone restores aged diaphragm myosin composition and performance after chronic undernutrition.

The effects of growth hormone (GH) on diaphragm muscle myosin heavy chain (MHC) composition and mechanical performance were investigated in Fischer 344 male rats aged to senescence (24.5 mo of age). Chronic undernutrition (UN), refeeding (RF), and RF+GH were compared with ad libitum feeding by using a model of UN that produced a 50% decrease in body weight over a 12-mo period. The effect of aging was assessed by comparing MHC composition of ad libitum-fed rats at 12 and 24.5 mo of age. At senescence, significant decreases in slow type I (-23%) and fast type IIA (-31%) MHC had occurred with aging. Conversely, UN over this aging period increased types I (32-73%) and IIA (22-23%) MHC and decreased fast types IIB (32-54%) and IIX (30-31%) MHC. RF and RF+GH reversed these shifts back toward control values. At senescence, maximal specific force, maximal velocity, and specific power capacity were not different across treatment groups. During repetitive isotonic contraction trials, the diaphragms of UN rats maintained power production over time (54% of initial power at 60 s), whereas the power production of diaphragms of ad libitum-fed rats fell to 0% (P < 0.05). In comparison with UN rats, the diaphragms of RF and RF+GH rats produced 23 (not significant) and 11% (P < 0.05) of initial power, respectively, suggesting that RF+GH treatment restored performance characteristics after UN. We conclude that RF+GH can reverse alterations in MHC composition and mechanical performance produced by chronic UN in the aged rat diaphragm.

Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.

OBJECTIVES: Recent studies in animal models of sepsis-induced acute respiratory distress syndrome (ARDS) have shown that a low-carbohydrate, high-fat diet combining the anti-inflammatory and vasodilatory properties of eicosapentaenoic acid (EPA; fish oil), gamma-linolenic acid (GLA; borage oil) (EPA+GLA), and antioxidants improves lung microvascular permeability, oxygenation, and cardiopulmonary function and reduces proinflammatory eicosanoid synthesis and lung inflammation. These findings suggest that enteral nutrition with EPA+GLA and antioxidants may reduce pulmonary inflammation and may improve oxygenation and clinical outcomes in patients with ARDS. DESIGN: Prospective, multicentered, double-blind, randomized controlled trial. SETTING: Intensive care units of five academic and teaching hospitals in the United States. PATIENTS: We enrolled 146 patients with ARDS (as defined by the American-European Consensus Conference) caused by sepsis/pneumonia, trauma, or aspiration injury in the study. INTERVENTIONS: Patients meeting entry criteria were randomized and continuously tube-fed either EPA+GLA or an isonitrogenous, isocaloric standard diet at a minimum caloric delivery of 75% of basal energy expenditure x 1.3 for at least 4-7 days. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were measured, and ventilator settings were recorded at baseline and study days 4 and 7 to enable calculation of PaO2/FIO2, a measure of gas exchange. Pulmonary neutrophil recruitment was assessed by measuring the number of neutrophils and the total cell count in bronchoalveolar lavage fluid at the same time points. Clinical outcomes were recorded. Baseline characteristics of 98 evaluable patients revealed that key demographic, physiologic, and ventilatory variables were similar at entry between both groups. Multiple bronchoalveolar lavages revealed significant decreases (approximately 2.5-fold) in the number of total cells and neutrophils per mL of recovered lavage fluid during the study with EPA+GLA compared with patients fed the control diet. Significant improvements in oxygenation (PaO2/FIO2) from baseline to study days 4 and 7 with lower ventilation variables (FIO2, positive end-expiratory pressure, and minute ventilation) occurred in patients fed EPA+GLA compared with controls. Patients fed EPA+GLA required significantly fewer days of ventilatory support (11 vs. 16.3 days; p = .011), and had a decreased length of stay in the intensive care unit (12.8 vs. 17.5 days; p = .016) compared with controls. Only four of 51 (8%) patients fed EPA+GLA vs. 13 of 47 (28%) control patients developed a new organ failure during the study (p = .015). CONCLUSIONS: The beneficial effects of the EPA+GLA diet on pulmonary neutrophil recruitment, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggest that this enteral nutrition formula would be a useful adjuvant therapy in the clinical management of patients with or at risk of developing ARDS.

Diaphragm myosin heavy chain composition shifts in aging chronically-undernourished Fischer 344 male rats.

The effects of chronic undernutrition (UN) on respiratory muscle were investigated during UN producing a 50% decrease in body weight over a prolonged period (45 weeks) in Fischer 344 male rats. This model focused on progressive, aging-related changes in myosin heavy chain (MHC) profile over time, in which the confounding effects of early development and late senescence were avoided. With aging toward late adulthood (68 weeks), MHC composition of control diaphragms was shifted, with decreased type I (slow) and IIA MHC, and increased type IIB and IIX (fast) MHC. UN produced a divergence of this profile, with an increase in type I and IIA MHC, and decreased type IIX MHC. UN diaphragms in vitro were more resistant to loss of active force with fatigue, during repetitive contractions. However, passive tension rose disproportionately during fatigue, suggesting increased fatigability. We conclude that the observed changes in diaphragm mechanical function are consistent with the UN-induced shifts in MHC composition; however, the elevated passive tension with fatigue suggests additional UN-induced changes in mechanical properties that are possibly detrimental to respiratory muscle function. The UN-dependent divergence in phenotype and mechanical properties may be amplified by aging-related shifts in muscle MHC composition over time, in the control group.

Nutritional aspects of lung disease.

The relationships between dietary intake, ventilatory demand, and respiratory muscle function are now well recognized. Malnutrition in patients with advanced COPD is associated with adverse effects on respiratory muscle function leading to reduced muscle strength and premature mortality. The relationships between nutrient intake and the host inflammatory response are just beginning to be explored. This article summarizes current knowledge regarding the relationship between nutritional status and the lung.

Nutritional support in advanced lung disease. The pulmonary cachexia syndrome.

Patients with advanced lung disease (ALD) demonstrate changes in body composition characteristically manifested by a progressive loss of body weight. The mechanisms of this pulmonary cachexia syndrome are multifactorial, and treatment must be comprehensive in nature. This article addresses our current knowledge regarding the relationship between nutrition and ALD.

Cocaine balloon aspiration: successful removal with bronchoscopy.

Ingestion of balloons containing illicit substances along with the potential toxic sequelae associated with these ingestions have been described in the literature. This report describes the successful bronchoscopic retrieval of a cocaine balloon after aspiration. A 39-year-old man was witnessed swallowing several balloons that were thought to contain heroin. Shortly after ingestion, the patient became unconscious and required nasotracheal intubation. Before intubation, several balloons were removed from the oropharynx. Naloxone 4 mg was administered en route to the emergency department (ED). Following naloxone, the patient awoke and became agitated and combative. On arrival in the ED, midazolam, succinylcholine, and vecuronium were required to manage his combativeness. Vital signs were: heart rate, 130 beats/min; blood pressure, 128/86 mm Hg; respirations, 12 breaths/min; temperature, 96.5 degrees F. A balloon and balloon tip were removed during lavage. Whole bowel irrigation with a polyethylene glycol electrolyte solution was initiated. A right upper lobe infiltrate was identified on chest X-ray and aspiration of a balloon was suspected. At bronchoscopy, a small yellow, intact balloon visualized in the basilar segment of the right lower lobe was removed. Toxicologic analysis of the balloon contents found cocaine. The rest of the patient's hospital course was unremarkable and he was discharged 5 days after admission. This case brings to light the potential concerns, such as respiratory compromise, associated with aspiration of small balloons in the body stuffer. Additionally, the potential for the development of toxicity if the balloon ruptures and toxin absorption occurs through through the lungs should be considered. Emergency physicians and toxicologists should be aware of this significant complication of packet ingestion in the body packer or stuffer and be prepared to intervene early during the course of the patient's treatment.

Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients.

The inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta), have been associated with accelerated metabolism and protein turnover following exogenous administration in normal humans. We hypothesized that these inflammatory cytokines might contribute to the weight-losing process in patients with chronic obstructive pulmonary disease (COPD). COPD patients were identified prospectively as "weight losers" (WL; n = 10) if they reported > 5% weight loss during the preceding year or as "weight stable" (WS; n = 10) if their body weight fluctuated < or = 5%. Age-matched healthy volunteers were selected as the control group (C; n = 13). Monocytes were isolated from a peripheral blood sample, cultured, and exposed to lipopolysaccharide (LPS). The concentration of TNF-alpha and IL-1 beta in the monocyte supernatant was measured using a four layer enhanced ELISA. No significant difference in LPS-stimulated IL-1 beta production was found in the three study populations. However, LPS-stimulated TNF-alpha production (mean [range] ng/ml) by monocytes was significantly higher in the WL COPD patients (20.2 [6.3 to 44.8]), compared with WS patients (6.9 [1.5 to 16.6]), and C subjects (5.7 [0 to 61.8]). This difference was not maintained at 6 mo follow-up in the absence of ongoing weight loss. Definition of a causal relationship between TNF-alpha production and weight loss will require further understanding of the relationship between energy metabolism and TNF-alpha production in these patients.

Nutrition in end-stage pulmonary disease.

Advanced pulmonary disease is frequently associated with the clinical syndrome of progressive weight loss. Current investigation has focused on both the etiology and treatment of this wasting syndrome. Important observations have been made regarding this frequent clinical problem and these will be reviewed. Continued investigation of practical clinical approaches to this frequent clinical problem, based on sound scientific inquiry, are needed.

Mechanisms of weight loss in chronic obstructive pulmonary disease.

The COPD patient population is susceptible to the onset of weight loss. The presence of this feature carries significant negative prognostic implications. Whether weight loss contributes to or is simply a marker of disease severity remains to be determined. Weight loss appears to result from an imbalance of metabolic demand and supply. The factors which produce this imbalance require further investigation.

Long-term outcome of critically ill elderly patients requiring intensive care.

OBJECTIVE: To evaluate the long-term mortality and morbidity of critically ill elderly patients requiring intensive care. DESIGN: Prospective comparison of outcome of critically ill patients aged 75 years and older with patients aged 65 to 74 years. PATIENTS: Critically ill patients aged 65 years and older who required intensive care and who were recruited during a 3-month period. MAIN OUTCOME MEASURES: Duration of hospitalization, hospital charges, procedures used in the intensive care unit, mortality in the hospital and during the follow-up period, and quality of life of survivors during the follow-up period. RESULTS: Ninety-seven patients were included in the study; 54 were 75 years or older and 43 were aged 65 to 74 years. No significant difference was noted between the two groups for length of stay in the hospital, hospital charges, or mortality at 1 year. Severity of illness, as assessed by Acute Physiology and Chronic Health Evaluation score at the time of intensive care unit admission, was a better predictor of survival than age. Quality of life, as assessed by activities of daily living, perceived quality of life, and Center for Epidemiologic Studies-Depression score, were not significantly different in either group at 1, 6, and 12 months after discharge from the hospital. Most patients in both groups described their quality of life as adequate and were willing to receive intensive care again, if necessary. CONCLUSION: Age alone is not an adequate predictor of long-term survival and quality of life in critically ill elderly patients.

Indirect calorimetry with a hood: flow requirements, accuracy, and minute ventilation measurement.

Flow-dilution-based hood systems for indirect calorimetry eliminate the conventional mouthpiece or mask of sealed-circuit systems allow measurements with improved patient comfort. This feature is particularly relevant when measurements are made over long periods of time or are repeated often. The flow of air pulled through the hood into the calorimeter in these systems is necessary to clear CO2 from inside the hood. The errors in these systems are greater than those in the sealed-circuit systems and are proportional to the flow. We show that the CO2 concentration within the hood at steady state does not depend on hood size. We describe the accuracy in determination of O2 consumption (VO2), CO2 production, and respiratory exchange ratio with a hood system as a function of the accuracy of the O2 and CO2 analyzers and the water vapor in collected gas. For example, we show that if there is a 1% error in O2 concentration, the percent error in VO2 changes from 5% in a sealed circuit to 51% when a cleansing flow of 50 l/min is introduced. The error in VO2 caused by a 5% error in CO2 determination is 10.6% at this cleansing flow. Removal of 90% of the water vapor (instead of 100%) before analysis of the expired gas introduces a 15.8% error in VO2. By use of the equations described, the accuracy of any measurement system can be determined. In addition, we demonstrate that the measurement of ventilation, usually lost in a hood system, can be preserved using dual pneumotachographs and a sealed hood.

Physiologic effects of oral supplemental feeding in malnourished patients with chronic obstructive pulmonary disease. A randomized control study.

The association between severe nutritional depletion and chronic obstructive pulmonary disease (COPD) has long been recognized. A potential therapeutic benefit to nutritional support was previously suggested by us in a pilot investigation. Subsequent studies have reported conflicting results regarding the role of nutritional therapy in this clinical population. We report a randomized controlled study of nutritional therapy in underweight patients with COPD that combines an initial inpatient investigation (controlled nutritional support) with a prolonged outpatient follow-up interval. Provision of adequate calorie and protein support, adjusted to metabolic requirements, resulted in weight gain (intervention = +2.4 kg versus control -0.5 kg), improved handgrip strength (intervention = +5.5 kg-force versus control -6.0 kg-force), expiratory muscle strength (intervention = +14.9 cm H2O versus control -9.2 cm H2O), and walking distance (intervention = +429 feet versus control -1.0 foot). Inspiratory muscle strength was also improved (intervention = +11.4 cm H2O versus control +4.8 cm H2O) although this did not quite reach statistical significance. We conclude that provision of adequate nutrient supply under controlled conditions results in significant clinical improvements in the COPD patient population. However, the intervention is costly, time-intensive, and of limited therapeutic magnitude. More detailed work of alternative outpatient strategies combined with additional rehabilitative measures is indicated to delineate the full therapeutic potential of nutritional support for this clinical population.