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Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue- and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue- and immune- versus cardiovascular/metabolic effect-selective glucocorticoids is available for study and further improvement. ‘Designer’ glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.

Noninvasive face mask ventilation has been used successfully in patients with paralytic respiratory failure. This study evaluated whether noninvasive face mask ventilation can be used for patients with acute respiratory failure due to intrinsic lung disease. Six patients with hypercapnia and four with hypoxemic acute respiratory failure met clinical and objective criteria for mechanical ventilation, which was delivered with pressure control and pressure support via a tightly strapped, clear face mask. No patient terminated the study because of inability to deliver adequate ventilation or to improve oxygen exchange; three eventually required endotracheal intubation. The mask was generally well tolerated. All patients had a nasogastric tube placed on suction, and none vomited or aspirated. The mean duration of treatment was 33 h (range, 3 to 88). The physiologic response was considered similar to that which would have been achieved with conventionally delivered ventilation. Noninvasive face mask ventilation may have a role in managing respiratory failure.

The aim of this study was to assess the feasibility and safety of noninvasive positive−pressure ventilation (NPPV) via a face mask to aid in performing fiberoptic bronchoscopy (FOB) with BAL in immunosuppressed patients with gas exchange abnormalities that contraindicate using conventional unassisted FOB.

To further improve the diagnostic value of bronchoscopy in the immunosuppressed population presenting with diffuse pulmonary infiltrates, we prospectively investigated the utility of bilateral bronchoalveolar lavage (BAL). We performed 62 bronchoscopies on 52 immunosuppressed patients. Of the 52 patients, 33 had pulmonary infections. The yield for Pneumocystis cariniipneumonia on bilateral BAL was 94 percent (31/33), compared to the 84 percent (51/61) previously obtained with unilateral BAL in our institution. The recovery of P cariniiwas unilateral in four of five patients without AIDS and in four of 26 patients with AIDS. Transbronchial biopsy gave a yield of 85 percent (11/13). In ten patients with definitive cytomegalovirus (CMV) pneumonia, recovery of CMV by combined culture and cytology was 100 percent. Of nine bronchoscopies with positive cytology for CMV, five showed cytopathologic changes in the BAL from both sides and four in the BAL from one side only. No complications were seen in the 14 patients with thrombocytopenia or the five patients receiving mechanical ventilation. Our findings indicate that bilateral BAL significantly increases the yield for recovery of P carinii(p<0.02) and CMV (p<0.001) in immunosuppressed patients.

The clinical significance of pulmonary function tests (including blood gas analysis) lies in their sensitivity for detecting PCP. PCP has most consistently been found to cause abnormalities in the DLCO and the exercise arterial blood gas; both are highly sensitive for the presence of Pneumocystisinfection. These tests are more sensitive for the detection of PCP than are the resting arterial blood gas and chest x-ray. Therefore, measuring these values can be especially helpful in evaluating HIV-infected individuals who have pulmonary symptoms but whose resting arterial blood gas and/or chest radiograph are normal. The advantage of performing the exercise test over measuring the DLCO is that the exercise test is simple. It can be done without pulmonary function equipment and without a technologist. Furthermore, since many AIDS patients with non-PCP pulmonary disorders maintain “normal” exercise tests despite abnormal DLCO, it can be useful in evaluating patients for PCP who have known underlying lung disease with progressive symptoms.

Mechanically assisted intermittent positive-pressure ventilation effectively provides ventilatory support in patients with respiratory failure but it requires placing an artificial airway. We have previously reported our successful experience delivering mechanical ventilation via a face mask (FMMV) rather than with an endotracheal tube in a pilot study of patients with acute respiratory failure. The present investigation evaluated an additional 18 patients with hypercapnic respiratory failure to determine the efficacy of FMMV in a more homogeneous group and to determine factors predicting its success. FMMV was successful in avoiding intubation in 13 of the 18 patients. A significant initial improvement in Pco2(>16 percent decrease) and in pH (from <7.30 to >7.30) predicted success. The five patients who failed on FMMV required endotracheal intubation because of inability to improve gas exchange (three patients), apnea due to sedatives (one patient), and management of secretions (one patient). FMMV was generally well accepted with only two patients withdrawn because of intolerance of the mask. The mean duration of FMMV was 25 h. Complications were seen in only two patients (11 percent): aspiration (one patient) and mild skin necrosis (one patient). Seven patients entered the study by meeting entrance criteria after an unsuccessful extubation attempt and therefore received both forms of mechanical ventilation. All but one patient avoided reintubation, and the face mask proved to be as effective as the endotracheal tube as a conduit for delivering the mechanical tidal volume and improving gas exchange. Our findings indicate that FMMV is a viable option for short-term (one to four days) ventilatory support of patients with hypercapnic respiratory failure and insufficiency.

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p<0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.