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Yale University School of Medicine, New Haven, Connecticut
PULMONARY INFECTIONS
James M. Beck Pulmonary/Critical Care Medicine University of Michigan Medical School Ann Arbor, Michigan
Concentrations of calcitonin precursors, including procalcitonin, are increased during bacterial infection. Christ-Crain and coworkers (1) capitalized on this fact to employ a procalcitonin-based treatment strategy to determine whether unnecessary empiric antibiotic use could be reduced without adversely affecting outcome. Two hundred forty-three patients with pneumonia, acute bronchitis, asthma, or other respiratory disorders were randomly assigned to either standard care (n = 119) or procalcitonin-guided therapy (n = 124). In the latter group antibiotic use was discouraged if procalictonin levels were 
0.25 µg/L, or encouraged if levels were 
0.25 µg/L. Patients were followed within 10 to 14 d of enrollment, with antibiotic usage the primary endpoint. The adjusted relative risk of antibiotic therapy for the procalcitonin group was 0.49 (p < 0.0001) compared with the standard care group. Thirty-nine fewer antibiotic courses per 100 patients were noted. No differences in clinical or laboratory outcomes were seen. Rapid measurement of procalcitonin may be an effective strategy to reduce unnecessary empiric antibiotic use.
While high-dose steroid therapy for severe infections and sepsis has been found not to improve outcomes (2, 3), Confalonieri and colleagues asked the question "will low dose constant infusion of hydrocortisone attenuate the inflammatory response to severe community-acquired pneumonia?" (4). Patients with severe community-acquired pneumonia admitted to intensive care units (n = 48) were treated with antibiotics by protocol and were randomized to receive hydrocortisone infusions (200 mg initially followed by 10 mg/h for 7 d; n = 24) or placebo (n = 24). At study entry, patients randomized to hydrocortisone proved to be more severely ill than the placebo group, as reflected by lower PaO2/FIO2 ratios and higher chest radiography scores. However, by Day 8 the hydrocortisone-treated patients demonstrated increased PaO2/FIO2 ratios, decreased need for mechanical ventilation, improved chest radiography scores, and fewer episodes of septic shock than placebo-treated patients. Mortality at Day 60 was reduced in the hydrocortisone group versus the placebo group (0% vs. 38%; p < 0.009). No untoward effects attributable to the hydrocortisone infusion were noted. The authors conclude that control of inflammation with low-dose corticosteroids improves outcomes in severe community-acquired pneumonia and that larger randomized trials seem warranted.
The use of genetic studies to define individual susceptibility to disease is an emerging tool in medicine in general. Quasney and coworkers (5) designed a prospective cohort study of 402 adult patients with community-acquired pneumonia and genotyped them to compare the presence of polymorphisms in pulmonary surfactant protein B (SP-B+1580) and outcomes. Forty-five percent had the thymidine-thymidine (TT) genotype, 40% had the cytosine-thymine (CT) genotype, and 15% had the cytosine-cytosine (CC) polymorphism. Sixty-three patients overall required mechanical ventilation, with 12 patients demonstrating adult respiratory distress syndrome (ARDS), and 35 developing septic shock. Patients with the CC genotype were more likely to require mechanical ventilation than those with the TT genotype (36% vs. 9%), and were also more likely to develop septic shock (20% vs. 5%) and ARDS (8.5% vs. 0.5%). Those with CT genotype demonstrated outcomes intermediate to those seen with the CC and TT genotypes. While not statistically significant, mortality was higher in the CC genotype group (10%) than in patients with other genotypes (6%). The authors concluded that carriage of the "C" allele at the SP-B+1580 site, especially the CC genotype, portends worse outcome in community-acquired pneumonia.
Because of operational problems inherent with the application and reading of skin tests for tuberculosis, a commercial test has been promoted to measure interferon-
production by blood cells in response to mycobacterial antigens. The test is known to have limited sensitivity in populations with previous bacille Calmette-Guérin (BCG) exposure or exposure to nontuberculous mycobacteria. In a study of a tuberculosis outbreak at a Danish high school, Brock and colleagues (6) studied 125 exposed individuals divided into low- and high-exposure groups based on extent of contact with the source case. An assay using purified protein derivative (PPD) as the antigen or one using the antigens ESAT-6 and CFP-10 were compared. In individuals not vaccinated to BCG, both assays were positive in about 50% of high-exposure contacts and 5% of low-exposure contacts. However, for the BCG-vaccinated individuals, the PPD Ag assay failed to discriminate between high- and low-exposure contacts. In contrast, the ESAT-6 and CFP-10 assay was positive in 50% of the high-exposure contacts and 6% of the low-exposure contacts. Agreement between skin tests and ESAT-6 and CFP-10 assays was 94% in individuals not vaccinated with BCG. Skin testing was not performed in the BCG-vaccinated individuals. The authors conclude that the modified test with ESAT-6/CFP-10 antigens allows more precise detection of latent tuberculosis infection in both unvaccinated and BCG-vaccinated populations.
DIAGNOSTIC IMAGING
Douglas S. Katz Department of Radiology Winthrop-University Hospital Mineola, New York
The use of contrast-enhanced computerized tomography (CT) in the diagnosis of acute pulmonary embolism (PE) has become increasingly popular, but its role in relation to the "gold" standard, pulmonary angiography (PA), remains controversial. Winer-Muram and coworkers (7) explored the sensitivity, specificity, and accuracy of CT in relation to PA. Ninety-three patients with suspected PE prospectively underwent four-channel multi-detector CT scanning and subsequent PA within 48 h. Three interventional radiologists independently and retrospectively reviewed the PA studies blinded to the CT results, while three chest radiologists independently and retrospectively reviewed the CT studies. Sensitivity, specificity, and accuracy of CT using PA as the "gold" reference standard were 100%, 89%, and 91%, respectively. Subsegmental PEs were missed in 8 of 15 patients; however, in all 8 of these patients, concurrent lobar or segmental emboli were identified on CT. In eight false-positives, four had CT studies with appearance highly suggestive of PE.
Another area of great controversy for the practicing clinician is the advisability of CT scanning for lung cancer. Henschke and colleagues (8) retrospectively reviewed two series of baseline CT screening in high-risk people from their institution. When the largest noncalcified nodule detected was less than 5 mm, in diameter the frequency with which malignancy was or could have been diagnosed was 0 out of 378, whereas with nodules in the 5- to 9-mm size, 13 our of 238 were or could have been diagnosed as malignant. The authors concluded that if persons with nodules smaller than 5 mm had merely been referred for annual repeat screening without more intermediate work-ups the referrals would have been reduced by 54% (from 817 down to 385 of 2,897 total patients screened). This has implication for the incidental small (< 5 mm) nodules commonly picked up by CT in both low- and high-risk populations, with the suggestion that yearly follow-up screening should be adequate.
The marriage of CT imaging with positron-emission tomography (PET) in the staging of non–small cell lung cancer (NSCLC) was the topic of an important study by Cerfolio and coworkers this year (9). In this prospective study of 129 consecutive patients with NSCLC, patients underwent integrated PET-CT scanning. A radiologist assigned tumor (T), nodal (N), and metastasis (M) status. No sooner than two weeks from the integrated PET-CT scan investigation, the same radiologist read the PET images without integrated CT data, and again assigned T, N, and M status. Of note, for both readings the most recent CT scan was available for visual correlation. All patients underwent biopsy of suspicious N2 and N3 lymph nodes, or distant metastases. If biopsy proved negative, pulmonary resection and lymphadenectomy was subsequently performed. The integrated PET-CT scan was a better predictor than PET for all stages of cancer, and achieved statistical significance for stage I (52 vs. 37%; p= 0.03) and stage II (70 vs. 36%; p= 0.04). Tumor size (T) was also more precisely predicted by PET-CT (70 vs. 47%); p= 0.001) as was node (N) status (78 vs. 56%; p= 0.008). N2 nodal accuracy was also greatest with integrated PET-CT scanning compared to PET alone (96 vs. 93%; p= 0.01). It was more sensitive, specific, and offered a higher positive predictive value for both N1 and N2 nodes. This study appears to confirm that the marriage of CT and PET scanning in the evaluation of NSCLC is, indeed, a happy one.
Palliative radiofrequency (RF) ablation of thoracic tumors has lagged behind its use in tumors at other sites (e.g., liver). Two studies of significance enhanced our understanding of this technique with thoracic tumors this year. Lee and colleagues (10) examined 26 patients with 27 inoperable NSCLC, along with 4 patients with 5 metastases who underwent RF ablation with cooled-tip electrodes under CT guidance. Contrast-enhanced CT was performed immediately at the time of RF ablation, again at 1 mo, and then every 3 mo after RF ablation. Twelve of 32 lesions demonstrated complete necrosis, with partial (> 50%) necrosis seen in the remaining 20. In tumors less than 3 cm in size, complete necrosis was universal, but larger tumors demonstrated complete necrosis in only 6 of 26 cases. Mean survival of patients with complete necrosis (19.7 mo) was significantly better than those achieving only partial necrosis (8.7 mo; p = 0.01). Palliation of hemopytsis was excellent, but less satisfactory for chest pain, dyspnea, and cough. Three complications were observed; ARDS in one patient, and pneumothorax in two. Yasui and coworkers (11) employed CT-fluoroscopy to guide ablation in 99 malignant thoracic tumors, ranging from 3 to 80 mm in size, in 35 patients. Ablation was performed using a single internally-cooled electrode. Treatment was concluded when ground-glass opacification emerged around the lesion on CT images. Mean follow-up was 7.1 mo with serial CTs performed. In each case, involution was seen on CTs performed 1 mo later. Ninety tumors showed no growth on follow-up CT; nine tumors showed evidence of recurrence. Mean diameter of those that recurred (19.6 mm) was not significantly different than those that did not (19.5 mm; p = 0.994). A 76% overall complication rate was reported and included fever, cough, hemoptysis, abscess formation, pleural effusions, hemothorax, and pneumothorax. However, only 4 of 23 pneumothoraces required chest tube placement, and only three complications were deemed "severe." Larger studies with longer follow-up periods are needed to assess the role of RF in thoracic tumors.
PLEURAL DISEASES
V. Courtney Broaddus Pulmonary and Critical Care Medicine San Francisco General Hospital University of California San Francisco, California
Despite numerous small studies of empyema showing benefits from fibronolytics, Maskell and colleagues (12) contributed the largest study to date establishing convincing lack of efficacy and even a slight increase in harm from intrapleural instillation of streptokinase. Four hundred twenty-seven patients with empyema were enrolled in a randomized, parallel, double-blind fashion at 52 centers in the United Kingdom. Patients received either 250,000 IU of streptokinase or placebo injected twice daily into the pleural space for a total of six doses. Requirement for surgery, survival, duration of hospital stay, and radiographic appearance and lung function at 3 mo were not different between the two groups. Streptokinase-treated patients had an excess of reported chest pain, fever, and allergic reactions (7 vs. 3%). Interestingly, no increase in local or systemic bleeding in the streptokinase group was seen. Of note, this study does not preclude the potential roll of fibrinolytics in malignant or noninfections loculated effusions.
Malignant pleural mesothelioma has proven difficult to treat despite numerous strategies employed in previous studies. Vogelzang and colleagues examined the role of pemetrexed, a potent multitargeted folate inhibitor, combined with cisplatin-based chemotherapy in treating this dreaded disease (13). In this phase III study of 456 patients, cisplatin alone was compared to cisplatin together with pemetrexed. Those receiving both agents had a greater median survival (12.1 vs. 9.3 mo), greater median time to progression (5.7 vs. 3.9 mo), and greater response rates (41 vs. 17%). Because of observed toxicity from folate inhibition, vitamin supplementation with folic acid and B12 was added to the protocol when the study was already underway. This appeared to reduce toxicity without apparent alteration in pemetrexed benefit. The authors concluded that pemetrexed combined with cisplatin is the new standard of care in malignant mesothelioma, although the 1.2-mo median survival time advantage implies that there is clearly room for improvement in our treatment of this disease.
In another study by Maskell and coworkers (14), the role of talc particle size in pleurodesis was examined. In the United States, mixed talc (average particle size < 15 µm) is generally available, while graded talc (average particle size 25 µm) is the standard preparation used in continental Europe. Before this trial, it was not clear if lung injury or the systemic reactions sometimes seen was related to particle size, an idiopathic reaction, or a product of the amount of talc administered. In the first portion of this trial, 20 patients with malignant effusions were randomized to receive either 4 g of mixed talc or tetracycline (20 mg/kg). Compared to tetracycline, talc caused greater inflammation to the lungs as measured by DPTA-isotope clearance from the contralateral lung. Greater falls in oxygen saturation (3 vs. 0.7%) and greater increases in C-reactive protein levels (200 vs. 75 mg/L) were also noted in the talc-treated patients. The authors concluded that talc induced systemic inflammation is probably due to systemic distribution. In the second portion of the study two types of talc were compared. Mixed (average particle size < 15 µm) was given to 24 patients and graded (average size 25 µm) was given to 24 patients with malignant effusion after randomized allocation. After 48 h, those with mixed talc had greater rates of fever (41 vs. 4%), greater falls in arterial partial pressure of oxygen (14.6 vs. 3.8 mm Hg), and greater increase in C-reactive protein (161 mg/L increase vs. 111 mg/L). Local effects as judged by interleukin-8 levels in the pleural fluid were not different between the two preparations. No apparent difference in success rates between the 2 preparations could be seen (79% mixed vs. 85% graded). It would seem, therefore, that "size does matter" when it comes to talc preparations, and that we should attempt to switch to the graded preparation here in the United States in the near future.
The use of thorocoscopy to address regions of subpleural blebs in those suffering spontaneous pneumothorax has been a welcomed advance over open thoracotomy. However, finding all the potential areas of weakness can be a challenge and somewhat subjective. Noppen and colleagues offered a new means of visualizing abnormal subpleural areas by use of a fluorescein aerosol before thorocoscopy (15). Compared to standard white light, autoflorescence enhanced by blue light enabled the detection of larger and more numerous areas of abnormality in this case study of one patient. A prospective study is now planned based on this "proof-of-concept" case report.
NEUROMUSCULAR DISEASE
Joshua O. Benditt Pulmonary and Critical Care Medicine University of Washington Seattle, Washington
Patients with spinal cord injury sometimes benefit from diaphragm pacing. Precise localization of the "motor point" for the phrenic nerve is crucial to the success of the intradiaphragm approach to this technique, previously used only in animal models and cadaveric experiments. In a cohort study of two groups of patients, Onders and coworkers describe the improvements in mapping that can be achieved by a laparascopic approach (16). Twenty-eight volunteers undergoing laprascopic surgery for cholecystectomy served as a vital test-bed for mapping of the phrenic nerve motor point, with subsequent placement of electrodes on the underside of the diaphragm in 6 patients with spinal cord injury based on the findings in these 28 volunteers. Improvements in mapping were documented by the authors with the advantage of lower costs and shorter hospitalizations over the traditional method of pacing the phrenic nerve by stimulation more rostral in its course.
The impact of noninvasive ventilation (NIV) on the quality of life in patients suffering with amyotrophic lateral sclerosis (ALS) was the subject of an investigation by Bourke and colleagues (17). Previous work had defined that survival is favorably impacted on by NIV (18), but it was unclear if using this method to unload the muscles of respiration improved symptoms and objective measures of quality of life. Twenty-two patients with established ALS were followed prospectively and offered NIV when they experienced orthopnea, daytime sleepiness, unrefreshing sleep daytime hypercapnia, nocturnal desaturations, or an apnea–hypopnea index (AHI) of greater than 10. Seventeen met the above criteria during the study and 15 accepted NIV. Ten subsequently continued with this modality. Pre- and postintervention assessment of pulmonary function, and administration of Sleep Apnea Quality of Life Index, Short Form-36 (SF-36) Questionnaire, and the Chronic Respiratory Disease Questionnaire were employed. The authors found that quality-of-life questionnaire domains assessing sleep-related problems and mental health improved (effect sizes 0.88–1.77; p< 0.05) and were maintained for 252 and 458 d, respectively, in those on NIV. Vital capacity declined more slowly with ongoing use of NIV. Orthopnea proved to be the best predictor of benefit from and compliance with NIV. The presence of daytime hypercarbia and nocturnal desaturations also predicted benefit, but were less sensitive than orthopnea. An AHI of greater than 10 was not predictive. Moderate or severe bulbar weaknesss was associated with lower compliance and less overall improvement in quality-of-life measures.
While NIV use in ALS improves survival (18) as noted above, the extent to which it is used and factors associated with its use have not been extensively studied. Lechtzin and coworkers (19) reviewed records from 1,458 patients in a cross-sectional study of NIV from the ALS Care Data Base. This revealed that only 15.8% of patients with ALS used NIV, with 2.1% receiving tracheostomy and mechanical ventilation and 88.2% receiving no ventilation at all. Patients who did receive NIV were more likely to be male and have higher incomes, more often had a gastrostomy tube, had lower vital capacities on pulmonary function testing, and had more severe disease in general. Bulbar involvement and poorer overall health status (as measured by the Short Form 12 and Sickness Impact Profiles) were also more likely to be associated with NIV use. Multivariate analysis revealed that lower FVC, higher income, and use of gastrotomy tube were independently associated with NIV use. The authors conclude that despite data supporting improved survival and quality of life, NIV is underused in patients with ALS in the United States.
In another study by Herridge and colleagues (20), the neuromuscular sequelae occurring in survivors of ARDS were explored. One hundred nine survivors of ARDS were prosepectively followed at 3-, 6-, and 12-mo time-points. Quality-of-life measures, pulmonary function testing, physical examinations, and six-minute walk testing were performed on each of these occasions. The patients enrolled were critically ill (median APACHE scores of 23) with a median intensive care unit (ICU) stay of 25 d. Patients lost, on average, 18% of their baseline body weight at the time of discharge from the ICU. Pulmonary function testing improved by 6 mo, with the exception of minor persistent abnormalities in the diffusing capacity of carbon monoxide. Quality-of-life measures, however, were well below normal, even at 12 mo. Six-minute walk distances also remained significantly abnormal throughout the 12 mo of monitoring. Functional limitations were due mainly to extrapulmonary disease (e.g., muscle weakness, foot drops from peroneal neuropathy, immobility from heterotopic ossification) rather than intrinsic pulmonary disease.
ACKNOWLEDGMENTS
T.K.T. has spoken at dinner programs and Grand Round formats for Actelion Pharmaceutical company.
FOOTNOTES
* Co-Chair, Clinical Year in Review 
REFERENCES
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