Karen L. Wood

Noninvasive Pulmonary Aspergillus Infections

Aspergillus can cause several forms of pulmonary disease ranging from colonization to invasive aspergillosis and largely depends on the underlying lung and immune function of the host. This article reviews the clinical presentation, diagnosis, pathogenesis, and treatment of noninvasive forms of Aspergillus infection, including allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and chronic pulmonary aspergillosis (CPA). ABPA is caused by a hypersensitivity reaction to Aspergillus species and is most commonly seen in patients who have asthma or cystic fibrosis. Aspergillomas, or fungus balls, can develop in previous areas of cavitary lung disease, most commonly from tuberculosis. CPA has also been termed semi-invasive aspergillosis and usually occurs in patients who have underlying lung disease or mild immunosuppression.

Nicotine Treatment Improves Toll-Like Receptor 2 and Toll-Like Receptor 9 Responsiveness in Active Pulmonary Sarcoidosis

BACKGROUND New evidence links nicotine to the regulation of T cell-mediated inflammation via a 7 nicotinic cholinergic receptor activation, and chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases. We sought to determine whether nicotine treatment was well tolerated while effectively normalizing immune responses in patients with active pulmonary sarcoidosis. METHODS Consenting adults with symptomatic sarcoidosis (n 5 13) were randomly assigned to receive 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone. Obtained blood cells were evaluated for their responsiveness to selected Toll-like receptor (TLR) and nucleotide oligomerization domain-like receptor ligands and T cell surface marker expression before and after nicotine treatment. Asymptomatic patients (n 5 6) and disease-free subjects (n 5 6) served as comparative control subjects. Adverse events were monitored for the duration of the study. RESULTS Compared with the asymptomatic group, symptomatic patients had impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy) and reduced peripheral populations of CD4 1 FoxP3 1 regulatory T cells (Tregs). Nicotine treatment was associated with restoration of TLR2 and TLR9 responsiveness, and expansion of Tregs, including the CD4 1 CD25 2 FoxP3 1 phenotype. There were no serious adverse events or signs of nicotine dependency. CONCLUSIONS Nicotine treatment in active pulmonary sarcoidosis was well tolerated and restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3 1 Tregs, including a specific “preactivated” (CD25 2 ) phenotype. The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population.

What Defines Abnormal Lung Function in Older Adults with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a very common lung disease most often related to a history of smoking. It becomes more prevalent with increasing age but remains under-diagnosed and under-treated in the elderly population. The Global Initiative for Obstructive Lung Disease (GOLD) programme has been instrumental in providing standard diagnostic criteria as well as recommendations for prevention and management of COPD. GOLD recommendations define COPD as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of <70%, with the severity based on the value of FEV1. This recommendation is different from that of many previous reports that have recommended diagnosing obstruction using the statistically derived lower limit of normal (LLN), which varies for each person according to age, height, ethnicity and gender. While the use of a 70% ratio may be simpler, it may result in under-diagnosis of airflow obstruction in younger people and over-diagnosis in the elderly. This is particularly important as the elderly may be most sensitive to many of the adverse effects of medications used in the treatment of COPD, including corticosteroids and anticholinergic bronchodilators.Most of the studies comparing the LLN and a fixed ratio of 70% have not been performed with post-bronchodilator testing as recommended by GOLD. Generation of post-bronchodilator reference sets and studies comparing the LLN with the post-bronchodilator FEV1/FVC ratio of <70% will help resolve this issue. One recent study examined patients admitted to hospitals who had an FEV1/FVC ratio of <70% but above the LLN, and found they were at increased risk of death and COPD complications. This would support the use of GOLD criteria. Further studies examining this population are needed.In addition to the uncertainties about what diagnostic criteria should be utilized for diagnosis of airflow obstruction, different organizations make different recommendations on screening spirometry. A conservative recommendation is to perform spirometry in symptomatic individuals. It is important to remember that while COPD is under-diagnosed in the elderly, this group is also at a higher risk of being falsely classified as having airflow obstruction using the 70% ratio recommended by GOLD. This can result in unnecessary use of medications and increased risk of adverse effects to which the elderly are more prone.

Comparison of Pulmonary Complications after Nonmyeloablative and Conventional Allogeneic Hematopoietic Cell Transplant

Nonmyeloablative conditioning before allogeneic hematopoietic cell transplant (HCT) is an alternative to conventional conditioning in older patients and those with comorbidities. It is not known whether the decreased tissue injury associated with nonmyeloablative conditioning lowers the risk of pulmonary complications. The medical records of patients who underwent transplantation were reviewed and all pulmonary complications documented. Sixty-two consecutive patients with hematologic malignancies who underwent minimally intensive HCT (subjects) were compared to 48 consecutive patients who received conventional myeloablative allogeneic peripheral blood HCT (controls) over the same period at Indiana University Hospital. Pulmonary complications were categorized according to the type of complication and the time of onset after transplantation. Median follow-up times were similar between groups (P = .70). The study population (minimal intensity recipients) was older (P < .01), and the incidence of chronic graft-versus-host disease (cGVHD) was higher in subjects than controls (P = .02). Sixty-nine percent of subjects and 73% of controls developed pulmonary complications (P = .70). There was a trend in the minimally conditioned patients towards a lower incidence of pulmonary complications in older patients in the early posttransplantation period and a higher incidence of infectious pneumonias and bronchiolitis obliterans syndrome at later time points. The frequency of pulmonary complications seems to be similar after minimally intensive or myeloablative conditioning and allotransplantation. There was no difference in overall mortality or pulmonary-related mortality between the 2 groups.

Pulmonary Rehabilitation for Bronchiolitis Obliterans Syndrome after Hematopoietic Stem Cell Transplantation

Bronchiolitis obliterans syndrome (BOS) is a progressive, insidious lung disease affecting allogeneic hematopoietic stem cell transplantation recipients. Unfortunately, there is no standardized approach for treatment of BOS in post-hematopoietic stem cell transplantation patients. Pulmonary rehabilitation is a standard treatment in emphysema, an irreversible obstructive lung disease secondary to tobacco abuse. The National Emphysema Treatment Trial (NETT) demonstrated improved exercise tolerance, decrease dyspnea, and increase of quality of life in patients with severe emphysema after pulmonary rehabilitation. We hypothesized that pulmonary rehabilitation may benefit patients with BOS. Patients with BOS were identified retrospectively from January 2005 to the present. Patients who enrolled in pulmonary rehabilitation were included in the study. We obtained summaries via chart review of each patients progress after pulmonary rehabilitation enrollment from his or her respective rehabilitation centers. Six-minute walk distances, spirometry, and pulmonary symptoms were compared before and after the completion of pulmonary rehabilitation. We identified 11 patients with BOS documented from their pulmonologists clinical notes who were enrolled into pulmonary rehabilitation. Ten of the 11 patients completed pulmonary rehabilitation. All patients had improvement in their 6-minute walk distances after the completion of pulmonary rehabilitation, with an average improvement in distance of 307 feet (P value = .005). Six of the 10 patients completed Short Form-36 (SF-36) questionnaires before and after rehabilitation. There was a significant improvement in the physical functioning score (P value = 0.029). Pulmonary rehabilitation seems to improve 6-minute walk distance, subjective symptoms of dyspnea, and exercise tolerance in patients with BOS. This may be an important adjunctive therapy for a debilitating disease with limited treatment options.

Cytometric analysis of BAL T cells labeled with a standardized antibody cocktail correlates with immunohistochemical staining

Determining T‐cell phenotypes of lung cells obtained by bronchoalveolar lavage (BAL) is frequently clinically useful, particularly for evaluating causes of interstitial lung disease. The current standard of determining CD4/CD8 T‐cell subsets by immunohistochemical (IHC) staining of cytocentrifuge slides is labor‐intensive and subject to interpreter variation. Flow cytometry (FCM) is a precise and rapid method commonly used in research to characterize cells in the lung. However, few studies address the methodology of analysis of BAL lymphocytes by FCM. 

The role of heat shock protein 27 in bronchiolitis obliterans syndrome after lung transplantation.

BACKGROUND Heat shock proteins (Hsps) are a family of evolutionary conserved proteins classified according to their size as small and large Hsps. They have a cytoprotective role and have been shown to be immunogenic molecules. In addition, self-reactivity to Hsps has been implicated in various autoimmune diseases and in the development of alloimmunity. This study examined the relationship of large and small Hsps and anti-Hsp antibodies in lung transplant (LTx) recipients who have bronchiolitis obliterans syndrome (BOS). METHODS Anti-Hsp27 and Hsp70 antibodies, and Hsp27, Hsp60, and Hsp70 protein expression levels were evaluated in serum and bronchoalveolar lavage samples collected from 8 LTx recipients with established BOS and 8 recipients without BOS (controls). Serum from 8 healthy individuals was examined for Hsp levels as a comparison. RESULTS Elevated serum Hsp27 levels were observed in recipients with BOS compared with controls or healthy individuals, whereas Hsp70 and Hsp60 expression showed no difference. Anti-Hsp27 antibody levels were significantly higher in the BAL of recipients with BOS than in those without BOS. In contrast, anti-Hsp70 antibodies levels in serum or BAL showed no difference between groups. CONCLUSIONS These results support the novel concept that Hsp27, but not the classic Hsp60 and Hsp70, may be associated with the development BOS. The expression of anti-Hsp27 antibodies found only in the BAL fluid suggests a local response occurring at the level of the alveoli and terminal airways.

The Small Heat Shock Protein 27 Is a Key Regulator of CD8+CD57+ Lymphocyte Survival

Differences in CD8+CD57− and CD8+CD57+ lymphocyte lifespan have been documented. Lower numbers and shorter lifespan are characteristic of CD8+CD57+ in normal individuals. However, CD8+CD57+ are expanded in certain disease states including T cell large granular leukemia and other hematologic malignancies. The mechanisms responsible for the differences in CD8+CD57− and CD8+CD57+ lifespan remain elusive. In this study, we demonstrate that the small heat shock protein (Hsp) 27 is a key regulator of CD8+CD57+ lymphocyte lifespan. We found that Hsp27 expression is significantly lower in CD8+CD57+ than in CD8+CD57− lymphocytes. In contrast, Hsp60 and Hsp70 are expressed at comparable levels. Unlike other antiapoptotic Bcl-2–like molecules, the expression of Hsp27 tightly correlates with CD8+CD57+ and CD8+CD57− lifespan. We demonstrate that Hsp27 overexpression in CD8+CD57+ lymphocytes to levels found normally in CD8+CD57− lymphocytes decreased apoptosis. Accordingly, silencing of Hsp27 in CD8+CD57− lymphocytes increased apoptosis. Collectively these results demonstrate that Hsp27 is a critical regulator of normal CD8+CD57+ lifespan supporting its use as a marker of lifespan in this lineage, and suggest a mechanism responsible for the decreased apoptosis and clonal expansion characteristic of certain disease states.

Chemotherapeutic Agents Increase the Risk for Pulmonary Function Test Abnormalities in Patients With Multiple Myeloma

UNLABELLED Case reports of pulmonary toxicity have been published regarding bortezomib, lenalidomide, and thalidomide but there are no published reports looking at the possible long-term pulmonary effects of these medications. This article describes a possible relationship between the administration of bortezomib and thalidomide and the development of pulmonary function test (PFT) abnormalities. It also suggests that routine pulmonary function testing may be required in patients receiving these medications until larger studies can be performed to confirm this observation. BACKGROUND Multiple myeloma is a common malignancy accounting for approximately 1% of all malignancies worldwide. Bortezomib, lenalidomide, and thalidomide are immunomodulatory derivatives that are used in the treatment of multiple myeloma (MM). There have been case reports of pulmonary disease associated with these agents, but the effect of these agents on pulmonary function test (PFT) results is unknown. PATIENTS AND METHODS We reviewed the records of 343 patients with MM who underwent PFTs before autologous stem cell transplantation. One hundred nine patients had not received any of the 3 medications, whereas 234 had received 1 or more of these agents. RESULTS Patients exposed to bortezomib were more likely to have obstructive PFT results (P = .015) when compared with patients not exposed to this medication. Restrictive PFT results were more likely after exposure to thalidomide (P = .017). A logistic regression model was performed and when adjusted for age, sex, Durie-Salmon (DS) stage, body mass index (BMI), time from diagnosis to transplantation in days, and smoking history, the odds of obstruction were 1.96 times higher for patients who received bortezomib. The odds of restriction were 1.97 times higher after exposure to thalidomide. CONCLUSION There appears to be a risk of PFT abnormalities developing in patients treated with bortezomib and thalidomide.

Perioperative Issues and Sleep-Disordered Breathing

Sleep-disordered breathing in the perioperative setting poses an increase in both perceived and demonstrated challenges for health care providers. Some of these challenges relate to identifying patients at high risk for obstructive sleep apnea prior to surgery. Other management challenges include identifying the proper monitoring techniques, using the correct mix of pharmacologic and nonpharmacologic strategies to manage these patients, and identifying the proper and safe disposition strategy after surgery. Additional populations, such as pediatrics and the morbidly obese, are also highlighted, which may help address questions in populations that are frequently managed in the critical care setting postoperatively.