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Biomedical subjects

H Y Reynolds

Publications and source records attributed to H Y Reynolds.

At least 19 recordsLinked to original sources

Sarcoidosis: impact of other illnesses on the presentation and management of multi-organ disease.

Sarcoidosis remains a fascinating illness that almost always affects the respiratory tract but often involves many other organs as well. Although many patients seem to have only an intrathoracic illness, with perhaps one other site or organ involved, others can experience a severe multi-organ disease. The inciting stimulus, even if unknown, can elicit an immunologic host response-the non-caseating granuloma-in almost every organ. It is intriguing that this stimulus can be so widespread throughout the body, while the biology of the disease can be so variable. Many series of patients with sarcoidosis have reported the multiple organs involved and the clinical presentation. Our series of 67 patients (40 female, 27 male, mean age 38.7 years +/- 13.2 (SD) at time of diagnosis) generally mirrors the clinical pattern found in five comparison series that span the past 60 years. However, more emphasis is given in this series to associated medical conditions that can complicate the presentation of sarcoidosis, as well as to co-morbid illnesses that must be managed in addition to the patient's sarcoidosis. Although most patients had intrathoracic sarcoidosis diagnosed at initial evaluation (40%), many had other organs or bodily sites involved in addition (or subsequently) as the illness evolved. Confounding the initial patient evaluation were two factors: (1) the presence of an occupational respiratory exposure(s) (n = 25 or 37% of patients); (2) a previously diagnosed malignancy (n = 6 or 9%) that heightened the possibility of a primary malignancy presenting in the chest, or the reactivation of a prior malignancy (breast, thyroid, and lymphoma) that could metastasize to the lung. Symptoms present when a patient's diagnosis was established usually differentiated respiratory and/or abdominal organ involvement. Although respiratory symptoms could be absent (n = 18 or 27%) for many patients with incidental thoracic findings, most had typical ones, including exertional dyspnea. For patients with an abdominal presenting illness (n = 11 or 16%), nonspecific digestive and abdominal symptoms were experienced as well as arthralgias. Almost every patient had at least one important other illness that factored significantly into the management of their sarcoidosis. Older patients had more illnesses, such as cardiovascular illness, diabetes mellitus, neurologic problems, and functional gastrointestinal symptoms. Depression affected all ages and was probably underrecognized; more emphasis on this illness is needed. Obesity was associated with disordered sleep syndromes, but not invariably so, as half the subjects had a good body habitus. Thus, many of the other illnesses experienced by sarcoidosis patients are common problems that middle-aged people develop. However, digestive and gastroenterological symptoms seemed disproportionately frequent in this series. This is a component of multi-organ sarcoidosis that has not received extensive coverage in the literature. Approximately one-third of sarcoidosis patients had one of two very common problems-gastroesophageal reflux or irritable bowel syndrome. But these are common problems, and it is thus necessary to separate these symptoms from those associated with abdominal visceral involvement of sarcoidosis. Although liver and/or splenic involvement with sarcoidosis do not cause organ dysfunction or insufficiency, they can contribute to abdominal symptoms. Finally, it remains of interest whether inflammatory bowel disease-Crohn's disease in particular-is another organ manifestation of sarcoidosis, or is it unrelated?

Adult↗

Sampling local respiratory tract sites for inflammation.

Although host defense mechanisms protect the health of the respiratory tract, deficiencies or excessive host responses such as inflammation can create sino-nasal and pulmonary illnesses. Analysis of expectorated secretions (sputum) is traditional, but selective site specific samples (surface washing) seem more applicable for studying illnesses such as rhinitis, bronchitis, or aveolitis. Regional samples should contain representative components (cells and proteins) that ideally reflect changes in adjacent tissue; however, biopsy of contiguous mucosa and lung parenchyma is required for a comprehensive analysis that can link surface samples and tissue pathology. Clinical strategies must be flexible so that maximal information about the host can be obtained through investigation of healthy normals, volunteer-patients with latent illness that can be induced locally and observed in situ, and patients with active illness. Implicit in studying inflammation is the adaptation of new analytic methods to surface or topical samples such as nasal, bronchial and bronchoalveolar lavage (BALF). More correlations between respective components in nasal fluids, bronchial and BAL specimens seem indicated, so that more readily available samples can be used for clinical monitoring. Moreover, further correlations between bronchial and BAL cells and immunohistochemical analysis of tissue for cells are needed.

Bronchoalveolar Lavage↗

Use of bronchoalveolar lavage in humans--past necessity and future imperative.

Limited bronchoalveolar lavage (BAL) as an extension of fiberoptic bronchoscopy has permitted the recovery of airway-alveolar space cells and soluble substances in the extracellular lining fluid that have been used diagnostically and as research specimens in patients with a variety of lung diseases and in normal subjects for the study of lung host defenses. During the past three decades, use of BAL specimens has stimulated immunologic and cellular research of pulmonary diseases, which has provided significant insight into local host immunity, inflammation, fibrogenesis, asthma mechanisms, and infections. From this research new methods of antifibrotic therapy of interstitial pulmonary fibrosis, for example, have followed. Moreover, BAL applications have greatly enhanced professional interest in the field of pulmonary medicine. This review attempts to analyze the history and impact of BAL, appraise its current status, and assess its future usefulness. Understanding the immunopathogenesis of many lung diseases is predicated on obtaining in situ specimens from affected lung tissue and airways. BAL provides a direct sample that can be compared with an endobronchial or transbronchial biopsy tissue specimen and with cellular and immunologic components in the vascular circulation. Thus, the recovery of BAL fluid and its components involved directly with a disease process or continguous with interstitial tissue permits a much more detailed assessment of new cellular mediators and cytokines participating in the pathologic process. Furthermore, subjecting BAL cells to microarrays of DNA to discern what genes, are activated will be one step closer to identifying intracellular processes involved or deranged. Identification of causative factors may solve questions of causation, so that preventive strategies or definitive therapy can be used.

Bronchoalveolar Lavage↗

Advances in understanding pulmonary host defense mechanisms: dendritic cell function and immunomodulation.

Mucosal host immunity in the respiratory tract can probably be manipulated to better improve defense against microbes and other antigens or particulates that cause infection and respiratory illness. An evolving strategy is to target the extensive network of dendritic cells in the lungs, especially dendritic cells located in the airway epithelium, which are super antigen-presenting cells that can initiate specific T-lymphocyte immune responses. Also, dendritic cells can elaborate cytokines such as interleukin 12 which drive other components of the immune response including antibody production. However, dendritic cells can be counter-regulated by inhibitory cytokines or certain microbes that create a dynamic interplay. This review emphasizes human studies and relevant animal models that provide a framework for future planning of experimental approaches to enhancing antimicrobial immunity and respiratory host defense.

Animals↗

Defense mechanisms against infections.

Respiratory infections remain common and may be more difficult to treat because new microbes have been identified; commensal flora can become pathogens; and antibiotic resistance is developing, especially to Streptococcus pneumoniae. Contributing to the severity of pneumonia is the increasing number of more susceptible hosts--immunodeficient patients, created as a by-product of modern medical therapy or from infection with HIV, and elderly patients who have associated illnesses. Better strategies to replete immunocompromised hosts are required. Vaccination to modify infection with S. pneumoniae must be given higher priority by health care providers. New means to immunize the respiratory mucosal surface are needed. Research approaches to consider involve 1) targeting (carrying) relevant antigens to appropriate antigen-processing cells in the airways, eg, dendritic cells; and 2) coupling the immunomodulatory effects of cytokines, eg, interleukin-12. Interleukin-12, for example, can stimulate mucosal antibody responses producing S-IgA and IgG and cause T lymphocytes to produce interferon-gamma that can enhance microbial killing by macrophages.

Bacterial Infections↗

Diagnostic and management strategies for diffuse interstitial lung disease.

Patients with diffuse interstitial lung diseases (DILD) are challenging to treat. Many patients with DILD have inadequate information about the disease process, an imprecise diagnosis, unsatisfactory treatment or unacceptable side effects associated with therapy, and poorly controlled symptoms of progressive illness. Establishing an accurate diagnosis is necessary so that the patient and his/her family can be provided with reasonable expectations about prognosis and outcome from therapy. A pragmatic approach is presented that emphasizes diagnostic strategies and plans for therapy that are effective and resource efficient and that will help maintain patient satisfaction.

Anti-Inflammatory Agents↗

Respiratory infections: community-acquired pneumonia and newer microbes.

Respiratory infections, especially community-acquired forms of pneumonia (CAP), are challenging for clinicians because (1) a causative microorganism can only be found in about 50% of cases; (2) initial therapy, therefore, must be based on a probable or most likely etiology in the context of the patient's overall medical condition; and (3) new microbes or those considered previously as normal flora or less virulent forms seem responsible for some cases. It is important to be acquainted with new causes of infection which include Legionella species, Chlamydia pneumoniae, diphtheroids in certain instances (Corynebacterium pseudodiphtheriticum), and viruses such as the Hanta strains. Infections with Bordetella pertussis are increasing. However, the ever present and most common cause of CAP, Streptococcus pneumoniae, continues to present problems because of increasing antibiotic resistance, the high case fatality rate when bacteremia accompanies pneumonia, and the inability to give prophylactic immunization to all people with risk factors for this infection.

Anti-Bacterial Agents↗

Pulmonary host defenses.

Well functioning host defenses in the respiratory tract effectively remove microbes and other debris that reach the conducting airways and alveoli, and this usually prevents infections. People with acute and chronic illnesses can experience failure of any number of these defense mechanisms that allow pneumonia (and bacteremia) to occur, often with considerable morbidity and mortality. People with alcohol-related illnesses are a susceptible group for infections, and many strategies are needed to help them such as moderating alcohol abuse and dependence, providing timely immunizations to create antibody against encapsulated bacteria, anticipating microbial colonization of mucosal areas that can promote infection, giving excellent supporting medical care in crisis situations, and prescribing appropriate antibiotics. New approaches to boosting inflammatory reactions to control lung infections better with cytokines and new immunomodulator therapies must be investigated now.

AIDS-Related Opportunistic Infections↗

Respiratory host defenses--surface immunity.

The mucosal surface of the respiratory tract has an operable immune system, specially designed for producing immunoglobulins (antibodies); however, it has not been harnessed effectively yet to provide local, immunospecific protection against many microbes that enter. Respiratory host responses in humans have been used in this review where possible. New research approaches seem necessary to manipulate the physical and immunologic barriers in the respiratory tract and this may require different antigen preparations, better and more specific vehicles for delivery and selective enhancement of cytokines and interleukins in the mucosa. The immunologic tools are available and need to be explored more in the human model.

Antibody Formation↗

Life-threatening pneumonia.

Severe pneumonia can be acquired by previously healthy patients, those with pre-existing illness, or those hospitalized for an unrelated illness. Because diagnosis is frequently difficult or delayed, treatment is usually empirically tailored to the most probable offending organisms and the patient's condition. This article reviews the pathogenesis of community- and hospital-acquired pneumonia, clinical features, and diagnostic techniques. An approach to selecting an antibiotic regimen is suggested.

Anti-Bacterial Agents↗

NHLBI workshop summary. Research needs and opportunities related to respiratory health of women.

To summarize, the overwhelming conclusion of the participants was that relatively little is known about respiratory health and disease in women. Much work will be required to obtain even the most basic information upon which hypotheses for future research can be developed and to determine whether pulmonary biology differs between men and women and between women of various ages. The many recommendations and suggestions generated at the workshop should serve to underscore the unique opportunities for research in the field of respiratory health of women.

Female↗

An analysis of the inter-relationships among multiple bronchoalveolar lavage and serum determinations, physiologic tests, and clinical disease activity in patients with sarcoidosis.

Analysis of epithelial lining fluid from the lungs of patients with sarcoidosis frequently suggests the presence of an alveolitis. Several markers of this inflammatory response were quantitated in bronchoalveolar lavage fluid and serum from 45 non-smoking patients with sarcoidosis. All markers were elevated significantly compared to those from 19 normal controls. The degree of statistical correlation among all data was assessed. Pulmonary function tests, 67Gallium lung scans, and a clinical index of disease activity also were quantitated. When patients were grouped by the number of abnormal BAL lavage and serum markers, those patients with elevated values of five or more of these markers had significantly worse clinical disease and lower carbon monoxide diffusing capacities. These results indicate that pulmonary sarcoidosis is an immunologically heterogeneous disease and that measurement of several markers of disease activity may be required to accurately estimate the activity of the lung disease.

Adult↗

Immunologic responses in the lung.

Placing 'immunologic' as an adjective before a collection of lung diseases implies that the host has responded to the illness by reacting with distinctive airway and/or alveolar space cells and proteins, i.e. lymphocytes, macrophages, inflammatory cells, immunoglobulin (antibodies), possibly complement components and various cytokine mediators. Also implicit in the usage of the term is that certain research methods have been used to study the host response. Direct immunologic investigation of the human lung has advanced greatly by the use of fiberoptic bronchoscopy, available for the past 20 years, which has permitted sampling of the airways and alveolar space with bronchoalveolar lavage (BAL). Values for immune components in BAL have been established for normals and used to contrast abnormal findings in many forms of lung disease. Examples of these findings in pulmonary sarcoidosis and hypersensitivity pneumonitis are given. In contrast an immunologic deficiency, as may be found with acquired immunodeficiency syndrome, illustrates how a lack or imbalance in immune components can contribute to infection and chronic disease. Overall, the analysis of immune components in BAL fluid has contributed to improved concepts about the immunopathogenesis of many lung diseases.

Bronchoalveolar Lavage Fluid↗

Macrophages and polymorphonuclear neutrophils in lung defense and injury.

Phagocytes, in particular macrophages and PMN, are now recognized as major components of inflammatory and immunologic reactions in the lung. Normally, macrophages represent the majority of phagocytes in the lower respiratory tract. These lung macrophages are morphologically and functionally heterogenous and include alveolar, interstitial, intravascular, and airway macrophages, each with characteristic morphologic and functional features. Through the presence of surface receptors for numerous ligands and through their large number of secretory products, lung macrophages can respond to environmental factors and account for most of the clearance of microparticles and microorganisms in the distal airways and the alveolar spaces. In addition, macrophages also play an important role in inflammatory processes through the release of oxygen radicals and proteolytic enzymes. Through the release of several cytokines, i.e., growth-promoting and inhibiting factors, lung macrophages may also influence both matrix damage and repair processes. Macrophages can also contribute to the alveolitis by recruitment of inflammatory and immune cells. This latter contribution is best demonstrated in migration movement of PMN. The normal distal airways generally contain a small number of PMN, but the pulmonary vascular bed represents a large reservoir of PMN. Some of them are in intimate contact with the endothelium, forming the so-called marginating pool of PMN. Because the capillary lumen is separated only from the alveolar space by a monolayer of endothelial and epithelial cells on each side of a thin interstitial matrix, it is likely that some inhibitory mechanism exists to prevent PMN from migrating towards the alveolar space. Such inhibitors of PMN migration are present both in serum and in the alveolar space, some being released by alveolar macrophages. However, alveolar macrophages can also secrete factors called chemotaxins that attract PMN to the airways, and this supports a central role for alveolar macrophages in the regulation of PMN traffic in the lungs. Thus, secretory products of alveolar macrophages are part of the regulatory mechanisms of PMN mobility and adherence that appears to be crucial in the initiation of some inflammatory reactions. The contribution of phagocytes to the defense against infection and tumor has been documented mostly in vitro. Thus, both oxygen radicals, in particular hydroxyl radicals and proteases such as lysozyme, are potent bactericidal agents. That phagocytes are also important defenders of the lungs in vivo is best supported by the observations in immunodeficient patients and animal models.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Altered immune status in the elderly.

The lung has an array of immunological defenses to protect itself against potentially invasive microorganisms, which include the immunoglobulin-rich alveolar lining fluid, alveolar macrophages, T lymphocytes, and polymorphonuclear neutrophils. Immunosenescence is a major predisposing factor to the increased incidence, morbidity, and mortality of pneumonia in the elderly. The progressive involution of the thymus gland in humans plays a pivotal role in the development of the immunodeficiency state characteristic of the older individual. Age takes its greatest toll on the cell-mediated arm of the immune system. Aged T cells are impaired in their ability to activate and proliferate in response to an antigen. This is partly due to age-associated structural and functional changes within the T cell. In addition, the ability of the T cell to secrete interleukin-2 (a cytokine necessary for the recruitment of other T cells) declines with age. The impaired antibody response of the elderly to foreign antigens, including the pneumococcal polysaccharide and the influenza vaccine, appears to be secondary to a deficiency of T helper cells. The macrophage functions well even in old age, but the recruitment of macrophages by senescent T cells is diminished. There also may be a blunted inflammatory response in the older individual secondary to impaired polymorphonuclear neutrophils chemotaxis and phagocytosis.

Aging↗

ELISA analysis of BACTEC bottles for the earlier diagnosis of tuberculosis.

Enzyme-linked immunosorbent assays (ELISA) have enabled earlier identification of Mycobacterium tuberculosis (TB) in clinical settings by utilizing both TB antibody and antigen detection. We studied the sensitivity and specificity of ELISA detection of TB antigen by using a commercially available anti-BCG antibody in conjunction with BACTEC 7H12B culture bottles. We compared these results against those obtained with cultures of Mycobacterium avium-intracellulare and Mycobacterium kansasii. All BACTEC bottles were inoculated with known concentrations of organisms. TB antigen was detected by ELISA in BACTEC culture bottles of TB 12 days before the BACTEC system could itself identify the species. A growth index of greater than or equal to 10 reliably indicated that tuberculosis antigen was detectable by ELISA. The correlation between growth index and antigen concentration was extremely high (r = 0.95 and p less than 0.001). There was insignificant cross-reactivity with the other atypical mycobacteria at the levels of growth tested. This technique potentially offers a sensitive and specific means for the early identification of TB in BACTEC culture bottles.

Antigens, Bacterial↗