Pulmonary disorders, including vocal cord dysfunction Paul A. Greenberger, MD, and Leslie C. Grammer, MD Chicago, Ill The lung is a very complex immunologic organ and responds in a variety of ways to inhaled antigens, organic or inorganic Abbreviations used materials, infectious or saprophytic agents, fumes, and irritants. ABPA: Allergic bronchopulmonary aspergillosis There might be airways obstruction, restriction, neither, or both ANCA: Antineutrophil cytoplasmic antibody accompanied by inflammatory destruction of the pulmonary ARDS: Acute respiratory distress syndrome BAL: Bronchoalveolar lavage interstitium, alveoli, or bronchioles. This review focuses on COPD: Chronic obstructive pulmonary disease diseases organized by their predominant immunologic CSS: Churg-Strauss syndrome responses, either innate or acquired. Pulmonary innate immune CT: Computed tomography conditions include transfusion-related acute lung injury, World FVC: Forced vital capacity Trade Center cough, and acute respiratory distress syndrome. HDAC: Histone deacetylase Adaptive immunity responses involve the systemic and mucosal LT: Leukotriene immune systems, activated lymphocytes, cytokines, and PMN: Polymorphonuclear leukocyte 1 antibodies that produce CD4 TH1 phenotypes, such as for RADS: Reactive airways dysfunction syndrome tuberculosis or acute forms of hypersensitivity pneumonitis, and TLR: Toll-like receptor 1 TRALI: Transfusion-related acute lung injury CD4 TH2 phenotypes, such as for asthma, Churg-Strauss VCD: Vocal cord dysfunction syndrome, and allergic bronchopulmonary aspergillosis. (J Allergy Clin Immunol 2010;125:S248-54.) Key words: Innate, acquired, hypersensitivity, eosinophilia, lympho- antibodies to human neutrophil antigens or HLA class I or II an- 2,3 cyte, tuberculosis, aspergillosis, bronchopulmonary, bronchiectasis, tigens. Neutrophil alloantibodies are found in 10% to 20% of immunologic female donors and 1% to 4% of male donors, yet the incidence of TRALI is about 1:5000 transfusions.3 Alloantibodies are gen- Pulmonary disorders can be organized according to whether the erated during pregnancy, but of course that would not explain the primary immune responses are characterized by innate or adap- presence of such antibodies in men. Some recipients have anti- tive immune responses. The innate responses use complement neutrophil antibodies. The immediate reaction, which might re- activation or activation of polymorphonuclear leukocytes (PMNs) semble anaphylaxis, involves sequestration of PMNs in the and occur without a period for sensitization. The adaptive pulmonary vasculature, complement activation, and generation of TGF-b, IL-8, and IL-13.2 Immune complexes activate PMNs responses include TH1 or TH2 lymphocytes, eosinophils, antibody mediated, and granuloma formation.1 This chapter will review the and cause disruption of the endothelium barrier to plasma. TRALI various pulmonary disorders with a predominant immunologic is extremely rare after intravenous immunoglobulin infusions but pattern and also discuss vocal cord dysfunction (VCD), which occurs with infusions of platelets (suspended in plasma), whole can coexist with asthma or occur independently and results in blood, cryoprecipitates, and fresh frozen plasma. cough, shortness of breath, and dyspnea. The immediate management includes stopping the infusion, oxygen, mechanical ventilation if indicated, and treatment of hypotension with vasopressors. Donors should be deferred from future donations. Indeed, some transfusion experts have recom- INNATE IMMUNE RESPONSES mended that the donor pool should not include women who have Transfusion-related acute lung injury been pregnant and that donor plasma be tested for alloanti- 2,3 Transfusion-related acute lung injury (TRALI) is a nonhemo- bodies. Neither of these suggestions are standard practice. lytic transfusion reaction that occurs within 10 minutes to as long as 6 hours after infusion of a blood product and causes very severe Acute respiratory distress syndrome and acute lung noncardiogenic pulmonary edema, cyanosis, arterial hypoxemia, 2,3 injury and respiratory failure. The donor plasma typically contains Acute respiratory distress syndrome (ARDS) and acute lung 4 From the Division of Allergy-Immunology, Department of Medicine, Northwestern injury represent diffuse pulmonary disease that can be fatal. ARDS University Feinberg School of Medicine. is a more severe form of acute lung injury. Causes include sepsis, 4 Supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and pneumonia, trauma, or aspiration pneumonia. Patients experience Northwestern University severe dyspnea, tachypnea, and hypoxemia. The chest roentgeno- Disclosure of potential conflict of interest: P. A. Greenberger has served as an expert gram and computed tomographic (CT) examination demonstrate witness on the topics of immunotheraphy, remote practice, ABPA misdiagnosis, and anaphylaxis. L. Grammer has received research support from S&C Electric Company. bilateral infiltrates, alveolar consolidation, and ‘‘white out’’ of the Received for publication May 18, 2009; revised August 28, 2009; accepted for publica- lung. The alveoli collapse as they become filled with protein and fi- tion September 2, 2009. brin-rich exudates (hyaline membranes), which inactivate surfac- Address for reprints: Paul A. Greenberger, MD, Division of Allergy-Immunology, 676 N tant.4,5 Neutrophils release oxidant proteases, which damage the St Clair Street, #14018, Chicago, IL 60611. E-mail: [email protected]. 0091-6749/$36.00 capillary endothelium. Bronchoalveolar lavage (BAL) reveals the Ó 2010 American Academy of Allergy, Asthma & Immunology presence of PMNs, procoagulant activity, IL-8 (chemotactic for doi:10.1016/j.jaci.2009.09.020 PMNs), IL-2, IL-6, and TGF-b. There is reduced apoptosis of S248 J ALLERGY CLIN IMMUNOL GREENBERGER AND GRAMMER S249 VOLUME 125, NUMBER 2 PMNs, which is attributable to increased concentrations of BAL The onset of symptoms is within 12 hours of inhalation of organic fluid IL-2, IL-8, granulocyte colony-stimulating factor, GM-CSF, dusts. Although the clinical presentation might mimic that of and growth-related oncogene a.6 Alternatively, there is enhanced acute hypersensitivity pneumonitis, there is no requirement for apoptosis of epithelial cells, resulting in the lack of a sufficient bar- prior exposure or immunologic sensitization (see the later section rier between the alveoli and capillaries. TNF-related apoptosis-in- on hypersensitivity pneumonitis). Various circumstances of ex- duced ligand levels are increased in BAL fluid in patients with posure have been described, such as from organic mulch, ARDS and are recognized as proapoptotic for epithelial cells.6 endotoxin-rich vegetables and grass seeds, and contaminated Patients requiring mechanical ventilation benefit from smaller seaweed. Massive inhalation of microbial products can cause an volumes, such as a tidal volume of 6 mL/kg, with positive end- ARDS-like presentation, and this is designated as organic dust 11 expiratory pressures of 5 to 10 cm H2O. Fluid replacement should toxic syndrome or pulmonary mycotoxicosis. be conservative. Corticosteroids and other interventions, such as In patients with silo-unloader’s disease, there is inhalation of 7 nitric oxide and surfactants, are not effective. nonorganic gases, such as NO, NO2, or N2O4. These nitrogen ox- ides then generate nitric and nitrous acids that cause noncardiac pul- monary edema and, in some patients, methemoglobinemia. Deaths Community-acquired pneumonia can occur, whereas survivors might have bronchiolitis obliterans. Community-acquired pneumonia presents with a productive Grain-handler’s disease occurs in agricultural workers with a cough, fever, pleuritic chest pain, and abnormal chest roentgen- chronic cough, symptoms of chronic bronchitis, or wheeze after 8 ographic results. On auscultation, there can be crackles and bron- exposure to grain dusts. Concurrent cigarette smoking appears to chial breath sounds. Most pathogens include viruses, be more injurious to the lung and associated with reductions in Streptococcus pneumoniae, Haemophilus influenzae, Myco- spirometric values. Measures to reduce exposure to dust are plasma pneumoniae, Staphylococcus aureus, and Legionella beneficial. Because of less implementation of safety standards, 8 pneumophila. There might be no recovered organisms in some there is a major concern that workers will experience grain- 8 patients. Comorbidities influence survival. handler’s disease and other respiratory disorders in the world’s Levels of proinflammatory cytokines, such as TNF-a and IL-6, emerging economies. and the anti-inflammatory cytokine IL-10 are increased in those patients who succumb compared with survivors.9 Impaired recog- nition of molecular patterns of bacteria is associated with decreased Reactive airways dysfunction syndrome 10 activation of innate immunity and worse clinical outcomes. Toll- The reactive airways dysfunction syndrome (RADS) describes like receptors (TLRs) recognize pathogen-associated molecular a single unexpected inhalation of high concentrations of irritant patterns, and genetic polymorphisms have been identified in fumes, vapors, fog, or smoke that results in acute cough, dyspnea, 10 patients who had invasive S pneumoniae infections. For example, and wheezing within 24 hours.12 An asthma-like syndrome begins polymorphisms of TLR4 impair its function in recognition of S that can last for months or years. Bronchial hyperreactivity can