• Definition: diverse group of diseases characterized by the presence of multiple granulomas (nodular inflammatory lesions)
• likely the result of chronic antigenic stimulation leading to the development of antigen-specific lymphocytes which recruit blood monocytes into specific tissue which then differentiate into epithelioid cells and multinucleated giant cells
• typically granulomas develop around infectious pathogens such as mycobacteria and fungi or inhaled antigens such as beryllium; may also develop within Wegener’s granulomatosis (a systemic vascular disorder)
• Sarcoid and Hypersensitivity Pneumonitis are examples of interstitial lung disease characterized by granulomatous inflammation; both sarcoid and hypersensitivity pneumonitis have better prognosis than other interstitial lung diseases

• multisystem disorder of unknown etiology characterized by noncaseating granulomas at sites of active disease
• Epidemiology – slightly more common in women than men; in the US it is more common in African Americans; seen most often in 20-40 year olds
• Etiology – unknown; theories include environmental exposures, infectious cause (mycobacterium), or autoimmune disease
• Pulmonary Disease – most common manifestation of sarcoidosis (90% of patients)
• respiratory symptoms – dry cough, dyspnea on exertion, and ill-defined chest pains
• CXR – bihilar lymphadenopathy (nonspecific finding)
• Stages of sarcoid based on radiographic appearances
• Stage 0: normal
• Stage 1: hilar and mediastinal adenopathy without parenchymal infiltrates
• Stage 2: hilar and mediastinal adenopathy with parenchymal infiltrates
• Stage 3: pulmonary infiltrates without adenopathy
• Stage 4: diffuse fibrosis
• Clinical – varies widely; ranges from asymptomatic X-ray abnormalities to fulminate course with fevers, night sweats, weight loss and rapid onset of respiratory symptoms
• acute course indicates an active inflammatory process and is associated with a better prognosis than an insidious progression of dyspnea
• Non Pulmonary Involvement
• ocular – photophobia, ß visual acuity (uveitis)
• dermatologic – nodules, plaques; commonly around nose and mouth
• nervous system – CNS and PNS neuropathy; especially cranial nerves
• cardiac – heart block, arrhythmias
• endocrine – hypercalcemia
• renal – renal insufficiency, calculi
• GI – granulomatous hepatitis
• Physical Exam and Labs – adenopathy (cervical, supraclavicular and epitrochlear) and splenomegaly
• lung – normal despite CXR abnormalities
• hypercalcemia, hypercalcuria, anemia, lymphopenia with ß CD4 to CD8 ratio
• bronchoalveolar lavage demonstrates lymphocytosis with an Ý CD4 to CD 8 ratio
• ß cell mediated immunity
• PFT’s demonstrate ß diffusion capacity and a restrictive ventilatory defect (obstruction may also be present)
• Kviem-Siltzbach reagent – injection of ground up tissue from individuals with sarcoidosis into patients and look for skin reaction; not used now
• Ý angiotensin-converting enzyme (ACE) level is typically present but is not specific for sarcoidosis
• Gallium scanning
• Diagnosis
• (1) Clinical presentation
• (2) Biopsy of involved tissues demonstrating noncaseating granulomas
• (3) Negative stains for other causes of granulomatous inflammation (mycobacteria and fungi)
• Treatment – most patients improve spontaneously and never require therapy
• indications for treatment include involvement of vital organs (eyes, heart, CNS) presence of hypercalcemia, disfigurement, disabling constitutional symptoms or loss of pulmonary function
• treat with oral prednisone, 60 mg/day

Hypersensitivity Pneumonitis (HP) – extrinsic alveolitis

• Definition – spectrum of granulomatous lung diseases resulting from repeated inhalation of and sensitization to a wide variety of organic dusts and low molecular weight chemical antigens
• Etiology – animal proteins and thermophilic bacteria are the most common causes of HP
• example: thermophilic organisms are found in stored crops Þ common where harvesting season is short and wet; growth of bacteria in the moldy hay can cause "farmer’s lung" whereas growth in sugarcane can cause Bagassosis ("sugar can worker’s lung")
• "Humidifier lung" Þ fungi and bacteria within humidifier
• "Bird breeder’s lung" Þ antigen causing immune reaction is from bird droppings and feathers
• "Animal Handler’s lung" Þ antigen is within animal proteins in urine and serum
• Clinical – acute, subacute or chronic disease
• Acute – most common form of HP and is characterized by explosive episodes of illness occurring 4-6 hours after a brief and intense exposure to an Ag
• Symptoms – may resemble flu Þ malaise, acute cough and dyspnea, fever, chills, myalgias; may last up to 18 hours
• PE – bibasilar crackles may be present and persist for weeks
• CXR – reticulonodular opacities with apical sparing
• Blood – WBC Ý with left shift and eosinophilia
• PFT – hypoxemia and restrictive ventilatory defect
• Note: Occupational Asthma occurs one hour after exposure and usually presents with obstructive disease
• Subacute – symptoms resemble chronic bronchitis
• Symptoms – cough, sputum production, anorexia and weight loss
• PE and Lab – are identical to acute form of the disorder
• CXR – nodular infiltrates or early fibrosis
• PFT – restrictive disease
• Chronic – result of less intense but prolonged exposure to sensitizing antigens
• Symptoms – slowly progressive dyspnea, chronic cough, weight loss and weakness; no acute episodes
• CXR and PFT– diffuse fibrosis; restrictive disease and hypoxemia
• As with sarcoidosis, more chronic the presentation Þ worse prognosis due to irreversible scarring of lungs
• Tests – bronchoalveolar lavage Þ lymphocytosis with CD8⁺ T cell predominance
• biopsies Þ poorly formed granulomas, lymphocytic inflammation, foamy macrophages, obstructive bronchiolitis
• inhalation challenge with suspected antigen
• Hypersensitivity Immune Response (Review)
• Type I: anaphylactic hypersensitivity: antigen interacts with preexisting IgE antibodies (example: bee sting allergy)
• Type II: antibody-dependent cytotoxicity: mediated by antibodies directed at cell-surface antigens, in which cell death results from phagocytosis via Fc or complement receptors, or from complement-mediated cell lysis (examples: ABO incompatibility, Goodpasture’s syndrome)
• Type III: immune complex-mediated hypersensitivity: deposition of antigen-antibody complexes in specific tissues results in local migration and activation neutrophils, platelets, and macrophages (example: post-streptococcal glomerulonephritis)
• Type IV: cell-mediated (delayed) hypersensitivity: the only type which cannot be transferred from sensitized to non-sensitized individuals via serum, and which is characterized by exaggerated response of antigen-specific T-cells causing tissue damage (example: mycobacterial infections).
• hypersensitivity pneumonitis is Type IV hypersensitivity reaction
• precipitating antibodies to specific causative antigens can be found in patients with HP and it was originally believed that HP was the result of Type III hypersensitivity response; it is now clear that precipitating antibodies are found in many individuals, and although they may correlate with the duration and degree of exposure that they are not the causative agent of the disease
• Treatment – avoidance of offending agent
• prednisone – 60 mg/day
• some individuals have progressive disease despite cessation of exposure