Immune and Inflammatory Lung Disease

Radiology

Chest radiograph almost always precedes the use of high-resolution computerized tomography (HRCT) of the chest in children because of the need for sedation and concerns regarding risk of irradiation dose from HRCT. The plain radiograph will often demonstrate a ground-glass appearance, interstitial prominence, with a predominant location in the upper and middle lung fields. It is common for a chest radiograph to be considered normal by a radiologist early in the disease progression. Late in the disease, interstitial fibrosis may become prominent in the presence of increasing dyspnea, hypoxemia on room air, and clubbing of the fingers. Mediastinum widening from lymphadenopathy is not usually present; when present, the lymph nodes are prominent along the airway near the carina, suggesting that the antigen source is inhaled and being responded to by the immune system.

Classical findings of mid zone and upper zone opacities with ground-glass appearance and nodularity on HRCT in the presence of typical clinical exam HP findings (lung crackles, cough, dyspnea) and lymphocytosis on BAL are almost sufficient to make a diagnosis ( Fig. 427.1 ). These findings must prompt the clinician to identify the exposure in order to secure the diagnosis and eliminate the offending antigen. Without therapy, the progressive inflammatory response leads to air trapping, honeycombing, emphysema, and mild fibrosis in the chronic state. It is in this latter stage that idiopathic pulmonary fibrosis and nonspecific interstitial fibrosis are hard to differentiate. Whether true idiopathic pulmonary fibrosis exists in children where fibroblast foci are found on biopsy with usual interstitial fibrosis has been questioned.

Bronchoalveolar Lavage

BAL is one of the most sensitive tests and very helpful to the clinician in supporting the diagnosis of HP. Lymphocytosis frequently exceeding 50% of the recovered cells is seen on the BAL and should alert the clinician to the possibility of HP. Sarcoid, idiopathic pulmonary fibrosis, cryptogenic organizing pneumonia, berylliosis, granite workers lung disease, amiodarone pneumonia, lymphoma, and Langerhans cell histiocytosis may demonstrate lymphocytosis on BAL. All BAL specimens should have flow cytometry measurements of T-cell markers (CD3, CD4, and CD8 at a minimum). The predominant phenotype of the lymphocytosis is CD3+/CD8+/CD56+/CD57+/CD10−. In the normal circulation, lymphocytes with CD4 markers predominate at a ratio of approximately 2 : 1 compared to CD8 lymphocytes. In the lung compartment with HP, this ratio becomes approximately equal to or less than 1 (CD4:CD8 ≤ 1) with either an increase in CD8 lymphocytes or a decline in CD4 lymphocytes. This ratio assists the clinician in making a diagnosis of HP. This is in sharp contrast to other lymphocytic granulomatous diseases, like sarcoidosis, where the CD4:CD8 is ≥ 2, or pulmonary fibrosis associated with connective tissue disease. Cryptogenic organizing pneumonia, a rare disease in children, also may present with BAL where the CD4:CD8 is ≤ 1 and may be confused initially with HP.

Lung Biopsy

Lung biopsy is necessary to confirm a diagnosis of HP in the absence of critical elements like antigen exposure, typical medical history, characteristic physical exam, and CD8+ lymphocytes in the BAL. Open lung biopsy is often the route of choice in young children because of the difficulty in safely obtaining satisfactory amounts of tissue by transbronchial biopsy. Lack of positive serum precipitins to offending antigen and exposure history are common reasons for obtaining lung biopsies. It is crucial to inform the pathologist about the suspicion of HP so that the findings can be interpreted appropriately.

Histological examination shows poorly formed, noncaseating granulomas near the respiratory and terminal bronchioles and multinucleated giant cells. This is in sharp contrast to the well-formed granulomas seen in sarcoidosis. Lymphocytes and plasma cells infiltrate the alveolar walls predominantly in a bronchocentric pattern. Fibrosis in the peribronchial region supports a diagnosis of HP. Foamy cytoplasm accompanying large histiocytes in the alveoli and interstitium may be characteristically found.

Antigen Challenge by Inhalation

Inhalation challenge can support the diagnosis of HP by demonstrating a causal relationship between environmental exposure and symptoms. Inhalation challenge can be performed by 2 methods: (1) reexposure of the patient to the environment where the suspected antigen is present and (2) direct inhalation challenge at the hospital to material collected from the suspected source of the antigen. As the second method has resulted in severe exacerbation of disease in some individuals, its use is discouraged.

Two abnormal response patterns may be seen. Most commonly, where there is HP without asthma, symptoms occur 8-12 hr after direct challenge in the hospital or reexposure at the source of the antigen. The challenges replicate some or all the symptoms observed in the acute syndrome with fever, dyspnea, fatigue, and crackles on lung auscultation. Blood drawn prior to challenge and then repeated during these symptoms often demonstrates an increased neutrophil count compared to baseline. Pulmonary function tests demonstrate a fall in forced vital capacity (FVC) and often a concurrent fall in the forced expiratory volume at 1 sec (FEV ₁ ) with a stable or increasing ratio of FEV ₁ :FVC percentage reflecting a restrictive defect. Hypoxemia may accompany this decline in pulmonary function as well as a fall in the diffusion capacity of carbon monoxide (DLCO). To see the complete effect, exercise during this period may show a considerable fall in oxygenation despite normal arterial blood gas oxygen tension and normal pulse oximetry at rest. This finding denotes the onset of worsening restrictive lung disease.

Atopic patients may experience a biphasic response to inhalation challenge. These patients may develop an early reduction in FEV ₁ , followed 4 to 6 hr by a second drop in FEV ₁ accompanied by decreased FEV ₁ and FVC, fever, and leukocytosis.

Occupational and Environmental Asthma

The general principles of diagnosis, clinical signs and symptoms, treatment, and causes of asthma are discussed in Chapter 169 . High molecular weight causes of occupational and environmental asthma can be characterized as allergens, which are normally proteins and enzymes, inhaled from multiple sources ( Table 427.5 ). These include various animals, shellfish, fish, enzymes (e.g., Bacillus subtilis in laundry detergent), and flour or cereals. Occupational and environmental asthma is also caused by a number of low molecular weight agents including reactive chemicals, transition metals, and wood dusts ( Table 427.6 ). These low molecular weight agents are sufficient to induce an immune response, but often not by an IgE-mediated mechanism. These low molecular weight chemicals appear to act as haptens that bind directly to human proteins, causing an immune response in the human host.

The pathogenesis of asthma in patients exposed to high molecular weight antigens follows the experience of nonoccupational asthma in patients where atopy, gender, genetics, concentration of antigen, duration of exposure, and other individual factors all contribute to the development of disease. Most individuals require a concentration and duration of exposure sufficient to cause IgE antibody sensitization to the offending allergen with development of bronchial hyperresponsiveness and airway inflammatory disease upon reexposure. If the allergen exposure is sufficient, these proteins can drive the immune response to a T-lymphocyte type 2 phenotype (Th2), even in patients without prior atopic disposition. This occurred in the case of latex allergy, where many nonatopic individuals and patients exposed to allergen in their personal healthcare developed occupational allergy to multiple proteins from natural rubber latex. Atopic individuals are at the highest risk of developing latex allergy. A longitudinal study demonstrated that powdered latex gloves with high allergen content were the reason for the epidemic of latex allergy and occupational asthma. Unfortunately, despite primary removal of the offending sensitizing agent, asthma symptoms and bronchial hyperresponsiveness induced from multiple causes persist in approximately 70% of individuals with occupational asthma.

Reactive Airways Disease Syndrome and Irritant-Induced Asthma

RADS presents with acute respiratory symptoms within minutes or hours following a single inhalation of a high concentration of irritant gas, aerosol, or smoke. The clinical manifestations and pathophysiology of RADS have been studied through experimental design or epidemiology studies following exposure to chlorine gas, acetic acid, dimethylaminoethanol, chlorofluorocarbons, epichlorohydrin, and diisocyanates.

Table 427.7 lists the criteria for diagnosis of RADS. Asthma-like symptoms and airway hyperresponsiveness then ensue, which often persist for prolonged periods. Unlike typical asthma, RADS is often not reversible by use of a bronchodilator. This is probably a consequence of the direct injury to the epithelium and subsequent submucosal fibrosis.

Irritant-induced asthma is a closely related form of asthma resulting from nonimmunologic provocation of bronchial hyperresponsiveness with airflow obstruction. In contrast to RADS, irritant-induced asthma occurs after single or multiple exposures to irritant chemicals in low concentration . If the resultant pulmonary symptoms occur after multiple exposures at a plant, it is termed nonimmunologic-induced asthma .

Predisposing factors for the development of RADS are not well characterized. Atopy and cigarette smoking may increase the risk of developing RADS when exposure through inhalation of irritant chemicals occurs. In addition to host factors, the type of chemical appears to be important. Higher concentrations of chemicals, the type of chemical (vapor or wet aerosols), and bleaching agents are the most offending agents to cause RADS. Dry particle aerosols are less likely to cause RADS. Analysis of the World Trade Center firefighters indicates that the presence of bronchial hyperresponsiveness prior to a chemical exposure does not increase the risk for an individual to develop RADS.

Pathogenesis of RADS follows a typical pattern, driven by the initial injury to the airway epithelium. Initial histology demonstrates rapid denudation of the mucosa accompanied by a submucosal fibrinous, hemorrhagic exudate. Subepithelial edema subsequently occurs with some regeneration of the epithelial layer, proliferation of basal and parabasal cells, and eventually areas of fibrosis. The desquamation, subepithelial fibrosis, thickening of the basement membrane, and regeneration of basal cells are all more prominent in RADS than in occupational asthma. This may explain the limited response to bronchodilator therapy in this syndrome compared to asthma.

The clinical manifestations of RADS and irritant-induced asthma are different from each other mostly in the onset of symptoms. Patients with RADS typically can pinpoint the exact time of onset of symptoms as well as the exact number of hours post exposure. The symptoms are so severe that nearly 80% of subjects in one study presented to an emergency department for care. The lower airway symptoms of cough, dyspnea, chest tightness, and wheezing are prominent features in RADS, with cough being most prevalent. Because of the toxic nature of the inhaled chemical, it is predictable that an upper airway syndrome of throat and nose burning will often accompany the lower airway symptoms. This part of the complex has been referred to as respiratory upper airway dysfunction syndrome.

Individuals with irritant-induced asthma present with a more insidious onset of symptoms. Because of the recurrent nature of the low concentration of chemical, patients may not be able to identify the underlying trigger initially. Similar to allergic rhinitis, patients may describe nasal congestion, rhinorrhea, sneezing, postnasal drip, ocular irritation, and conjunctival injection. Pulmonary symptoms include those typically seen with asthma exacerbations.

Initial evaluation of the patient with RADS or irritant-induced asthma usually includes the medical history, physical examination, and pulse oximetry. Because of the acute nature of RADS, a chest radiograph is obtained in order to rule out other acute causes of dyspnea including pneumonia or pulmonary edema. In patients with RADS and irritant-induced asthma, the chest radiograph is frequently normal or may show hyperinflation. Ideally, if the patient is not in significant distress, complete pulmonary function testing with spirometry, lung volumes, and diffusion capacity are very helpful in the initial evaluation. The lack of abnormality on initial chest radiograph reassures the clinician that HRCT is not indicated.

Etiology and Epidemiology

The prevalence of GPA disease appears to be increasing by up to 4-fold in the last 2 decades, but without male or female predominance. Improved diagnostic tests, such as antineutrophil antibodies, may explain some of this increased prevalence.

Pathogenesis

Clinically, the development of both upper and lower airway disease with granulomas in GPA implies that exposure to antigen in the airway of endogenous or exogenous source is involved with aberrant cell-mediated immune response. Cytokine expression by peripheral blood CD4+ lymphocytes and cells collected by BAL indicate there is a predominantly T-lymphocyte type 1 response with overexpression of interferon-γ (IFN-γ) and tumor necrosis factor (TNF). In vitro studies demonstrate a skewed T-lymphocyte type 17 response by blood CD4+ T cells in GPA, suggesting there is an immune regulatory defect that leads to excessive production of T-lymphocyte type 1/T-lymphocyte type 17 cytokines (interleukin [IL]-17, TNF, and IFN-γ) presumed to be from the environment or autoantigens. Such an inflammatory response may be sufficient to induce and sustain granuloma formation.

Detection of autoantibodies reactive against proteins in the cytoplasmic granules of neutrophils and monocytes (antineutrophil cytoplasmic antibodies [ANCAs]) are found in 90% of the patients with GPA. The first major type of ANCA is directed against cytoplasmic proteinase-3 and is frequently named c-ANCA . The second major type of ANCA recognizes the enzyme myeloperoxidase. It is found in a small number (<10%) of patients with GPA but is frequent in microscopic polyangiitis . Anti-myeloperoxidase antibodies fluoresce in a perinuclear pattern and are often referred to as perinuclear or p-ANCA . In contrast, some patients develop the clinical phenotype of GPA in the absence of detectable ANCA.

Clinical Manifestations

Children with GPA present with respiratory complaints accompanied by fever, loss of energy, and vague joint complaints. Some may present with severe nasal disease manifested as ulceration, septal perforation, pain, sinusitis, and/or epistaxis. The septal perforation may lead to deformation of the nasal bridge from erosion of the underlying cartilage but is more common in adults. Pulmonary disease occurs in the majority of patients as noted above. Symptoms range from cough, hemoptysis (seen in less than 50% of patients), dyspnea, and chest discomfort to asymptomatic infiltrates on chest radiography. Occasionally, patients with GPA will present with hemoptysis or recurrent fleeting infiltrates from pulmonary hemorrhage . The pathology is confusing because granulomatous disease may be difficult to demonstrate, and pulmonary capillaritis , the other main component seen on histology, can be seen in other disorders including anti-GBM disease, microscopic polyangiitis, idiopathic pulmonary capillaritis, and Henoch-Schönlein purpura. Distinguishing GPA from other pulmonary renal syndromes is easiest when there are classical symptoms of upper airway disease (nasal/sinus), lower airway disease with necrosis, granulomas on biopsy of the lung with vasculitis, and renal disease consistent with glomerulonephritis.

As many as 20% of patients with GPA will present with subglottic or endobronchial stenosis from scarring and inflammatory changes. Although it may be the presenting symptom, it often occurs in conjunction with other disease manifestations. Dyspnea and voice changes are common complaints from the patients.

Skin, ocular (uveitis), and joint symptoms are common in GPA and have been found to accompany the lung and renal disease in most series 50% or more of the time. Biopsy of the skin may show nonspecific leukocytoclastic vasculitis, venulitis, or capillaritis.

Laboratory and Pathology

c-ANCA or anti–proteinase-3 antibodies are found in 90% of patients with GPA. However, they are also found in other types of vasculitis and are not sufficient in themselves to make a diagnosis without a tissue biopsy (see Chapter 192 ). Because of the necrotizing nature of the vasculitis, lung tissue is required for definitive diagnosis of pulmonary disease. Biopsy of the upper airway may demonstrate evidence of granulomatous disease, but it is uncommon to find evidence of vasculitis therefore lung biopsy is warranted. Usual pathology demonstrates multiple parenchymal nodules that may be located in either the bronchial, vascular, or interstitial tissues ( Fig. 427.2 ). The granulomatous inflammation is often found in areas of necrosis and/or vasculitis.

Renal biopsy rarely demonstrates granulomas or vasculitis. Rather, kidney tissues may show focal, segmental, or necrotizing glomerulonephritis without deposits of immune complexes. When the tissues fail to demonstrate classical findings, a variety of diseases (e.g., tuberculosis, sarcoid, microscopic polyangiitis, malignancy, and other autoimmune disorders) must be considered in the evaluation.

Radiology

Chest radiography in GPA will show multiple infiltrates, nodules, cavitary lesions, or ILD. Fleeting infiltrates may be seen when recurrent hemorrhage is a part of the clinical manifestation. HRCT often demonstrates more extensive lung disease and the cavitation associated with the necrotizing nature of the disease ( Fig. 427.3 ).

Treatment

Rapidly progressive, debilitating disease may occur when failure to diagnose GPA leads to inadequate treatment. One series of patients showed death occurred in 90% of patients within 2 yr of diagnosis. Glucocorticoid therapy alone resulted in relapses and inadequate control of disease in many subjects.

Therapy is divided into induction and maintenance phases. Systemic corticosteroids, while ineffective as monotherapy, are a mainstay of therapy in conjunction with other immune suppressive agents. Prednisone can be given orally at a dosage of 1-2 mg/kg/day (max 60 mg). Alternatively, intravenous methylprednisolone may be used at a dosage of 10-30 mg/kg (max 1 gram) given either weekly or for 3 consecutive days monthly. Combination therapy traditionally included cyclophosphamide given either orally at 2 mg/kg/day or intravenous dosing at 15 mg/kg monthly. Rituximab, an anti-CD20 antibody, is as effective as cyclophosphamide in inducing remission of the GPA. Rituximab dosing is either 350 mg/m ² given weekly for the first 4 wk or 500 mg/m ² given on initiation of therapy and 2 wk after initiation. A second dose of 500 mg/m ² is often given 6 mo after the first dosage of rituximab. Induction therapy should be continued for 3-6 mo.

Continued therapy is required past the initial induction phase to maintain remission, however, due to the toxicity of cyclophosphamide, other immune-suppressive agents are preferred. Both methotrexate and azathioprine have been shown to be equally effective as cyclophosphamide in maintaining remission. Mycophenolate mofetil, in contrast, has higher relapse rates than azathioprine and should be avoided in ANCA-associated vasculitis. Systemic steroid dosages should be progressively weaned at the beginning of the maintenance phase of therapy to a dosage of 5-10 mg/day. Therapy should be continued for an additional 1.5-2 yr. Rituximab, given every 6 mo for 2 yr, is at least as effective in maintaining remission as other regimens.

Adjuvant therapy with plasma exchange may be considered when life-threatening GPA disease presents. This is advocated on the premise that ANCAs are inducing disease and will be removed from the circulation with this intervention; its use has been favorably evaluated in GPA-induced renal disease. Adjuvant plasma exchange has been studied mainly in patients with severe renal vasculitis, but there are also reports of success in severe pulmonary hemorrhage. The results of a meta-analysis of patients with renal vasculitis in 9 trials suggest that adjuvant plasma exchange may be associated with improved renal outcome.

Recurrent disease remains a major problem with relapse rates of up to 50% reported in most studies. ANCA levels have not been shown to correlate with activity of disease or severity. Patients with isolated disease of the sinuses and nose may not warrant such toxic therapy. Therapy with topical corticosteroid and antibiotics for infection appear to be warranted. If unsuccessful, steroid with methotrexate appears to be an effective therapy.

The development of subglottic stenosis requires specific treatment. Use of cyclophosphamide with oral corticosteroid may have an incomplete or no response in the airway. Local injection of a prolonged acting corticosteroid locally appears to be indicated to reduce the inflammation and prevent further scarring. If this complication is found at presentation, simultaneous airway intervention with induction of corticosteroid and cyclophosphamide is warranted and encouraged.

Epidemiology and Pathogenesis

African-American females are disproportionately affected by sarcoidosis; however, it can present in any group. Because an asymptomatic sarcoid-like distribution of noncaseating granulomas may be frequently found at autopsy, the contribution of the granulomas to the disease is not always clear. Some countries do mass chest radiograph screening for multiple diseases. In that setting, up to 50% of diagnosed sarcoidosis is asymptomatic. The severity of the disease appears to be worse in African-Americans who tend to have acute illness, whereas white subjects are more likely to be asymptomatic with a more chronic disease. There have been clusters of disease in families and genetic testing suggests that MHC linkage on the short arm of chromosome 6 is most likely to be observed.

Sarcoidosis is rarely found in children younger than the age of 8 yr; those of African descent are most affected. The disease presentation is similar to adults with multisystem disease being the most common. Skin rash, iridocyclitis, and arthritis are seen most often without pulmonary symptoms. In northern Europe, erythema nodosum with the ocular involvement of iridocyclitis is seen most frequently. Despite the lack of symptoms, chest radiography may be abnormal in approximately 90% of children. The pulmonary disease appears to be less progressive compared to adults and patients recover spontaneously without corticosteroids. Rarely, pulmonary disease may progress to fibrosis. Ocular disease is more likely to be progressive and warrant intervention as the inflammatory response may lead to blindness from complications of iritis.

Unrecognized infection or inhalation of an immune response–inducing antigen continues to be at the forefront of consideration as a cause of the disease. Clusters of sarcoidosis in small populations, variable prevalence by geography and race, transfer of disease by organ transplant, and the reproducible granuloma formation only in patients with sarcoidosis in the skin when homogenized lymph node tissue from patients with sarcoid is injected intradermally (Kveim-Siltzbach test) have supported this hypothesis.

Clinical Manifestations

Patients with lung disease are more likely to be asymptomatic as the presentation often may be an abnormal chest radiograph. When symptomatic, patients demonstrate shortness of breath, cough, and dyspnea. Children are more likely to manifest the disease as iridocyclitis, skin rash, and arthritis. African-American children appear to have more frequent lymph node involvement, nonspecific elevations of gamma globulin, erythema nodosum, and hypercalcemia. Physical exam may reveal only an elevated respiratory rate without crackles or rales by auscultation. Pleural involvement has been seen but is uncommon. When present, a lymphocytic predominant exudate may be observed with laboratory evaluation of the pleural fluid. Unusual but reported findings include cases of pneumothorax, hemothorax, and chylothorax. One specific syndrome, Lofgren syndrome , with hilar lymphadenopathy, erythema nodosum, and migratory polyarthralgias, is almost exclusively seen in females. This syndrome has a strong association with HLA-DQB1*0201 and polymorphisms in the C-C chemokine receptor 2 (CCR2); these genetic markers are a predictor of a good outcome.

Although almost 90% of patients with sarcoidosis demonstrate parenchymal or mediastinal disease on chest radiography, there are many who have minimal to no symptoms. Approximately 40% of adults with stage 1 disease have endobronchial involvement found at bronchoscopy. The higher the staging level of disease, the more likely patients are to have airway involvement.

Diagnostic Laboratory Testing

The most common but nonspecific findings are hypergammaglobulinemia, hypercalciuria, hypercalcemia, elevated alkaline phosphatase when liver disease is present, and, occasionally, anemia of chronic disease. Serum angiotensin-converting enzyme may be elevated in 75% of patients with untreated sarcoid. False-positive tests occur from other diseases so that it is not considered a diagnostic test but rather a test that strongly supports the diagnosis.

Pulmonary function tests can be performed accurately in most children older than the age of 4 yr. There are no specific diagnostic findings of spirometry, lung volumes, or diffusion capacity in sarcoidosis. Exercise coupled with pulmonary function tests may demonstrate a decline in diffusion capacity when alveolitis is present in hypersensitivity pneumonitis and could add diagnostic help to the clinician when attempting to differentiate sarcoidosis from HP prior to biopsy.

BAL is of great help when differentiating HP from sarcoid. BAL in sarcoid shows a marked predominance of CD4 cells. A lymphocyte percentage > 16% on BAL, a CD4:CD8 ratio > 4, and noncaseating granulomas on bronchial biopsy in the presence of abnormal angiotensin-converting enzyme levels are nearly completely diagnostic for sarcoid. In addition, T cells are activated on BAL. BAL in HP shows a significant change in the balance of CD4 to CD8 cells with the 2 cell types being nearly equal compared to the normal mild predominance of CD4 cells in the circulation. A ratio of CD4:CD8 of <1 predicts 100% of patients with BAL lymphocytosis to not have sarcoidosis. Neutrophil counts >2% and/or eosinophil counts >1% exclude the diagnosis of sarcoidosis.

The analysis of D-dimers in BAL fluid from subjects with sarcoidosis demonstrates an elevation in 80% of patients compared to no detectable D-dimers in unaffected control.

Histopathology

The characteristic feature of sarcoidosis is the noncaseating granuloma formation in the lung ( Fig. 427.4 ). These granulomas are found in the bronchial walls, alveolar septa, and vascular walls of pulmonary arteries and veins. The formation of noncaseating granulomas is likely preceded by alveolitis involving the interstitium more than the alveolar spaces. There is accumulation of inflammatory cells, including monocytes, macrophages, and lymphocytes that accompany the granulomas. Multinucleated giant cells are frequently found among the epithelioid cells within the granuloma follicle. These may show cytoplasmic inclusions (e.g., asteroid bodies and Schaumann bodies) as well as some birefringent crystalline particles made of calcium oxalate and other calcium salts. These are most often identified in the upper lobes of the lungs which may lead to confusion with diseases such as hypersensitivity pneumonitis, eosinophilic granuloma, collagen vascular disease, pneumoconiosis, berylliosis, and infectious disease such as tuberculosis or histoplasmosis.

Radiology

Pulmonary imaging in sarcoid has included plain chest radiography, HRCT, positron emission tomography using fluorine-18-fluorodeoxyglucose, and radiotracer using gallium-67. The staging of sarcoid is performed using plain radiography and is outlined as follows:

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  Stage I—Bilateral hilar lymphadenopathy accompanied by right paratracheal lymphadenopathy

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  Stage II—Bilateral hilar lymphadenopathy accompanied by reticular opacities are present. If symptomatic, patients have cough and dyspnea. Occasional fever and fatigue accompany the respiratory symptoms.

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  Stage III—Reticular opacities are found predominantly in the upper lobes with regression of hilar lymphadenopathy.

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  Stage IV—Reticular opacities start to coalesce and lead to volume loss in the lung fields, traction bronchiectasis from conglomeration of the inflamed tissues. Extensive calcium deposits may be seen at this stage.

HRCT may be helpful in further staging of the disease, as well as in revealing abnormalities not appreciated on chest radiography. Findings in patients with sarcoidosis by HRCT include hilar lymphadenopathy, paratracheal nodules, middle to upper lung parenchymal ground-glass appearance, bronchial wall thickening, bronchiectasis, cystic changes, and fibrosis. The ground-glass appearance suggests that alveolitis, as seen in hypersensitivity pneumonitis, may be present. Biopsy has usually shown granuloma formation as the predominant histologic finding.

Treatment

Because pulmonary sarcoidosis spontaneously resolves without therapy in almost 75% of patients, clear guidelines for treatment focused on minimizing side effects of therapy is required. Glucocorticosteroids (GCSs) have long been the mainstay of therapy in sarcoid and are often used because of extra pulmonary disease. When pulmonary disease is progressive, GCS therapy is aimed at prevention of fibrosis, honeycombing, and irreversible lung disease. Assuring that disseminated infections, heart failure, thromboembolism, or pulmonary hypertension are not present is important. In addition to HRCT of the chest, performance of pulmonary function tests, electrocardiogram, and echocardiogram should be considered prior to starting GCS therapy.

GCS therapy is often not started when stage I or II is present without symptoms. This scrutiny of the benefit of therapy was highlighted when prospective evaluation of GCS therapy for pulmonary disease found that nearly 50% of patients receiving GCSs had active or relapsing disease 2 yr later. In contrast, 90% of patients who did not receive GCSs had spontaneous remission of disease with the other 10% needing intervention 2 yr later. Absolute indications include progressive stage III disease with symptoms of shortness of breath, cough, or other chest symptoms such as pain. Progressive restriction shown on pulmonary function testing is an indication for therapy. Specific pulmonary function changes where lung capacity declines a total of 10% or greater, FVC declines 15% or more, or diffusion capacity degradation is seen of 20% or more are all indications for GCS intervention.

Dosage with oral prednisone at 0.3-0.5 mg/kg is a reasonable starting point depending on the severity of symptoms. Stability is usually achieved within 6-8 wk, after which slow progressive tapering of GCS may occur every 4-8 wk. Many favor the use of alternate-day steroids to reduce the side effects of GCSs, but little data exist to show efficacy.

For patients who do not tolerate GCSs or develop progressive disease, alternative immunosuppressive agents may add benefit to the regimen. Progressive disease also is a reminder for the clinician to reassess the diagnosis of sarcoid and review the chance that beryllium may have been the underlying reason for the progressive disease.

Inhaled GCSs have been evaluated in patients with stage I disease with variable results. Evaluation of therapy with pulmonary function testing and symptoms are the best methods to judge responsiveness to this therapy. Persistent symptoms after 4-8 wk of therapy suggest that systemic GCSs may be indicated.