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* From the Division of Pulmonary and Critical Care and Department of Medicine, Stanford University Hospital; and Division of Pulmonary and Critical Care, VA Medical Center, Palo Alto, CA.
Correspondence to: Chandra K. Katikireddy, MD, Division of Pulmonary and Critical Care, Stanford University Hospital, Palo Alto, CA 94309; e-mail: Chandra.katikireddy{at}stanford.edu
A 35-year-old white man presented with fever, myalgias, and fatigue for 6 weeks. He also had dry cough and dyspnea with mild exertion. During the past few weeks, he received multiple courses of oral antibiotics without improvement for a diagnosis of pneumonia. He smoked 1 pack of cigarettes per day for 20 years. He smoked crystalline methamphetamine regularly for the past 5 years. His medical history was otherwise unremarkable. Occupational and family histories were noncontributory.
Physical Examination
Vital signs were remarkable for a temperature of 38.6°C, heart rate of 120 beats/min, and respiratory rate of 24 breaths/min. Oxygen saturation by digital pulse oximetry was 94% while breathing ambient air at rest. There was no respiratory distress. Chest auscultation revealed bilateral inspiratory crackles. The rest of the examination was unremarkable.
Laboratory and Radiographic Findings
WBC count was 14.0 x 109/L with neutrophilia of 87%. Platelet count was 720 x 109/L. Serum creatinine kinase level was 5,016 U/L, alanine transaminase was 70 IU/L, and aspartate transaminase level was 64 IU/L. Serum electrolytes and renal functions were normal. Urinalysis was unremarkable. Erythrocyte sedimentation rate was 81 mm/h. Rheumatoid factor was > 100 U, and the perinuclear anti-neutrophil cytoplasmic antibody was positive at a titer of > 1:100 as measured by indirect immunofluorescence. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibody against myeloperoxidase and proteinase 3 were undetectable by enzyme-linked immunosorbent assay. Blood culture and serologic findings for infections were negative. Chest radiography (Fig 1 ) showed low lung volumes and bilateral reticular densities. A high-resolution CT of the chest (Fig 2 ) revealed bilateral, predominantly peripheral ground-glass opacities. Pulmonary function testing showed a severe restrictive ventilatory defect and markedly reduced diffusing capacity. Microbiology and cytopathologic findings in BAL fluid were negative. The BAL cell profile was normal.
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The patient underwent lung biopsy by video-assisted thoracoscopic surgery. Low-power magnification of the histopathology revealed infiltration of the alveolar interstitium with chronic inflammatory cells (Fig 3 ). High-power magnification demonstrated lymphocytic and plasma cell infiltrate of the alveolar interstitium (Fig 4 ). Alveolar wall thickening by edema and mild degree of fibrosis were apparent. Type II pneumocyte hyperplasia was also present.
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What is your diagnosis? What is the treatment of choice?
Interstitial pneumonia, nonspecific interstitial pneumonitis (NSIP) variant secondary to RA. Systemic steroids are the treatment of choice.
Discussion
We describe a case of RA manifesting as NSIP-pattern interstitial pneumonia prior to articular symptoms. In 1994, Katzenstein and Fiorelli described NSIP as a histologic pattern of interstitial pneumonia that does not concur with any other idiopathic interstitial pneumonias such as usual interstitial pneumonitis (UIP), organizing pneumonia, acute interstitial pneumonitis, lymphocytic interstitial pneumonitis, and desquamative interstitial pneumonitis. A heterogeneous group of pathologic entities with a variety of clinicoradiologic features manifest as a well-recognized and distinctive NSIP histologic pattern.
The etiologic factors are either idiopathic in nature or they are well-recognized causes such as connective tissue diseases (CTDs), drugs, occupational or environmental inhalational exposures, and infections (Table 1 ). NSIP is the most common form of interstitial pneumonia associated with CTD with the exception of RA, in which UIP is the commonly reported pattern. There are rare cases of NSIP reported in association with primary lung malignancy. NSIP may be the sole histopathologic finding of the hypersensitivity pneumonitis. Our patient was an active smoker of crystal methylamphetamine, but we are aware of no reports in the literature documenting an association between interstitial pneumonitis and crystal methylamphetamine.
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Pulmonary function testing shows restrictive ventilatory defect in majority of the patients. Mild airflow obstruction may be seen in a few patients. All patients demonstrate decreased diffusion capacity. The predominant cause of hypoxemia at rest is the ventilation-perfusion mismatching. Anatomic alveolar capillary barrier (thickened interstitium) results in impairment of the diffusion and may contribute to hypoxemia with exercise. Serial pulmonary function tests and 6-min walk tests may be useful in monitoring the clinical course, disease activity, and therapeutic response.
The chest radiograph typically reveals low lung volumes. Reticular shadows and patchy parenchymal opacities may be seen. Lower lung zones are predominantly involved. The most common chest CT finding is ground-glass opacities. Typically, they are bilateral, subpleural, and symmetric. Reticular opacities with traction bronchiectasis may be seen. Upper-lobe emphysematous changes and lower-lobe cystic changes were noted in idiopathic group of NSIP patients identified by the 2002 American Thoracic Society/European Respiratory Society report on the classification of idiopathic interstitial pneumonias. Honeycombing is a rare finding, predominantly seen in the fibrotic variant of NSIP. The CT appearance of typical UIP-pattern interstitial pneumonia is distinctive, with subpleural honeycombing, reticular opacities, and traction bronchiectasis, predominantly seen in lower zones. At times, the radiologic features of fibrotic NSIP are indistinguishable from atypical UIP, mandating the histopathologic examination necessary to differentiate between them.
BAL is useful to exclude other etiologies such as infections. In NSIP, BAL may be lymphocytic with a decreased CD4/CD8 ratio. In the fibrotic variant of NSIP, the cellular profile is similar to UIP, with paucity of lymphocytes and increased neutrophils or eosinophils. Transbronchial biopsies may be considered when certain diffuse parenchymal lung diseases such as sarcoidosis, hypersensitivity pneumonitis, granulomatous infections, and lymphangitic carcinomatosis are considered in the differential diagnosis. With the exception of classic presentation of UIP-pattern idiopathic interstitial pneumonia (idiopathic pulmonary fibrosis), the clinicoradiologic features of interstitial pneumonias are relatively nonspecific, necessitating the histopathologic examination of lung tissue essential to establish the diagnosis.
The term NSIP pattern may be used to indicate the histopathologic appearance, while the term NSIP refers to the clinical diagnosis. Histopathology reveals mild-to-moderate, mononuclear (predominantly lymphocytes and few plasma cells), chronic interstitial inflammation with varying degrees of fibrosis. Inflammatory infiltrate predominantly involves the alveolar interstitium. Katzenstein and Fiorelli divided the histologic pattern of NSIP into three subgroups based on the degree of inflammation and fibrosis: group 1, primarily interstitial inflammation (cellular pattern); group 2, combination of both inflammation and fibrosis (mixed pattern); and group 3, primarily fibrosis (fibrotic pattern). Type II pneumocyte hyperplasia may be seen in cellular pattern. In fibrosing form, dense or loose fibrosis with temporal homogeneity is seen, and the fibroblastic foci that give the heterogeneous appearance in UIP are characteristically absent. Hematoxylin-eosin stains may show altered architecture, but elastin stains typically reveal more preserved lung architecture. The alveolar septal lymphocytic infiltrate is less severe and less extensive as compared with lymphocytic interstitial pneumonitis. Similarly, intraluminal organizing fibrosis may be seen in distal airspaces, but it is not a prominent finding as seen in organizing pneumonia pattern. The granulomas, infections by special stains, intra-alveolar pigmented macrophages as seen in desquamative interstitial pneumonitis, hyaline membranes, and severe acute alveolar wall inflammation are absent or inconspicuous.
Occasionally multiple lung biopsies from the same patient may show histologic variability revealing NSIP pattern associated with the UIP pattern. There are no reports suggestive of one histologic pattern of interstitial pneumonia transforming or progressing into another pattern. The clinical course and prognosis of a patient with lung biopsies demonstrating histologic discordance (coexistence of UIP and NSIP patterns) is similar to idiopathic pulmonary fibrosis and should be managed accordingly. The possibility of histologic variability from different biopsy specimens emphasizes the importance of obtaining multilobar biopsies. In the context of histologic inconsistency or ambiguity, the clinicoradiopathologic correlation plays a crucial role in establishing the diagnosis. The histologic characterization and differentiation of NSIP pattern from other interstitial pneumonias is significant because of the underlying therapeutic and prognostic implications.
As it is not a specific and distinctive clinical entity, NSIP was identified by the American Thoracic Society/European Respiratory Society international multidisciplinary consensus statement (2002) as a provisional diagnosis of interstitial pneumonia, until further evaluation reveals the associated clinical disease. The histologic diagnosis of NSIP pattern should prompt the aggressive search for the underlying etiologic factors. At the conclusion of the etiologic investigative workup, NSIP should be categorized as either idiopathic or secondary, indicating the underlying pathophysiology.
As reviewed above, arriving at the diagnosis of NSIP is a dynamic process involving the analysis and correlation of clinical, radiologic, and pathologic findings to achieve a unifying diagnosis. There are no prospective, randomized trials to guide the treatment of NSIP. Retrospective studies demonstrate that NSIP responds well to corticosteroids. The predominant cellular subgroup appears to have better response to steroids compared to the fibrotic subgroup. The optimal dosage and duration of steroid treatment is variable and largely depends on the therapeutic response, which can be monitored by serial chest imaging studies and pulmonary function tests. The typical initiating dosage of prednisone is 1 to 1.5 mg/ kg/d, with gradual tapering over few months. Relapses may occur with tapering of the steroids, which indicate a poor outcome. Some case reports and observational studies suggest that cytotoxic agents such as azathioprine, cytoxan, and cyclosporine A in combination with steroids may benefit the cases of NSIP unresponsive to steroids alone. Treatment response, frequency of relapses, and prognosis appear to be related to the degree of chronicity, the natural course of the underlying etiologic mechanism, and severity of fibrosis on histopathology. The prognosis is, in general, favorable as compared to the other idiopathic interstitial pneumonias, in particular UIP.
The present patient was started on oral prednisone, 60 mg qd; within 3 days, he showed remarkable clinical improvement. Symptoms of dyspnea and arthralgias improved significantly, and temperatures normalized. The gradual tapering of the prednisone to 30 mg over next 3 months resulted in moderately improved pulmonary function test and chest imaging results. As the relapses tend to occur at lower steroid dosage, we will taper the prednisone slowly at a rate of 5 mg every month. The disease activity will be monitored by clinical examination, chest imaging, pulmonary function tests, and serologic markers such as rhematoid factor and erythrocyte sedimentation rate.
Clinical Pearls
1. NSIP should be considered in the differential diagnosis of a patient presenting with the subacute onset of fever, dyspnea, cough, and diffuse reticular opacities when more common causes, such as infection, have been excluded.
2. Patients with RA may rarely present with respiratory symptoms due to NSIP-pattern interstitial pneumonia in advance of arthralgias or arthritis.
3. A histologic pattern of NSIP on a lung biopsy should alert a clinician to investigate thoroughly for underlying etiologic factors such as drug toxicity, occupational and environmental exposures, CTD, and infections including HIV.
4. NSIP, idiopathic or secondary to CTD, responds well to systemic steroids with a more favorable prognosis as compared with other idiopathic interstitial pneumonias such as UIP.
Acknowledgements
The authors would like to thank Dr. Jon Kosek for providing histopathologic images.
Footnotes
This work was performed at the VA Hospital, Palo Alto, CA.
Received for publication July 27, 2005. Accepted for publication August 26, 2005.
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