Desquamative interstitial pneumonia and hepatitis C virus infection: a rare association.

Abstract: Extrahepatic manifestations of hepatitis C virus (HCV) infection are common. The authors report the unusual occurrence of desquamative interstitial pneumonia (DIP) in a patient with HCV. An immunologic response to HCV infection may have a role in the pathogenesis of DIP in patients with chronic HCV. Since DIP is treatable, HCV patients with pulmonary infiltrates should be thoroughly investigated for this disorder. In our experience, the use of steroids in HCV-associated DIP improved the patient's respiratory status without increasing the viral load.

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Hepatitis C virus (HCV) is a common infecting agent. It is estimated that 2.7 million people in the United States have chronic HCV infection. Ten to 15% of HCV-infected patients progress to liver cirrhosis. Data from death certificates indicate that at least 10,000 deaths a year result from chronic HCV in the United States. (1-3)

While liver disease typically dominates the clinical picture of patients with chronic HCV, 38% of patients will manifest at least one extrahepatic symptom. Autoimmune, hematological, dermatological, and rheumatic disorders with or without mixed cryoglobulinemia have been associated with HCV infection. (4-7) This multisystem expression of HCV infection is thought to be due to the virus' effect upon the lymphoproliferative system, ultimately causing chronic stimulation of the immune system.

Respiratory complications of HCV infection include pulmonary vasculitis, alveolitis, decreased diffusing capacity, bronchiolitis obliterans organizing pneumonia, and mixed cryoglobulinemia associated with acute respiratory distress syndrome. (8,9) The medical literature suggests there is evidence linking HCV to idiopathic pulmonary fibrosis (IPF). Some studies have found an increased prevalence of antibodies to HCV in patients diagnosed with IPF, (6,7) while other researchers have failed to confirm such a relationship. (10) Desquamative interstitial pneumonitis (DIP) has been described in two patients with HCV infection. (5) We present an additional patient with HCV who developed acute respiratory failure due to biopsy-proven DIP.

Case Report

A 46-year-old male complained of dyspnea, cough, and pleuritic chest pain of 10-days' duration. He denied hemoptysis, weight loss, nausea, vomiting, or loss of consciousness. He had no arthralgias or skin rash. The patient could not recall a recent viral or bacterial infection. The patient smoked cigarettes. He denied exposure to other fumes, vapors, and dusts. He had been diagnosed with chronic HCV infection one year before presentation, but had received no therapy for this disorder.

His temperature was 100.9[degrees]F. His blood pressure was 160/90 mm Hg, his heart rate was 110 beats per minute, and his respiratory rate was 30 breaths per minute. He had no jugular venous distention or peripheral edema. Auscultation of his chest demonstrated crackles in the left lower base. He did not have digital clubbing.

Arterial blood gas analysis on room air yielded a hemoglobin saturation of 80% with a partial pressure of oxygen of 48 mm Hg, a partial pressure of carbon dioxide of 35 mm Hg, and a pH of 7.5. His hemoglobin was 12.5 g/dL (normal: 13.6-17.3), platelets 74 X [10.sup.3]/mcL (normal: 166-383), and his white blood cell count was 18.9 X [10.sup.3]/mcL (normal: 4.8-10.5) with 83% granulocytes but no band forms. Serum levels of alanine aminotransferase and aspartate aminotransferase were elevated at 82 U/L (normal: 7-56) and 157 U/L (normal: 15-46), respectively. His serum albumin was 3.1 g/dL (normal: 3.5-5). A chest radiograph demonstrated a left lower lobe infiltrate (Fig. 1).

Despite aggressive treatment for hypoxemia that included empiric use of antibiotics, respiratory failure ensued. The patient required endotracheal intubation and mechanical ventilation. Computed tomographic scan of the chest documented ground-glass infiltrates bilaterally (Fig. 2).

Diagnostic fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy was performed. Stains and cultures of samples obtained at bronchoscopy failed to identify a pathogen as the cause of his respiratory process. Histopathologic examination of the transbronchial biopsies documented DIP.

His Westergren sedimentation rate was 125 mm/h (normal: males under 50 yr of age <15 mm/h) and his C-reactive protein was 204.6 mg/L (normal: 0-4.9). Additional laboratory data included negative testing results for antinuclear antibody, anti-Jo-1 antibody, anti-topoisomerase-1, anti-smooth muscle, perinuclear and cytoplasmic antineutrophil cytoplasmic antibodies, antimitochondrial antibody, antiglomerular basement membrane antibody, cryoglobulins, and human immunodeficiency virus antibody. His complement level was normal, but his rheumatoid factor tested positive at a 1:4 dilution. His HCV infection was identified as genotype I. His viral titer by quantitative HCV RNA polymerase chain reaction (PCR) assay was 2,760,000 IU/mL.

The patient was treated with high-dose parenteral glucocorticosteroids. Within 24 hours of the initiation of this therapy his hypoxemia improved. The patient was extubated four days after steroids were implemented and was eventually discharged from the hospital on a tapering dose of oral prednisone. His chest radiograph returned to normal. His viral titer by quantitative HCV RNA polymerase chain reaction assay after 10 days of corticosteroid therapy was 699,000 IU/mL. Subsequently he was weaned off his steroid therapy. To date, he has not suffered a recurrence of DIP.

Discussion

Idiopathic interstitial pneumonias are a challenging group of diffuse parenchymal lung diseases. The most recent classification schema emphasizes the importance of an integrated clinical, radiologic, and pathologic approach to the diagnosis. This new categorization recognizes six entities: usual interstitial pneumonia or IPF, nonspecific interstitial pneumonia, desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated lung disease, cryptogenic organizing pneumonia, and lymphoid interstitial pneumonia. (11,12)

[FIGURE 1 OMITTED]

Desquamative interstitial pneumonitis is a rare disorder that primarily affects cigarette smokers in their fourth or fifth decade of life. (13) DIP is more common in men than in women by a ratio of 2:1. Insidious onset of dyspnea and dry cough over weeks or months is typical and patients may progress to respiratory failure. Digital clubbing is present in 50% of patients. A diffuse ground-glass pattern in the middle and lower lung zones is the usual radiographic appearance. Hypoxemia may be present on arterial blood gas analysis. Lung function testing may demonstrate a restrictive ventilatory defect with a decrease in the diffusion capacity of the lung. (12) Chronic cigarette smoking is a recurrent feature that appears to be important in the pathogenesis of DIP in susceptible individuals. Other disease-inciting factors include infections, environmental exposures, collagen vascular diseases, drug reactions, malignancies, and possibly a genetic predisposition. (14-17) The histopathology of DIP demonstrates diffuse accumulation of pigmented macrophages throughout the alveolar spaces, with an accentuated concentration within the peribronchial alveoli. The alveolar septa are thickened with minimal inflammatory infiltration.

[FIGURE 2 OMITTED]

Our patient is the third report of chronic HCV and biopsy-proven DIP in the literature (Table). (5) The average age of these patients is 57.3 years old, among 2 males and one female. Two patients smoked cigarettes. Each of the patients presented with complaints of dyspnea. Our patient was the only one to have hypoxemia demonstrated by arterial blood gas analysis. The paucity of observations of DIP given the number of HCV-infected individuals raises the possibility that the association might merely be serendipitous.

There is, however, data that indirectly supports a causal relationship. First, bronchoalveolar lavage performed on patients with HCV has demonstrated an increased number of alveolar lymphocytes, mainly T-cells. Second, an increase in the epithelial permeability of the lung has also been noted in patients with HCV. (9,18) T-lymphocytic alveolitis and increased epithelial permeability of the lung may ultimately manifest itself as DIP. (13) Third, patients with only DIP and patients with only HCV infection have an increase in eosinophils in bronchoalveolar fluid. (9,18) The presence of eosinophils in the alveoli of patients with DIP predicts a worse prognosis and a more rapid decline in the vital capacity of these patients. (19) The exact role these cells may play in HCV and DIP is not known but suggests the possibility of a final common pathway. Finally, the positive rheumatoid factor observed in all three patients with HCV-associated DIP indicates a possible immunologic mechanism. (20,21)

The most effective treatment for DIP is corticosteroids. Typically an initial dose of oral prednisone at 40 to 60 mg daily is given for several months, and if a favorable response is obtained, the prednisone is tapered slowly to 15 to 20 mg daily or an equivalent alternate-day dosage. Corticosteroids should be continued for at least 1 year. Cytotoxic agents, such as azathioprine and cyclophosphamide, are used as second-line drugs, usually in combination with oral corticosteroids. (12) On follow-up high-resolution computed tomographic scan, patients receiving corticosteroid treatment can be expected to show partial or complete resolution of areas of ground glass opacification. (12)

Our patient was the only patient with HCV-associated DIP documented to have received corticosteroid therapy. He responded well to this treatment. Moreover, his viral load, as ascertained by quantitative HCV RNA polymerase chain reaction, did not increase. One patient had slow progression of his DIP despite alpha interferon therapy for his HCV infection. The third patient's DIP remained stable without therapy for either her DIP or HCV infection. (5)

The prognosis of DIP is generally good. Most patients improve with smoking cessation and corticosteroid therapy. The overall 10-year survival for patients with DIP is 70%. (22) However, further studies are needed to determine the exact relationship between HCV infection and DIP, the effectiveness of alpha interferon and ribavirin therapy on DIP in patients with HCV, and the prognosis of HCV-associated DIP.

We have art to save ourselves from the truth.
--Friedrich Nietzsche

Table. Reports of chronic HCV and DIP (a)

                                 Patient 1

Age and sex                      68 M
Chronic hepatitis duration (Yr)  22
Rheumatic symptoms               Nonerosive arthritis
ANA                              Positive (b)
RF                               Positive (c)
Complement                       Normal
Anti-HCV                         Positive
Serum HCV RNA                    Positive
Symptoms and signs               Dyspnea, clubbing
Clinical follow-up               Slow progression over a follow-up of
                                   4.9 years. Alpha interferon was
                                   carried out with no effect on
                                   dyspnea.
Smoker                           Yes
Cryoglobulin                     Positive, with no symptoms of mixed
                                   cryoglobulinemia

                                 Patient 2         Our patient

Age and sex                      58 F              46 M
Chronic hepatitis duration (Yr)  11                1
Rheumatic symptoms               None              None
ANA                              Negative          Negative
RF                               Positive (c)      Positive
Complement                       Normal            Normal
Anti-HCV                         Positive          Positive
Serum HCV RNA                    Positive          Positive
Symptoms and signs               Dyspnea, cough    Dyspnea, cough
Clinical follow-up               Stable with no    Amelioration after
                                   therapy           steroid therapy
Smoker                           No                Yes
Cryoglobulin                     Positive, with    Negative
                                 no symptoms of
                                 mixed
                                 cryoglobulinemia

(a) HCV, hepatitis C virus; DIP, desquamative interstitial pneumonia;
ANA, antinuclear antibody; RF, rheumatoid factor.
(b) Titer not available, homogenous pattern.
(c) Titer not available.

Accepted May 4, 2004.

References

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17. Buchino JJ, Keenan WJ, Algren JT, et al. Familial desquamative pneumonitis occurring in infants. Am J Genet 1987;3:S285-S291.

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19. Kula M, Gulmez I, Tutus A, et al. Impaired lung epithelial permeability in hepatitis C virus antibody positive patients detected by 99mTc-DTPA aerosol scintigraphy. Nucl Med Commun 2002;23:441-446.

20. Hakala M, Paakko P, Huhti E, et al. Open lung biopsy of patients with rheumatoid arthritis. Clin Rheumatol 1990;9:452-460.

21. Lamblin C, Bergoin C, Saelens T, et al. Interstitial lung diseases in collagen vascular diseases. Eur Respir J 2001;32:S69-S80.

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RELATED ARTICLE: Key Points

* Extrahepatic manifestations of hepatitis C virus infection, including involvement of the respiratory system, are common.

* Desquamative interstitial pneumonitis appears to be a rare complication of hepatitis C virus infection.

* Treatment of the affected patient's desquamative interstitial pneumonitis with glucocorticosteroids did not result in an increased viral load.

Said B. Iskandar, MD, Lisa A. McKinney, DO, Lata Shah, MD, Thomas M. Roy, MD, and Ryland P. Byrd Jr, MD

From The Veterans Affairs Medical Center, Mountain Home, TN, and the Division of Pulmonary Diseases and Critical Care Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

Reprint requests to Dr. Ryland P. Byrd Jr, Veterans Affairs Medical Center 111-B, PO Box 4000, Mountain Home, TN 37684-4000. Email: [e-mail]