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(Chest. 2004;125:1239-1247.)
© 2004 American College of Chest Physicians

Clinical Similarities and Differences Between Human T-Cell Lymphotropic Virus Type 1-Associated Bronchiolitis and Diffuse Panbronchiolitis*

Jun-ichi Kadota, MD, PhD; Hiroshi Mukae, MD, PhD; Takeshi Fujii, MD, PhD; Masafumi Seki, MD, PhD; Kazunori Tomono, MD, PhD and Shigeru Kohno, MD, PhD, FCCP

* From the Division of Pathogenesis and Disease Control (Dr. Kadota), Department of Infectious Diseases, Oita University Faculty of Medicine, Oita, Japan; and the Second Department of Internal Medicine (Drs. Mukae, Fujii, Seki, Tomono, and Kohno), Nagasaki University School of Medicine, Nagasaki, Japan.

Correspondence to: Jun-ichi Kadota, MD, PhD, Division of Pathogenesis and Disease Control, Department of Infectious Diseases, Oita University Faculty of Medicine, 1–1 Hasama, Oita 879-5593, Japan; e-mail: kadota{at}med.oita-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Human T-cell lymphotropic virus type 1 (HTLV-1)-associated bronchiolitis and diffuse panbronchiolitis might overlap. We examined whether these conditions can be differentiated by comparing their clinical features and the effect of long-term macrolide treatment.

Patients and methods: Fifty-eight Japanese patients, including 15 with HTLV-1–associated bronchiolitis and 43 with diffuse panbronchiolitis. Both conditions were clinically compared using the clinical criteria for diffuse panbronchiolitis, including findings from CT scans and BAL fluid testing. Pulmonary function, blood gas levels, and cold hemagglutinin (CHA) levels were assessed before and after long-term treatment with macrolides. Interleukin-2 receptor (IL-2R) expression in T cells obtained from the BAL fluid of patients with HTLV-1–associated bronchiolitis or diffuse panbronchiolitis was analyzed by flow cytometry.

Results: Clinical, laboratory, radiologic, and bacterial features were strikingly similar in both groups, except for the fact that patients with HTLV-1–associated bronchiolitis had a higher ratio of IL-2R–positive cells in the BAL fluid. The histopathologic features were also similar. Long-term treatment with macrolides improved PaO2, FEV1, and CHA in patients with HTLV-1–associated bronchiolitis to a lesser extent than in those with diffuse panbronchiolitis, and PaO2 and FEV1 in the group of patients with HTLV-1–associated bronchiolitis who had high IL-2R levels did not respond after therapy.

Conclusions: These findings showed that the clinicopathologic features of the two conditions are quite similar, suggesting that diffuse panbronchiolitis is a chronic pulmonary manifestation of HTLV-1 infection. However, HTLV-1–associated bronchiolitis might be associated with conditions that are distinct from those of diffuse panbronchiolitis based on the different responses to macrolide treatment and the difference in the number of activated T cells bearing IL-2R in the lungs.

Key Words: BAL • bronchiolitis • diffuse panbronchiolitis • human T-cell lymphotropic virus type 1 • interleukin-2 receptor • macrolide antibiotic


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Diffuse panbronchiolitis principally affects the respiratory bronchioli causing a severe obstructive respiratory disorder, and it has been found almost exclusively in Japan.1 The prognosis of patients with this disease had been poor, with 5-year and 10-year survival rates in 1983 of 62.1% and 33.2%, respectively, but long-term treatment with erythromycin has increased the 10-year survival rate to > 90%.2 Some reports345 have indicated that bronchiolitis occurs in association with rheumatoid arthritis (RA). The clinical features of RA-associated bronchiolitis are strikingly similar to those of diffuse panbronchiolitis, and although the histologic profiles of both conditions are generally similar, some features are distinct.45 Long-term treatment with erythromycin, however, has been less effective against RA-associated bronchiolitis than against diffuse panbronchiolitis.5

Another form of bronchiolitis is associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 retrovirus is involved in the pathogenesis of adult T-cell leukemia and nonneoplastic inflammatory diseases of various organs. These include HTLV-1–associated myelopathy/tropical spastic paraparesis, HTLV-1–associated uveitis, arthropathy, Sjogren syndrome, and pneumonopathy.6 With respect to pulmonary involvement in HTLV-1 infection, patients with HTLV-1–associated myelopathy/tropical spastic paraparesis and uveitis or asymptomatic carriers frequently exhibit pul-monary complications that are characterized by T-lymphocyte alveolitis or lymphocytic interstitial pneumonia.78 Immunologic mechanisms are believed to play an important role in the pathogenesis of T-lymphocyte alveolitis in patients infected with HTLV-1. This is because the cytotoxic immune responses by CD8+ T cells might be responsible for pulmonary involvement,9 and circulating CD8+ cytotoxic T cells specific for the HTLV-1 pX region have been identified in patients with HTLV-1–associated myelopathy/tropical spastic paraparesis.10 HTLV-1 tax, which is encoded by the pX region of the HTLV-1 proviral genome, can induce the expression of host cellular genes, including interleukin (IL)-2, IL-2 receptor {alpha} (IL-2R{alpha} [CD25]), and many other cytokines, as well as the HTLV-1 gene.1112 In this context, we have demonstrated the presence of high levels of soluble IL-2R{alpha}, as well as a high percentage of CD3+CD25+ cells in BAL fluid and their correlation with tax messenger RNA expression in the pulmonary lesions of HTLV-1 carriers.13 Pulmonary involvement in these patients, however, is mostly subclinical and is assessed mainly by BAL.

A nationwide histopathologic study14 in Japan to characterize pulmonary involvement in 32 HTLV-1 carriers with symptomatic chronic pulmonary diseases demonstrated that 72% of the patients had bronchiolar involvement, rather than interstitial involvement, including diffuse panbronchiolitis in 9 patients and chronic bronchiolitis in 14 patients. Chronic bronchiolitis is pathologically characterized by the lymphocytic inflammation of small bronchi and membranous bronchioles with or without fibrotic changes of surrounding lung parenchyma. None of these patients with chronic bronchiolitis had foamy cells, which are frequently characteristic of patients with diffuse panbronchiolitis.14 Ono and colleagues15 identified three patients with diffuse panbronchiolitis as a pulmonary complication in 43 cases with adult T-cell leukemia. These observations indicate that bronchiolitis is a characteristic feature of HTLV-1–associated chronic pulmonary diseases (ie, HTLV-1–associated bronchiolitis), and that HTLV-1–associated bronchiolitis and diffuse panbronchiolitis overlap. Therefore, we assessed whether these two conditions can be differentiated. We compared both conditions based on the clinical features, including IL-2R expression on BAL lymphocytes and the value of long-term treatment with macrolides.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Among the 58 Japanese patients studied, there were 15 with HTLV-1–associated bronchiolitis and 43 with diffuse panbronchiolitis. All patients provided written informed consent to participate in the study, which was approved by the Ethics Committee of Nagasaki University Hospital. Diffuse panbronchiolitis was diagnosed using the following clinical criteria established by the Ministry of Health and Welfare of Japan in 1995: (1) symptoms included chronic cough, sputum, and dyspnea on exertion; (2) physical signs consisted of coarse crackles, rhonchi, or wheezes on auscultation of the chest; (3) radiographic findings showed bilateral fine nodular shadows mainly in the lower lung fields, often with hyperinflation of the lungs. All patients underwent chest CT scans, since findings of small rounded areas of high attenuation with a centrilobular distribution, branching linear areas of high attenuation, and hypoattenuation in the peripheral lung are more helpful as a basis of diagnosis16; (4) pulmonary function tests revealed an FEV1 of < 70% predicted, and blood gas measurements showed a PaO2 of < 80 mm Hg; (5) titers of cold hemagglutinin (CHA) were elevated at x64 (26) or higher; and (6) patients had a history of or coexistent chronic parasinusitis. Patients with HTLV-1 infections were enrolled in this study as having HTLV-1–associated bronchiolitis if they had no history of exposure to organic or inorganic dust, or drugs known to cause bronchiolitis. Those patients with connective tissue disease or other chronic lung diseases causing bronchiolitis were excluded too. Patients with other obstructive pulmonary diseases, such as chronic bronchitis, bronchial asthma, chronic emphysema and cystic fibrosis were also excluded. Histologic studies were possible for 5 of the 15 patients with HTLV-1–associated bronchiolitis and for 18 of the 43 patients with diffuse panbronchiolitis. The characteristic features of diffuse panbronchiolitis include lymphocytes and plasma cells accumulating predominantly in the respiratory bronchioles and adjacent centrilobular regions, and foamy macrophages in the respiratory bronchiole walls, adjacent alveolar ducts, and alveoli with infiltration of lymphoid cells. The clinical features of HTLV-1–associated bronchiolitis and diffuse panbronchiolitis were compared using the clinical diagnostic criteria for diffuse panbronchiolitis, by measuring the effect of long-term macrolide administration and the levels of IL-2R expression on lymphocytes in BAL fluid.

HTLV-1 Infection
Seropositivity was detected by gelatin particle agglutination (Serodia-HTLV-1; Fuji Rebio; Tokyo, Japan) and was confirmed by immunoblotting. The monoclonal integration of HTLV-1 proviral DNA was determined in peripheral lymphocytes. This procedure confirmed that among the 15 patients with HTLV-1–associated bronchiolitis, 3 had chronic adult T-cell leukemia and the remainder were HTLV-1 carriers. Patients with diffuse panbronchiolitis were all seronegative for HTLV-1.

Therapy
After diagnosis, the patients were treated with low doses of 14-membered ring macrolide antibiotics. Erythromycin (600 mg), roxithromycin (150 mg), or clarithromycin at 200 mg was administered daily to 4, 4, or 7 patients, respectively, with HTLV-1–associated bronchiolitis and to 30, 7, or 6 patients, respectively, with diffuse panbronchiolitis, since 14-membered macrolides other than erythromycin have shown similar clinical benefits.1718 Patients who developed signs or radiograph findings suggesting pneumonia or acute exacerbation of the disease before enrollment in the study, were administered the appropriate antibiotics. Thus, none of the enrolled patients had experienced an acute pulmonary infection in the month prior to the study. Patients did not receive any other medication during the entire study, except for short-term antibiotics if their condition became acutely exacerbated.

BAL and Flow Cytometry
To examine the expression of IL-2R in pulmonary T cells, BAL and flow cytometry were performed using the described standard procedures19 in 13 healthy volunteers, in all of the patients with HTLV-1–associated bronchiolitis, and in 23 patients with diffuse panbronchiolitis at the start of the study before they received macrolide therapy. Briefly, 50 mL saline solution was instilled four times. The BAL fluid was passed through two sheets of gauze and was centrifuged at 500g for 10 min at 4°C. After two washes with phosphate-buffered saline (PBS) solution, cells were suspended in 10% heat-inactivated fetal calf serum and then incubated in plastic flasks for 90 min at 37°C in humidified 5% CO2-air to deplete alveolar macrophages. The cells then were centrifuged at 500g for 5 min at 4°C, the supernatant was discarded, and the cells were resuspended in PBS solution. The cells were washed twice in PBS solution, filtered through a 100-µm nylon mesh, and adjusted to a concentration of 1 x 106 cells/mL. Viable cells constituted > 90% of nonadherent cells, which were collected for flow cytometry, using the Trypan blue exclusion test. The monoclonal antibodies used for flow cytometric analysis were fluorescein isothiocyanate-conjugated anti-CD25 (ie, IL-2R{alpha}) and a phycoerythrin-conjugated anti-CD3 (ie, Leu 4) [Becton Dickinson; Mountain View, CA]. Each monoclonal antibody (5 µL) was placed into 12 x 15 mm polystyrene tubes (Falcon Plastics; Oxnard, CA), and 100 µL cell suspension (1 x 105 cells) was added. The cells were incubated for 30 min on ice in the dark, were washed once in cold PBS solution containing 0.1% sodium azide, and then were resuspended in cold PBS solution containing 0.5% paraformaldehyde. The fixed cells were stored in darkness at 4°C. Stained cells were analyzed on a flow cytometer equipped with an argon-ion laser set at 488 nm (FACScan; Becton Dickinson). Data were acquired and analyzed using a compatible computer system (Consort 30; Becton Dickinson). A minimum of 10,000 events per sample was collected. A cell gate containing lymphocytes was established on the basis of forward and side light scatter. To determine the borderline between stained and unstained cells, we also stained the cells with mouse IgG1-conjugated fluorescein isothiocyanate or phycoerythrin. The ratios were calculated based on the number of lymphocytes found in each quadrant. Interassay reproducibility was confirmed using beads (CaliBRITE; Becton Dickinson) and a specific software program (AutoCOMP; Becton Dickinson).

Statistical Analysis
All values were normally distributed and are expressed as the mean ± SE. Differences in the clinical characteristics between patients with HTLV-1–associated bronchiolitis and diffuse panbronchiolitis were compared by the Student unpaired t test or Fisher exact test, and mean changes in pretreatment and posttreatment values were compared using the Student paired t test. Differences among the three groups were compared by one-factor analysis of variance with Tukey-Kramer post hoc analysis. All statistical analyses were performed with a statistical package (StatView, version 5.0; SAS Institute; Cary, NC). Significance was established at a p value of < 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Characteristics
The clinical characteristics of the 58 patients, including 15 with HTLV-1–associated bronchiolitis and 43 with diffuse panbronchiolitis, are summarized in Table 1 . The mean age at presentation was not statistically different between the two groups. There was a significant difference in gender between HTLV-1–associated bronchiolitis and diffuse panbronchiolitis. The majority of both groups had no history of smoking, although 8 of the 43 patients with diffuse panbronchiolitis (19%) were current smokers. Patients with diffuse panbronchiolitis or HTLV-1–associated bronchiolitis had similar chronic respiratory symptoms, including productive cough and, less frequently, dyspnea. Audible coarse crackles and chronic sinusitis were also common to patients with both conditions.


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  		Table 1. Clinical Characteristics of 58 Japanese Patients*

 
Chest CT scans demonstrated centrilobular small nodules and linear branching high attenuation in all patients, and bronchial wall thickening or bronchioloectasis in 79% and 67%, respec-tively, of patients with diffuse panbronchiolitis and HTLV-1–associated bronchiolitis, which were typical CT scan indications of diffuse panbronchiolitis (Fig 1 ).16 The levels of FEV1 percent predicted or PaO2 in both conditions were similarly decreased. Although the CHA titer was much higher in patients with diffuse panbronchiolitis than in those with HTLV-1–associated bronchiolitis (p < 0.005), the difference was not considered to be significant because it was less than a fourfold dilution. Bacteria such as Haemophilus influenzae, Streptococcus pneumoniae, and Pseudomonas aeruginosa were similarly isolated from the sputum of 88% and 80%, respectively, of patients with diffuse panbronchiolitis and HTLV-1–associated bronchiolitis. Other infections such as Mycoplasma pneumoniae that are associated with elevated CHA were ruled out in this study. Patients, regardless of condition, generally fulfilled five of the six clinical diagnostic criteria for diffuse panbronchiolitis.



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  		Figure 1. Representative CT scans from patients with diffuse panbronchiolitis (top) and HTLV-1–associated bronchiolitis (bottom).

 
Five of the 15 patients with HTLV-1–associated bronchiolitis underwent surgical lung biopsies before the therapy, and 1 patient was confirmed as having diffuse panbronchiolitis (20%). The others had bronchiolitis obliterans (one patient), bronchiectasis (one patient), and chronic bronchiolitis (two patients). None of these patients had any indications of lymphocyte alveolitis or interstitial pneumonia. In contrast, surgical lung biopsies of 18 of the 43 patients with diffuse panbronchiolitis before therapy revealed diffuse panbronchiolitis in 11 (61%), chronic bronchiolitis in 5, and bronchi-bronchiolo-ectasis in 2.

CD3+CD25+ Cells in BAL Fluid
Since IL-2 and IL-2R gene expression are induced in HTLV-1–infected T lymphocytes by the viral pX gene product,1120 we used flow cytometry to investigate the expression of CD25 on T cells in BAL fluid obtained from patients and healthy volunteers. Figure 2 shows that the percentage of CD3+CD25+ cells significantly increased in patients with HTLV-1–associated bronchiolitis compared with that in both patients with diffuse panbronchiolitis and in healthy volunteers (11.8 ± 1.7 vs 5.1 ± 0.7 and 4.7 ± 3.4, respectively; p < 0.0005). Five of the 15 patients with HTLV-1–associated bronchiolitis had much higher ratios (15%) of CD3+CD25+ cells, which were above the value established from the healthy volunteers as the mean + 3SEs (high IL-2R group; open circles in Fig 2). The ratios of CD3+CD25+ cells were < 15% in the other HTLV-1–associated bronchiolitis patients (low IL-2R group; closed circles in Fig 2) and in the 23 patients with diffuse panbronchiolitis. The mean ratio of CD3+CD25+ cells in the high IL-2R group was significantly higher than that in the low IL-2R group or the diffuse panbronchiolitis patients (19.5 ± 1.5 vs 8.0 ± 1.3 or 5.1 ± 0.7, respectively; p < 0.0001). However, the clinical features, including pulmonary function test results, did not differ among the high and low IL-2R groups and the diffuse panbronchiolitis patients. Lung biopsy specimens from three of the patients in the high IL-2R group did not show the histologic profile that is typical of diffuse panbronchiolitis.



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  		Figure 2. Ratios of CD3+CD25+ cells in BAL fluid obtained from patients with HTLV-1–associated bronchiolitis, diffuse panbronchiolitis, and healthy volunteers. Values are expressed as the mean ± SE. {circ} = high IL-2R group of HTLV-1–associated bronchiolitis patients with > 15% CD3+CD25+ cells (horizontal bar).

 
Effects of Macrolides
Table 1 shows that the duration of therapy did not differ between the groups. Long-term treatment with macrolides in diffuse panbronchiolitis patients significantly improved mean PaO2 from 71.8 ± 1.6 to 82.9 ± 1.5 mm Hg, but did not elicit such an obvious improvement in HTLV-1–associated bronchiolitis patients (71.2 ± 2.4 to 75.3 ± 3.1 mm Hg) [Fig 3 ]. When HTLV-1–associated bronchiolitis patients were divided into high and low IL-2R groups (open and closed circles, respectively, in Fig 3), PaO2 decreased from 71.6 ± 3.3 to 68.9 ± 6.1 mm Hg after therapy for a mean duration of 37.8 months in the high IL-2R group. In contrast, the increase from 71.0 ± 3.2 to 78.4 ± 3.4 mm Hg was observed after therapy for a mean duration of 13.0 months in the low IL-2R group. Figure 4 shows a significant improvement in FEV1 after the therapy in patients with diffuse panbronchiolitis (1.64 ± 0.10 L to 2.21 ± 0.12 L; p < 0.0001) and HTLV-1–associated bronchiolitis (1.43 ± 0.13 to 1.82 ± 0.20 L; p < 0.05). However, no change was significant in the high IL-2R group after therapy (1.47 ± 0.18 to 1.62 ± 0.27 L) compared with that in the low IL-2R group (1.41 ± 0.18 to 1.91 ± 0.27 L; p < 0.01). The serial changes between pretreatment and posttreatment in PaO2 and FEV1 were greater in patients with diffuse panbronchiolitis than in those with HTLV-1–associated bronchiolitis (PaO2, 16.7 ± 3.0% vs 7.1 ± 5.7%, respectively; FEV1, 44.7 ± 7.1% vs 30.1 ± 10.2%, respectively), although the values were statistically insignificant. Additionally, the serial changes of PaO2 between patients with diffuse panbronchiolitis and those in the high IL-2R group with HTLV-1–associated bronchiolitis significantly differed (16.7 ± 3.0% vs –3.7 ± 7.2%, respectively; p < 0.05). The CHA titer significantly decreased after the therapy in patients with diffuse panbronchiolitis (7.8 ± 0.2 to 6.1 ± 0.2, respectively; p < 0.0001) in contrast to that in patients with HTLV-1–associated bronchiolitis (6.3 ± 0.4 to 7.0 ± 0.3, respectively; low IL-2R group, 6.3 ± 0.4 to 7.0 ± 0.5, respectively; high IL-2R group, 6.2 ± 1.1 to 7.0 ± 0.3, respectively). All of the study results were similar even when the smokers in the diffuse panbronchiolitis group were excluded.



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  		Figure 3. Changes in PaO2 after macrolide treatment of patients with diffuse panbronchiolitis and HTLV-1–associated bronchiolitis. Values are expressed as the mean ± SE. {circ} = high IL-2R group of HTLV-1–associated bronchiolitis patients; • = low IL-2R group of HTLV-1–associated bronchiolitis patients.

 


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  		Figure 4. Changes in FEV1 after macrolide treatment of patients with diffuse panbronchiolitis and HTLV-1–associated bronchiolitis. Values are expressed as the mean ± SE. {circ} = high IL-2R group of HTLV-1–associated bronchiolitis patients; • = low IL-2R group of HTLV-1–associated bronchiolitis patients.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrated that clinical, laboratory, radiologic, and bacterial features were strikingly similar in patients with HTLV-1–associated bronchiolitis and in those with diffuse panbronchiolitis, except that the former patients had a higher ratio of IL-2R–positive cells in BAL fluid. The CT scans revealed an appearance that is typical of diffuse panbronchiolitis in all patients with HTLV-1–associated bronchiolitis, since the appearance of diffuse panbronchiolitis on CT scans is not usually seen in other forms of bronchiolitis except for that associated with RA.4516 These findings indicate that HTLV-1–associated bronchiolitis is difficult to distinguish from diffuse panbronchiolitis and confirms the previous findings that HTLV-1 infection can cause a diffuse panbronchiolitis-like disease.15 A histopathologic examination revealed diffuse panbronchiolitis histology in 20% of HTLV-1–associated bronchiolitis patients and in 61% of those with diffuse panbronchiolitis, even though few lung biopsy specimens from HTLV-1–associated bronchiolitis patients could be evaluated. This was similar to the results of a nationwide histopathologic study14 of 32 HTLV-1 carriers with symptomatic chronic pulmonary diseases, which demonstrated diffuse panbronchiolitis histology in nine patients (28%). Other common histologic findings in both groups were of chronic bronchiolitis, bronchiectasis, and bronchioloectasis. These findings indicate an overlap even in histopathologic features between patients with diffuse panbronchiolitis and those with HTLV-1–associated bronchiolitis, although only a small fraction of patients in the two groups could be evaluated in this manner.

We previously demonstrated the presence of a high percentage of CD3+CD25+ cells in BAL fluid and its correlation with tax messenger RNA expression in the pulmonary lesions of HTLV-1 carriers.13 We have provided evidence that the BAL fluid concentrations of macrophage inflammatory peptide-1{alpha} are significantly high in HTLV-1 carriers and correlate with the ratios of CD3+CD25+ cells in BAL fluid.21 Lymphocyte accumulation around respiratory bronchioles, as well as neutrophil accumulation in the large airways are important features in the pathogenesis of diffuse panbronchiolitis. The BAL technique showed increased numbers of T lymphocytes, especially of activated cytotoxic CD8+ and CD4+ cells, which correlated with the levels of the chemokine, macrophage inflammatory peptide-1{alpha} in BAL fluid.19 When considered together, these results indicate similarities, even in the immunopathogenesis of pulmonary involvement, between patients with HTLV-1–associated bronchiolitis and those with diffuse panbronchiolitis.

Diffuse panbronchiolitis became curable by treatment with 14-membered ring macrolides after 1985.2 The mechanism of the clinical efficacy is considered to be via the anti-inflammatory action elicited by suppressing neutrophil accumulation into the large airway of the lungs,22 and by the inhibition of IL-8 production by neutrophils,23 macrophages,1724 and bronchial epithelial cells.25 Macrolides also decrease the number of activated cytotoxic CD8+ cells in the BAL fluid of patients with diffuse panbronchiolitis,2627 and erythromycin partially suppresses lymphocyte proliferation when these cells are activated by lectins and antigens in vitro.28 This action on lymphocytes suggests an additional mechanism in the clinical value of macrolides. However, long-term treatment with macrolides resulted in less PaO2 improvement in patients with HTLV-1–associated bronchiolitis than in those with diffuse panbronchiolitis. The PaO2 value of the high IL-2R group deteriorated after receiving therapy. Although FEV1 significantly improved in both conditions after the therapy, the high IL-2R group identified from among the HTLV-1–associated bronchiolitis patients did not respond. The CHA titer also significantly improved in the patients with diffuse panbronchiolitis but not in those with HTLV-1–associated bronchiolitis.

Kawakami and colleagues29 provided strong evidence of a direct relationship between HTLV-1 and the development of bronchopulmonary infection in the lung tissues of transgenic mice that expressed gene segments of HTLV-1 p40tax regions. This was supported by the findings that the pulmonary pathologic changes, with infiltration of lymphocytes in peribronchial and perivascular areas and in alveolar septa, correlated with the levels of p40tax messenger RNA expression in the lungs of transgenic mice.29 This indicates that high levels of p40tax messenger RNA are expressed in the lungs of patients in the high IL-2R group, leading to the continuous accumulation or proliferation of activated T cells bearing CD25. This might explain why macrolides have no effect on clinical improvements in the high IL-2R group of HTLV-1–associated bronchiolitis patients. Additionally, surgical lung biopsy specimens were obtained from three patients in this group, and all revealed pathologic changes unlike those of diffuse panbronchiolitis. Thus, HTLV-1–associated bronchiolitis can be distinguished from diffuse panbronchiolitis until the mechanisms of the positive effects of macrolides against this disease are defined. However, although it is clear that, on average, patients with HTLV-1–associated bronchiolitis did not respond to therapy with macrolides, there were at least two patients whose PaO2 and one patient whose FEV1 improved markedly (Fig 3, 4). One of these patients did not have the diffuse panbronchiolitis, as determined by pathologic study of a lung biopsy specimen. This suggests that at least some patients with HTLV-1 infection and diffuse panbronchiolitis may have the idiopathic type of bronchiolitis with a coincidental HTLV-1 infection and that all patients with diffuse panbronchiolitis should be given a course of macrolide therapy.

In conclusion, the clinicopathologic and immunopathogenic features of HTLV-1–associated bronchiolitis and diffuse panbronchiolitis are quite similar, suggesting that diffuse panbronchiolitis is a chronic pulmonary manifestation of HTLV-1 infection. However, HTLV-1–associated bronchiolitis might be associated with conditions that are distinct from those of diffuse panbronchiolitis based on the different response to macrolides and the difference in activated T cells bearing CD25 in the lungs. However, further studies of the mechanisms involved and a deeper understanding of the etiologies of diffuse panbronchiolitis and HTLV-1–associated bronchiolitis will help to distinguish these two conditions. In addition, whether or not these conditions are distinct entities should be addressed in the future.


   Acknowledgements
 
Authors thank Masanori Kitaichi, MD (Department of Anatomic Pathology, Kyoto University Hospital, Kyoto) for advice on pathology.


   Footnotes
 
Abbreviations: CHA = cold hemagglutinin; HTLV-1 = human T-cell lymphotropic virus type 1; IL = interleukin; IL-2R = interleukin-2 receptor; PBS = phosphate-buffered saline; RA = rheumatoid arthritis

Received for publication March 27, 2003. Accepted for publication November 18, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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