Interaction between Primary Care Physicians and Specialists for Diagnosis and Management of Hypersensitivity Pneumonitis ()
1. Introduction
Hypersensitivity pneumonitis (HP) is a complex syndrome of varying intensity, clinical presentation, and natural history rather than a single, uniform disease entity [1-3]. On the basis of a nationwide epidemiological study, the Japanese Research Committee on Diffuse Pulmonary Disease for Hypersensitivity Pneumonitis has proposed diagnostic criteria for HP [4-6]. The survey, which was sponsored by the Japanese Ministry of Health, Labor and Welfare, revealed that summer-type HP (S-HP) is the most common type of HP in Japan. Of the 835 surveyed patients, 621 (74.4%) were diagnosed with S-HP [4]. According to its clinical presentation, HP can be categorized as acute, subacute, or chronic illness [1,7,8]. Although there may be a considerable overlap among these 3 types of HP, this classification is a useful approach for categorizing the variations in clinical presentations that are seen in this disease [8,9]. With regard to research on HP, 2 practical issues need to be pointed out: one is a lack of sufficient information on the clinical criteria for chronic or subacute types of S-HP [8,9] and another is the inadequate collaboration between primary care physicians and core community hospital staff in terms of clinical service for HP. HP is rarely encountered during primary care; however, when it is suspected, the patient might be referred for secondary care or to a hospital for chest diseases. Our hospital, which specializes in chest diseases, is located outside the central Tokyo area, and receives patients as a core hospital and as referrals from local clinics as well as from clinics in the central area of Tokyo.
In this study, we studied these issues in HP diagnosis in patients who were diagnosed with HP over a 10-year period. Furthermore, we investigated the role of interactive communication between primary care physicians and specialists and revisited the diagnostic criteria for HP in Japan.
2. Methods and Patients
2.1. Case Selection and Examinations
All patients who were suspected of having HP on the basis of clinical diagnosis and were hospitalized at the Fukujuji Chest Hospital, Tokyo, between January 1994 and November 2005 were included in this study. The diagnosis of HP was made on the basis of exposure history and the results of clinical assessments, including blood analysis and determination of KL-6 levels, which served as a specific biomarker for interstitial lung disease [10]. In addition, high-resolution computed tomography (HRCT) images of the chest were analyzed. The effect of removing the patient from the suspected etiologic exposure was also considered. Other tests such as bronchoalveolar lavage and transbronchial lung biopsy were used to rule out other potential diagnoses and to lend further support to the diagnosis of HP. This retrospective study was performed by taking into account all available clinical records described above.
2.2. Diagnostic Criteria
The diagnosis of HP in this study was essentially based on the diagnostic criteria of the Japanese Research Committee on Diffuse Pulmonary Disease for Hypersensitivity Pneumonitis, [6] which are similar to criteria described in previous studies [1,7,11-14]. Acute, subacute, or chronic HP [1,7-9] and the possible causes of HP [1,6, 7,11-14] were determined by performing previously reported procedures [8,9]. Summer-type, bird-fancier’s lung, or ventilator-related types of HP were also determined using these protocols.
2.2.1. Compatible Clinical and Environmental Information
Patients who showed respiratory and/or constitutional symptoms and signs such as crackles on chest auscultation, cough, breathlessness, febrile episodes, wheezing, and fatigue were enrolled as possible cases of HP. Particular attention was paid to the assessment of each clinical course in terms of acute, subacute, or chronic illness described above.
2.2.2. Laboratory Testing and Radiographic Findings
Reticular, nodular, or ground-glass opacity on chest radiographs or HRCT images comparable with the opacities reported in a previous study on HP were assessed [14]. Appropriate laboratory tests, including KL-6 detection when available, were performed on initial examination [10]. The presence of specific serum IgG antibodies against the identified antigen (serum precipitins) was reviewed. Exposure to known offending antigen (s) was determined on the basis of a history of appropriate exposure or aerobiologic or microbiologic investigations of the environment to confirm the presence of an inciting antigen. On the basis of the recommendations for the diagnosis of S-HP in Japan, serum precipitins for the following 4 organisms were measured in patients suspected of having HP: Trichosporon (T) cutaneum, T. asahii, T. domesticum, and Cryptococcus [4,5,9].
2.2.3. Bronchoalveolar Fluid and Lung Pathology
Lymphocytosis in bronchoalveolar lavage fluid (BALF) and the CD4/CD8 ratio [13] were examined. Histopathology showed compatible changes, which included pathological findings of poorly formed, non-caseating granulomas or mononuclear cell infiltration [13].
2.2.4. Challenge Tests
The findings of these tests are especially suggestive if they are present, appearing, or worsening several hours after antigen exposure [13]. A positive inhalation challenge test based on re-exposure to the environment was conducted; in this test, the subject was required to stay at his/her home/workplace for more than 12 h. In this study, subjects suspected of having S-HP underwent returnhome testing [6].
2.3. Statistics
Data were analyzed using the Statistical Package for the Social Sciences (SPSS) Version 11.1 for Windows (SPSS Inc., Chicago, Illinois, U.S.A.). We used Student’s t test or analysis of variance for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Data are expressed as mean ± 1SD; all reported P-values are 2-sided, and P values less than 0.05 were considered significant.
3. Results
Over 10 consecutive years, a total of 37 patients received a clinical diagnosis of HP. Among these, 3 patients were excluded from our study because of insufficient data, and 6 patients whose data did not satisfy the clinical criteria were also excluded. Thus, a total of 28 cases were assessed in the study.
3.1. Diagnosis and Treatment by Primary Care Physicians before Admission
All 28 patients were treated by primary care physicians before admission to our hospital. The initial diagnoses made by the primary care physicians were as follows: acute upper respiratory infection (n = 4), bronchitis (n = 11), pneumonia caused by Mycoplasma infection (n = 1), bacterial pneumonia (n = 3), interstitial pneumonia (n = 5), HP (n = 1), bronchial asthma (n = 1), and undetermined diagnosis (n = 2). The mean interval between the initial clinical symptoms and referral to our hospital was 10.5 ± 8.3 wk. The distribution of this interval is shown in Figure 1, which roughly shows at least 3 groups; short, intermediate, and long interval. In this study, we assumed that the short, intermediate, and long interval groups corresponded with acute (n = 19), subacute (n = 4), and chronic (n = 2) disease, respectively. Three cases could not be classified into any of the groups. The medications prescribed by the primary care physicians were as follows: none (n = 2), antibiotics (n = 21), bronchodilator (n = 3), cough medicine (n = 6), systemic steroid (n = 2), and unknown (n = 2) (redundant counts were allowed).
3.2. Clinical History, Initial Symptoms, and Physical Findings after Admission
The subjects included 14 men and 14 women with a mean age of 53.0 years (range: 22 - 74 years). The subjective symptoms at the initial visit to the institute were cough (17.9%), fever (46.4%), and dyspnea either at rest or on exertion (21.4%). Information on the place of work just before the onset of symptoms was available in 22 patients, including householders (n = 9), company employees (n = 7), and office workers (n = 6), but 6 patients did not show an obvious or known exposure to specific agents. Eleven patients smoked or had a history of smoking. Three patients had underlying lung diseases, including bronchial asthma (n = 2) and chronic obstructive pulmonary disease (COPD; n = 1). In 2 cases, one each in the shortand the long-interval groups, an initial diagnosis of interstitial pulmonary fibrosis (IPF) was made on the basis of the HRCT images (see below). All chest radiographs were evaluated by both radiologists and chest specialist. Each radiograph was carefully re-assessed by 3 authors.
3.3. Data after Admission
The percentages of eosinophils and lymphocytes in the peripheral blood were 4.6% ± 4.7% and 19.5% ± 9.9%, respectively. Cell populations in the peripheral blood showed significant differences among the various types of HP, e.g., the number of white blood cells in the ventilator-related type was greater than those in the bird fancier’s lung type (p = 0.033) and undetectable antigen type (p = 0.003). However, such differences were not observed in the number of neutrophils or lymphocytes. Furthermore, the proportion of neutrophils was greater in the cases of acute HP (acute vs. chronic, p = 0.028), while the proportion of lymphocytes was smaller in the same disease group (acute vs. subacute, p = 0.010; acute vs. chronic, p = 0.003).
Serum-specific antibodies (precipitins) were detected
Figure 1. Distribution of the mean interval between onset of initial symptoms and referral to our hospital. Acute, subacute, and chronic illness categories may be reflective of the interval between onset of symptoms and time of referral to our hospital, namely short (0 wk - 14 wk), intermediate (15 wk - 24 wk), and long interval (>25 wk).
in 13 patients; this included antibodies for antigens of T. cutaneum (n = 9; 32.1%), T. asahii (n = 6; 21.4%), T. domesticum (n = 4; 14.3%), and Cryptococcus (n = 8; 28.6%).
Data on KL-6 levels were available for 17 patients. The mean KL-6 concentration was 2386 U/ml (range: 215 - 8580 U/ml; normal range: less than 499 U/ml). As shown in Figure 2, cases with KL-6 levels between 500 and 5000 U/ml were compatible with various types of HP. Nonetheless, these also included cases with undetectable levels of serum precipitin (s). Serum concentration of KL-6 was determined in 19 cases; the sensitivity was 82.4%, however the specificity was unable to calculate, because of insufficient samples.
3.4. HRCT Findings
A summary of the HRCT findings is shown in Table 1. In 1 case, which was diagnosed as idiopathic pulmonary fibrosis by the primary care physician, a honeycomb appearance was observed on the HRCT image; a similar finding was obtained in another case. However, none of the other cases showed such HRCT findings.
3.5. BALF, Lung Pathology, and Outcome of Challenge Tests
Table 2 shows a summary of the pathological findings for cellular components in the lung samples and BALF samples. The percentages of lymphocytes (p = 0.008) and eosinophils (p = 0.045) in BALF significantly increased with granuloma formation or Masson’s body formation with eosinophil components (p = 0.039) in the lung samples. However, there was no correlation between the percentages of eosinophils in blood and BALF. No significant differences were found among the CD4/ CD8 ratios in BALF in S-HP (0.43 ± 0.29), ventilatorrelated HP (0.43 ± 0.21), and undetectable antigen group (0.21 ± 0.09).