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(Chest. 1999;116:1625-1631.)
© 1999 American College of Chest Physicians

Delayed Type of Hypersensitivity and Late Allergic Reactions in Patients with Stable COPD*

Inger Dahlén, MD; Eva Lindberg, MD; Christer Janson, MD and Gunnemar Stålenheim, MD

* From the Department of Medical Sciences, Respiratory Medicine, and Allergology, Akademiska sjukhuset, Uppsala University, Sweden.

Correspondence to: Inger Dahlén, MD, Department of Medical Sciences, Respiratory Medicine, and Allergology, Akademiska sjukhuset, SE-751 85 Uppsala, Sweden; e-mail: inger.dahlen{at}lungmed.uu.se


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Malnutrition, a common feature among patients with COPD, has adverse effects on the immune system. Delayed type of hypersensitivity (DTH) tests have been used to evaluate the nutritional and immune status of patients and to predict outcome in various conditions. DTH is known to be and late allergic reaction (LAR) has been suggested to be dependent on T-lymphocyte function.

Study objectives: To compare DTH and LAR tests in COPD patients and healthy controls, to investigate whether skin tests have any value in estimating nutritional status and outcome in COPD patients, and to see whether there is any relationship between DTH and LAR.

Methods: Twenty-five patients with stable COPD and 20 healthy controls were tested for DTH and LAR. The patients were investigated with spirometry and anthropometric measurements and were followed for 1 year.

Results: Both the LAR and DTH reactions were diminished in the patient group (p < 0.001) compared with controls. The skin tests did not correlate with anthropometric parameters. DTH correlated to lung function, which was expressed as FEV1 (percent predicted) (r = 0.56; p < 0.01), and LAR correlated to the number of exacerbations (at 3 months, r = - 0.61; p < 0.01). No correlation was found between LAR and DTH reactions.

Conclusions: We conclude that patients with COPD in stable condition have diminished DTHs and LARs. Our results indicate that the magnitude of the LAR may be a prognostic marker in patients with COPD.

Key Words: anthropometry • COPD • delayed hypersensitivity • immunocompetence • late allergic reaction • nutritional status


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
C OPD is often associated with impaired nutrition.1 The reason for this is not clearly understood, but decreased food intake as well as increased work of breathing are probably important factors.2 3 4 5 Malnourished patients have a poorer prognosis,6 they are predisposed to respiratory failure,7 and they have higher mortality.1 8 Poor nutritional status has an adverse effect on both cell-mediated9 and humoral immunity10 with an increased risk of infection.11

In a number of diseases with immunologic components, the patient’s capacity to develop the delayed type of hypersensitivity (DTH) is diminished ("anergy"). This is probably an effect of impaired T-lymphocyte function and CD4+ cell function in particular.12 DTH tests have been widely used to evaluate the nutritional status of patients13 and also to predict outcome.14 However, critical opinions about the utility of skin testing in nutritional assessment have also been expressed.15 16 The discovery of good instruments to assess nutritional status and prognosis in COPD patients would be of great value.

The immediate allergic skin reaction is caused by crosslinking with an antigen of immunoglobulin E (IgE) molecules on mast cells. The pathogenesis of the late phase of the allergic skin reaction is not completely understood, but it has been suggested that the T lymphocytes play an important role in inducing the inflammation that is necessary for the late allergic reaction (LAR) to develop.12 17 This reaction can also be induced by injecting antibodies to IgE intracutaneously in nonallergic persons.18 In this case, the antibodies crosslink IgE on the cell surface. We have previously shown that patients with lung cancer have an abnormally low capacity to elicit this reaction.19

The aim of this study was to compare LAR and DTH reactions in a group of COPD patients in the stable phase in comparison with healthy controls. Another aim was to investigate whether skin tests are useful for estimating nutritional status and whether DTH reactivity and LAR have any prognostic value in COPD patients. Finally, the aim was to compare DTH and LAR in order to see whether they are dependent on the same parts of the immune system.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and Controls
Twenty-five COPD patients were recruited from our out-patient clinic. They met the criteria for the diagnosis of chronic bronchitis according to the American Thoracic Society.20 Patients were excluded if their FEV1, which was measured after bronchodilation on visit 1, was >= 75% of the predicted value. Patients were also excluded if they had taken oral steroids during the 2 weeks prior to visit 1 or if they had a daily dose of inhaled steroids of > 400 µg. Patients with a history of allergy or other immunologic disorders were excluded. Treatment with any immunomodulating agents was not permitted during the 2 weeks immediately prior to skin testing.

The control group consisted of 20 healthy, nonpregnant, nonallergic persons.

Each patient and control person gave his/her informed consent. The study was approved by the Ethics Committee at the Uppsala University Medical Faculty.

Study Design
The study design is presented in Figure 1 . The controls participated at visit 1 with skin and blood testing and at visit 2 (48 h). The skin tests procedures were started at 9:00 AM on every patient and healthy control. The study ran throughout the year. At visits 3 and 4 (6 and 12 months) and during telephone contact (3 and 9 months), patients were asked how many exacerbations they had had in the past 3 months. An exacerbation was defined as an increase in dyspnea, increased or discolored sputum, or any hospital contact in which bronchodilators or antibiotics were given.



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  		Figure 1.. Study design.

 
Spirometry
Spirometry was performed 20 min after bronchodilatation with 5 mg salbutamol and 0.25 mg ipratropium bromide using a spirometer (Alpha Vitalograph; Vitalograph; Buckingham, UK). The best of three tests was chosen. The reference values for calculating the predicted FEV1 and FVC were defined by Hedenström et al.21 22 Spirometry was repeated at visit 4 (12 months) using the same procedure as was used on visit 1.

DTH Tests
Delayed skin reactivity was tested by injecting 0.1 mL of the following antigens: Candida (Monilia albicans diluted in physiologic saline solution, 1,000 protein nitrogen units/mL, using the Dome-Hollister-Stier; Newbury, Berks, United Kingdom); streptokinase-streptodornase, 50 U/mL (Lederle/Cyanamid); mumps, 20 cfu/mL (Connaught Lab; Swiftwater, PA); Trichophyton, 1/100 w/v (Connaught Lab); purified protein derivative, 2 tuberculin units (SBL AB vaccine; Stockholm, Sweden); and isotonic saline solution as the negative control. One single batch of each allergen was used throughout the study. These antigens were injected intracutaneously on the left forearm. After 48 h, the maximum diameter of the indured part and the diameter at the right angle were measured. A sum of the two perpendicular diameters of at least 10 mm was assessed as positive and the number of positive tests was summarized. In addition, the mean size of all the DTH tests in each individual was calculated. Subjects without any positive DTH tests were classified as anergic.

IgE-Mediated Skin Reactions
On the right forearm, 100 µL of rabbit antihuman IgE (1/50 v/v [Sigma; St. Louis, MO]) was injected intracutaneously. A single batch of antibody solution was kept frozen in an undiluted state and was thawed and diluted shortly before use. The size of the indured swelling of the skin (the weal) was measured. The sum of the largest diameter and its perpendicular was registered. The reaction at 20 min was defined as the immediate allergic skin reaction, and that observed at 4 to 24h was defined as the LAR. The maximum diameter sum measured at 4, 8, or 12 h was recorded as the size of the LAR.

Blood Samples
Serum albumin and retinol-binding protein were measured as indicators of visceral protein stores, and total lymphocyte count was measured as an indicator of immunocompetence. In addition, hemoglobin was measured. The analyses were made using standard techniques at the hospital’s Department of Clinical Chemistry.

Anthropometric Measurements
The following anthropometric measurements were performed: weight, height, triceps skinfold thickness (TSF), and arm circumference (AC). In healthy controls, only weight and height were measured. Body mass index (BMI) was calculated as (weight in kilograms)/(height in meters)2. TSF, which is an indicator of the subcutaneous fat store, was measured with a skinfold caliper on the posterior aspect of the nondominant arm by pinching a fold of skin from the underlying triceps muscle. AC was measured 15 cm above the olecranon. The mid-arm muscle circumference (MAC) reflects the skeletal muscle mass and was calculated from the following equation:

The TSF, AC, and MAC values are each expressed as a percentage of reference values related to sex and age as defined by Bishop et al.23

Statistical Methods
The statistical analyses were performed using software (StatViewSE+graphics; Abacus Concepts; Berkeley, CA). Comparisons between patients and controls were performed using the Mann-Whitney U test for continuous variables, whereas the {chi}2 test was used for comparisons of proportions. To find a correlation between continuous variables and variables on an ordinal scale, Spearman’s rank correlation test was performed. For the simultaneous evaluation of more than two factors, multiple linear regression was performed. A p value <= 0.05 was regarded as statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The characteristics of the patients and controls are shown in Table 1 . The patients were older than the controls, but there were more women in the control group. There were eight current smokers and 17 ex-smokers in the patient group. In the control group, 5 persons had never smoked, 11 were ex-smokers, and 4 were current smokers. The mean BMI did not differ significantly between the patients and the controls, but the range was wider in the patient group (16 to 43 kg/m2) than in the control group (20 to 33 kg/m2). The mean TSF value was 58%, but the AC and the MAC were within normal limits.


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  		Table 1.. Characteristics of the Patients and Healthy Controls*

 
All of the healthy controls had at least two positive DTH reactions. The COPD group displayed significantly fewer and smaller DTH reactions than the controls (Table 2 ). Five patients were anergic. All of the patients and controls obtained an immediate allergic reaction, and the mean size did not differ between the groups. The size of the LAR was significantly smaller in the COPD group than it was in the control group (Table 2) . The differences between the COPD and the control groups in terms of LAR and DTH reactions were still significant after adjustments for age and sex in a multivariate analysis. No correlation was found between the number or size of the DTH or LAR and age in the COPD or the control group.


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  		Table 2.. Results of Skin and Blood Tests in COPD Patients and in Healthy Controls*

 
The hemoglobin level was significantly higher and the total lymphocyte count was significantly lower in the COPD group. Albumin and retinol-binding protein were lower in the patient group, but the difference was only significant for albumin (Table 2) .

In the COPD group, neither the DTH reaction nor the LAR correlated with the BMI or the other anthropometric parameters (Table 3 ). However, the patient with the lowest BMI and MAC (16.0 kg/m2 and 72.5% of the reference value) was anergic in terms of both DTH and LAR. Another three patients had a BMI < 20 kg/m2, but their MAC was normal. The four patients with a BMI < 20 kg/mg2 had decreased skin reactivity in comparison with the others. The number of positive DTH reactions was 0.5 vs 1.5 (p = 0.052), whereas the mean size of all DTH reactions was 2.45 mm vs 8.53 mm (p = 0.058) and the mean size of LAR was 72 mm vs 112 mm (p = 0.36). There was no significant correlation between the blood parameters, albumin and retinol-binding protein, and the DTH or LAR.


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  		Table 3.. Rank Correlation Between Skin Tests and Total Lymphocyte Count and Anthropometric Measurements in the 25 COPD Patients*

 
In the COPD group, both the number of positive DTH reactions and the mean size of all DTHs correlated with FEV1 (percent predicted) (Table 4 and Fig 2 ). There was no association between the LAR and lung function, whereas the number of exacerbations seen at 3, 6, 9, and 12 months after skin testing correlated inversely to the size of the LAR (Fig 3 and Table 4 ). At 3 months, the mean (range) number of exacerbations reported was 1.0 (0 to 4), and at 12 months, it was 3.6 (0 to 18). The mean change in FEV1 during the following year was - 83 mL (range, - 670 to 290 mL). No significant association was found between the DTH or LAR and changes in FEV1.


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  		Table 4.. Rank Correlation Between Skin Tests and Total Lymphocyte Count and Lung Function Related to the Number of Exacerbations at 3 and 12 Months*

 


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  		Figure 2.. The number of positive DTH reactions and FEV1 (percent predicted) in COPD patients. The box plots show the values of median and interquartile range and the 10th ({perp}) and 90th percentiles ({top}), respectively.

 


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  		Figure 3.. LAR in COPD patients with no exacerbation at 3 months and in COPD patients with one to four exacerbations at 3 months. The box plots show the values of median and interquartile range and the 10th ({perp}) and 90th percentiles ({top}), respectively. Two patients were not tested with anti-IgE because of allergy to animals. One patient did not report the number of exacerbations at 3 months.

 
No significant association was found between the size of the LAR and the size (r = 0.15) or number (r = 0.08) of DTH reactions in the patient group. No correlation was found between the immediate allergic reaction and the LAR (r = - 0.22). The total lymphocyte count did not correlate with the LAR (r = - 0.17) or with the number of positive DTH reactions (r = -0.05). Neither the fact that patients were smokers or ex-smokers nor the number of pack-years influenced the DTH and LAR.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main findings in this study were that both the DTH reaction and the LAR were diminished in the COPD patients, although no correlation was found between the DTH and the LAR. The anthropometric parameters did not correlate to the skin tests, but among the COPD patients, DTH reactivity correlated to lung function, and the LAR correlated to the exacerbation rate.

All of the healthy controls had at least two positive DTH reactions that correspond with previous studies in healthy subjects.24 The decrease in DTH reaction and LAR among the COPD patients indicates an impairment in their immune status. In addition, the total lymphocyte count, which also mirrors the immune status, decreased as compared to healthy controls.

DTH tests have been widely used in assessing nutritional status. Several studies have reported impaired DTH reactions among malnourished, hospitalized patients,25 26 as well as improved DTH reactivity after nutritional intervention.27 28 Hunter et al11 reported impaired DTH reactions and malnutrition in a group of COPD patients in stable condition. In the study by Laaban et al,29 DTH tests were performed in COPD patients with acute respiratory failure, and it was found that 85% of the patients who required mechanical ventilation were anergic. That result was influenced not only by malnutrition, but also by nonnutritional factors such as infection and old age. In the present study, five patients (20%) were anergic. Our patients were, however, obviously less sick than those of Laaban et al.29

DTH tests have also been claimed to be valuable prognostic indicators when it comes to mortality in heart-transplant14 and cancer patients.30 Patients with impaired DTH reactivity tended to have a poorer prognosis. In our study, we were not able to demonstrate any significant correlation between DTH reactivity and prognosis when looking at the number of exacerbations within 12 months. On the other hand, the DTH tests correlated to the severity of the disease in terms of lung function (FEV1 [percent predicted]). However, the LAR test was a better prognostic factor because it showed a negative correlation to exacerbations within 12 months.

The immediate allergic reaction was not affected in the COPD patients in this study. The same result was found previously19 when patients with uremia, sarcoidosis, or cancer also had normal immediate allergic reactions, although cancer patients had an impaired LAR. This difference may be due to the fact that the immediate reactions are mainly effects of histamine being released from mast cells, whereas the LARs are the results of complex inflammatory reactions.

The mean BMI (24 kg/m2) in our patient group appears to indicate that nutritional status in the group was normal. On the other hand, the range was very large (16 to 43 kg/m2), which means that both underweight and overweight patients participated in the study. When TSF was examined, the mean value was very low, which means that subcutaneous fat stores were affected in this group. In contrast, the MAC (reflecting the skeletal muscle mass) was normal. In our study, we found no correlation between DTH or LAR tests and the anthropometric variables. This might be explained by the limited number of patients enrolled and the fact that so few of them were severely malnourished. However, this may also be due to the difficulties involved in assessing the nutritional status of COPD patients. So, although body weight and BMI are both easy to measure, they could be misleading in the event of fluid retention, which is common among COPD patients.31 One indication of poorer protein stores was the lower levels of albumin and retinol-binding protein seen in the patient group compared with the control group. The anthropometric measurements, TSF and AC, are simple and inexpensive. Serial measurements in the same patient are more valuable and the method is better in patients with long-term nutritional problems.32 There is also a limitation in that the distribution of total body fat is not always uniform. Particularly in the elderly, adipose tissue may be concentrated in the trunk.33 In our view, the COPD patients in the study were undernourished as a group, in spite of anthropometric parameters, which were not always especially abnormal.

The control group in this study was not age- or sex-matched with the patients, which is a weakness. Whereas the differing proportions of men and women in the two groups probably had no influence on the results, the age difference could have influenced the results. In the elderly, the response to DTH tests is reduced in frequency and size, and antibody production could also be reduced in old age.34 It is not known whether the LAR is affected by age. In our study, the differences between the COPD and control group remained after adjustments for age and sex, thereby indicating that the difference in age or sex is not the cause of the difference in skin reactivity. One disadvantage of the study is the fact that the number of exacerbations was only based on the patient’s own reports and not on objective parameters.

The study ran throughout the year. Allergen-induced immediate skin reactions are known to vary with season,35 but seasonal variation in anti-IgE-induced or DTH reactions has not been reported in the literature.

Even if both the DTH reaction and the LAR decreased in this group of patients with a stable COPD condition, there was no statistically significant correlation between the two of them. The DTH reaction was related to the severity of the disease, and the LAR was related to the prognosis. T lymphocytes are important in the development of both types of reactions.12 17 36 The DTH reaction appears to be more dependent on the TH137 and the LAR appears to be more dependent on the TH212 type of T cells. The malnutrition or other components of the COPD disease may thus affect the two parts of the immune system in different ways.

We conclude that patients with COPD in stable condition have a diminished DTH and LAR, which can be caused in part by malnutrition, but other factors that affect immunocompetence in COPD may play a role. Our results indicate that the magnitude of the LAR may be a prognostic marker in patients with COPD.


   Acknowledgements
 
The assistance of Ulrike Spetz-Nyström, RN and Maria Järvensson, RN is greatly appreciated.


   Footnotes
 
Abbreviations: AC = arm circumference; BMI = body mass index; DTH = delayed type of hypersensitivity; IgE = immunoglobulin E; LAR = late allergic reaction; MAC = mid-arm muscle circumference; TSF = triceps skinfold thickness

This study was supported by the Bror Hjerpstedt Foundation, Sweden; the Swedish Heart and Lung Foundation, Sweden; and Astra, Sweden.

Received for publication February 18, 1999. Accepted for publication June 10, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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