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(Chest. 2002;121:1239-1244.)
© 2002 American College of Chest Physicians

Delayed Cutaneous Hypersensitivity Tests and Lymphopenia as Activity Markers in Sarcoidosis*

Ferran Morell, MD{dagger}; Gur Levy, MD{dagger}; Ramon Orriols, MD; Jaume Ferrer, MD; Javier De Gracia, MD and Gabriel Sampol, MD

* From the Servei de Pneumologia (Drs. Morell, Orriols, Ferrer, De Gracia, and Sampol), Hospital General Vall d’Hebron, Barcelona, Spain; and the Servicio de Neumología (Dr. Levy), Hospital Clínico Universitario de Caracas, Caracas, Venezuela. {dagger} These authors contributed equally to the design of the study and to the writing of the article.

Correspondence to: Ferran Morell, MD, Servei de Pneumologia, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron, 119–129, 08035 Barcelona, Spain; e-mail: fmorell{at}hg.vhebron.es


   Abstract
TOP
 Abstract
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: To evaluate new and already known biological markers of activity in patients with sarcoidosis.

Design: A 10-year prospective clinical evaluation, including a battery of delayed cutaneous hypersensitivity tests (DCHTs) and other markers of activity.

Setting: Outpatient department of a university teaching hospital.

Patients: Forty patients with biopsy-proven sarcoidosis were prospectively evaluated every 6 months. In this study, only the visits that fulfilled the situation of active period (AcP) or of asymptomatic period (AsP) were taken into account. Twenty-one visits were considered to be in the AcP, and 26 were considered to be in the AsP. Seven patients were studied both in the AcP and the AsP.

Interventions: DCHTs and blood sample extraction every 6 months.

Measurements and results: The mean diameter of the cutaneous wheal for each antigen (AG) was lower in the AcP group than in the AsP group (candidine, p < 0.0001; tuberculin, p < 0.0009; trichophytin, p < 0.02; streptokinase-streptodornase, p < 0.001). Also, the mean (± SD) diameter for the four AGs taken together was lower in the AcP group (2.3 ± 4.2 mm) than in the AsP group (16.8 ± 9.3 mm; p < 0.0001). The mean serum angiotensin-converting enzyme (S-ACE) value was higher in the AcP group than in the AsP group (p < 0.02). A low lymphocyte count and a percentage of the lymphocyte count (< 20%) also were detected more frequently in the AcP group than in the AsP group (p < 0.02 and p < 0.0001, respectively).

Conclusions: DCHTs appear to be a simple, reliable, and easily performed marker of inflammatory activity in sarcoidosis patients. Furthermore, serum total and differential lymphocyte count and the S-ACE level proved to be useful inflammatory markers in this study.

Key Words: angiotensin-converting enzyme • delayed cutaneous hypersensitivity tests • sarcoidosis markers

Sarcoidosis, a granulomatous disease of unknown etiology, may affect different organs, particularly the lung.1 2 Although its evolution is usually benign, some patients develop more severe forms, which may lead to pulmonary fibrosis and/or the formation of bronchiectasis.3 In clinical practice, for treatment purposes, it would be useful to have available validated parameters indicating that a patient is in an inflammatory phase. The correlation between the so-called inflammatory "activity" and different markers, such as raised serum angiotensin-converting enzyme (S-ACE) levels, increased lymphocyte counts in BAL fluid, and enhanced lung uptake of 67Ga, has been investigated in recent years.4 5 6 A common problem in these studies is that the performance of the proposed parameters was assessed in determined clinical situations in which it was not objectively established whether the patients were in an active inflammatory period or a noninflammatory period, given the lack of an available "gold standard" test of active sarcoidotic inflammation. In the present study, inflammatory activity was defined according to objective, clinical, and radiologic manifestations.

The main aim of this study was to evaluate the utility of delayed cutaneous hypersensitivity tests (DCHTs) as a marker of activity. Since the results of DCHTs are frequently negative in sarcoidotic patients,7 8 9 10 11 12 it is hypothesized that their negativity could be directly correlated to a period of activity. Moreover, the results of DCHTs were compared with those of other activity markers such as S-ACE level, serum leukocyte and lymphocyte counts, serum calcium (S-Ca) level, 24-h urinary calcium (UC) measurement, and levels of serum lactate dehydrogenase (LDH) and its isoenzymes.


   Materials and Methods
TOP
 Abstract
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Study Population
The study protocol was prospectively applied for a period of 10 years to a series of 40 patients with biopsy-proven sarcoidosis, who were consecutively included in the study during this period. In each patient, this protocol was applied both at diagnosis and every 6 months during follow-up.

Clinical Evaluation
At each clinical visit, all patients were asked about their clinical manifestations and the findings of the following examinations that had been performed during the previous 30 days were assessed: posteroanterior and lateral chest radiograph; pulmonary function tests (ie, FVC, FEV1, FVC/FEV1 ratio, and diffusing capacity of the lung for carbon monoxide), S-ACE level; leukocyte number and differential count; S-Ca determination; 24-h UC level; LDH and isoenzyme level; and DCHTs.

Definitions of Active Period and of Asymptomatic Period Population for Each Group
During a particular visit, a patient was considered to fulfill the criteria for the active period (AcP) of sarcoidosis when at least one of the three following criteria was presented: (1) the presence of erythema nodosum; (2) the appearance or recent doubling in volume of a sarcoidotic lymph node; (3) the presence of mediastinal lymph adenopathies or a diffuse interstitial or alveolar-type radiologic pattern accompanied by fever (ie, temperature of > 37°C) for a minimum of 15 previous days and/or arthritis.

Patients who, at the beginning of the study or at some time during the 10 years of follow-up, had remained free of a period of clinical activity for at least > 5 years constituted the asymptomatic period (AsP) group. The data obtained at the first clinical visit, after they had accomplished the 5 years without clinical manifestations, were used in this study.

Twenty-one patients (14 men; 7 women; mean [± SD] age, 43 ± 9.42 years) met the criteria for the AcP in one of the clinical visits and 26 patients (15 men; 11 women; mean age, 48.3 ± 11.1 years) fulfilled the criteria for the AsP. Throughout the follow-up period, seven patients on occasion fulfilled the AcP criteria and on other occasions fulfilled those of the AsP at different clinical appointments.

When patients were receiving corticosteroids, therapy was suspended 1 month before their clinical appointment to avoid interference with their responses to DCHTs. Also, none of the patients presented a known cause of decrease in delayed cutaneous immunity.13

DCHTs
Responses to a battery of the following antigens (AGs) were tested: candidine (C); tuberculin (PPD); trichophytin (Tr); and streptokinase-streptodornase (SK-SD). The antigenic reagents used to perform the DCHTs were the following: C (1/100 [w/v]; Leti; Barcelona, Spain); PPD (2 U PPD per 0.1 mL; Berra; Madrid, Spain); Tr (1/100 [w/v]; Labs Leti), and SK-SD (4U-IU per 0.01 mL; Wyeth Lederle; Madrid, Spain). Since it loses potency, the SK-SD solution must be used in the same week of preparation. Using a hypodermic needle, 0.1 mL was injected intradermally into skin from the volar part of the forearm, with a distance of at least 2 cm between injections. The reading was made at 48 h, and the thickened area was assessed by the ballpoint-pen method.14 In brief, a line is drawn with a "medium" ballpoint from a point 1 to 2 cm away from the margin of the skin-test reaction toward its center. Moderate pressure is exerted against the skin, and the pen is moved slowly. (When the subject’s skin turgidity is decreased, it is desirable to maintain tension on the skin by exerting slight traction opposite to the direction of the pen movement, from a point behind the pen). When the ballpoint pen reaches the margin of the indurated area, definite resistance to further movement is noted, and the pen then is lifted. This procedure is repeated from the opposite side of the reaction. The lines drawn by the pen provide a visible record of the margins of induration, and the distance between opposing lines can be measured accurately.

Quantitative DCHT evaluations (ie, the mean between longitudinal and transverse diameters) and qualitative DCHT evaluations (the test was considered to be positive when one of the two diameters was > 5 mm in length) were calculated for each AG and globally for the four AGs tested. The following measurements were made: single-AG quantitative evaluation (the average mean diameter of a determined AG in the AcP and the AsP groups; overall quantitative evaluation (the average mean diameter of the four AGs taken together in the AcP and the AsP groups; single-AG qualitative evaluation (the number of tests that were positive for a determined AG in the AcP and the AsP groups); and overall qualitative evaluation (the percentage of positive test results among all those performed in each group).

In the AcP, 16 batteries of DCHTs were assessed at the 21 clinical visits. In the remaining five visits, DCHTs could not be evaluated owing to the continuation of steroid therapy in three patients and to noncompliance in two patients. DCHTs were performed in the 26 clinical visits of the AsP, although in 2 of them neither Tr nor SK-SD were available for testing.

All tests and readings were performed by two trained nurses who were unaware of the conditions of the study. The time spent on carrying out the procedure was approximately 7 min, and the cost was $2 for the four tests. No adverse effects were registered as a consequence of performing DCHTs.

Statistical Analysis
The Mann-Whitney test was used to assess significant differences in quantitative data, and {chi}2 tests with Yates correction and Fisher’s Exact Test were used for qualitative data evaluation. Statistical significance was set at p < 0.05. The predictive power was obtained quantitatively according to whether the overall DCHT response was 5 mm. The predictive power was obtained qualitatively in the groups (AcP or AsP) when DCHTs were assessed both qualitatively and quantitatively by the percentage of positive tests over the total of tests performed, with which we obtained the percentage distributions of DCHTs when these were positive in 0%, 25%, 50%, 75%, and 100% of the tests performed. The relative risk with a 95% confidence interval was obtained to include a patient in either of the two groups (AcP or AsP) when DCHTs were assessed both qualitatively and quantitatively.


   Results
TOP
 Abstract
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
The clinical features of patients belonging to the AcP or the AsP groups are shown in Table 1 . Biochemical and hematologic parameters are shown in Table 2 . With respect to the DCHTs (Table 3 ), their positivity was lower in the AcP than in the AsP, taking into account quantitative data (ie, mean diameter) and qualitative data (No. of positive tests) and considering the AGs separately (ie, the single-AG evaluation) or together (ie, global evaluation).


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  		Table 1.. Clinical, Functional, and Radiologic Stage Characteristics of Patients in the AcP and the AsP*

 

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  		Table 2.. Laboratory Data of Patients in the AcP and the AsP*

 

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  		Table 3.. Quantitative and Qualitative DCHTs in the AcP and the AsP

 
The percentages of periods (ie, appointments) studied with none or one, two, three, or four tests having positive results are shown in Figure 1 . For the AcP in 52.4% of episodes, the results of the four tests were negative, and in 33.4% only one test had a positive result. Hence, the percentage of episodes with more than one positive AG was only 14.3% (9.5% plus 4.8%). Conversely, in the AsP 96.2% of episodes had more than one positive AG (two positive AGs, 42.3%; three positive AGs, 23.1%; four positive AGs, 30.8%).



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  		Figure 1.. The fine line represents the results of patients studied in the AcP, and the thick line represents the results of patients studied in the AsP.

 
The ability of DCHTs that were evaluated qualitatively to predict the type of episode in an individual patient is shown in Figure 2 , in which we can observe that the probability of an episode occurring during the AcP was 98.4% if all four AGs were negative and 83% if only one AG was positive. In contrast, the probability of occurrence in the AcP was only 2.7% and 0.2%, respectively, if three or four AGs were positive.



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  		Figure 2.. The probability of an individual being in an AcP at a determined clinical appointment if results of none of the four tests was positive was 98.4%, and 83% if the individual had only one positive test result. Conversely, if at a clinical visit a patient had positive responses to all four tests, the probability of being in the AsP was 99.8% and was 97.3% if three test responses were positive.

 
The classification of patients presenting none or only one positive reaction to a skin test when considering the AcP is shown in Table 4 . This disease activity criterion showed 81% sensitivity, 96% specificity, a positive predictive value of 94%, and a negative predictive value of 86%.


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  		Table 4.. Classification of AcP and AsP Patients

 
DCHT measurements in the seven patients who fulfilled the criteria for AcP or AsP at different visits throughout the follow-up period are shown in Table 5 , which demonstrates that, as a whole, there was significantly more negativity in the AcP than in the AsP, and that for the AGs overall the difference was 0.002.


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  		Table 5.. Quantitative and Qualitative DCHT Results for the Seven Patients Studied Throughout Their Follow-up Period in Both the AcP and the AsP*

 
The mean value of the absolute lymphocyte count was lower in the AcP (Table 2) , showing statistically significant differences between the two groups (p < 0.02). Also, the number of individuals with a percentage of lymphocytes < 20% was significantly lower in the AcP group (10 of 18 individuals) than in the AsP group (0 of 20 individuals; p < 0.0001).

An analysis of the correlation between lymphopenia and the overall quantitative DCHT measurements showed the mean diameter to be 6.4 mm (SD, 9.72 mm) in the 18 episodes in which lymphopenia was detected and 12.85 mm (SD, 9.34 mm) in the 20 episodes in which lymphopenia was not detected (p < 0.04).


   Discussion
TOP
 Abstract
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The results of the present study show that the response to a DCHT, both qualitatively and quantitatively evaluated, is significantly lower during clinically active periods of the disease than in asymptomatic clinical situations. This difference exists both for each individual AG and for the sum of the four AGs (p < 0.0001) [Table 3] . Further, in the seven patients who throughout the follow-up period were studied both in AcPs and in AsPs, the difference for the sum of the four AGs was also lower during AcPs (p < 0.002) [Table 5] . The sensitivity of DCHTs to detect an AcP if responses to the four AG are negative is nearly 100%, and it is 83% if the response to only one AG is positive. Taking as a criterion of activity those visits in which the test results were all negative or only one result was positive, a sensitivity of 81% and a specificity of 96% are obtained. Hence, when an individual patient is considered during follow-up, the DCHT results can help to predict whether that patient is in an AcP or an AsP.

The battery of AGs used in the present study constitutes one of the panels recommended to evaluate delayed cutaneous hypersensitivity response. The responses of a control population in our country13 were 49% for C, 69% for PPD, 42% for Tr, and 44% for SK-SD. In countries where the PPD response is much lower, the use of another AG is recommended, which yields more frequent positive responses in the general population.

The mechanism by which DCHT responses are decreased in patients with sarcoidosis seems to be related to the fact that at sites of granulomatous inflammation a cluster of helper T lymphocytes exists that proliferate and secrete lymphokines (eg, interleukin-2, macrophage chemotactic factor, and macrophage inhibitor factor). These lymphokines induce and amplify the response by enhancing T-lymphocyte proliferation and by recruiting and retaining monocytes from the circulation. According to this, patients with sarcoidosis have an increase in the number of lymphocytes in the lung or in the sites of granuloma formation, which is reflected in the high number of lymphocytes in BAL fluid and by a predominance of T-suppressor lymphocytes and low levels of T-helper cells and monocytes in the peripheral blood.15 Compartmentalization could thereby account for the impairment in cellular immunity and, consequently, the negativity of responses to DCHTs in patients with sarcoidotic inflammation. Compartmentalization also has been proposed to explain the fact that the PPD skin test is negative in at least 25%16 and even in 57% of miliary tuberculosis cases17 18 in which inflammation of the lung is profuse. The fact that patients with hypersensitivity pneumonitis who were observed by our group converted their previously negative DCHT responses to positive after avoiding exposure to the AG and having improved clinically would support this theory.19 The results of the present study, showing that lymphopenia is associated with an impairment in DCHT positivity, also contribute to supporting this hypothesis.

Although our study was especially designed to observe DCHT capacity as an inflammatory activity marker, the results obtained from the other tests also deserve to be discussed. S-ACE is one of the parameters most used and correlated with the definition of sarcoidotic "activity." In the present study, a high S-ACE value was detected in only 31.5% of AcP episodes, which indicates low sensitivity. However, the specificity of S-ACE was good, since in AsPs S-ACE was above the normal range in only 4.1% of patients. The reason for the low sensitivity of the S-ACE in AcPs may be that the normal range of S-ACE is very wide. When the S-ACE value is assessed taking the genotype-based normal values for S-ACE into account,20 the range for a given individual will be narrower and possibly a greater number of S-ACE elevations will be detected above this range.

Similar comments can be made regarding the presence of absolute lymphopenia and a low-percentage lymphocyte count as an activity marker. It is noteworthy that in no case in the AsP did we find lymphopenia < 20%, and in contrast during the AcP a figure < 20% was detected in 55.5% of patients (p < 0.0001). This means that, like elevated S-ACE level, lymphopenia acts as a moderately sensitive, but highly specific, marker of inflammatory activity. Hence, the present data suggest that although not formally recommended in the recent statement on sarcoidosis,21 greater attention should be paid to absolute lymphocyte values and their percentage in the evaluation of activity in sarcoidosis.

In this study, the determination of urinary 24-h UC levels or serum calcemia proved to be less useful markers of sarcoidotic inflammatory activity. Although calciuria is a more sensitive marker than S-Ca and is found to be high six times more frequently than S-Ca in the AcP, it is also true that calciuria is occasionally found to be high in the AsP. Thus, its determination did not make it possible to distinguish whether a patient was in an AcP or an AsP.

In respect to LDH determination, only the mean LDH1 level, evaluated both quantitatively and qualitatively, shows a significant difference between the two groups, being lower in the AcP. Since no other studies on sarcoidosis deal with the behavior of such isoenzymes, the present results cannot currently be compared with those of other experiences.

The results of the present study allow us to indicate that the decrease in DCHT response may have clinical value when determining whether an individual with sarcoidosis is or is not in an active period. DCHT is a noninvasive, cheap, and easily performed test, and its interpretation is objective. In the present experience, DCHT renders the best yield compared with other noninvasive tests. From the practical point of view, the results of the present study showed that when a given patient is evaluated and the DCHT shows the results of only one test or none to be positive, the patient has a probability of suffering an inflammatory outbreak of 83% or nearly 100%, respectively. Conversely, if the results of three or even four tests are positive, it is very unlikely (only 2.7% and 0.2%, respectively) that the patient is in an AcP.


   Conclusion
TOP
 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The results of the present study make it advisable to perform DCHTs as an activity marker in patients with sarcoidosis. S-ACE elevation and lymphopenia are also useful parameters that can be used in addition to DCHT results in the determination of disease activity. Other studies with longer follow-up periods should be conducted to determine whether the maintenance of repeatedly negative results during the follow-up of DCHTs implies a worsening in the clinical evolution of the disease.


   Acknowledgements
 
We thank Tina Guerrero (graduate student in Mathematics) for help with statistical analysis of the data, Christine O’Hara for help with the English version of the article, and Rosa Llòria for editorial assistance.


   Footnotes
 
Abbreviations: AcP = active period; AG = antigen; AsP = asymptomatic period; C = candidine; DCHT = delayed cutaneous hypersensitivity test; LDH = lactate dehydrogenase; PPD = tuberculin; S-ACE = serum angiotensin-converting enzyme; S-Ca = serum calcium; SK-SD = streptokinase-streptodornase; Tr = trichophytin; UC = urinary calcium

This research was supported by a grant from the Fundació Catalana de Pneumologia (FUCAP) and was presented in part at the 1998 International Conference of the American Thoracic Society in Chicago, IL.

Received for publication March 23, 2001. Accepted for publication August 21, 2001.


   References
TOP
 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Mitchell, DN, Scadding, JG (1974) Sarcoidosis. Am Rev Respir Dis 110,774-802[ISI][Medline]
  2. Thomas, PD, Hunninghake, GW (1987) Current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis 135,747-760[ISI][Medline]
  3. Dibenedetto, RJ, Ribaudo, C (1996) Bronchopulmonary sarcoidosis. Am Rev Respir Dis 94,952-955
  4. Crystal, RG, Roberts, WC, Hunninghake, GW, et al (1981) Pulmonary sarcoidosis: a disease characterized and perpetuated by activated lung T lymphocytes. Ann Intern Med 94,73-94
  5. Maga J, Salazar A, Pujol R, et al. Are the pulmonary function tests and the markers of activity helpful to establish the prognosis of sarcoidosis? Respiration 63:298–303
  6. . World Association of Sarcoidosis Other Granulomatous Disorders. (1994) Consensus conference: activity of sarcoidosis; third WASOG meeting, Los Angeles, USA, September 8–11, 1993. Eur Respir J 7,624-627[CrossRef][ISI][Medline]
  7. Friou, GJ (1952) A study of the cutaneous reactions to oidiomycin, trichophytin and mumps skin test antigens in patients with sarcoidosis. Yale J Biol Med 24,533-539
  8. Sones, M, Israel, HL (1954) Altered immunologic reaction in sarcoidosis. Ann Intern Med 40,260-268
  9. Quinn, EL, Bunch, DC, Yagle, EM (1955) The mumps skin test and complement fixation test as a diagnostic tool in sarcoidosis. J Invest Dermatol 24,595-598[ISI][Medline]
  10. James, GD (1996) Immunology of sarcoidosis. Lancet 2,633-634
  11. Sharma, OP (1971) Correlation of in vivo delayed-type hypersensitivity with in vitro lymphocyte transformation in sarcoidosis. Chest 60,15-17
  12. Mitchell, DN, Scadding, JC (1974) Sarcoidosis. Am Respir Dis 110,774-802
  13. Orriols, R, Morell, F, Fité, E, et al (1981) Reactividad cutánea retardada en una población de 400 pacientes hospitalizados. Estudio control. Med Clin (Barc) 77,240-242[Medline]
  14. Sokal, JE (1975) Measurement of delayed skin test response. N Engl J Med 4,501-502
  15. Kataria, YP, Holter, JF (1997) Immunology of sarcoidosis. Clin Chest Med 18,719-739[CrossRef][ISI][Medline]
  16. Fraser, R, Peter Paré, J, Fraser, R, et al (1994) Infectious disease of the lungs. Synopsis of diseases of the chest 2nd ed. ,287-391 W.B. Saunders Philadelphia, PA.
  17. Vidal R, Vilaplana M, Richart C, et al. Presentación clínica y métodos diagnósticos en 113 casos de tuberculosis miliar. Med Clin (Barc) 1982:173–178
  18. Richart C, Roca A, Pedro-Botet J, et al. Nuevos aspectos diagnósticos de la tuberculosis miliar. Med Clin (Barc) 1982:173–178
  19. Orriols, R, Morell, F, Curull, V, et al (1989) Impaired non-specific delayed cutaneous hypersensitivity in bird fancier’s lung. Thorax 44,132-135[Abstract]
  20. Tomita, H, Ina, Y, Sugiura, Y, et al (1997) Polymorphism in the angiotensin-converting enzyme (ACE) gene and sarcoidosis. Am J Respir Crit Care Med 156,255-259[Abstract/Free Full Text]
  21. . American Thoracic Society, the European Respiratory Society, and the World Association of Sarcoidosis and Other Granulomatous Disorders. (1999) Statement on sarcoidosis: joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS), and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 160,736-755[Free Full Text]



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