Multiple skin testing of tuberculosis patients with a range of new tuberculins, and a comparison with leprosy and Mycobacterium ulcerans infection

SUMMARYFour hundred and seventy tuberculosis patients were each skin tested with four of a range of 17 mycobacterial reagents in four countries in all of which tuberculosis and leprosy were endemic. Sixteen of the reagents were new tuberculins prepared from extracts of living mycobacteria disrupted by ultrasonic disintegration and the last was PPD, RT23.The effect that tuberculosis exerted on the delayed-type skin test response to these antigens was assessed by comparing results for tuberculosis patients with those for Tuberculin positive and Tuberculin negative control populations. Tuberculosis patients on Rifampicin therapy showed no difference in their skin test responses to any of the antigens from those patients on other forms of anti-tuberculosis treatment.Amongst the normal population it was found that possession of Tuberculin positivity was associated with an enhanced response to all the other mycobacterial antigens with the exception of A*-in which demonstrated a reciprocal relationship with Tuberculin in Burma. It was also noted, in Burma particularly, that sensitization to mycobacterial species other than Mycobacterium tuberculosis, especially to the slow growers, plays a role in determining responses to different mycobacterial species.In tuberculosis patients enhanced skin test responses were also seen but only in those countries, e.g. Libya, where the prevalence of mycobacterial species was low. Where mycobacteria were common, as in Burma, the converse was true and tuberculosis was associated with a diminished skin test response to each antigen. The high prevalence of A*-in positivity in Burma, its reciprocal relationship with Tuberculin there and the results for all the antigens in the tuberculosis patients indicate that the cell mediated skin test response may have a threshold. If this is exceeded the skin test becomes negative so that non-reactors then include those who have been excessively sensitized as well as those who have not been sensitized. Despite this, a greater percentage of tuberculosis patients in each country responded to the specific reagent Tuberculin than did the control populations and their mean positive induration sizes were consistently larger. Nevertheless, amongst the tuberculosis patients in Burma 13% were complete non-reactors to Tuberculim and this apparent anergy also applied to the other reagents with which these individuals were tested.This differs from lepromatous leprosy where the anergic state pertain exclusively to M. leprae and a few seemingly closely related species. The breadth of anergy in M. ulcerans infection has not been measured but it is known to effect both Burulin and the PPD, RT23.Just as in leprosy and M. ulcerans infection, tuberculosis can be shown to have a disease spectrum here detected by multiple skin testing. The significance of this spectrum and its similarities with and differences from that of the other mycobacterioses is discussed.

Download Full-text

Use of Mycobacterium tuberculosisComplex-Specific Antigen Cocktails for a Skin Test Specific for Tuberculosis

Infection and Immunity ◽

10.1128/iai.66.8.3606-3610.1998 ◽

1998 ◽

Vol 66 (8) ◽

pp. 3606-3610 ◽

Cited By ~ 35

Author(s):

Konstantin Lyashchenko ◽

Claudia Manca ◽

Roberto Colangeli ◽

Anna Heijbel ◽

Alan Williams ◽

...

Keyword(s):

Tuberculin Skin Test ◽

Skin Test ◽

Guinea Pigs ◽

Nontuberculous Mycobacteria ◽

Skin Testing ◽

Specific Antigen ◽

Diagnostic Value ◽

Mycobacterial Species ◽

Diagnostic Specificity ◽

Single Antigen

ABSTRACT The tuberculin skin test currently used to diagnose infection withMycobacterium tuberculosis has poor diagnostic value, especially in geographic areas where the prevalence of tuberculosis is low or where the environmental burden of saprophytic, nontuberculous mycobacteria is high. Inaccuracy of the tuberculin skin test often reflects a low diagnostic specificity due to the presence in tuberculin of antigens shared by many mycobacterial species. Thus, a skin test specific for tuberculosis requires the development of new tuberculins consisting of antigens specific to M. tuberculosis. We have formulated cocktails of two to eight antigens of M. tuberculosis purified from recombinant Escherichia coli. Multiantigen cocktails were evaluated by skin testing guinea pigs sensitized with M. bovis BCG. Reactivity of multiantigen cocktails was greater than that of any single antigen. Cocktail activity increased with the number of antigens in the cocktail even when the same amount of total protein was used for cocktails and for each single antigen. A cocktail of four purified antigens specific for the M. tuberculosis complex elicited skin test responses only in BCG-immunized guinea pigs, not in control animals immunized with M. avium. These findings open the way to designing a multiantigen formulation for a skin test specific for tuberculosis.

Download Full-text

The Importance of Glycerin-Containing Negative Control Tests in Allergy Research Studies that Use Intradermal Skin Tests

Otolaryngology ◽

10.1067/mhn.2002.127890 ◽

2002 ◽

Vol 127 (3) ◽

pp. 177-181 ◽

Cited By ~ 12

Author(s):

David S. Hurst ◽

Bruce R. Gordon ◽

John H. Krouse

Keyword(s):

Skin Test ◽

False Positive ◽

Negative Control ◽

Intradermal Injection ◽

Skin Tests ◽

Positive Skin ◽

Test Response ◽

Timothy Grass ◽

Skin Response

OBJECTIVE: We sought to assess skin whealing with glycerin-containing control injections for intradermal skin tests. DESIGN: Observational. METHODS: Wheal sizes were measured at 0, 10, and 15 minutes after intradermal injection of 0.01 and 0.02 mL of phenolated normal saline and 0.5% and 5% concentrations of glycerin in the same quantity of phenolated saline. RESULTS: Intradermal injection of 0.01 mL of phenolated saline produced an average 4.9-mm wheal, which expanded to 5.2 mm at 10 minutes and to 6.0 mm at 15 minutes. Intradermal injection of 0.02 mL of phenolated saline produced a 6.4-mm wheal, which expanded to 7.0 mm at 10 minutes and 8.0 mm at 15 minutes. The addition of glycerin produced proportionally larger wheals. CONCLUSIONS: Because glycerin increases whealing beyond that with phenolated saline, skin tests containing glycerin must be compared with glycerin-containing negative controls. Intradermal skin tests that fail to compare findings in this manner contain an inherent methodologic flaw and are uninterpretable. A major issue in allergy testing is deciding whether the observed skin response is truly indicative of the patient having a clinically relevant, IgE-mediated reaction. 1 Skin test results are influenced by many variables, including patient skin response, specific technique, and tester consistency. Wheal measurement, comparisons with positive and negative control solutions, and interpretation are of equal importance. The development of in vitro methods for allergy diagnosis has helped to independently verify the accuracy of skin tests. In some cases, poor standardization of antigen sources and testing techniques has been shown to lead to discrepancies between skin tests and in vitro IgE antibody results of more than 100-fold. 2 It is also possible for skin tests to be falsely negative, as has been shown by comparing IgE blood tests with both skin tests and challenge tests. 3 Conversely, skin tests may be falsely positive because of nonspecific irritants, such as glycerin, present in allergen solutions. 4,5 Recommendations for immunotherapy must be based on clinical appropriateness as related to valid testing of proposed therapeutic agents. Recent reports by Nelson et al 6 and Wood et al 7 have suggested that skin prick tests (SPTs), even when negative, are sufficiently sensitive to diagnose clinical atopy without the need for further intradermal skin tests (IDTs). Both authors describe performance of a single IDT with injection of 0.02 mL of antigen solution. The basic tenant of their methodology is that all wheals resulting from an IDT measuring 6 mm or greater, accompanied by erythema, are to be recorded as positive. Nelson et al took measurements at 15 minutes, and Wood et al took measurements at an unspecified time. We were concerned that their methodology for IDTs created many false-positive results. This led to the condemnation of IDTs by these authors, stating that “a positive intradermal skin test response to Timothy grass in the presence of a negative skin prick test response to Timothy grass did not indicate the presence of clinically significant sensitivity to Timothy grass.” 6 We found the conclusion based on their particular IDT method to be suspect for 2 reasons: (1) it categorically assumes that an injection of 0.02 would produce a wheal of less than 6 mm and (2) it ignores the effects of small concentrations of the preservative glycerin, used in most all allergy test solutions, on whealing. Either assumption would lead to frequent false-positive skin test interpretations and discredit 60 years of intradermal testing. We therefore sought to evaluate control tests appropriate for use with the methodologies published in the general allergy literature to determine whether a 6-mm wheal with erythema should appropriately be interpreted as a positive or as a negative test.

Download Full-text

High Histamine Control Concentration Leads to False Negative Allergy Skin Testing

American Journal of Rhinology and Allergy ◽

10.1177/19458924211008685 ◽

2021 ◽

pp. 194589242110086

Author(s):

Amulya Amirneni ◽

Jody Tversky

Keyword(s):

Skin Prick Test ◽

Skin Test ◽

Skin Testing ◽

False Negative ◽

The Other ◽

Skin Tests ◽

Prick Test ◽

Timothy Grass ◽

Significant Difference ◽

Dust Mite

Background Allergy skin test reliability depends on the reagents and controls selected. Histamine is used at 1 mg/ml and 6 mg/ml concentration but few studies address the rationale for selecting one versus the other and how this may impact diagnostic accuracy. Objective To determine the rate of false negative allergen skin tests responses between UniTest PC (using the 1 mg/mL histamine) and Quintip devices (using 6 mg/mL) for 4 common aeroallergens. Methods Subjects aged 18-65 with symptoms of allergy to cat and/or ragweed received skin testing with 4 aeroallergens (dust mite mix, timothy grass, ragweed, cat), histamine and control diluent. Those individuals who tested positive to cat or ragweed with one skin prick test (SPT) device but not the other then proceeded to nasal allergen challenge (NAC). The primary outcomes were the aeroallergen false negative rates and sensitivities of the skin test devices followed by nasal allergen (NAC). Results Twenty-five individuals were recruited and underwent a total of 300 SPTs. SPT to allergens (ragweed, dust mite, cat, and timothy grass) resulted in a statistically significant difference in wheal size among the two skin testing devices ( p value <0.0001, 0.0001, 0.0006, and 0.0053 respectively). Six NAC procedures were performed to cat/ragweed and 5 of 6 (83% were positive). The overall allergen sensitivity rate for UniTest and Quintip were 97% and 78% respectively with most false negatives due to the use of 6 mg/ml histamine control reagent. Conclusion Our study shows that 6 mg/ml concentration of histamine control reagent may contribute to a false interpretation of aeroallergen skin prick test results.

Download Full-text

The effect of homologous blood transfusion on delayed hypersensitivity skin test response has been studied using tetanus and diphtheria toxoids, streptococcus, tuberculin, Proteus, Candida and trichophyton antigens (4). Postoperative skin test response area decreased 57% in transfused patients compared to a 38% decrease in untransfused patients. Since transfused and untransfused patients differed significantly in duration of surgery, preoperative blood hemoglobin and serum albumin, the authors reanalyzed their data with 64 pairs of patients matched for these variables with the same results. The predictive value of delayed hypersensitivity skin testing for sepsis and mortality has not been accepted by all investigators. Brown et al. (5) agree that anergic patients have significantly higher rates of sepsis and mortality than normal responders, however "careful study of the temporal relationship between skin reactions and clinical events in individual patients suggested that these differences were not of value in clinical practice. Abnormal reactions usually followed obvious complications such as sepsis or secondary hemorrhage rather than predicted them. Anergy to skin testing may be related to a circulating serum factor which appears after trauma and causes lymphocyte suppression. There is no proven association of blood transfusion with serum suppressive activity or with anergy. Infectious complications and hospital stay are both significantly related to immunosuppressive serum and anergy. Lymphocyte Subsets Lymphocytes, B cells, T cells, helper cells and suppresser cells drop significantly five days after surgery and the decline is twice as great in the transfused patients compared to the untransfused (6). Helper cell number declines in transfused patients cause the helper/suppresser ratio to decrease significantly despite a significant decline in suppresser cell number. Changes in cell numbers recover somewhat by ten days so the differences between transfused and untransfused patients are no longer statistically significant although cell numbers in transfused patients are still lower than those in untransfused patients. Lymphocyte responses to ConA and PHA decline significantly in transfused groups, remaining below preoperative levels even one year following surgery. Response to ConA and PHA and MLR's in untransfused patients are significantly higher than in transfused patients at 90 days and 45 - 60 days respectively. Significant declines in immunoglobulin G, A and M cells are noted postoperatively in both transfused and untransfused patients. Other authors have not observed consistent changes in lymphocyte subsets in relation to transfusion. Changes in the numbers of lymphocytes in the various subsets in relation to surgery with and without blood transfusions studied in patients tested before and after surgery and in patients tested one week following transfusion alone, surgery alone or both reveal no evidence of suppression of immunity by surgery or blood transfusion (7). Generally surgery is followed by significant decreases in peripheral blood lymphocyte numbers affecting all lymphocyte subsets to some degree. Declines in helper cell numbers are associated with a significant decrease in the helper/suppresser ratio. It is not clear if transfused patients exhibit greater declines in lymphocytes due to the transfusion, due to the operative trauma, or due to pre-existing anemia which caused physicians to transfuse blood.

Transfusion Immunology and Medicine ◽

10.1201/9781482273441-22 ◽

1995 ◽

pp. 293-293

Keyword(s):

Blood Transfusion ◽

Skin Test ◽

Lymphocyte Subsets ◽

Skin Testing ◽

Cell Number ◽

Delayed Hypersensitivity ◽

Helper Cell ◽

Cell Numbers ◽

Test Response ◽

Hypersensitivity Skin

Download Full-text

Cutaneous Anergy in Pregnant and Nonpregnant Women With Human Immunodeficiency Virus

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744998000040 ◽

1998 ◽

Vol 6 (1) ◽

pp. 13-17 ◽

Cited By ~ 6

Author(s):

N. L. Eriksen ◽

A. W. Helfgott

Keyword(s):

Human Immunodeficiency Virus ◽

Skin Test ◽

T Lymphocyte ◽

Lymphocyte Count ◽

Skin Testing ◽

The Other ◽

Tuberculin Skin Testing ◽

Test Results ◽

Significant Difference ◽

Immunodeficiency Virus

Objective:To determine the prevalence of cutaneous anergy in pregnant and nonpregnant women who are seropositive for human immunodeficiency virus.Methods and materials:The medical records of 159 women seropositive for human immunodeficiency virus were reviewed. Demographic characteristics and tuberculin skin test results were abstracted from the chart. Tuberculin skin testing was performed by the Mantoux method (5 tuberculin units of purified protein derivative injected intradermally). Anergy testing was performed using any two of the three following antigens; tetanus toxoid, mumps, orCandidaskin test antigen. A positive tuberculin test was defined as induration of 5 mm or more, and a positive test for the other antigens was defined as any amount of induration over the skin test area. Anergy was defined as any amount of induration to the other antigens. A CD4+T lymphocyte count was obtained at the time of skin testing. Continuous variables were analyzed using the Mann Whitney—U test. Categorical data were analyzed with the chi-square or Fisher's exact test as appropriate. A two-tailedPvalue <0.05 was considered significant.Results:There were 102 nonpregnant and 57 pregnant women who returned to have their skin test results read. There was no significant difference in the prevalence of positive, negative or anergic skin test results between groups. The CD4+T lymphocyte count (mean ± standard deviation) in patients with anergic results was similar between pregnant (375 ± 256/mm3) and nonpregnant (358 ± 305/mm3) women (P= 0.64).Conclusion:The prevalence of cutaneous anergy is similar among pregnant and nonpregnant women seropositive for human immunodeficiency virus.

Download Full-text

Comparison of Subject-Reported Allergy versus Skin Test Results in a Common Cold Trial

American Journal of Rhinology ◽

10.1177/194589240301700309 ◽

2003 ◽

Vol 17 (3) ◽

pp. 159-162

Author(s):

Jason S. Krahnke ◽

Deborah A. Gentile ◽

Kelly M. Cordoro ◽

Betty L. Angelini ◽

Sheldon A. Cohen ◽

...

Keyword(s):

Skin Test ◽

Common Cold ◽

Skin Testing ◽

Positive Skin Test ◽

Poor Correlation ◽

Test Results ◽

Positive Skin ◽

Test Response ◽

History Of ◽

Allergy Skin Testing

Background Few studies have examined the relationship between subject-reported allergy and results of allergy skin testing in large unselected or unbiased cohorts. The objective of this study was to compare the results of self-reported allergy via verbal questioning with the results of allergy skin testing by the puncture method in 237 healthy adult subjects enrolled in a common cold study. Methods On enrollment, all subjects were verbally asked if they had a history of allergy and then underwent puncture skin testing to 19 relevant aeroallergens, as well as appropriate positive and negative controls. A skin test was considered positive if its wheal diameter was at least 3 mm larger than that obtained with the negative control. Results Forty-eight (20%) subjects reported a history of allergy and 124 (52%) subjects had at least one positive skin test response. A history of allergy was reported in 40 (32%) of the skin test-positive subjects and 8 (7%) of the skin test-negative subjects. At least one positive skin test response was found in 40 (83%) of those subjects reporting a history of allergy and 84 (44%) of those subjects denying a history of allergy. Conclusion These data indicate that there is a relatively poor correlation between self-reported history of allergy and skin test results in subjects enrolled in a common cold study. These results have implications in both clinical practice and research settings.

Download Full-text

The production and preliminary investigation of Burulin, a new skin test reagent for Mycobacterium ulcerans infection

Journal of Hygiene ◽

10.1017/s0022172400046659 ◽

1975 ◽

Vol 74 (1) ◽

pp. 7-16 ◽

Cited By ~ 60

Author(s):

J. L. Stanford ◽

W. D. L. Revill ◽

W. J. Gunthorpe ◽

J. M. Grange

Keyword(s):

Skin Test ◽

School Children ◽

Preliminary Investigation ◽

Cross Reaction ◽

Mycobacterium Ulcerans ◽

The Other ◽

Normal School ◽

Test Antigen ◽

Other Hand ◽

New Skin

SUMMARYThe preparation of a skin test antigen from Mycobacterium ulcerans by ultrasonic disintegration and filtration is described. The reagent, called Burulin, was tested in Africa in normal school children, and in patients with leprosy, tuberculosis or M. ulcerans disease. Those with tuberculosis or M. ulcerans disease were simultaneously tested with Tuberculin PPD. Burulin was found to be highly specific for patients in the reactive stage of M. ulcerans disease, and there was no cross-reaction in patients with other mycobacterioses. On the other hand, the majority of patients with M. ulcerans disease reacting to Burulin also produce positive reactions to Tuberculin PPD.

Download Full-text

Computed Tomography in the Elderly: 1. the Normal Population

The British Journal of Psychiatry ◽

10.1192/bjp.136.3.249 ◽

1980 ◽

Vol 136 (3) ◽

pp. 249-255 ◽

Cited By ~ 114

Author(s):

Robin J. Jacoby ◽

Raymond Levy ◽

John M. Dawson

Keyword(s):

Psychiatric Patients ◽

Normal Population ◽

The Elderly ◽

Reciprocal Relationship ◽

Cortical Atrophy ◽

Global Rating ◽

Computed Tomographic ◽

Methodological Problems ◽

Ct Data ◽

Healthy Community

SummaryComputed tomographic (CT) and brief psychometric findings on 50 psychiatrically and neurologically healthy community residents over 60 years old are presented. The need for normative CT data is emphasized, and the methodological problems in obtaining them are discussed. Measures of ventricular size were generally found to be greater than those reported by other workers, and variation with age was also found to be less marked than hitherto reported. A reciprocal relationship was found between a global rating of cortical atrophy and a test of memory and orientation. This communication forms the basis for comparison with groups of psychiatric patients to be presented in subsequent articles.

Download Full-text