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EDITORIAL
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 73-74

Purified protein derivative immunotherapy for viral warts and interpretation of tuberculin skin tests and interferon gamma release assay for diagnosis of tuberculosis in India


1 Department of Dermatology, NKP Salve Institute of Medical Sciences, Lata Mangeshkar Hospital, Nagpur, Maharashtra, India
2 Department of TB and Chest Medicine, NKP Salve Institute of Medical Sciences, Lata Mangeshkar Hospital, Nagpur, Maharashtra, India

Date of Web Publication20-Dec-2016

Correspondence Address:
Anil Sontakke
Department TB and Chest Medicine, NKP Salve Institute of Medical Sciences, Lata Mangeshkar Hospital, Digdoh Hills, Digdoh Hills, Hingna, Nagpur - 440 019, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2455-3972.196165

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How to cite this article:
Pande S, Sontakke A, Tayade B O. Purified protein derivative immunotherapy for viral warts and interpretation of tuberculin skin tests and interferon gamma release assay for diagnosis of tuberculosis in India . Indian J Drugs Dermatol 2016;2:73-4

How to cite this URL:
Pande S, Sontakke A, Tayade B O. Purified protein derivative immunotherapy for viral warts and interpretation of tuberculin skin tests and interferon gamma release assay for diagnosis of tuberculosis in India . Indian J Drugs Dermatol [serial online] 2016 [cited 2017 Aug 17];2:73-4. Available from: http://www.ijdd.in/text.asp?2016/2/2/73/196165

Tuberculosis (TB) is common in India adding to significant morbidity and mortality. Timely diagnosis and correct treatment is very essential to decrease mortality and morbidity and reducing the spread of the disease in community. Latent TB is said to be present in nearly 1/3 rd of the Indian population. [1] As the prevalence of TB infection is high, bacillus Calmette-Guérin (BCG) vaccination is recommended and well-established vaccination practice in India. It is aimed to prevent TB infection or prevent dissemination of TB infection, especially in children.

Under Revised National Tuberculosis Control Program of India, since many years, Mantoux test or tuberculin skin test (TST) is used for detection of latent TB. Mantoux test uses purified protein derivative (PPD) as tubercular antigens which consist of approximately 200 protein allergens obtained from the precipitate of Mycobacterium tuberculosis culture supernatant. When these antigens are injected intradermally into the skin, activated T-lymphocytes mount granulomatous response to these antigens leading to induration of the skin at the site of PPD injection. Hypersensitivity to these tuberculin antigens as measured by positive skin induration of more than 10 mm is termed as positive Mantoux test or positive TST. Positive TST indicates that individual has developed type IV hypersensitivity to mixture of tubercular antigens. Thus, positive TST in Indian sitting suggests the following possibilities. (1) Active TB infection, (2) latent TB, (3) intact or persistent cell-mediated immunity (CMI) to BCG vaccination, (4) active or latent infection by lepra bacilli or nontuberculous mycobacteria, and (5) booster reaction due to previous Mantoux test as received for diagnostic or therapeutic purposes. In short, TST is a nonspecific test with high chances of false positivity. For the similar reason, positive TST has no diagnostic specificity in the Indian context where BCG vaccination is the rule and exposure to tubercular or nontubercular mycobacteria is very common. On the other hand, when CMI as obtained after BCG vaccination is on the decline, or when active or latent TB exists in patients with immunocompromised status due to HIV infection, lymphoreticular malignancies, immunosuppressive drugs, improper technique, etc. TST may not be positive, thus leading to false-negative reactions. This represents poor sensitivity of TST in the diagnosis of TB. Because of these reasons, TST has limited role in the diagnosis of TB in India. However, when TST is positive and when there is other clinical evidence along with supporting radiological, microbiological, or histologic evidence, the chances of actual TB infection being present are very high. Adding to this, there is limited evidence to suggest that more strongly positive or necrotic TST indicates more bacterial load. Degree of positivity depends on status of individual's immune or hypersensitive response to PPD antigens.

Quantiferon TB gold test evaluates interferon gamma release assay (IGRA) by ELISA. Early versions of IGRA used PPD as the stimulating antigen; however, it has been replaced by newer versions that use antigens that are more specific to M. tuberculosis than the PPD. Among this, antigens such as ESAT-6 and CPP-10 are encoded by genes located within the region of difference 1 segment of M. tuberculosis genomes, and they are more specific than PPD because they are not shared with any of the BCG vaccine stains nor by nontuberculous mycobacteria. [2] Considering this, IGRA appears to be more specific than TST for the diagnosis of latent or active TB more so in the Indian context. However, there is a lack of prospective data about validity of IGRA in large-scale cohort or experimental studies.

PPD immunotherapy which has gained popularity among dermatologists in the recent times for the treatment of warts involves single or multiple intradermal injections of PPD antigens in the substance of viral warts at the specific interval till there is a disappearance of viral warts. [3],[4],[5] Repeated injections definitely mount booster response to PPD antigens as present in the Mantoux test. Live attenuated BCG vaccine is not used for the treatment of viral warts as it the risk of introducing live tubercular bacilli within the skin. In short, PPD injections can itself induce exaggerated or booster response creating difficulty in interpretation of TST for diagnosis of latent TB in patients who have received PPD immunotherapy. Mahmood Dhahir Al-Mendalawi in a letter to editor has expressed such concerns. [6] It is agreed by us that frequent use of PPD injection for viral wart is an additional reason for false positivity of TST reactions in India. However, as mentioned above, this is not used as very reliable diagnostic test in India and always require clinical and laboratory correlation. Similar concerns also apply to patients from Western countries where latent or active TB is very uncommon, and BCG vaccination is not done; PPD if used for the treatment of viral warts in their population may be responsible for false-positive TST and may not be used as reliable diagnostic test in their population.

Activated T-lymphocytes are postulated to release gamma interferons at the site of intradermal PPD injections, thereby killing viral particles of human papillomavirus (HPV). It has also been observed in various studies that distant noninjected viral warts at the site away from PPD injections also respond to the therapy indicating that the release of interferon gamma is not just local but a systemic response. When PPD injections are postulated to release interferon gamma, it can also be postulated that repeated PPD injections can make IGRA positive in the absence of latent or active TB infections. However, this hypothesis remains to be explored further by additional studies. It can also hold true for no PPD-based immunotherapy with mumps, Candida, and Trichophyton test antigens. This immunotherapy for warts is also postulated to release Th1 cytokines such as interleukin (IL)-4, IL-5, IL-8, interferon gamma, and tumor necrosis factor-alpha which activates natural killer cells that stimulate a strong immune response against HPV. [7],[8]

Thus to conclude, TST and IGRA continue to have limited diagnostic value in the diagnosis of latent or active TB infection in India, and PPD immunotherapy has only added as one more reason for high false positivity rates to these tests. Nevertheless, history of PPD injection for the treatment of viral warts should be actively sought before interpreting reasons for these false positivity reactions.

 
  References Top

1.
Technical and Operational Guidelines for TB Control in India 2016. Central Tuberculosis Division. Available from: http://www.tbcindia.nic.in/index1.php?lang=1&level=2&sublinkid=4573 and lid=3177. [Last accessed on 2016 Dec 14; Last updated on 2016 May 11].  Back to cited text no. 1
    
2.
Menzies D, Schwartzman K, Pai M. Immune-based tests for tuberculosis. In: Schaaf HS, Zumla AI, editors. Tuberculosis: A Comprehensive Clinical Reference. 1 st ed. New Delhi: Elsevier; 2009. p. 185-6.  Back to cited text no. 2
    
3.
Nimbalkar A, Pande S, Sharma R, Borkar M. Tuberculin purified protein derivative immunotherapy in the treatment of viral warts. Indian J Drugs Dermatol 2016;2:19-23.  Back to cited text no. 3
  Medknow Journal  
4.
Elela IM, Elshahid AR, Mosbeh AS. Intradermal vs. intralesional purified protein derivatives in treatment of warts. Gulf J Deramatol Venereol 2011;18:21-6.  Back to cited text no. 4
    
5.
Kus S, Ergun T, Gun D, Akin O. Intralesional tuberculin for treatment of refractory warts. J Eur Acad Dermatol Venereol 2005;19:515-6.  Back to cited text no. 5
    
6.
Al-Mendalawi MD. Tuberculin purified protein derivative immunotherapy in the treatment of viral warts. Indian J Drugs Dermatol 2016;2:105.  Back to cited text no. 6
  Medknow Journal  
7.
Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of ano-genital warts: An open label pilot study. J Eur Acad Dermatol Venereol 2008;22:1089-93.  Back to cited text no. 7
    
8.
Horn TD, Johnson SM, Helm RM, Roberson PK. Intralesional immunotherapy of warts with mumps, Candida, and Trichophyton skin test antigens: A single-blinded, randomized, and controlled trial. Arch Dermatol 2005;141:589-94.  Back to cited text no. 8
    




 

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