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Necrotic Tuberculin Skin (Mantoux) Test ReactionNecrotic Tuberculin Skin Test Case: A Case Report and an Estimation of Frequency FREE TO VIEW

Dim Bunnet, MD; Alexandra Kerleguer, MD; Peou Kim, MD; Polidy Pean, MD, PhD; Viseth Phuong, MD; Nayyim Heng, MD; Yiksing Peng, MD; Laurence Borand, PharmD, PhD; Arnaud Tarantola, MD
Author and Funding Information

From the Epidemiology and Public Health Unit (Drs Bunnet, Phuong, Heng, Peng, Borand, and Tarantola), International Vaccination Center (Drs Phuong, Heng, Peng, and Tarantola), the Clinical Laboratory (Dr Kerleguer), and the Immunology Unit (Dr Pean), Institut Pasteur du Cambodge; and the National Pediatric Hospital (Dr Kim), Phnom Penh, Cambodia.

CORRESPONDENCE TO: Arnaud Tarantola, MD, Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, 5, Blvd Monivong, BP 983 - Phnom Penh, Cambodia; e-mail: atarantola@pasteur-kh.org


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(1):e1-e4. doi:10.1378/chest.14-2463
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Published online

Tuberculin skin testing was performed on a 5-year-old girl in Phnom Penh, Cambodia. She had been immunized by Bacille de Calmette et Guérin. She was tested because of a palpable cervical node and a slightly elevated temperature. Within 48 h, a deep necrotic lesion appeared on the volar aspect of the left arm. The lesion was treated locally, and the child was not treated for suspected TB. To our knowledge, this is the first instance of necrosis in 11,392 people who received Tubersol doses since 1996 to date at our International Vaccination Center, for an estimated incidence of 0.18 per 1,000 (95% Poisson 0.04-0.70 per 1,000 doses used). At a follow-up consultation after 77 days, the lesion had scarred and the child showed no signs suggestive of active TB. Although latent TB infection remains the most likely diagnosis, other types of mycobacterial infection may be considered in the tropical setting and in the absence of signs suggestive of active TB.

Figures in this Article

TB remains a major concern at the global level.1 Despite improved nutritional status and constant efforts by the national TB program, the burden of TB in Cambodia remains among the highest in the world.1 Diagnosing TB can be especially challenging in young children who have difficulty producing sputum. Tuberculin skin testing (TST), also called Mantoux test or purified protein derivative (PPD) test, remains a useful tool to diagnose TB in children.2,3 Here we report a severe necrotic reaction to TST in an apparently healthy child.

The case is a Cambodian 5-year-old girl residing in Phnom Penh, referred by a community physician to the International Vaccination Center at Institut Pasteur du Cambodge (IPC) for TST. The child had a mild fever (oscillating between 38°C and 38.5°C axillary temperature) and a cervical adenopathy for the past month. According to the mother there was no long-term fever and no significant night sweats, weight loss, or respiratory signs.

A TST was performed on the volar aspect of the left arm of the child at IPC on April 21, 2014, by intradermal injection of 0.1 mL of 5 tuberculin units (Tubersol, lot number: C4462AB, date expired: 02.2016; Sanofi-Pasteur). A lesion appeared at the injection site 10 h after the injection. It began with a painful erythematous lesion, rapidly becoming bullous and necrotic by day 2. At the 72-h reading, the aspect of the injection site (Fig 1) was necrotic and depressed, with a 25-mm-diameter black eschar surrounded by swollen, almost keloid tissue, which prevented visualizing whether the bottom was dry and clean or whether it was fibrinous or serous.

Figure Jump LinkFigure 1 –  Location of the tuberculin skin test on the left forearm, as observed April 24. (Provided courtesy of the Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location

The child had a Bacille de Calmette et Guérin (BCG) scar on her left shoulder, having been vaccinated by BCG immediately after birth in a Phnom Penh hospital. There was no identified TB case in the household or family, but the family had rented accommodations next door to a person treated for TB.

The child’s temperature was normal. There was no axillary adenopathy and no trace of lymphangitis around the ulcer. A cervical lymphadenopathy on the right side was measured at < 1 cm. The cell blood count revealed anemia at 12.4 g/dL, with microcytosis (77 μm3) and thrombocytosis (459 103/mm3). C-reactive protein titers were normal. A QuantiFERON-TB Gold In-Tube (Cellestis) test performed at IPC on May 2, 2014, was positive (Nil value, 0.262; TB Ag, 2.536). The child was confirmed HIV-negative.

The child’s mother was informed that the child now had a contraindication to future TST testing, and the child was referred to a pediatric TB ward. No biopsy of the lesion or the cervical adenopathy could be performed, as the family refused. A chest radiograph was considered normal (Fig 2). The necrotic lesion was managed with local treatment and gauze dressings and healed within 7 days. The lesion diameter was measured again at 25 mm on May 2 and at 12 mm on May 23. The child’s condition reportedly improved, and the family did not return for TB treatment. The child was again seen on July 10, at which date she presented no respiratory sign but had not gained weight despite a normal appetite. A small (< 1 cm in diameter) mobile, painless cervical lymph node persisted on the right side. The TST injection site had healed, with a heart-shaped scar (Fig 3). The mother was informed that she should consult the same physicians again should any sign suggestive of TB appear.

Figure Jump LinkFigure 2 –  Chest radiograph of the child on May 2. (Provided courtesy of Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location
Figure Jump LinkFigure 3 –  Scar on the left forearm, as observed July 10. (Provided courtesy of Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location

TST causes an immune cell-based “delayed” hypersensitivity reaction (Type 4) after local injection of tuberculin. Swelling begins slowly within a few hours and is maximal between 48 and 72 h when induration—not redness—is measured to provide elements to guide TB diagnosis. Unlike BCG vaccination, which is based on the injection of live attenuated Mycobacterium bovis and may cause local infection,4 tuberculin PPD is composed of > 200 noninfective purified proteins from Mycobacterium tuberculosis and cannot cause local infection. A quick verification of the information on the vaccination sheet confirmed that BCG had not been mistakenly injected and that we were not facing BCG lymphadenitis. Bacterial contamination of PPD vials was unlikely, as the lot had been used for weeks before this case underwent TST, with no cases of necrosis or lymphangitis recorded.

“Immediate” hypersensitivity to tuberculin occurs within 48 h after injection and often involves general signs of allergy. Tuberculin PPD also contains a small amount of phenol,5 which could in theory have contributed at least initially to a strong response and necrosis.

A series published by Froeschle et al6 described nine reported cases of reaction to Tubersol within 48 h over an 11-year period, during which approximately 300 million doses were distributed, for an estimated frequency of 0.08 reported reactions per million doses of tuberculin distributed.6 These data, however, may be underestimated because of underreporting to the manufacturer. Immediate reaction to injection of 10 tuberculin units may be more frequent and was noted in 76 of 3,248 (2.3%) patients in an allergy clinic in Ontario, Canada.7

Cases descriptions of delayed but “giant” blistering or bullous reactions following TST have been published.8-11 Available data estimate that a positive tuberculin reaction will associate some blistering in around 1% to 2% of cases.12 In a series from Germany, two cases (0.5%) of blister reactions to TST were documented among 422 patients who had received pretesting with low doses of tuberculin.13

Necrotic reactions to TST, however, are extremely rare. One case was published from India and another from Taiwan, both tropical countries, and both in patients with cervical lymphadenopathy.14,15 To our knowledge, the case we describe is the first instance of necrosis among 11,392 people who came for evaluation after receiving Tubersol doses since 1996 to date at IPC’s international vaccination center, for an estimated incidence of 0.18 per 1,000 (95% Poisson CI 0.04-0.70 per 1,000 doses used). To further refine these incidence estimates we will continue to document the number of doses used and eventual side effects.

The case we describe is under observation and shows no general sign of active TB to date. There are few data on the correlation between TST size and activity of TB. According to some authors, large TST results indicate latent rather than active TB,16-18 perhaps due to immune system sensitization and underlying nutritional status in groups with high disease incidence. Positivity must remain a strong argument in favor of mostly latent and in some cases active infection by M tuberculosis, yet the Mantoux TST uses tuberculin to test hypersensitivity to BCG and all other mycobacteria. “Giant” responses to Mantoux testing are described in patients with lepromatous leprosy caused by Mycobacterium leprae.19 Although it has been estimated to be low, the link between a strongly positive TST reaction and exposure to non-TB mycobacteria, which are very prevalent in humid tropical settings such as Cambodia, is unclear.20-22

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

BCG

Bacille de Calmette et Guérin

IPC

Institut Pasteur du Cambodge

PPD

purified protein derivative

TST

tuberculin skin test

World Health Organization. Global tuberculosis report 2013. World Health Organization website. http://www.who.int/tb/publications/global_report/en/. Accessed December 16, 2013.
 
Stop TB Partnership Childhood TB Subgroup World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 1: introduction and diagnosis of tuberculosis in children. Int J Tuberc Lung Dis. 2006;10(10):1091-1097. [PubMed]
 
Britton P, Perez-Velez CM, Marais BJ. Diagnosis, treatment and prevention of tuberculosis in children. N S W Public Health Bull. 2013;24(1):15-21. [CrossRef] [PubMed]
 
Goraya JS, Virdi VS. Bacille Calmette-Guérin lymphadenitis. Postgrad Med J. 2002;78(920):327-329. [CrossRef] [PubMed]
 
Landi S, Held HR, Pivnick H. Studies on phenol and chinosol used as preservatives in tuberculin PPD solutions. Bull World Health Organ. 1968;39(5):809-820. [PubMed]
 
Froeschle JE, Ruben FL, Bloh AM. Immediate hypersensitivity reactions after use of tuberculin skin testing. Clin Infect Dis. 2002;34(1):E12-E13. [CrossRef] [PubMed]
 
Tarlo SM, Day JH, Mann P, Day MP. Immediate hypersensitivity to tuberculin. In vivo and in vitro studies. Chest. 1977;71(1):33-37. [CrossRef] [PubMed]
 
Blossom AP, Cleary JD. Atypical tuberculosis skin test reaction. Ann Pharmacother. 2003;37(3):451. [CrossRef] [PubMed]
 
Nicolás-Sánchez FJ, Moreno-Arias G, Cabau-Rubies J. Tuberculin skin test with an atypical blistering reaction [in Spanish]. Arch Bronconeumol. 2006;42(2):100. [CrossRef] [PubMed]
 
Varma C, Aroor S, Mundkur SC. An atypical giant Mantoux reaction. Our Dermatol Online. 2012;3(3):234. [CrossRef]
 
Avasthi R, Chaudhary SC, Mohanty D. Giant Mantoux reaction. Indian J Med Microbiol. 2009;27(1):78-79. [PubMed]
 
Menzies D, Tannenbaum TN, FitzGerald JM. Tuberculosis: 10. Prevention. CMAJ. 1999;161(6):717-724. [PubMed]
 
Föll M. Reduction of excessive reactions after tuberculin skin test (mendel-mantoux method) [in German]. Gesundheitswesen. 2002;64(10):544-547. [CrossRef] [PubMed]
 
Khan UH, Koul PA. A young 20-year-old woman with an atypical tuberculin reaction. BMJ Case Rep. 2013. http://casereports.bmj.com/content/2013/bcr-2013-010500. Accessed June 18, 2014.
 
Lu CY, Lee PI, Chang LY, Chen CM, Huang LM. Picture of the month. Severe skin ulceration after tuberculin skin test. Arch Pediatr Adolesc Med. 2007;161(3):303-304. [CrossRef] [PubMed]
 
Sermise-Gadian FE, Tuazon AO. Correlation of tuberculin skin test result with severity of tuberculosis in children 0-5 years old. Paediatr Respir Rev. 2012;13(suppl 1):S47-S48. [CrossRef]
 
Auld SC, Click ES, Heilig CM, et al. Association between tuberculin skin test result and clinical presentation of tuberculosis disease. BMC Infect Dis. 2013;13:460. [CrossRef] [PubMed]
 
Al Zahrani K, Al Jahdali H, Menzies D. Does size matter? Utility of size of tuberculin reactions for the diagnosis of mycobacterial disease. Am J Respir Crit Care Med. 2000;162(4 pt 1):1419-1422. [CrossRef] [PubMed]
 
Sampaio EP, Duppre NC, Nery JA, Moreira AL, Sarno EN. Development of giant reaction in response to PPD skin test in lepromatous leprosy patients. Int J Lepr Other Mycobact Dis. 1993;61(2):205-213. [PubMed]
 
Burl S, Adetifa UJ, Cox M, et al. The tuberculin skin test (TST) is affected by recent BCG vaccination but not by exposure to non-tuberculosis mycobacteria (NTM) during early life. PLoS ONE. 2010;5(8):e12287. [CrossRef] [PubMed]
 
Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006;10(11):1192-1204. [PubMed]
 
Hoefsloot W, van Ingen J, Andrejak C, et al; Nontuberculous Mycobacteria Network European Trials Group. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur Respir J. 2013;42(6):1604-1613. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Location of the tuberculin skin test on the left forearm, as observed April 24. (Provided courtesy of the Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location
Figure Jump LinkFigure 2 –  Chest radiograph of the child on May 2. (Provided courtesy of Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location
Figure Jump LinkFigure 3 –  Scar on the left forearm, as observed July 10. (Provided courtesy of Institut Pasteur du Cambodge.) (The patient’s parent provided written consent for the use of this photograph.)Grahic Jump Location

Tables

References

World Health Organization. Global tuberculosis report 2013. World Health Organization website. http://www.who.int/tb/publications/global_report/en/. Accessed December 16, 2013.
 
Stop TB Partnership Childhood TB Subgroup World Health Organization. Guidance for National Tuberculosis Programmes on the management of tuberculosis in children. Chapter 1: introduction and diagnosis of tuberculosis in children. Int J Tuberc Lung Dis. 2006;10(10):1091-1097. [PubMed]
 
Britton P, Perez-Velez CM, Marais BJ. Diagnosis, treatment and prevention of tuberculosis in children. N S W Public Health Bull. 2013;24(1):15-21. [CrossRef] [PubMed]
 
Goraya JS, Virdi VS. Bacille Calmette-Guérin lymphadenitis. Postgrad Med J. 2002;78(920):327-329. [CrossRef] [PubMed]
 
Landi S, Held HR, Pivnick H. Studies on phenol and chinosol used as preservatives in tuberculin PPD solutions. Bull World Health Organ. 1968;39(5):809-820. [PubMed]
 
Froeschle JE, Ruben FL, Bloh AM. Immediate hypersensitivity reactions after use of tuberculin skin testing. Clin Infect Dis. 2002;34(1):E12-E13. [CrossRef] [PubMed]
 
Tarlo SM, Day JH, Mann P, Day MP. Immediate hypersensitivity to tuberculin. In vivo and in vitro studies. Chest. 1977;71(1):33-37. [CrossRef] [PubMed]
 
Blossom AP, Cleary JD. Atypical tuberculosis skin test reaction. Ann Pharmacother. 2003;37(3):451. [CrossRef] [PubMed]
 
Nicolás-Sánchez FJ, Moreno-Arias G, Cabau-Rubies J. Tuberculin skin test with an atypical blistering reaction [in Spanish]. Arch Bronconeumol. 2006;42(2):100. [CrossRef] [PubMed]
 
Varma C, Aroor S, Mundkur SC. An atypical giant Mantoux reaction. Our Dermatol Online. 2012;3(3):234. [CrossRef]
 
Avasthi R, Chaudhary SC, Mohanty D. Giant Mantoux reaction. Indian J Med Microbiol. 2009;27(1):78-79. [PubMed]
 
Menzies D, Tannenbaum TN, FitzGerald JM. Tuberculosis: 10. Prevention. CMAJ. 1999;161(6):717-724. [PubMed]
 
Föll M. Reduction of excessive reactions after tuberculin skin test (mendel-mantoux method) [in German]. Gesundheitswesen. 2002;64(10):544-547. [CrossRef] [PubMed]
 
Khan UH, Koul PA. A young 20-year-old woman with an atypical tuberculin reaction. BMJ Case Rep. 2013. http://casereports.bmj.com/content/2013/bcr-2013-010500. Accessed June 18, 2014.
 
Lu CY, Lee PI, Chang LY, Chen CM, Huang LM. Picture of the month. Severe skin ulceration after tuberculin skin test. Arch Pediatr Adolesc Med. 2007;161(3):303-304. [CrossRef] [PubMed]
 
Sermise-Gadian FE, Tuazon AO. Correlation of tuberculin skin test result with severity of tuberculosis in children 0-5 years old. Paediatr Respir Rev. 2012;13(suppl 1):S47-S48. [CrossRef]
 
Auld SC, Click ES, Heilig CM, et al. Association between tuberculin skin test result and clinical presentation of tuberculosis disease. BMC Infect Dis. 2013;13:460. [CrossRef] [PubMed]
 
Al Zahrani K, Al Jahdali H, Menzies D. Does size matter? Utility of size of tuberculin reactions for the diagnosis of mycobacterial disease. Am J Respir Crit Care Med. 2000;162(4 pt 1):1419-1422. [CrossRef] [PubMed]
 
Sampaio EP, Duppre NC, Nery JA, Moreira AL, Sarno EN. Development of giant reaction in response to PPD skin test in lepromatous leprosy patients. Int J Lepr Other Mycobact Dis. 1993;61(2):205-213. [PubMed]
 
Burl S, Adetifa UJ, Cox M, et al. The tuberculin skin test (TST) is affected by recent BCG vaccination but not by exposure to non-tuberculosis mycobacteria (NTM) during early life. PLoS ONE. 2010;5(8):e12287. [CrossRef] [PubMed]
 
Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? Int J Tuberc Lung Dis. 2006;10(11):1192-1204. [PubMed]
 
Hoefsloot W, van Ingen J, Andrejak C, et al; Nontuberculous Mycobacteria Network European Trials Group. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur Respir J. 2013;42(6):1604-1613. [CrossRef] [PubMed]
 
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