We recently had a 29-year-old leprosy patient with a giant 13-cm PPD skin reaction including induration plus erythema. He had a positive QuantiFERON-TB Gold assay, a negative chest X-ray, and was without any signs or symptoms of active tuberculosis (TB) infection. The patient was borderline lepromatous with a type 2 erythema nodosum leprosum (ENL) reaction controlled on low dose thalidomide 50 mg at bedtime. He was arrested and while incarcerated experienced a recurrence of ENL two days after receiving a screening PPD test, presenting with a chief complaint of pain in his ears. The ENL reaction was subsequently controlled on thalidomide 100 mg three times daily. The patient had been receiving treatment for two full years but still had a high bacillary load and was in his final six months of treatment.
Similar cases of giant PPD skin reactions in lepromatous patients have been reported in the literature. In 1985, Waters et al. described "giant reactions" (GR) to tuberculin in 28 Hansen's patients across Malaysia, Uganda, Spain, and England. Twenty-seven of these cases were lepromatous patients (24 LL, 3 BL), and among these only three were untreated (1 LL, 2 BL). Waters et al. noted that GR was uncommon in patients untreated for leprosy as well as in patients who had undergone very long-term treatment, while it was relatively common during the first 1 to 3 years of chemotherapy, occurring in up to 20% of these patients.1 It was therefore postulated that most GR occurred "during a period of temporary lack of immune regulation associated with changing levels of antigenic load."1
Sampaio et al. described further instances of GR to PPD inoculation in a Brazilian leprosy unit in 1993. Out of 147 PPD-tested multibacillary leprosy patients, 16 (8 BL, 8 LL) developed GR, defined as a skin induration of > 22 mm surrounded by an edematous, erythematous area 60 mm or greater in diameter, in some cases involving the entire circumference of the forearm.2 Interestingly, 12 of the 16 GR patients (75%) developed ENL over the courses of their disease, with GR closely preceding ENL reactions in 3 patients, as in ours. Of the 131 non-GR leprosy patients, only 42% developed ENL (P<0.01). Patients with GR also showed significantly higher IFN-gamma levels on IFN-gamma release assays (138 +/- 42 U per mL) compared to patients with either a positive or negative in vivo PPD reaction (36.5 +/- 23.2 and 17.2 +/-12 U per mL, respectively).2 Of the 16 GR cases, 5 reported prior contact with TB. All of them, however, had normal chest X-rays and sputum examinations and were without any clinical symptoms of active Mycobacterium tuberculosis infection. Furthermore, none developed active TB during the subsequent 5 years of follow-up study.2
These cases, in addition to the one we describe, raise the question of how best to diagnose latent M tuberculosis infection in patients with lepromatous leprosy. IFN-gamma release assays like QuantiFERON-TB Gold have been used since their FDA approval in 2003 for the diagnosis of latent M tuberculosis infection. Prior exposure is assessed by measuring IFN-gamma release from cultured whole blood after incubation with M tuberculosis antigens, including early secretory antigenic target-6 kDa (ESAT-6) and culture filtrate protein-10 kDa (CFP-10).3, 4 Recent studies, however, suggest that distinct Mycobacterium leprae antigens share molecular homology with M tuberculosis ESAT-6 and CFP-10. Gey Van Pittius et al., for example, have characterized an M leprae ESAT-6 homologue called L-ESAT-6, which was found to stimulate T-cell dependent IFN-gamma production in individuals with M leprae infection as well as in individuals with exposure to M tuberculosis, suggesting significant cross-reactivity.5 Furthermore, Geluk et al. have described an M leprae CFP-10 homologue, ML0050, which was found to stimulate IFN-gamma release by T-cells from leprosy patients as well as from individuals with M tuberculosis infection, again suggesting antigenic cross-reactivity.6 The existence of M tuberculosis ESAT-6 and CFP-10 homologues in M leprae therefore has implications for the diagnostic utility of the QuantiFERON-TB Gold assay in areas endemic for both tuberculosis and leprosy.
We conclude that the QuantiFERON-TB Gold assay cannot reliably measure latent M tuberculosis infection in leprosy patients.7 It is best used in this population as a measure of anergy, defined as the absence of IFN-gamma production in patient-derived whole blood cultures upon exposure to the mycobacterial antigens ESAT-6 and CFP-10. Newer tests are required to detect latent TB in the leprosy population. The management of leprosy patients, such as those described herein, who demonstrate GR to PPD inoculation with positive QuantiFERON-TB Gold assays should depend on whether they are known to have confirmed contacts with TB. Continued observation with serial chest X-rays can be considered versus prophylactic treatment of latent tuberculosis or treatment for active disease. Future sequential studies will be of interest to determine how the QuantiFERON-TB Gold assay functions in terms of its potential to measure the changing anergy status of leprosy patients during ENL reactions. Physicians working