Am. J. Trop. Med. Hyg., 79(3), 2008, pp.

452454 Copyright 2008 by The American Society of Tropical Medicine and Hygiene

Short Report: Five-year Experience with Type 1 and Type 2 Reactions in Hansen Disease at a US Travel Clinic
Jesse T. Jacob, Phyllis Kozarsky, Roberta Dismukes, Vicki Bynoe, Lindsay Margoles, Michael Leonard, Ildefonso Tellez, and Carlos Franco-Paredes*
Division of Infectious Diseases, Emory University, Atlanta, Georgia; Emory TravelWell Clinic, Atlanta, Georgia; Hospital Infantil de Mexico, Federico Gomez, Mexico

Abstract. Very few data have been reported on the epidemiology and clinical features of leprosy reactions in non-endemic settings. We performed a retrospective descriptive analysis to define the frequency and features of Type 1 and Type 2 leprosy reactions in a cohort of patients followed at a US travel and tropical medicine clinic in a 5-year period. We identified that leprosy reactions presented in 10/14 (71.4%) patients with leprosy seen at our clinic. We identified that leprosy reactions occur frequently among patients living in non-endemic areas and may occur before the initiation of multi-drug therapy (MDT), during MDT, or even years after completion of therapy and may produce significant neurologic sequelae. This group of patients needs long-term clinical monitoring even after completion of MDT because of the need to continue either anti-inflammatory therapy, presence of severe neurologic sequelae after reactions, or the potential occurrence of late leprosy reactions. Although the worldwide prevalence of Hansen disease (HD) has decreased in the era of multi-drug therapy (MDT), the global incidence of leprosy remains the same, while the number of annual reported cases in the United States increased by 22% in 2005, suggesting that HD will remain a clinical and public health issue for the foreseeable future.14 The World Health Organization guidelines have simplified the diagnosis and management of uncomplicated HD. However, the recognition and care of complex patients is challenging because the pathogenesis of leprosy is still unclear in many aspects. Chief among these are leprosy reactions, which have been reported to occur in 2550% of HD patients in regions with a high prevalence of HD. Outside these areas, the frequency and severity of leprosy reactions, both Type 1 or reversal reaction and Type 2 or erythema nodosum leprosum, have not been well characterized in the MDT era. By promoting nerve damage, leprosy reactions contribute significantly to the accompanying disability and deformity associated to leprosy. We were interested in evaluating the frequency and outcome of leprosy reactions in HD patients seeking medical care in a US travel and tropical medicine clinic. We retrospectively examined our experience with HD reactions over a 5-year period (January 2002 to March 2008). Medical records of patients with HD seen in Emory Universitys TravelWell Clinic were systematically reviewed to assess the frequency and outcomes of leprosy reactions. Variables collected included age, sex, ethnicity, country of origin, age at diagnosis, start and end dates of MDT, dates of reaction, and reaction treatment. Categorical variables were assessed with frequencies, and numeric variables were described using mean, median, and range. The protocol was approved by the Emory Institutional Review Board. Of the 563 patients seen in TravelWell for post-travel clinic visits from January 2002 to 2007, 14 (2.4%) had HD (Table 1). Historically, our clinic has served as a referral center for tropical infectious diseases and HD patients in Georgia. In fact, 12 of the 14 patients with HD were referred to our clinic from other clinical sites; 2 of the 14 patients were self-referred by word of mouth in the community. All patients referred by other clinics were already been diagnosed with HD by clinical findings and biopsy criteria. Seven of these patients were referred to our clinic by dermatologists and two by neurologists in Georgia; the other three patients were directly referred to us by the National Hansen Disease Program (NHDP) in the United States because these three patients lived in Georgia. In our clinic, we were responsible for confirming a diagnosis of leprosy in only the two self-referred patients. However, in our clinic, we were responsible for supervising MDT or managed leprosy reactions in 13 patients in coordination with the NHDP medical officer (only 1 patient had already completed a full course of MDT in Brazil). Among patients with HD see in our clinic, 10/14 (71%) were men. The median age at presentation to the TravelWell Clinic was 47.1 years, and median age at diagnosis was 39 years. Diagnosis of HD was established in all patients by clinical diagnostic criteria using the 1997 case definition and by the demonstration of acid-fast bacilli in full-thickness skin punch biopsy (Table 1). Skin biopsies were done on initial exam and at the end of treatment to document microbiological improvement. By using the Ridley-Jopling classification, six patients (42.8%) were classified as having lepromatous forms (LL), two patients presented with borderline lepromatous (BL) forms (14.3%), one patient (7.1%) presented with the borderline borderline (BB) form, one (7.1%) with the tuberculoid form (TT), and the remaining presented with borderline tuberculoid (BT) forms (28.6%; Table 1). Bacterial index was estimated in only six patients at the initial diagnosis and was categorized as > 2+ in four patients with either borderline or lepromatous forms and < 2+ in the one patient with TT. Most patients originated from Brazil (50%), followed by Mexico (14%), with one patient each from Somalia, Trinidad and Tobago, India, the United States, and Vietnam (Table 1). Of the seven patients from Brazil, three came from a single family consisting of two parents and a son. All patients were treated with standard MDT options for an average of 2 years for multibacillary forms (BT, BB, BL, and LL) and 6 months for the case of TT; second-line therapy was used in three cases because of drug toxicity or resistance.

* Address correspondence to Carlos Franco-Paredes, Assistant Professor of Medicine, Division of Infectious Diseases, 550 Peachtree Street, MOT 7th Floor, TravelWell Clinic, Atlanta, GA 30308. E-mail: cfranco@sph.emory.edu

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TABLE 1 Characteristics of 14 patients with leprosy seen at a US travel clinic (January 2002March 2008)
Characteristic Frequency (%) Median Range

Sex Male Female Age at presentation Age at diagnosis* Classification of disease Lepromatous (LL) Borderline lepromatous (BL) Borderline borderline (BB) Borderline tuberculoid (BT) Tuberculoid (TT) Country of birth Brazil Mexico Somalia Trinidad and Tobago Vietnam India United States Reactions Type 1 Type 2 Time from initiation of MDT to onset of reaction Timing of reaction Before MDT During MDT After MDT

10 (71.4) 4 (28.6) 47.1 years 39.0 years 6 (42.9) 2 (14.3) 1 (7.1) 4 (28.6) 1 (7.1) 7 (50) 2 (14.3) 1 (7.1) 1 (7.1) 1 (7.1) 1 (7.1) 1 (7.1) 5 (50) 5 (50) 16.2 months 3 (30%) 5 (50%) 2 (20%) 3.9149.2 months 21.264.9 years 21.864.4 years

* Diagnosis of HD was established in all patients by clinical diagnostic criteria using the 1997 CDC case definition15 and by the demonstration of acid-fast bacilli in full-thickness skin punch biopsy. Skin biopsies were done on initial exam and at the end of treatment to document microbiological improvement. Ridley-Jopling classification. One patient presented 5 years after completion of MDT; the second one presented 8 years after completion of MDT. Type 1 reactions presented in three patients with BT and in one patient with BL. Two patients presented late type 1 reactions. Type 2 reactions presented in four patients with LL and in the one patient with BL.

Reactions occurred in 10 (71.4%) of patients, of which 5 (50%) were Type 1 and five were Type 2 (50%). The diagnosis of reactions was clinical in all patients and confirmed by biopsy in only 6/10 patients: in four patients with Type 2 reaction and in two patients with Type 1 reaction. In these two patients with Type 1 reactions and prior history of treated BT disease, comparisons with previous biopsies were made. Both cases were considered as having late Type 1 reactions because of new skin findings, histopathologic changes, and evidence of neuritis (Table 1). Type 1 reactions presented in three patients with BT and one patient with BL. Type 2 reactions presented in four patients with LL and one patient with BL. Reactions occurred before the use of MDT in three patients (30%), during MDT in five patients (50%), or after completion of MDT in two patients (20%). The median time from initiation of MDT to onset of reaction was 16.2 months. Of note, only four patients, two with Type 1 reaction and two with Type 2 reactions, were diagnosed with these reactions before our initial evaluation and were already receiving therapy for these reactions. The other six patients with reactions were diagnosed in our clinic at the time of the initial evaluation, and during follow-up (Table 1). One patient with Type 1 reaction and one patient with Type 2 reaction who presented with these reactions before initiation of MDT had significant peripheral nerve deficits. All patients with Type 1 reactions were treated with prednisone. Patients with Type 2 reactions were also treated with prednisone, but three (60%) patients with Type 2 reactions required both thalidomide and prednisone to control the reaction. Of these, one patient with BL became pregnant during

MDT and subsequently developed a Type 2 reaction in the postpartum period that was successfully treated with thalidomide and prednisone. Corticosteroid use lasting > 6 months was required in four (40%) patients with reactions, with an average daily prednisone dose of 30 mg. Most patients with either Type 1 or Type 2 reactions have required long-term medical follow-up to manage complications associated with permanent neurologic sequelae such as foot drop in 2/10 (20%) and significant sensory loss in lower extremity limbs in 6/10 (60%). One patient developed foot ulcers that required surgical debridement and antibiotic therapy. DISCUSSION According to the most recent data from the National Hansens Program in the United States, 75% (125 of 166 cases of HD in 2005) were recorded in foreign-born individuals.2 Of these, the majority were recorded in individuals born in Mexico, Brazil, Philippines, Dominican Republic, and India. In addition, some autochthonous cases have also been recognized in the United States, particularly in the western Gulf of Mexico, Hawaii, and Puerto Rico.2 We identified that in our population by national origin, the majority of HD cases presented in individuals from Brazil, followed by patients from Mexico. Both Type 1 and Type 2 reactions can occur anytime within the course of leprosy but are often observed after starting treatment and are considered medical emergencies because they can result in irreversible nerve damage.3 The incidence of Type 1 and Type 2 reactions in endemic areas has been well described.511 Other possible risk factors for Type 1 reactions

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include age at diagnosis of HD, World Health Organization classification, positive bacillary index, pregnancy, or puberty.3,4 Type 1 reactions are generally heralded by increasing swelling, erythema, and tenderness in skin lesions accompanied by increased neuritis associated with pain and loss of function. Type 2 reaction, which occurs in lepromatous leprosy, can also be precipitated by vaccination, tuberculin skin testing, or other immune system stimulants.3 It generally presents with crops of new tender subcutaneous nodules and may be associated with fever, arthralgias, and occasionally vasculitis, adenopathy, orchitis, and dactylitis. In this retrospective study, we found that leprosy reactions occur frequently in our cohort of patients with equal amounts of Type 1 and Type 2 reactions. This may reflect a selection bias in a non-endemic area because sicker patients will seek medical care more frequently. For example, in a 14-year French study of leprosy treatment, 22/67 patients developed reversal reactions, and 18/67 developed Type 2 reaction after an average of 15 months on MDT.12 The diagnosis of Type 2 reactions was clinical and most patients required long-term corticosteroid therapy. This mirrors the experience from an 11-year study from India, where flares lasted a mean of 16.9 months and required an average of 222 mg of prednisone per month among 55/116 patients.5 With increasing global migration, HD should be considered an increasingly relevant infectious disease in many areas of the world including the United States.5,1214 HD is often complicated by reactions, often requiring chronic corticosteroid therapy. We can conclude from our clinical experience at a US travel and tropical medicine clinic that leprosy reactions represent a significant source of morbidity in patients with HD. Furthermore, leprosy reactions may be more common than previously thought among patients living in non-endemic areas and may occur before the initiation of MDT, during MDT, or even years after completion of therapy. Indeed, patients who have suffered a leprosy reaction require longterm medical monitoring and supportive therapy with rehabilitation and physical therapy. Similarly, we suggest longterm follow-up of individuals who have successfully completed appropriate MDT regimens for the potential occurrence of late reactions as seen in two of our patients. Further research into the epidemiology, pathogenesis, and optimal clinical management of reactions is urgently needed.
Received February 19, 2008. Accepted for publication May 20, 2008. Financial support: This study was supported by the grant Global Health without Travel of the Global Health Institute of Emory University.

Authors addresses: Jesse T. Jacob, Phyllis Kozarsky, Roberta Dismukes, Vicki Bynoe, Lindsay Margoles, Michael Leonard, Ildefonso Tellez, and Carlos Franco-Paredes, Division of Infectious Diseases, 550 Peachtree Street, MOT 7th Floor, TravelWell Clinic, Atlanta, GA 30308, Tel: 404-686-5885, Fax: 404-686-4508, E-mails: frs7@ cdc.gov, phyllis_kozarsky@emoryhealthcare.org, roberta_dismukes@ emoryhealthcare.org, vicki_bynoe@emoryhealthcare.org, lmmargo@ learnlink.emory.edu, mkleona@emory.edu, itellez@emory.edu, and cfranco@sph.emory.edu.

REFERENCES
1. Rinaldi A, 2005. The global campaign to eliminate leprosy. PLoS Medicine 2: e341. 2. Truman R, Kearney MT, Lea JW, 2006. A Summary of Hansens Disease in the United States2005: National Hansens Disease Program HHS/HRSA/BPHC. 3. Boggild AK, Keystone JS, Kain KC, 2004. Leprosy: a primer for Canadian physicians. CMAJ Canadian Medical Association Journal 170: 7178. 4. Ranque B, Nguyen VT, Vu HT, Nguyen TH, Nguyen NB, Pham XK, Schurr E, Abel L, Alcais A, 2007. Age is an important risk factor for onset and sequelae of reversal reactions in Vietnamese patients with leprosy. Clin Infect Dis 44: 3340. 5. Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, Lockwood DNJ, 2006. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 74: 868879. 6. Lockwood DN, Vinayakumar S, Stanley JN, McAdam KP, Colston MJ, 1993. Clinical features and outcome of reversal (type 1) reactions in Hyderabad, India. Int J Lepr Other Mycobact Dis 61: 815. 7. Saunderson P, Gebre S, Byass P, 2000. ENL reactions in the multibacillary cases of the AMFES cohort in central Ethiopia: incidence and risk factors. Lepr Rev 71: 318324. 8. Kumar B, Dogra S, Kaur I, 2004. Epidemiological characteristics of leprosy reactions: 15 years experience from north India. Int J Lepr Other Mycobact Dis 72: 125133. 9. Bwire R, Kawuma HJ, 1993. Hospital-based epidemiological study of reactions, Buluba Hospital, 198589. Lepr Rev 64: 325329. 10. Van Brakel WH, Khawas IB, Lucas SB, 1994. Reactions in leprosy: an epidemiological study of 386 patients in west Nepal. Lepr Rev 65: 190203. 11. Manandhar R, LeMaster JW, Roche PW, 1999. Risk factors for erythema nodosum leprosum. Int J Lepr Other Mycobact Dis 67: 270278. 12. de Carsalade GY, Wallach D, Spindler E, Pennec J, Cottenot F, Flageul B, 1997. Daily multidrug therapy for leprosy; results of a fourteen-year experience. Int J Lepr Other Mycobact Dis 65: 3744. 13. Anderson H, Stryjewska B, Boyanton BL, Schwartz MR, 2007. Hansen disease in the United States in the 21st Century. Arch Pathol Lab Med 131: 982986. 14. Ooi WW, Moschella SL, 2001. Update on leprosy in immigrants in the United States: Status in the year 2000. Clin Infect Dis 32: 930937.