INTERNATIONAL JOURNAL OF LEPROSY^ Volume 68, Number 3

Printed in the U.S.A.(ISSN 0148-916X)

Relapse as Histoid Leprosy after Receiving MultidrugTherapy (MDT); a Report of Three Cases'

issac N. Shaw, Gigi Ebenezer, Geetha S. Rao, Mani Mozhi Natrajan, andBabu Balasundaram2

Histoid leprosy is an unusual variant oflepromatous leprosy. It was first describedby Wade in 1960 (13)• It is a well-recognizedentity, having characteristic skin lesions,histopathology and bacterial morphology. Itoccurs in patients on long-term dapsonemonotherapy, showing initial improvementfollowed by relapse (1.57).

7). Irregular and in-adequate therapy with dapsone (E.9) and thedevelopment of dapsone resistance (2' 5. 9)

are thought to be important for the develop-ment of histoid leprosy. It has also been re-ported in untreated leprosy patients (6' 9).

Here we report three cases of relapse ashistoid leprosy in patients who had receivedmultidrug therapy (MDT) for 2 years. Alithree patients were part of the THELEP-sponsored field trials of MDT in multibacil-lary (MB) leprosy patients which began atSchieffelin Leprosy Research and TrainingCentre (SLR&TC) in Karigiri, India, in De-cember of 1981. Two regimens, each con-sisting of dapsone, rifampin and clofaz-imine, were used to treat the patients.

CASE REPORTSCase No. 1. A 10-year-old boy was diag-

nosed as a case of lepromatous leprosy inApril 1968. A skin-smear examination fromthe routine sites (routine sites for skinsmear at SLR&TC are right earlobe, left

' Received for publication on 10 July 2000. Ac-cepted for publication in revised form on 30 August2000.

1. N. Shaw, M.B.B.S., M.D., Specialist, Depart-ment of Community Health; G. Ebenezer, M.B.B.S.,M.D., Head, Department of Histopathology and Ex-perimental Pathology; G. S. Rao, M.B.B.S., M.D.,D.N.B., Head; M. M. Natrajan, M.B.B.S., D.H.E.,Specialist; B. Balasundaram, M.B.B.S., Medical Offi-cer, Department of Community Health, SchieffelinLeprosy Research and Training Center, Karigiri, Vel-lore District, Tamil Nadu, South India 632 106.

forehead, right chin and left buttock or leftthigh) showed a bacterial index (BI) of3.5+, and a skin biopsy from a patch on hisback was consistent with lepromatous lep-rosy.

He was treated with dapsone monother-apy for 14 years. His BI decreased gradu-ally, and he became skin-smear negative in5 years. Treatment with dapsone was con-tinued. In June 1982, during the 14th yearof dapsone monotherapy, after remainingskin-smear negative for 9 years, he againbecame skin-smear positive with a mean BIof 0.75+. However, clinically he was stillinactive. He was lepromin negative. He re-ceived conventional MDT (WHO/MDT)consisting of monthly supervised pulses of600 mg rifampin and 300 mg clofaziminealong with a daily unsupervised dosage of50 mg clofazimine and 100 mg dapsone.After 2 years, he was released from treat-ment (RFT). At the time of RFT he wasclinically inactive and his skin smears fromthe routine sites were negative for acid-fastbacilli (AFB). He was followed up at leastonce a year after RFT when clinical andbacteriological assessments were done.Eleven years after RFT he was lost for fol-low up.

He presented again in August of 1998,15 years after completion of MDT, withnontender, firm, shiny nodules on thecheeks, each about 1.5 x 1.5 cm. The BIfrom one of the nodules on the left cheekwas 5+; his overall BI was 1.25+. A biopsyof a nodule showed features of nodular lep-romatous leprosy with histoid areas (Figs.1, 2, 3). On mouse foot pad inoculation thebacilli were found to be fully resistant todapsone and to the lowest concentration ofclofazimine (0.0001%) (The Table).

He was re-started on WHO/MDT, andhis nodules regressed and disappeared after

272

68, 3^Shaw, et al.: Histoid Relapse After MDT^

273

THE TABLE.^Result of mouse foot pad inoe-ulation in Case No. I.

DrugConcentration Result

in diet^Resistant" Sensitive

DDS 0.01%0.001%

0.0001%Clofazimine 0.01% +

0.001%0.0001%

Rifampin 0.03%0.003%

" Resistance at a given concentration: Ten-fold in-crease of AFB in the harvest count above inoculumcount per foot pad of test mice when control miceshow 50-fold increase.

8 months of therapy. After 1 year of MDThe was clinically inactive. His skin smearsfrom the routine sites were negative forAFB, although a selective skin smear fromthe left cheek was positive with a BI of 2+.His initial BI at this site was 5+.

Case No. 2. A 16-year-old male pre-sented in March 1977 with multiple, ill-de-fined, asymmetrically distributed anestheticpatches and nerve thickening. A skin-smearexamination showed a BI of 2+. He wasclinically diagnosed as a case of borderlinelepromatous (BL) leprosy and was startedon dapsone monotherapy which he receivedirregularly for a period of 1 year, afterwhich he discontinued treatment;

Six years later, in February 1984, he pre-sented with thickening of the earlobes,supraciliary madarosis, diffuse infiltrationof the skin ali over the body, glove-and-stocking anesthesia, a few nodules on thebuttocks, and an arca with patchy loss ofsensation on the right thigh. Both ulnar andboth radial cutaneous nerves were thick-ened. Skin smears from routine sitesshowed a mean BI of 3.75+. He was lep-romin negative and the skin biopsy donefrom a nodule on bis right buttock was con-sistent with borderline lepromatous leprosy.

He received MDT consisting of monthlysupervised doses of 600 mg rifampin, 300mg clofazimine on two consecutive days,bimonthly injections of 225 mg of acedap-sone, and a daily unsupervised dose of 100mg dapsone. After 2 years he was releasedfrom treatment (RFT), at which time his BI

FIG. 1. Photomicrograph showing epidermal atro-phy. The dermis is replaced by macrophages arrangedin a nodular pattern (H&E x40).

was 3.25+. He was followed up every yearat which time a clinicai examination wasdone and skin smears from routine siteswere taken. His skin smears gradually be-carne negative 5 years after RFT.

Twelve years after RFT, in October1998, he presented with multiple, tirm,shiny, asymptomatic nodules on the backand abdomen. A skin smear from one of thenodules showed a BI of 6+; his mean BIwas 4+. A biopsy from a nodule on the ab-domen was reported as nodular leproma-tous leprosy with histoid arcas.

Although the mouse foot pad studyshowed viable bacilli in T900r mice, thedrug sensitivity tests were inconclusivesince both the drug group and the controlgroup of the normal CBA mice did notshow multiplication of AFB.

He was started on WHO/MDT. At the endof 1 year of treatment the nodules showed re-gression and bis BI carne down to 3.75+.

274^ International Journal of Leprosy^ 2000

Fio. 2. Photomicrograph showing spindle-shapedmacrophages arranged in a whorl (H&E x200).

Case No. 3. A 42-year-old female wasseen in 1973 with diffuse skin infiltrationali over the body and bilateral thickening ofthe ulnar nerves. Her skin smears from theroutine sites showed a mean BI of 3.5+. Shewas diagnosed as lepromatous leprosy andstarted on dapsone monotherapy. After 5years of treatment with dapsone her skinsmears were negative for AFB. She wascontinued on dapsone monotherapy, whichshe had for a total period of 9 years. In July1982 she was included in the THELEP-sponsored field trials of MDT. At the timeof induction into the trial she was clinicallyinactive, her skin smears were negative forAFB, and she was lepromin negative. Shereceived MDT consisting of monthly super-vised doses of 600 mg rifampin and 600 mgclofazimine on two consecutive days amonth, bimonthly injections of 225 mgacedapsone, and a daily dosage of 100 mgof dapsone unsupervised. After 2 years shewas released from treatment. During theyearly follow up she was clinically inactive

FIG. 3. Photomicrograph showing clumps ofacid-fast bacilli within the macrophages (modifiedFite-Faraco stain x1000).

and her skin smears from routine sites werenegative for AFB.

Fourteen years after completion of MDT,in November 1998, she reported with mui-tiple firm, shiny, nontender nodules ingroups on her upper limbs and back. Hermean BI was 3.25+. A biopsy from a noduleon the right arm was consistent with nodu-lar lepromatous leprosy with histoid arcas.

Although the mouse foot pad studyshowed viable bacilli in T900r mice, thedrug susceptible tests were inconclusivesince both the drug group and the controlgroup of the normal CBA mice did notshow multiplication of AFB.

She was started on WHO/MDT, but washighly irregular in treatment. One year afterstarting treatment she had received onlyfive pulses of MDT. At the end of 1 year thenodules were still present and she was clin-ically active, although her mean BI hadfallen to 2.83+.

68, 3^Shaw, et al.: Histoid Relapse After MDT^275

DISCUSSION

Histoid leprosy occurs in lepromatousleprosy patients who relapse after receivingtreatment with dapsone monotherapy formany years (1. 5. 13). In 1982 the WorldHealth Organization (WHO) introducedmultidrug therapy (WHO/MDT), consistingof dapsone, rifampin and clofazimine forthe treatment of MB leprosy patients (7).MDT has shortened the duration of treat-ment, brought down the prevalence of lep-rosy drastically, and has a very low relapserate (<1%) (14).

Our patients received adequate doses ofMDT containing dapsone, clofazimine andrifampin for a period of 2 years. They wererepeatedly found to be clinically inactiveand their skin smears were negative duringthe yearly follow up. Twelve to 15 years af-ter completion of treatment with MDT theyrelapsed as histoid leprosy. We report thesecases because they relapsed as histoid lep-rosy after taking MDT consisting of dap-sone, rifampin and clofazimine for 2 years.Relapse as histoid leprosy, which was seenin the dapsone monotherapy era, was not re-ported in post-MDT relapses until recently.To the best of our knowledge only one caseof leprosy relapsing as histoid after receiv-ing MDT has been reported so far (3).

Two THELEP-supported field trials havebeen conducted at SLR&TC, Karigiri. Inthe first trial, 1067 BI and LL patients wereinducted between December 1981 and De-cember 1982 and were treated with WHO-recommended MDT regimens for a mini-mum period of 2 years or until skin-smearnegativity, whichever occurred later. No re-lapse was observed in any patient until theend of July 1995 after a total duration offollow up of 8244 person-years after RFT(4). Most of the patients had had long-termdapsone monotherapy prior to inclusion inthe trial. Only 44 were newly detected andhad had no previous therapy for leprosy. Ofthese 44 patients, 34 (3 had died and 7 hadmigrated) could be re-evaluated 17 yearsafter induction into the trial. No relapse wasseen by the end of December 1999 after amean duration of follow up of 13.7 -± 1.38years and a total duration of follow up of 466person-years (submitted for publication).

In the second trial, 360 newly diagnosedand previously untreated BL and LL pa-

tients were included from 1984 to 1994 andwere treated with the same regimens for afixed duration of 2 years (FDT). Until theend of July 1995, after a total duration offollow up of 886 person-years after RFT, norelapse was seen in this trial also (I2). In thistrial, 65 patients had a mean BI of 3+ ormore, of which 57 had successfully com-pleted the treatment. Of these 57 patients,46 with a mean BI of 3.79 ± 0.55+ were re-evaluated (5 had died and 6 had migrated).By the end of March 2000 after a total du-ration of follow up of 424 person-years anda mean duration of follow up of 9.3 ± 2.98years, only one relapse was seen, giving arate of 2.17% ora risk of 0.23 per 100 per-son-years in patients with a BI of 3+ (sub-mitted for publication).

Relapse in our patients could have beencaused by persisters or re-infection with ex-ogenous Myeobacterium leprae. Persistersare bacilli that adapt to adverse conditionsin their environment by reducing their me-tabolism to a minimum. They are capableof surviving in their host despite adequatechemotherapy. They may remain in thisdormant state for some time; a proportionof them may die, but some bacilli may re-gain normal metabolism and start multiply-ing, causing relapse. The duration of thisdormant stage is not known; it may be afew months to a few years (").

In leprosy, more so in BL and LL pa-tients, there is impaired host cellular im-mune response to M. leprae (W); a treatedcase of leprosy remains susceptible to re-in-fection with exogenous M. leprae afterRFT. The risk is more prominent in arcaswhere leprosy is endemic.

Since our patients, treated cases of BLand LL leprosy belonging to a leprosy-en-demic arca, relapsed 12 to 15 years afterRFT, the exact cause of relapse—persistersor re-infection with dapsone-resistantbacilli—could be anybody's guess.

SUMMARYThe histoid type of leprosy has been de-

scribed as occurring in lepromatous leprosypatients who relapse after many years of ap-parently successful dapsone monotherapy.

Three patients who had received theWorld Health Organization-recommendedregimens of multidrug therapy (WHO/MDT) relapsed as histoid leprosy 12-15

276^International Journal of Leprosy^ 2000

years after completion of treatment. In onepatient, through mouse foot pad studies, thebacilli were found to be sensitive to ri-fampin and clofazimine and resistant todapsone. In the other two patients mousefoot pad studies were inconclusive.

The patients were re-started on WHO/MDT. Two patients took regular treatmentand improved, both clinically and bacterio-logically. One patient was irregular in treat-ment, and 1 year after re-starting WHO/MDT nodules were still present althoughthe bacterial index had fallen slightly.

RESUMENEl tipo histoide de la lepra se ha descrito en pa-

cientes lepromatosos que muestran recaída después demuchos atios de tratamiento aparentemente exitosocon dapsona. Tres pacientes que habían recibido lapoliquimioterapia recomendada por la OrganizaciónMundial de la Salud (PQT/OMS) recayeron con leprahistoide 12 a 15 afios después de completar eltratamiento. En un paciente, los bacilos fueron sensi-bles a la rifampina y clofazimina, y resistentes a ladapsona en el modelo de la almohadilla plantar deiratón. En los otros dos pacientes los resultados nofueron concluyentes.

Los pacientes fueron vueltos a tratar con la PQT/OMS. Dos pacientes tomaron el tratamiento de maneraregular y mejoraron clínica- y bacteriológicamente. Unpaciente fue irregular en su tratamiento y un afio des-pués de reiniciar cl tratamiento con PQT/QMS todaviapresentaba nódulos, aunque el índice bacteriano habíadisminuido ligeramente.

RÉSUMÉLa lèpre de type histoïde a été originellement

décrite chez des patients souffrant originellement delèpre lépromateuse qui ont rechuté après plusieurs an-nées de rémission suivant une mono thérapie à la dap-sone. Trois patients qui avaient reçu un traitement depoly chimiothérapie recommandée par l'organisationmondiale de la santé (OMS/PCT) ont rechuté sousforme d' une lèpre histoïde 12 à 15 années après ia fim dutraitement. Chez un patient, à l'aide d'études d'inocu-lation à la plante des pattes de souris, les bacilles furentdémontrés être sensibles à la rifampicine, la clofazimineet résistantes à la dapsone. Chez les autres patients, lesétudes d'inoculation aux plantes des pattes de souris sesont révélées non concluantes. Un traitement OMS/PCT fur ré-institué chez ces patients. Deux patients quiprirent régulièrement leur traitement s' améliorèrent à

la fois cliniquement et bactériologiquement. Un pa-tient fit un traitement irrégulier et un an après la reprisedu traitement, des modules étaient encore présents avecun indice bactérioscopique légèrement

Acknowledgment. We are thankful to ProfessorCharles K. Job, Consultant Pathologist, St. ThomasHospital and Leprosy Center, Chettupattu; Dr. P. S. S.Sundar Rao, Director, SLR&TC, Karigiri and Dr. S.Arunthathi, Head, Department of Medicine, SLR8zTC,Karigiri, for their encouragement and guidance.

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