Volume 65, Number 3Printed in the (ISA.

(ISSN 0148-916X)

INTERNATIONAL JOURNAL 01 LEPROSY

INTERNATIONAL JOURNAL OF LEPROSYand Other Mycobacterial Diseases

OFFICIAL ORGAN OF THE INTERNATIONAL LEPROSY ASSOCIATION

EDITORIAL OFFICE

Gillis W. Long Hansen's Disease Centeraí Louisiana State University

Baton Rouge, Louisiana 70894, U.S.A.

VOLUME 65, NUMBER 3^

SEPTEMBER 1 997

CLINICAL NOTES

lo ao effOrt to increase the utility of the JOURNAL in continuing medicai education, in finssection ice welcome contributions dealing with procurai problems lo leprosy work. ,S'ulonissionsto this section will undergo minimal editorial ehanges and may well contain controversial points.Letters to the Editor pointing out other viewpoints are welcome.

Disseminated Intravascular Coagulopathy as anAdverse Reaction to Intermittent Rifampin

Schedule in the Treatment of Leprosy

Rifampin has proved to be effective forthe treatment of leprosy,' and multicenterclinicai studies2,3 have demonstrated its ef-ficacy when administered in intermittent ordaily doses. Thus, rifampin has been in-dicated for treatment in monthly dosesas part of the multiple drug therapy pro-gram of leprosy control proposed by theWorld Health Organization (WHO/MDT)

' Rees, R. J. W., Pearson, J.M.H. and Waters, M. F.R. Experimental and clinicai studies on rifampicin intreaunent of leprosy. Br. Med. J. 1 ( 1970) 89-92.

= Oppromolla, D. V., Tonello, C. J. S., McDougall,A. C. and Yawalkar, S. J. A controlled trial to com-pare the therapeutic effects of dapsone in combinationwith daily or once-monthly rifampicin in patients withlepromatous leprosy. Int. J. Lepr. 49 (1981) 393-397.

' Languillon, J., Yawalkar, S. J. and McDougall, A.C. Therapeutic effects of adeling RimactaneO (ri-fampin) 450 milligrams daily or 1200 milligrams oncemonthly in a single dose to dapsone 50 tnilligramsdaily in patients with lepromatous leprosy. Int. J. Lepr.47 (1979) 37-43.

in 1981,4 which consists of the following dif-ferent regimens: 100 mg dapsone self-admin-istered daily and 600 mg of monthly super-vised rifampin for 6 months for paucibacil-lary (PB) patients, and 100 mg dapsone and50 mg clofazimine self-administered dailyand 600 mg of monthly supervise(' ri fampinin combination \vith 300 mg clofamizine for24 months for multibacillary (MB) patients.

Remas of peculiar adverse reactions to ri-fampin have been published since the late1960s when the drug was administered inter-mittently in an attempt to treat tuberculosis.5-7

WHO Study Group. Chemotherapy of leprosy forcontrol programmes. Geneva: World Health Organiza-tion, 1982. Tech. Rep. Ser. 675.

Poole, G., Stradling, P. and Worlledge, S. Poten-Uai!), serious side effects of high-dose twice-weekly ri-fampicin. Br. Med. J. 3(197!) 343-347.

' Worlledge, S. The detection of rifampicin-depen-dent antibodies. Scand. J. Respir. Dis. Suppl. 84 ( 1973)60-63.

' Mattson, K. Side effects of rifampicin—a clinicaistudy. Scand. J. Respir. Dis. Suppl. 82 (1973) 1-52.

366

65, 3^ Chiiical Notes^ 367

Ti IP TABU:. .S'equential laboratorv tesis obtained at the time of. admission and after theuse aí superrised rij aram)! dos(lge.

Time (lir) atter admission/MBIC 0/7 10/17 12/19 22/29

1 lemoelobin (dd 1 ) 8.1 8.7 6.4 5.81 lemaiocrit 18% 14% 16% 13%C4rculatim2. erythroblasts 56%

(x 1 ()'/u1) 17.3 8.9Platelets (xl()Vpl ) 146 166 152PT (INIZ) >11.9vrr (sec.) >120Fibrino2en (nigidl) ()

total/direct (ing/d1) 12.6/4.8SGOT (U/1) 250 910SGPT (U/1) 610C'reatinine mg/d1 1.0 2.1 2.4tlrea ing/d1 95 98

Reference values

12-1638-50%

5.0-10.0130-400up to 1.311200-4000.2-1.2/0.0-0.3up to 21up to 240.6-1.6up to 40

'MOR: time (hr) atter supervised oral drug intake (multibacillary regimen—W110).Control time = 31.6 sec.Denotes :ibsence.

The adverse reactions observed with dailyor intermittent doses were skin rashes(<5%), zastro-intestinal disorders (vari-able), hepatitis (<1%), and rarely purpura.Reactions observed only after intermittentadministration were a Ilu-like syndromeand rare, potentially serious, effects requir-ing immediate discontinuation of treatmentand admission of patients for immediatetreatment such as shock, respiratory disor-ders (shortness of breath), hematologic al-terations (hemolysis and thrombocytopenia),renal insulticiency, and pancreatitis.7.' Con-siderine the efficacy and cost of rifampinand its possible toxic effects observed afterits intermittent use, but not in clinicai stud-ies using the drug for the treatment of lep-rosy,'• the WHO recommended a pro-gram of leprosy control using monthlydoses of rifampin under supervised admin-istration in order to facilitate the detectionof possible adverse effects.

Since the end of the 1970s, the NationalDivision for Sanitary Dermatology and theMinistry of Health (NDSD/MH) of Brazilhave indicated the association of rifampin,600 mg/day for 3 months, and dapsone, 100mg/day, with curative objectives for border-line and lepromatous leprosy patients, whilePB patients should receive only a 2-year

Girling, 1). J. and llitze, K. II. Adverse reactionsto rifampicin. Bull. W110 57 (1979) 45-49.

"12ees, R. J. W. Rifampicin: the investigation of abactericidal antileprosy drug. Lepr. Rev. Suppl. 46(1975) 121-124.

course of daily dapsone.'" However, in 1991the WHO/MDT was officially adopted inBrazil for ali new cases and also for thosewho had not completed 5 years of treatmentor who had clinicai signs of active disease,or with a positive bacilloscopy.")

We report here the occurrence of dissem-inated intravascular coaeulation (DIC) andhemorrhagic liver necrosis due to themonthly use of rifampin at the recom-mended dose for leprosy treatment (600mg). A 46-year-old female patient with lep-romatous leprosy, with a 3.0 bacterial index(BI), presented with multiple nodules onthe alae nasi, earlobes, upper limbs includ-ing the hands, lower limbs and trunk, to-gether with madarosis, erythema and infil-tration of the face and of extensive arcas ofLhe tegument. The patient was treated withsulfone (100 mg/day) for 6 years, in combi-nation with rifampin (600 mg/day) for thefirst 3 months of treatment, accordine to theNDSD/MH regimen, and showed goodprogress, disinfiltration of the involved ar-cas, flattening of the lesions and a reductionof the BI without relevant adverse effects.She then began a multiple drug therapy reg-imen for MB patients (WHO/MDT) andtolerated well the first two superviseddoses, with no explicit complaints. How-

Brasil Ministério da Saúde. Fundação Nacionalde Saúde. Normas técnicas e procedimentos pare uti-lização dos esquemas de poliquimioterapia no trata-mento da hanseníase. Brasilia: Ministério da Saúde,1990.

368^ /men/afio/ia/ Journ(1/^/.epros.N.^ 1997

ever, 1 In atter her third supervised dose suepresented with intense headache, pain in theprecordial, epiistric and 'milhar regionsassociated \vith heinatemesis and macro-scopic hematuria. lixamination upon ad-inission to the hospital revealed ali agitatedpatient with profuse sweating, paIlor. coldextreinities, tachycardia (120 bpin), and ar-terial hypertension (180/110 min Hg).Seven hours atter the beginning of thesesymptonis, the pain lessened and the arte-rial pressure and hem.' rate tended to stabi-lize (130/90 min llg and 92 bpin, respec-tively ). Jaundice was observe(' in additionto the initial clinicai signs and symptoms,and laboratory tests showed intense bilint-bineinia (mainly unconjugated bilirubin)and anemia, with normal renal function(The 'rabie). Digestive hemorrhage wasconlirmed and gastroseopy revealed multi-pie hemorrhagie sites, especially upon en-doscopic trauma. The paliem progressed inan unstable manner and 12 ltr after admis-sion her general conclition worsened, withmarked dehydration, moderate pailor, dys-pnea, evident jaundice, cyanosis of lips andextremities, tachycardia (120 bpin), eccity-moses of the upper limbs and spontaneousgingival and genital bleeding. Laboratorytests revealed a marked fali in hemoglobinlevei (Hb = 6.4 g/dl) and discrete creatinineand urea elevation. A clinicai dia,,:mosis ofdisseminated intravascular coagulation waslater contirmed by significam changes inprothrombin time (PT), activated partia'thromboplastin time (APTT), with a verylow tibrinogen levei (The Table). Therapeu-tic measures (fresh plasma, cryoprecipitate,heparin, corticotherapy) did not prevent theprogressive deterioration of the generalcondition and neurological impairment ofthe patient, v t h respiratory insulliciencyand cardiac arrest culininating in cleath 22hr after achnission to the hospital. The au-topsy report revealeci hemorrhagic hepaticnecrosis with histological features compati-ble with sensitization to the drug.

DISCUSSIONThe use of rifampin has been related to

hematoiogic alterations, the most frequentbeing hemolytie anemia, 4 -23 purpura asso-eiated or not with thromboeytopenia, andasymptomatie thrombocytopenia.' 12'Aeute hemolysis of discrete-to-massix'e in-

tensity has been reporte(' to oceur"--23 afterthe intermittent irregular use of rifampin oreven atter reintroduction ol rifampin foi-lowed by a period without daily administra-do') that may vary from a few days to sev-era! years.'" A few cases of disseminatedintravascular coagtdation relate(' to the useof rifampin have been documented.".Mattson' subdivided systemic reactions intolive symptom complexes: 1) flu-like syn-drome (tremors, feVCF, 11111SCIC pains,headache, malaise, and joint edema); 2) ab-dominal syndrome (abdominal pain, nau-sea, diarrhea and vomiting,); 3) cutaneoussyndrome (ilushing and itching with orwithout a cutaneous rash, especially on theface and neck ); 4) respiratory syndrome(dyspnea with bronchospasm); 5) hemato-logic syndrome (laboratory abnormalitiesof Moo(' components and clinicai correla-tion). Characteristically, the syndromes ini-tiate 2-4 hr after drug ingestion and mayoccur simultaneously or in sequence, with ali ti - li ke syndrome alone or in combinationwith other syndromes being the most fre-quent presentation. It tias beenstrated in clinicai assays that the flu-likesyndrome was associated with ali inereasein plasina-free hemoglobin, reticulocytes,and bilirubins and with a gradual decreasein blood hemoglobin and hematocrit.'" He-molysis associated with a flu-like syndromeis ais() supported by the increase in reticulo-cytes in sequential analyses, suggesting thatthis reaction may represent the first sign ofintravascular hemolysis, differing only inquantitative terms from more serious reac-dons, ' pointing out that the flu-like syn-drome shotdd be comi sidered potentiallyhazardous.

Adverse effects have been described withmonthly rifampin administration (600 ing)for the treatment of leprosy, including the

syndrome,24.2'." actue renal fali-shortness of breath and ur-

ficaria,'" intravascular hemolysis,2".31 throm-boeytopenia'2. -".1' and shoek.33

In the present case there was strong evi-dence of massive hemolysis progressing toD1C, as suggested by the clinicai data andconfirmed by altered laboratory tests (PT,APTT and low librinogen), temporally re-late(' to the use of a monthly dose of ri-fampin. Hepatic involvement might be dueto the massive immune hemolysis added to

65, 3^ Chnical Notes^ 369

aggression by the drug, leading to acutepairment of the hepatic production of coag-ulation proteins and worsening the ilumi-nem DIC. A direct relationship bctween in-termittent doses (some studies with hi!.,,hdoses) of rifampin and the increased fre-quency of peculiar side effects is frequentlydescribed.5.7.^"

" Wilawska-Orlowska, B. and Pniewski,^Haema-tological changes during intermittent treatment with ri-

Scand. J. Respir. Dis. Suppl. 84 (1973)94-97.

Nishioka, S. A., Goulart, 1. NI. B., Nunes-Araujo,F. R. F., Arames, S. C. F., Burgarelli, M. K. N., Fer-reira, M. S., Santos, R. R and Lopes, V. R. Severethrombocytopenia and intermittent use to rifampin. Int.J. Lepr. 60 (1992) 273-274.

" Stradling, P. Side effects observed during inter-minem rilampicin therapy. Scand. J. Respir. Dis.Suppl. 84 (1973) 129-131.

Lakshminarayan, S., Salm, S. A. and I ludson, L.D. Massive haemolysis causei! by rifampicin. Br.Med. J. 2(1973) 282-283.

Criei, A. and Verwilghen, R. L. Intravascularhaemolysis and renal failure causei! by intermittent ri-fampicin treatment. Blut 40 (1980) 147-150.

Manso!), K. and Janne, J. !Alie! intravasal haemol-ysis associated with tlu-syndrome during intermittentrifampicin treatment. Eur. J. Respir. Dis. 63 (1982)68-72.

Denis, J., Robert, A., Johanet, C., Flomberg, J. C.,Opolon, P. and Levy, V. G. Accident iint;)unoal-lergique à la rifampicine avec coagulation intravascu-laire disséminée. Presse Méd. 12 (1983) 1479-1481.

nitra!), S. R., Diamond, J. R., Blank, J. M. andHora!), R. F. Acute hemolysis and renal failure withrifampicin-dependent antibodies after discontinuousadministration. Transfusion 25 (1985) 124-127.

Assenfeld, A. II. W. Renal failure and haemolysiscaused by rifampicin. Tubercle 67 (1986) 234-235.

Papaiordanou, P. M. O., Branchini, M. L. M.,Gonçales Junir, F. I., Aoki, F. 1., Boccato, R. S. B. S.,Ramos, M. C. and Pedro, R. J. Efeito adverso do usointermitente de Rifampicina para tratamento daFlanseníase. Rev. Inst. Med. Trop. São Paulo 30 (1988)383-386.

Govoni, M., Moretti, M., Menini, C. and Hoochi,F. Rifampicin-induced immune hemolytic anemia:therapeutic relevance of plasma exchange. Vox59 (1990) 246-247.

" Pereira, A., Sanz, C., Cervantes, F. and Castillo,R. Immune hemolytic anemia and renal failure assoei-ated with rifampicin-dependent antibodies with anti-Ispecilicity. Ann. Ilematol. 63 (1991) 56-58.

lp, M., Cheng, K. P. and Cheung, W.C. Dissemi-nated intravascular coagulopathy associated with ri-fampicin. Tubercle 72 (1991) 291-293.

Vai., M., Jacob, A. J. and Rajendran, A. 'TI u''syndrome on once monthly rifampicin: a case report.Lepr. Rev. 60 (1989) 300-302.

" Dhar, S., Kaur, I., Sharma, V. K. and Kumar, B."Flu- syndrome due to rifampin; experience with f6urcases. Int. J. Lepr. 63 (1995) 92-94.

Opinions about the mechanisms causingthe adverse reactions attributed to rifampinare divergem, and it Iras been sm.:,..e.ested thatthe 'tatue of the systemic reaction is moreinumme than toxic." R is postulated that ri-fampin is a potentially immunogenic mole-cule because of its ability to participate inlipophilic reactions with circulating freeproteins (albumin, gamma-globulin, etc.) or

Kar, li. K. and Roy, R. G. Reversible acute renalfailure doe to monthly administration of rifampin in aleprosy panem. Incha!) J. Lepr. 56 (1984) 835-839.

" Declina, N. M., Almeida A. F., Khanna, U. B.,Mil, 0. V. and Acharya, V. M. Acute renal fitilure: acomplication of new multidrug regime)) for treatmentof leprosy. Int. J. Lepr. 54 (1986) 380-328.

" Cusumano, A., Cal de ntey, D., Marise, C., Rai-mondo, M. and lbarra, R. Renal cortical necrosis ascomplication of leprosy treatment. (Letter) Clin.Nephrol. 38 (1992): 172-173.

Gordan, P. A., Grion, C. M. C., Sousa, V., Car-valho, V. P., Deltino, V. I). A., Mendes, M. F., Matini,A. M. and NIocelini, A. J. Insuficiência renal agudapelo uso do esquema multidroga na hanseníase.Ilansenol. Int. 17 (1992) 21-26.

Gupta, C. NI. and Bhate, R. D. Shortness ofbreath with urticaria due to once monthly rifampicin.(Letter) Lepr. Rev. 58 (1987) 308-309.

Gupta, A., Sakhuja, V., Gupta, K. L. and Chugh,K. S. Intravascular hemolysis and acme renal fai lure161lowing intermittent rifampin therapy. Int. .1. Lepr. 60(1992) 185-188.

'1 Kakaiya, R. M., Dehertogh, D., Walker, F. J.,Cummings, E. and Uzdejczyk, M. Rifampin-inducedimmune thrombocytopenia; a case report. Vox Sang.57 (1989) 185-187.

" Ramachandran, A. and Bhatia, V. N. Rifampicininduced shock-a case report. Indian J. Lepr. 62(1990) 228-229.

Brasil, M. T. L. R. F., Opromolla, D. V. A., Mar-zliak, M. L. and Nogueira, W. Pesults of a surveil-lance system for adverse et fects in leprosy'sWHO/MDT. Int. J. Lepr. 64 (1996) 97-104.

Aquinas, S. M., AlIan, W. G. L.,11orsfall, I'. A. L.,Jenkins, P. K., llung-Yan, W., Girling, D., Tall, R. andFoa, W. Adverse reaction to daily and intermittentt'ampicin regimens for pulmonary tuberculosis in HongKonr. Br. Med. J. 1 (1972) 765-771.

Riska, N. and Manson. K. Adverse reactions dur-ing rifampicin treatment. Scand. J. Respir. Dis. 53(1'972) 87-96.

Rothwell, D. L. and Richmond, D. E. Ilepatore-nal failure with self-initiated intermittent rifitmpicintherapy. Br. Med. J. 2 (1974) 481-482.

's Manso!), K. and Riska, N. Effect of cortisone onsystemic reactions provoked by ri fampicin. Scand. J.Respir. Dis. 53 (1972) 97-100.

Dukor, R, Schumann, G. and Dietrich, F. M. 1m-munological studies with rifampicin. Scand. J. Respir.Dis. Suppl. 84 (1973) 73-82.

Pujet, J. C., Flomberg, J. C. and Decroix, G. Sen-sitivity to rifampicin: incidence, mechanism and pre-vendo!). 13r. Med. J. 2 (1974) 415-418.

370^ International lourna1 of Leprosy^ 1997

with proteins associated with the cell mem-brane, resulting in an antigen-carrier com-lex with potential immunogenicity." The

formation of immune complexes from pro-tein-bound rifampin, plus anti-rifampin an-tibodies and complement activation, maytrigger the clinicai syndrome. In a stucly oíthe affinity of the drug for red blood cens,Dukor, et 01.3" detected rifampin bound to thecell inembrane. However, it lias also beenproposed that red blood cells and plateletsmay be simply "innocent bystanders- due toLhe nonspecific interactions of rifampin withblood cells.22.39Anti-rifampin antibodies canbe detecte(' in patients using rifampin and aremore frequently related to adverse reac-tions»(( 17, 21, 22, 40 suggesting the potentialrole of the antigen-antibody complex, al-though these complexes have not beendemonstrated in ali patients.5.''' '3 Interpreta-tion of the data is difficult because of the vari-able results obtained by the different tech-fiques for antibocly detection and, perhapsmore importantly, because there is demon-strated nonspecific interaction of rifampinwith gamma- giohulin,3 autom.!, other serumproteins, a fact that may simulate specificity.

In the case reported here the hemolyticreaction that developed from antibody for-mation was strongly suggested by the posi-tivity of the direct antiglobulin test'assoei-ated with a progressive fali in hemoglobinleveis and the more pronounced increase inunconjugated bilirubin. Intermittent adminis-tration of certain antigens is particularly ap-propriate for the induction of antibodies. In-deed, sensitization may occur more frequentlyin patients receiving rifampin intermittentlyor irregularly rather than at daily doses. Thepresent data suggest that sensitization oc-curred during the inalai exposure to ri-fitmpin in the first therapeutic regimen ad-ministered to the patient and that re-expo-sure to an intermittent rifampin scheduletriggered the fatal outcome.

In the case reported here the patient wastreated with dapsone in combination withrifampin for 3 months and dapsone alonefor 6 years, with no adverse effects, a factsuggesting that dapsone as part of the WHO/MDT for MB patients was not causally re-lata, to the adverse outcome. Furthermore,we identitied similar cases of DIC in the lit-

erature'' which involved patients usimY, atherapeutic schedule for tuberculosis.temporal association of severe side effectswith rifampin use was then unequivocal.7.'Also, early diagnosis of the systemic ad-verse reaction resulting in rapid interruptionof ri fampin reduces the severity of the ad-verse effects, permitting the safe continua-tion of treatment with dapsone and clolaz-imine in combination with a rifampin sub-stitute.31

The suspected occurrence of adverse re-actions, including death, related to the im-plementado') of WHO/MDT in the state ofSão Paulo, Brazil, has led to the organiza-tion of a surveillance approach, and the col-lected data have been reported by Brasil, et01." Adverse effects were evaluated in20,667 patients treated with WHO/MDTfrom 1991 to 1993. Of these, 7020 caseswere newly diagnosed and 13,647 had re-ceived previous treatment. There were 127notitications of adverse effects subdividedas follows: a) !lu-like syndrome (54 cases),h) acute renal fai lure (20 cases), c) throm-bocytopenic purpura (2 cases), and d) dis-seminated intravascular coagailation (pres-ent case). Adverse effects were 7.3/1000for MB patients treated with WHO/MDTafter beimg previously treated with daily ri-fampin for 3 months as in the national pro-gram (NDSD/MH). These patients weremore severely involved, with 73.3% havinga flu-like syndrome or acute renal failure.

The WHO/MDT is the best therapeuticoption available at present for the treatmentof leprosy and has had an unequivocal im-pact on the reduction of its prevalence withthe ability to provide a cure. However, itshould be pointed out that patients receiv-ing intermittent treatment with rifampin forLhe control of leprosy need appropriate su-pervision, as recommended by the WHO.4Although adverse reactions are rare, healthprofessionals should be prepared to antici-pate them. Patients submitted to continuouslong-lasting treatment who re-initiate theuse of rifampin after previous exposure areconsidered to be at risk for adverse effects.Thus, any systemic symptom should be analert for the appropriate investigation andevaluation of the discontinuation of ri-fampin.

65, 3^ Clinica/ Notes^ 371

—Caeilda S. Souza, M.D.Assistant ProfessorDirisioil of. Dermatology

Fernando L. Alberto, M.D.Senior ResidemDirision of. Ilematology

—Norma T. Foss, M.D., Ph.D.Associate Proli'ssm-Division DermatologyDepartment of. Infernal MedicineSchool of. Medicine of. Ribeira() PretoUniversitv Of Sao Paulo14049-900 Ribeirao Preto, SP, Brazil