DAVAO MEDICAL SCHOOL FOUNDATION, INC.

College of Medicine
Department of Community Medicine

Jamiana, Nikita Marie G.

Jardinel, Genevieve Anne L.
Julao, Fritz Adrian C.
Julhan, Fatima Dhiena D.
Jumilla, Jed Espiridon II
Jurilla, Joanna Ruth R.
Kho, Nicole Alexandra P.
Labang, Sean Clarke P.
Labradores, Anjola Gerchily
Lacar, Zandralyn T.
Lagmay, Paul Angelo A.
Laguialam, Fatma L.

MEDICINE 4

December 17-30, 2019

 Leprosy, first described in ancient Indian texts from the sixth century b.c., is a nonfatal,

chronic infectious disease caused by Mycobacterium leprae, the clinical manifestations of which

are largely confined to the skin, peripheral nervous system, upper respiratory tract, eyes, and testes.

The unique tropism of M. leprae for peripheral nerves (from large nerve trunks to microscopic

dermal nerves) and certain immunologically mediated reactional states are the major causes of

morbidity in leprosy. The propensity of the disease, when untreated, to result in characteristic

deformities and the recognition in most cultures that the disease is communicable from person to

person have resulted historically in a profound social stigma. Today, with early diagnosis and the

institution of appropriate and effective antimicrobial therapy, patients can lead productive lives in

the community, and deformities and other visible manifestations can largely be prevented.

Established agents used to treat leprosy include dapsone (50–100 mg/d), clofazimine (50–

100 mg/d, 100 mg three times weekly, or 300 mg monthly), and rifampin (600 mg daily or

monthly; see “Choice of Regimens,” below). Of these drugs, only rifampin is bactericidal. The

sulfones (folate antagonists), the foremost of which is dapsone, were the first antimicrobial agents

found to be effective for the treatment of leprosy and are still the mainstays of therapy. With

sulfone treatment, skin lesions resolve and numbers of viable bacilli in the skin are reduced.

Although primarily bacteriostatic, dapsone monotherapy results in a resistance-related relapse rate

of only 2.5%; after ≥18 years of therapy and subsequent discontinuation, only another 10% of

patients relapse, developing new, usually asymptomatic, shiny, “histoid” nodules. Dapsone is

generally safe and inexpensive. Individuals with glucose-6-phosphate dehydrogenase deficiency

who are treated with dapsone may develop severe hemolysis; those without this deficiency also

have reduced red cell survival and a hemoglobin decrease averaging 1 g/dL. Dapsone’s usefulness

is limited occasionally by allergic dermatitis and rarely by the sulfone syndrome (including high

fever, anemia, exfoliative dermatitis, and a mononucleosis-type blood picture). It must be

remembered that rifampin induces microsomal enzymes, necessitating increased doses of

medications such as glucocorticoids and oral birth control regimens. Clofazimine is often

cosmetically unacceptable to light-skinned leprosy patients because it causes a red-black skin

discoloration that accumulates, particularly in lesional areas, and makes the patient’s diagnosis

obvious to members of the community.

Other antimicrobial agents active against M. leprae in animal models and at the usual daily

doses used in clinical trials include ethionamide/prothionamide; the aminoglycosides

streptomycin, kanamycin, and amikacin (but not gentamicin or tobramycin); minocycline;

clarithromycin; and several fluoroquinolones, particularly ofloxacin. Next to rifampin,

minocycline, clarithromycin, and ofloxacin appear to be most bactericidal for M. leprae, but these

drugs have not been used extensively in leprosy control programs. Most recently, rifapentine and

moxifloxacin have been found to be especially potent against M. leprae in mice. In a clinical trial

in lepromatous leprosy, moxifloxacin was profoundly bactericidal, matched in potency only by

rifampin.
Adverse effects from Multi-drug therapy in leprosy: a Brazilian study

PATRICIA D. DEPS*, SOFIA NASSER*,

PATRICIA GUERRA*, MARISA SIMON*, RITA DE CA ́ SSIA BIRSHNER** & LAURA C.
RODRIGUES*** *Federal University of Esp ́ırito Santo
**Leprosy Control Programme, Health Unit of Maru ́ıpe ***London School of Hygiene &
Tropical Medicine

Accepted for publication 13 July 2007

In 1981, The World Health Organization (WHO) recommended the use of multi-drug
therapy (MDT) against leprosy, using dapsone, rifampicin and clofazimine. The introduction of
this regimen aimed to control primary and secondary resistance to drug monotherapy, to prevent
further resistance of Mycobacterium leprae developing to other antibiotics and to prevent relapses.
MDT introduction came with additional benefits such as an intense monitoring of patients,
coverage of affected populations, improvement of the closeness between leprosy patients and
medical care, and that leprosy changed into a curable disease.

Among those three drugs, rifampicin is the most important anti-leprosy drug and is
included in regimens for both paucibacillary (PB) and multibacillary (MB) patients. Although,
WHO has stated that no toxic effects have been reported in monthly administration, many authors
have reported rifampicin as the cause of cutaneous eruptions, thrombocytopenic purpura, hepatitis,
a flu-like syndrome, hemolytic anemia, shock, respiratory insufficiency and acute renal failure.

Clofazimine is most active when administered daily; it is well tolerated and virtually non-
toxic in the usual dosage.

Dapsone is very safe in the dosage used in MDT and according to WHO, side-effects are
rare. The main side-effect is skin allergic reaction, however hemolytic anemia,
methemoglobinemia, jaundice, agranulocytosis, psychotic reactions and ‘dapsone syndrome’ have
also been reported.

MDT introduction met with considerable resistance in Brazil because of a significant risk
of side-effects. Despite this, in 1991, MDT was adopted as the sole treatment for leprosy patients
in Brazil.
 Fixed-duration treatment was adopted and smear examination was no longer a requirement
for declaring patients cured. In 1997, the WHO Expert Committee stated that ‘it is possible that
duration of the current MDT regimen for MB leprosy could be further shortened to 12 months
without increasing the risk of developing rifampicin resistance’, the Brazilian Ministry of Health
followed this recommendation 3 years later.

A wide range of frequency of side-effects caused by MDT has been reported from Brazil.
In a recent publication, Goulart et al.i n Minas Gerais, reported that 37·9% of patients taking MDT
had side-effects, and 39·4% of them received an alternative regimen. However, elsewhere in Brazil
the published frequencies of side-effects attributed to MDT were 0·61% and 0·63%, and in both
reports most patients had received alternative regimens, so removing the drugs suspected of
causing undesirable reactions.

WHO has noted that the frequency of adverse reactions caused by MDT is very low, and
when such reactions occur, the standard regimen should simply be adjusted, so that treatment can
continue. Treatment of leprosy with only one anti-leprosy drug may result in development of
resistance to that drug; and treatment with dapsone or any other anti-leprosy drug used as
monotherapy should be considered unethical. In addition, it would be considerably more hazardous
to use the compounds separately.

Stopping of MDT is not routinely reported by the LCP Reports and depends on the
judgment of the LCP team. Usually in Brazil, leprosy patients are removed from the leprosy
register system only when they are cured or abandon treatment.

In 2005 in Brazil 38,410 new leprosy cases were diagnosed and the prevalence rate in 2006
was 1·5/10,000 inhabitants.

This paper reports side-effects attributed to MDT, the frequency and stoppage of the MDT
components in a Health Unit in Vito ́ria, Brazil.
DAPSONE-INDUCED AGRANULOCYTOSIS IN PATIENTS WITH HANSEN'S
DISEASE 2017 NOV-DEC

Tania Rita Moreno de Oliveira Fernandes, Bruno Nascimento de Jesus, Tathyane Trajano
Barreto, and Anderson de Almeida Pereira

Agranulocytosis induced by sulphonamide or dapsone (44-diaminodiphenylsulphone -

DDS) is characterized by a low concentration or absence of granulocytes due to sulfone
cytotoxicity effects on bone marrow and mononuclear cells.

DDS is a structural analogue of para-aminobenzoic acid (PABA) that acts as a competitive

inhibitor of the enzyme dihydropteroate synthase in the folate pathway. It has anti-inflammatory,
antibacterial, antiprotozoal, and antifungal activities. Used since 1943 to treat leprosy, it is also
indicated for the treatment of malaria, rheumatoid arthritis, granuloma annulare, dermatitis
herpetiformis, and other vesiculobullous diseases. DDS adverse effects include hemolytic anemia,
methemoglobinemia, gastritis, headache, agranulocytosis, hepatitis, peripheral neuropathy,
nephrotic syndrome, dapsone syndrome, among others.

DDS is part of the multidrug therapy (MDT) used to treat leprosy. The regimen is a
combination of rifampicin (supervised monthly dose of 600mg) and dapsone (supervised monthly
dose of 100mg and 100mg/daily) for paucibacillary patients, with the addition of clofazimine
(supervised monthly dose of 300mg and 50mg/ daily) for multibacillar patients.

We report a 61-year-old Caucasian female patient, resident in Juazeiro, state of Bahia,

Brazil, complaining of a spot on the right elbow, which appeared 1 year before. Physical
examination revealed a single hypochromic patch, approximately 1cm in diameter, with
micropapular edges and absent thermal sensitivity. With a diagnosis of tuberculoid leprosy, we
started a MDT regimen for paucibacillary leprosy. At day 14 after the first administration, the
patient presented with adynamia, exertional dyspnea, normochromic normocytic anemia with
anisocytosis, and normal white blood cell (WBC) count. At day 34, she presented with fever, chills,
adynamia, oropharyngeal pain, and cutaneous pallor associated with leukopenia with severe
neutropenia. We suspended the MDT and, advised by a hematologist, introduced amoxicillin
clavulanate, ciprofloxacin, and filgrastim (rHu G-CSF) 300 µg/daily for 5 days.

Serial blood test collection revealed a typical clinical presentation of agranulocytosis.

 After 8 days, the patient showed clinical and laboratorial improvement. Test levels
remained normal during 1-month follow-up when we reintroduced the MDT substituting DDS by
clofazimine. The patient completed 6 months of MDT.

Agranulocytosis is a rare but serious complication of sulfones caused by the myelotoxic

effect of these drugs. An occurrence of 0.2-0.4% has been described in patients treated with
dapsone. Although reversible, this infection can lead to sepsis and even death.

Agranulocytosis is an adverse effect of dapsone manifested as bone marrow suppression,

which is caused by the formation of antibodies against neutrophil progenitor cells, decreasing the
granulocyte formation. Another possible mechanism is the sensitization to the drug that forms
hydroxylamine, a toxic metabolite of dapsone responsible for methemoglobinemia and hemolysis.

For the treatment of leprosy, the risk of developing DDS-induced agranulocytosis is about
25-33 times higher because of reduced immunity and high dosage of the drug, as compared, for
example to the treatment of malaria with an incidence between 1:10,000 and 1: 20,000 is reported.

According to Silva et al. (2009), Mishra and Chhetia (2006), Bhat and Radhakrishnan
(2003),4 Carneiro et al. (2011), and our case, the patients presented with abrupt symptoms
associated with fever, oropharyngeal pain, chills, adynamia, hypotension, tachypnea, and chest
pain. All of them, except Mishra and Chhetia (2006), showed a significant reduction in WBC
counts to values below 1,000 cells/ mm3, with neutropenia below 500 cells/mm3.

Although Silva et al. (2009),1 Mishra and Chhetia (2006), and Bhat and Radhakrishnan
(2003)4 reported cases in male patients; our report is in agreement with the literature in relation to
the female predilection.5In relation to age, our report agrees Bhat and Radhakrishnan
(2003),4 showing a higher incidence around 60 years of age.

According to Mishra and Chhetia (2006), Carneiro et al. (2011), and our report,
agranulocytosis occurs between 3 weeks and 3 months after the onset of the MDT.

In the literature and in our case, patients started MDT to treat agranulocytosis, but DDS
had to be discontinued due to side effects. The treatments continued with antibiotic therapy and
filgrastim revealing leucometric and clinical improvement in a few days, except for the patient
followed by Bhat and Radhakrishnan (2003), who died.
 After clinical improvement, some patients had their MDT altered for ofloxacin,
clofazimine, and minocycline, with each drug introduced at 30-day intervals, or for rifampicin and
clofazimine, as in our report.

According to the literature, hospitalization is required in some cases, which did not happen
in our case because of the early intervention.

Considering a reduced risk of agranulocytosis development and in accordance with

Carneiro et al. (2011), our aim was not to question DDS therapy for leprosy, but to stimulate
clinical awareness of its risks by showing non-specific symptoms of agranulocytosis. We also
highlight the need for laboratory test monitoring patients treated with DDS in order to favor the
early treatment of this adverse effect, thus enhancing patient prognosis.
EVALUATION SHEETS/ INDEX CARDS
DERMATOLOGY
December 17, 2018 to December 30, 2018
CLERK'S COORDINATOR
Dr. Michaela M. Tabalon
ROTATORS
Jamiana, Nikita Marie G.
Jardinel, Genevieve Anne L.
Julao, Fritz Adrian C.
Julhan, Fatima Dhiena D.
Jumilla, Jed Espiridon II
Jurilla, Joanna Ruth R.
Kho, Nicole Alexandra P.
Labang, Sean Clarke P.
Labradores, Anjola Gerchily
Lacar, Zandralyn T.
Lagmay, Paul Angelo A.
Laguialam, Fatma L.
CLEARANCE
DERMATOLOGY
December 17, 2018 to December 30, 2018
CLERK'S COORDINATOR
Dr. Michaela M. Tabalon
ROTATORS
Jamiana, Nikita Marie G.
Jardinel, Genevieve Anne L.
Julao, Fritz Adrian C.
Julhan, Fatima Dhiena D.
Jumilla, Jed Espiridon II
Jurilla, Joanna Ruth R.
Kho, Nicole Alexandra P.
Labang, Sean Clarke P.
Labradores, Anjola Gerchily
Lacar, Zandralyn T.
Lagmay, Paul Angelo A.
Laguialam, Fatma L.