SciELO - Scientific Electronic Library Online

 
vol.92 número6Pseudo "fringe sign" in frontal fibrosing alopeciaPseudoxanthoma elasticum-like papillary dermal elastolysis índice de autoresíndice de assuntospesquisa de artigos
Home Pagelista alfabética de periódicos  

Serviços Personalizados

Journal

Artigo

Indicadores

Links relacionados

Compartilhar


Anais Brasileiros de Dermatologia

versão impressa ISSN 0365-0596versão On-line ISSN 1806-4841

An. Bras. Dermatol. vol.92 no.6 Rio de Janeiro nov./dez. 2017

http://dx.doi.org/10.1590/abd1806-4841.20176649 

Letters

Dapsone-induced agranulocytosis in patients with Hansen's disease*

Tania Rita Moreno de Oliveira Fernandes1  2 

Bruno Nascimento de Jesus3 

Tathyane Trajano Barreto3 

Anderson de Almeida Pereira3 

1Department of Medical and Surgical Pathology of the Integumentary System at Universidade Federal do Vale do São Francisco (Univasf) - Petrolina (PE), Brazil

2Leprosy and Tuberculosis Reference Center in Juazeiro (BA), Brazil

3Medical Student at Universidade Federal do Vale do São Francisco (Univasf) - Petrolina (PE), Brazil


Dear Editor,

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.1

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.1,2

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.2

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 (Table 1).

Table 1 Monitoring of a female patient with leprosy during paucibacillary multidrug therapy 

DATE 06.30.2014 11.06.2014 11.26.2014 11.28.2014 11.30.2014 12.04.2014 01.28.2015 Standards
After 2 After 5 prescribed
filgrastim injections injections
Period of Before starting Day 14 Day 34 Dapsone
Treatment treatment with Interrup-
(MDT) dapsone tion
Hemoglobin 11.9 10.9 8.8 8.9 10 9.8 14.5 13-18 (men)
(g/dL) 12-16
(women)
Hematocrit 35.8 32.5 27 27.6 32.6 30.7 42.2 40-52
(%) 37-47
WBC count 4400 4000 1520 1000 1090 6300 4700 4000-11000
(mm3)
Bands (%) 13 1 1-5%
Segmented - 74 74 11 10 48 77 50-70%
(%)
Limphocytes 21 22 25 8 84 24 20 20-45%
(%)
Eosinophils 0 1 1 0 1 0 1 1-4%
(%)
Basophils 0 1 0 2 0 2 0 0-1%
(%)
Monocytes 2 2 0 1 5 0 1 2-12%
(%)
Platelets/ 211000 225000 212000 285000 324000 315000 206000 140-450 x
mm3 103

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.3

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.3

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. 2,4

According to Silva et al. (2009),1 Mishra and Chhetia (2006),3 Bhat and Radhakrishnan (2003),4 Carneiro et al. (2011),5 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),3 showed a significant reduction in WBC counts to values below 1,000 cells/ mm3, with neutropenia below 500 cells/mm3.4

Although Silva et al. (2009),1 Mishra and Chhetia (2006),3 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.5 In 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),3 Carneiro et al. (2011),5 and our report, agranulocytosis occurs between 3 weeks and 3 months after the onset of the MDT.5

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,5 except for the patient followed by Bhat and Radhakrishnan (2003),4 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 (Table 2).5

Table 2 Literature review of case reports about dapsone-induced agranulocytosis in patients with leprosy 

YEAR LOCA- AGE GEN- ETHNICITY TIME UNTIL CLINICAL DIAG- MANAGEMENT CHANGES IN HOSPI- OUT-
TION DER SYMPTOMS PRESENTATION NOSIS MDT TALIZA- COMES
APPEARANCE TION
Current paper 2015 Brazil 61 F Non-Cauca- After 34 days Fever - Suspension of Rifampicin No Patient
sian Chills MDT ; Amoxicil- and Clofazime improved
Adynamia lin-Clavulanate; Replaces after 8
Odynophagia Ciprofloxacin; Dapsone; days
Paleness Filgastrim Ofloxacin +
Rifampicin +
Minocycline
Silva et al. 2011 Brazil 28 M Non-Cauca- before 30 days Odynophagia Severe Suspension of * * Patient
sian Fever febrile MDT; broad spec- improved
neutro- trum antibiotic; after 16
penia folic acid days
Carneiro et al. 2011 Brazil 56 F Non-Cauca- After 8 weeks Odynophagia Tonsil- Suspension of Ofloxacin + Yes Patient
sian Fever litis DDS; amoxicil- Clofazime + improved
Dry cough lin clavulanate; Minocycline after 14
Progressive dyspnea Ciprofloxacin; days
Respiratory-dependent Cefepime; Oxacil-
chest pain lin; Filgastrim
Silva et al. 2009 Brazil 28 F Non-Cauca- After 35 days Fever Tonsil- Suspension of Restarted Yes *
sian Chills litis DDS ;Figastrim; Rifampicin
Odynophagia benzathine peni- (600mg/
cillin; broad spec- month) and
trum antibiotic Clofazimine
(100 mg/day)
Ranawaka et al. 2008 Sri 21 M Non-Cauca- After 19 weeks Fever Hemo- Suspension of * Yes Patient
Lanka sian Odynophagia lytic MDT; broad spec- improved
anemia trum antibiotic; after 8
and Filgastrim. days
hepatitis Linezolid; Amik-
acin; Filgastrim; Prednisolone;
Vasopressors
Cefotaxime;
Prednisolone
Mishra e Chhetia 2006 India 25 M Non-Cauca- * High fever; Tachypnea; Pneu- Linezolid; Amik- * Yes Patient
sian Hypotension; Pharyngeal monia acin; Filgastrim; improved
congestion; Dyspnea; Prednisolone; after 7
Cough; Lymphadenopathy Vasopressors days
Bhat e Radhakrishnan 2003 India 60 M Non-Caucasian After 21 days Low fever; Cough; Dyspnea; Chest pain Pneumonia Cefotaxime; Prednisolone * Yes Death

Considering a reduced risk of agranulocytosis development and in accordance with Carneiro et al. (2011),5 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.

*Work performed at the Universidade Federal do Vale do São Francisco (Univasf) - Petrolina (PE), Brazil

Financial support: None.

REFERENCES

1 Silva IM, Oliveira CA, Guedes WR, Oliveira BB, Oliveira DA, Guedes Filho G. Agranulocytosis Induced by Multidrug Therapy in Leprosy Treatment: A Case Report. Braz J Infect Dis. 2009;13:158-60. [ Links ]

2 Brunton LL, Chabner BA, Knollmann BC. As Bases Farmacológicas da Terapêutica de Goodman & Gilman. 12.ed. Rio de Janeiro: McGraw-Hill; 2012. [ Links ]

3 Mishra M, Chhetia R. Dapsone induced agranuilocytosis in a patient of leprosy. Indian J Dermatol Venereol Leprol. 2006;72:456-7. [ Links ]

4 Bhat RM, Radhakrishnan K. A case report of fatal dapsoneinduced agranulocytosis in an Indian midborderline leprosy patient. Lepr Rev. 2003;74:167-70. [ Links ]

5 Carneiro JA, Poswar FO, Ramos MIA, Nassau DC, Veloso DC. Agranulocitose induzida por dapsona em paciente com hanseníase. Relato de caso. Rev Bras Clin Med. 2011;9:242-4. [ Links ]

Received: October 28, 2016; Accepted: March 23, 2017

Mailing address: Tania Rita Moreno de Oliveira Fernandes Av. José de Sá Maniçoba, s/n Centro Petrolina, PE, Brazil E-mail: trmofernandes@gmail.com

Conflict of interests: None.

Creative Commons License This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited.