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

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.
• ²
  Brunton LL, Chabner BA, Knollmann BC. As Bases Farmacológicas da Terapêutica de Goodman & Gilman. 12.ed. Rio de Janeiro: McGraw-Hill; 2012.
• ³
  Mishra M, Chhetia R. Dapsone induced agranuilocytosis in a patient of leprosy. Indian J Dermatol Venereol Leprol. 2006;72:456-7.
• ⁴
  Bhat RM, Radhakrishnan K. A case report of fatal dapsoneinduced agranulocytosis in an Indian midborderline leprosy patient. Lepr Rev. 2003;74:167-70.
• 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.

Publication Dates

• Publication in this collection
  Nov-Dec 2017

History

• Received
  28 Oct 2016
• Accepted
  23 Mar 2017