ABSTRACT diagnosis of DHS and to develop screening policies

ABSTRACT

Dapsone is a sulfone derived drug used
in the treatment of leprosy and several chronic inflammatory dermatological
diseases. Dapsone therapy rarely develop Dapsone hypersensitivity syndrome (DHS)
characterized by fever, hepatitis,generalized exfoliative dermatitis and
lymphadenopathy and is potentially fatal. We present a case report of a middle
aged female patient with a recent history of antecedent dapsone exposure of 100
mg daily for 2 weeks. She developed fever after 10 days of exposure to dapsone
therapy and was treated in various primary and tertiary centers for features of
sepsis. When presented to us, she  had
clinical features of multi-organ dysfunction and intractable sepsis. She was
successfully managed with intravenous corticosteroids and other supportive
therapy.This case of DHS is unique due to pulmonary, hepatic, colonic involvement
along with secondary bacterial and fungal infection, which  raises the risk of mortality. As Dapsone is a
mainstay in the treatment several infections and inflammatory conditions, more
research has to be done to characterize markers for diagnosis of DHS and to
develop screening policies prior to initiation of Dapsone therapay.

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Key words: Dapsone, Dapsone hypersensitivity,Exfoliative
dermatitis.

INTRODUCTION

Dapsone belongs to the sulfonamide drug
class. It was initially used to treat leprosy and later it was also found to
have anti-inflammatory properties. At present, it is used in a wide variety of dermatological
conditions, especially those with a neutrophil predominance as dapsone inhibits
neutrophil activation and recruitment through a number of pathways. The
effective dose of Dapsone is 100 mg daily, and a maximum up to 300 mg daily can
be used 1. Generally Dapsone is well tolerated,but at an incidence of 0.2-
0.5 %, it can cause DHS,which  is a form
of drug induced hypersensitivity syndrome, also known as DRESS       (Drug, rash, Eosinophilia and systemic
symptoms) 2. It also typically occurs as a reaction to drugs like
Carbamazepine, Phenytoin, Phenobarbital, Allopurinol, Sulfasalazine and Minocycline,
which mimics a severe form of sepsis. DHS is characterized by fever, rash and
multi- organ failure. It can be fatal and cause irreversible organ damage. The
mortality associated with DHS is 12-23%. Generally DHS can develop in 1-8 weeks
after Dapsone initiation. But in some cases, it can occur in as long as six
months after treatment initiation or in as short as 6 hours in previously
sensitized patients 3.

 

 

 

 

 

CASE
REPORT

A 52 years old  Indian female presented with fever of twenty
days duration associated with itching all over her body.She  had complaints of breathing difficulty of ten
days duration not associated with cough. She also complained of abdominal pain
associated with loose stools of ten days duration. Her medical and medication history
revealed that two months prior to current admission, she was treated with tablet
dapsone100 mg daily by a dermatologist for suspected dermatitis. She developed
fever and other constitutional symptoms after 10 days of exposure to Dapsone,
following which Dapsone was withdrawn on the 14th day. This was
followed by admission at a local hospital 
and even in a tertiary care center, wherein her symptoms worsened. Thorough
examination of  her previous medical
reports revealed that she was diagnosed to have hepatitis and a chest infection
for which she was treated with high-end antibiotics and bronchodilators.

On 
physical examination, she was pale,afebrile and had Icterus. She was
found to have  continuous hyperpigmented exfoliative
skin lesions all over her body, including face.Electro cardiography showed
sinus tachycardia. Ultra sonography of abdomen showed mild hepatomegaly with moderate
fatty infiltration, splenomegaly, right minimal pleural effusion with
consolidation, and also edematous bowel wall thickening of the ascending colon.
Colonoscopy revealed no abnormalities. Blood culture was sterile initially.
Sputum culture showed moderate growth of budding yeast.Stool and urine culture
was negative.Evaluations for her infectious etiologies were negative, this
included hepatitis panel, Human Immuno Virus, Hepatitis B surface Antigen, Anti
Leptospira IgM Antibody, Weilfelix test and Scrub typhus IgM Antibody.

Laboratory investigations showed anemia,
eosinophilic leucocytosis, deranged liver enzymes, hypoalbuminemia along with raised
lactate dehydrogenase and procalcitonin level  
(Table 1, 2).  A diagnosis of DHS with
co-existing secondary sepsis was made, based on the patient’s treatment
history, exfoliative dermatitis and multiorgan dysfunction with reasonable time
relationship to Dapsone exposure.

During the hospital stay, our  patient had high grade fever,dyspnea with
wheezing and loose stools. From second day she experienced, productive cough, and
her peripheral capillary oxygen saturation had dropped below 85%. Systemic
hydrocortisone 50 mg every 8 hours was started from the second day. Bronchodilators,
antihistamine, antibiotics and antifungal along with supportive therapy was
provided.Least possible medications were prescribed to prevent further drug
induced problems. She was also monitored for Dapsone induced secondary seizure.

The erosions on skin started healing
dramatically after 2 days of corticosteroid therapy and no acute symptoms were
noted.  On eighth day 1 unit of packed
cell transfusion was done. She was discharged on day 9 with oral
corticosteroids, antihistamine and other supportive medications.

 

Table
1 : Abnormal parameters in complete blood count

Laboratory
Parameters

Day 1

Day 4

Day 7
 
 
 

RBC (×106/µL)
Ref :
(4 – 4.8)

2.43

2.05

1.95

Haemoglobin
(g/dl)
Ref:
(12-15)

8.5

7.1

6.6

PCV  (%)
Ref:
(36-46)
 

25

21.5

20.4

MCV
(fL)
Ref:
(80-100)

102.9

104.9

104.5

MCHC
(g/dl)
Ref: (32-35)

34

33.3

17

RDW
(%)
Ref :
(10-15)

16.7

18.3

17

WBC ((×103/µL)
Ref:
(4-10)

19.6

10.1

9

Monocyte(%)
Ref:
(20-40)

15.1

4.1

6.1

Eosoninophil
(%)
Ref:
(1-6)
 

16.3

19.7

0

Absolute
eosinophil (×103/µL)
Ref:
(0.02-0.5)

2

3.2

0

ESR(mm)
Ref:
(4-12)
 

 

17

38

Lactate
dehydrogenase(U/L)
Ref:
(135-214)
 

1149

 

 

Procalcitonin
(g/ml)
Ref :
<0.5   2.47                   Table 2 :Abnormal liver parameters Laboratory parameters   Day 1 Day 4 Day 7 Serum glutamic pyruvic transaminase (U/L) Ref:  (5 – 38) 260 279 141 Serum glutamic oxaloacetic transaminase (U/L) Ref: ( 5 – 41) 855 940 83 Alkaline Phosphatase (U/L) Ref :  (40 -129) 505 402 426 Direct Bilirubin (mg/dl) Ref: (0.0 - 0.2) 5.4 4.9 3.7 Indirect Bilirubin (mg/dl) Ref :  (0.2 – 0.8) 0.5 0.3 0.2 Total Bilirubin (mg/dl) Ref: (0.2 - 1) 5.9 5.2 3.9 Albumin (g/dl) Ref: (3.4 – 4.8) 2.3 2 2.4   DISCUSSION Sulfonamides are compounds that contain sulfamoyl group (-SO2NH2).Dapsone is structurally the simplest of all sulfones. Absorption of orally administered Dapsone from  gastrointestinal tract occurs readily, with bioavailability about 86%. It undergoes portal circulation and metabolized via either N-hydroxylation or N-acetylation, which leads to toxic intermediate metabolites.These metabolites form haptens with the production of Anti-dapsone antibodies. DHS is thought to be an immune mediated reaction, involving T-lymphocyte activation, macrophage and cytokine release. Dapsone induced delayed hypersensitivity syndrome is directed by Dapsone specific T cells. It develops typically  between 2 to 8 weeks after  Dapsone administration and clinical features lasts even after withdrawal of the drug 4. Our patient developed DHS after ten days from initiation of the drug and clinical features were apparent for more than a month after drug withdrawal. The skin eruption in DHS is often initially morbilliform which later develop into exfoliative dermatitis 5. Our patient developed exfoliative dermatitis after ten days from initiation of Dapsone. The skin rash severity is usually associated with fatal outcomes, especially if the damage occurs in more than 30 percent of the body surface 6. Our patient had the involvement all over the body, including  trunk, limbs and face which increased the risk. Hepatic involvement in DHS displays a mixed hepatocellular and cholestatic pattern. A similar pattern was present in our patient with high Alkaline phosphatase and modest increase in transaminases. Hyperbilirubinemia in DHS can occur partly due to hepatotoxicity and partly due to hemolysis. Hypoalbuminemia is also reported with DHS probably due to binding of Dapsone to the circulating serum albumin. Hypoalbuminemia was apparent in the patient described by us 5. Agranulocytosis is caused by DHS, which increases the risk of the patient to be susceptible to infections 4. Thus, secondary bacterial and fungal infection in our patient can be attributed  to the after effect of drug reaction. This can complicate the illness and management of DHS. Due to hemolysis, the lifespan of RBS is reduced in all subjects on Dapsone 7. The marked anemia in our patient can be attributed to this. Dapsone is known to produce acute eosinophilic pneumonia with hypoxia and pleural effusion 3. The presence of pleural effusion and severe hypoxemia in our patient might be an interplay between drug reaction and secondary infection.Oral erosion, splenomegaly and colitis have also been reported with Dapsone 8. All these manifestations were evident in our patient. Rechallenge with Dapsone is not recommended as it can be hazardous. Appropriate management of DHS includes prompt discontinuation of Dapsone and introduction of systemic steroids 3. Our patient was managed with Hydrocortisone 50 mg every 8 hours along with supportive therapy. Since Dapsone has a long elimination half life of 24-30 hours and since it persists in organs for about 35 days, slow tapering off of the corticosteroid therapy is recommended 5. Abrupt discontinuation may cause relapse. After 5 days of systemic corticosteroids, our patient was switched to Tablet Prednisolone 30 mg daily. It was then tapered and stopped over a period of 6 weeks. But the patient had relapsed with skin manifestations, due to which the oral corticosteroid was continued over 6 months and gradually our patient achieved remission. The major route of elimination of Dapsone is by N-Acetylation which exhibits genetic polymorphism. Dapsone and sulfonamides contain an aromatic group which is readily acetylated by cytosolic hepatic acetyl transferases. Hence, fast acetylators are at a low risk of DHS as a lower proportion of drug is available for N-Hydroxylation. Serious  adverse drug reaction to Dapsone arise as an inter-individual variation in acetylation and oxidation of Dapsone and also due to variation in detoxificatiom of Dapsone metabolites in particular cells 3,7. Susceptibility to DHS can be increased with reduced glutathione reserve, as in conditions like AIDS (Acquired Immunodeficiency  syndrome). Environmental factors such as smoking, drugs inhibiting CYP 450 and deficiency of antioxidants such as Vitamin E,Vitamin C and selenium can also pose a risk in developing DHS 8. Recent studies show that HLA-B*13 allele, sensitively and selectively predicted DHS. The presence of this allele in Indians is 1-12% and its absence is associated with 7-fold risk reduction 6. Evidence suggests that there is no obligatory cross-reactivity between sulfonamides and other sulfonamide non antibiotic drug such as Dapsone due to the difference in chemical structures between these compounds 9. CONCLUSION Physicians should be familiarized with protypical features of Dapsone hypersensitivity syndrome. If not treated early, DHS can be deleterious to manage. Pulmonary or systemic manifestations can be mistaken for other disorders. DHS if and when it occurs can also be mistaken for progression of the primary disease. . The steroid sparing effect of Dapsone is quite promising and is useful in numerous clinical setting outside the field of dermatology. This requisites the newer physicians and clinical pharmacists to be aware about the possibile hypersensitivity, management and monitoring of Dapsone. Our case report highlights the importance of  history taking of antecent drug exposure in patients presenting to the physicians. Periodic monitoring in patients on Dapsone is necessary to detect early warning signs of DHS. We also emphasize that early tapering and rapid withdrawal of corticosteroids in DHS is not recommended. REFERENCE 1  Evan W. Piette, Victoria P. Werth. Dapsone in the management of the autoimmune bullous diseases. Immunol Allergy Clin North Am.2012;32(2):561-64 2  Kamal Kumar Sawlani, Shyam Chand Chaudhary, Jitendra Singh, Deep Chandh Raja, Sanjay Mishra, Madhu Mati Goel. Dapsone-induced pure red cell aplasia and cholestatic jaundice: A new experience for diagnosis and management. J Res Pharm Pract.2016;5(3):215-18 3  Kolar Vishwanath Vinoth, Karyampundi Arun, Tarun Kumar Dutta. Dapsone Hypersensitivity syndrome: A rare life threatening complication of dapsone therapy. J Pharmacol Pharmacother. 2013;4(2):158-60 4  So Yoon Choi, Ho Yeon Hwang, Jung Hyun Lee, Jae Sun Park, Min Soo Jang. Severe dapsone hypersensitivity syndrome in a child.Korean J Pediatr.2013;56(6):260-64.  5  Mary Grace. An unusual case of dapsone syndrome.Indian Dermatol Online J.2011;2(2):88-90 6  Na Wang, Leela Parimi, Hong Liu, Furen Zhang. A Review on dapsone Hypersensitivity Syndrome Among Chinese Patients with an Emphasis on Preventing Adverse Drug Reaction with Genetic Testing. Am. J. Trop. Med. Hyg., 2017;96(5):1014-18 7  M.D. Coleman, A.M. Breckenridge, B.K. Park. Bioactivation of dapsone to a  cytotoxic metabolite by human hepatic microsomal enzymes. Br. J. Clin. Pharmac. 1989;28:389-95 8 Semaan G kosseifi, Bhuvana Guha, Dima N Nassour, David S Chi, Guhan Krishnaswamy. The Dapsone Hypersensitivity Syndrome Revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations. J Occup Med Toxicol. 2006;1(9). 9  Gottfried Wozel, Christian Blasum. Arch Dermatol Res.2014;306:130-24