Case Report: Type 2 Leprosy Reaction Mimicking Sweet Syndrome: A Case Report and Literature Review

ABSTRACT.

Type 2 leprosy reaction is a type of acute inflammation that predominantly affects borderline lepromatous leprosy and lepromatous leprosy patients and occurs before, during, or after therapy. The atypical variant, which resembles Sweet syndrome, could easily lead to misdiagnosis. Here, we report a case of a 52-year-old man who presented with type 2 leprosy reaction that mimicked Sweet syndrome. In addition, we review published cases and summarize their features to raise awareness of this atypical variant to enable improved diagnosis and management.

CASE REPORT

A 52-year-old man presented with recurring painful erythema, plaques, and nodules on his face, trunk, and extremities, accompanied by intermittent fever (peak body temperature 39.2°C) and intermittent slight numbness of the upper extremities for 3 years. He denied having family and friends with similar manifestations or a history of malignancy. Treatment involving systemic corticosteroids and antimicrobials proved effective, although the specific drugs were unknown. However, the lesions and fever returned after treatment cessation. Physical examination showed minor hypoesthesia and xerosis in the hands and forearms without thickened nerves. The patient had multiple, tender, well-defined erythematous plaques and nodules with pseudo-vesiculation on the face, trunk, and extremities (Figure 1A and B). Additionally, the patient displayed edema in the right leg and bilateral painful cervical lymphadenopathy. Laboratory findings indicated leukocytosis of 15.08 × 10⁹/L, neutrophilia of 71.48%, C-reactive protein of 33.30 mg/L, and erythrocyte sedimentation rate (ESR) of 66 mm/hour. Dermatopathological examination revealed a slight superficial dermal edema, perivascular and periadnexal infiltration of neutrophils and foamy cells, focal vasculitis, and perineural histiocytic infiltration (Figure 2A). Acid-fast staining (Fite–Faraco method) demonstrated intraneural acid-fast bacilli and bacilli in histiocytes with a bacteriological index (BI) of 3+ (Figure 2B–D). Subsequently, the slit-skin smear test (SSST) was performed in the eyebrow arch, mandibular, supraorbital, and retroauricular areas and acid-fast bacilli with a BI of 5+ was found. The patient was diagnosed with borderline lepromatous leprosy with erythema nodosum leprosum resembling Sweet syndrome (SS). Multidrug therapy recommended by the WHO, including dapsone, clofazimine, and rifampin, along with tapering prednisolone at a dose of 40 mg/day, was administered. The fever and lesions were effectively controlled within 3 weeks, and no recurrence was reported during the 2-year follow-up.

Figure 1.

Clinical manifestations of the patient. (A and B) Multiple, irregular, well-defined, erythematous plaques and nodules on the face, trunk, and extremities among which pseudo-vesiculation was noted.

Figure 2.

Dermatopathological manifestations of the patient. (A) Slight superficial dermal edema, diffuse, perivascular, and periadnexal infiltration of neutrophils and histiocytes (H&E ×40). (B) Foamy cells and focal vasculitis (black circle) (hematoxylin and eosin [H&E] ×400). (C) Perineural infiltration of histiocytes and intraneural bacilli (red arrow) were observed (H&E ×400). (D) Acid-fast bacilli in (red arrow) and around the nerve (Fite–Faraco method, ×1000).

DISCUSSION

Leprosy, caused by Mycobacterium leprae, is a chronic infectious disease that affects the skin and peripheral nerves. The global incidence remains steady at ∼250,000 new cases each year.¹ A leprosy reaction, an inflammatory episode, may occur in patients prior to, during, or after multidrug therapy.² Erythema nodosum leprosum (ENL), a type 2 leprosy reaction, is frequent in borderline lepromatous leprosy (BL) and lepromatous leprosy (LL). Chatterjee et al.³ reported an incidence of 19.5% of ENL in 1,195 leprosy patients. Clinical features of ENL include the presence of tender, erythematous nodules on the face and extremities, as well as potential systemic manifestations, such as fever, malaise, lymphadenitis, neuritis, iridocyclitis, and arthritis. Histopathologically, ENL is characterized by infiltration of bacteria-filled histiocytes (Virchow cells), rarefaction of adnexal structures, perivascular infiltration of neutrophils, leukocytoclastic vasculitis (LCV), neural inflammation, and intraneural bacilli.⁴

Sweet syndrome is a rare acute febrile neutrophilic dermatosis characterized by fever, neutrophilia, and painful violaceous or erythematous plaques that can develop into pseudo-vesiculation. The incidence of SS is higher in females (4:1) and usually occurs between the ages of 30 and 60 years.⁵ The common cutaneous presentation involves tender erythematous plaques and nodules on the face, trunk, and extremities, accompanied by systemic symptoms such as fever, arthralgia, and general malaise. Extracutaneously, osteoarticular, neurological, renal, intestinal, hepatic, cardiovascular, and ophthalmic involvement may occur. Histopathologically, it is characterized by superficial dermal edema, neutrophilic infiltration, and absence of LCV.⁶

Erythema nodosum leprosum may occur in 50% of BL and LL patients within the first 2 years of therapy and may be triggered by pregnancy, parturition, or infection.² Alakad et al.² categorized the atypical forms of ENL as pustular, vesiculobullous, ulceronecrotic, erythema multiforme-like, and SS-like, with prevalence rates of 9%, 46%, 41%, 28%, and 11%, respectively. They share the typical pathological features of ENL.² Sweet syndrome–like ENL presents clinical features similar to SS. Delayed diagnosis may lead to health burdens for patients and their contacts. A cohort study revealed that the new leprosy cases were 636.3 per 100,000 person-years at risk (95% CI: 594.4–681.1) among household contacts, emphasizing the early diagnosis of this atypical variant.⁷

Here, we review the published cases of ENL mimicking SS. A bibliographic review was conducted using the PUBMED database, with keywords Sweet syndrome, acute febrile neutrophilic dermatosis, leprosy, type 2 leprosy reaction, and erythema nodosum leprosum. Seventeen articles and 25 patients were identified in this study. Summary information on characteristics of SS-like ENL patients included in this study is presented in Table 1 (and in greater detail in Supplemental Table 1). Among these patients, male predilection was observed (60.00%, 15/25), and the median age of onset was 44.44 (26–61) years. The median duration from disease onset to diagnosis was 14.79 (0.1–36) months. Twenty-one cases reported their past medical history, and 11 patients (52.38%) experienced disease onset without a prior leprosy diagnosis. Nine patients reported triggering factors, including infection, malignancy, interrupted therapy, and drug use. The most common systemic symptom identified was fever (60%). Only one patient (6.67%) reported a thickened nerve. The face, trunk, and extremities were the most common sites, with the upper extremities the most frequently involved sites (100%). Frequent lesion types were plaque (72.22%) and pseudo-vesiculation (50%), consistent with SS. Histopathologically, SS-like ENL had some features of SS, such as superficial dermal edema (17.39%) and neutrophilic infiltration (69.57%), and some features of leprosy, such as Globi (8.69%), foamy cells (91.30%), and LCV (30.43%). It is noted that the histopathological aspects in Table 1 were common features of leprosy rather than ENL because it was a mixture of background leprosy and reactional immunological phenomenon. Leukocytosis and ESR elevation were the frequent laboratory results, and nine out of 12 (83.33%) patients reported BI ≥ 3+ in SSST. Prior diagnoses were BL (57.14%) and LL (42.85%). Multidrug therapy in combination with corticosteroid prescription was prescribed in most cases. After reducing or discontinuing medication, two patients (16.67%, 2/11) experienced relapses, which matched the reported ENL relapse rate (16.2%).⁸

Table 1.

Demographic characteristics of Sweet syndrome–like erythema nodosum leprosum patients

Characteristics	Patients (N = 25)
Age, years, median (range)	44.44 (26–61)
Sex, men	15 (60)
Disease duration between onset to diagnosis, months, median (range)	14.79 (0.1–36)
Prior diagnosed leprosy (n = 21)
Yes	10 (47.62)
No	11 (52.38)
Triggering factor (n = 9)
Interrupted therapy	3 (33.33)
Drug	2 (22.22)
Asthma	1 (11.11)
Infection	1 (11.11)
Malignancy	1 (11.11)
Gestation	1 (11.11)
Symptoms and signs (n = 15)
Fever	9 (60.00)
Malaise	5 (33.33)
Thickened nerves	1 (6.67)
Joint pain	4 (26.67)
Urinary tract inflammation	2 (13.34)
Ophthalmological inflammation	1 (6.67)
Others	6 (40.00)
Lesion site (n = 14)
Face	11 (78.57)
Trunk	12 (85.71)
Upper extremities	14 (100.0)
Lower extremities	12 (85.71)
Others	3 (21.42)
Lesion description (n = 18)
Plaque	13 (72.22)
Pseudo-vesiculation/vesicle	9 (50.00)
Edema	8 (44.44)
Nodule	8 (44.44)
Papule	6 (33.33)
Pustule	6 (33.33)
Erosion/ulceration	5 (27.77)
Crust	2 (11.11)
Onset before multidrug therapy (n = 22)
Yes	10 (45.46)
No	12 (54.54)
Histopathology (n = 23)
Superficial dermal edema	4 (17.39)
Inflammatory cells infiltrate	23 (100.00)
Neutrophilic infiltrate	16 (69.57)
Lymphocytic infiltrate	8 (34.78)
Foamy cells/histiocytes infiltrate	21 (91.30)
Perivascular infiltrate	11 (47.82)
Periadnexal infiltrate	5 (21.74)
Nerves involvement	4 (17.39)
Leukocytoclasis	7 (30.43)
Grenz zone	2 (8.69)
Vasculitis	8 (34.78)
Globi	2 (8.69)
Laboratory examination (n = 22)
Leukocytosis	11 (50.00)
Neutrophilia	10 (45.45)
ESR elevation	9 (40.90)
BI ≥ 3+ (n = 12)	10 (83.33)
Diagnosis (n = 21)
Borderline lepromatous leprosy	12 (57.14)
Lepromatous leprosy	9 (42.85)
Therapy (n = 21)
Multidrug therapy	20 (95.23)
Steroid	18 (85.71)
Thalidomide	8 (38.09)
Others	4 (20.00)
Prognosis (n = 12)
Well controlled	10 (83.33)
Relapsed	2 (16.67)

Due to report bias, some data were missing. We analyzed the available data and marked the number of patients in every subtitle. Data are presented as n (%) or median (range). BI = bacteriological index; ESR = erythrocyte sedimentation rate.

Similar clinical symptoms of fever, rash, histopathological features of superficial dermal edema and neutrophilic infiltration, and laboratory findings of leukocytosis and elevated ESR make it challenging to differentiate SS-like ENL from SS. The WHO guideline emphasizes neural involvement and bacteriological evidence in diagnosing leprosy.⁹ Clinically, it is recommended to perform a peripheral nerve examination and inquire about medical history. Objectively, the presence of LCV indicates exclusion of SS, whereas pathological characteristics such as Virchow cells, neural involvement, and intraneural acid-fast bacilli suggest SS-like ENL.⁶ Acid-fast staining and polymerase chain reaction are commonly used methods for diagnosing M. leprae and confirming leprosy diagnosis.¹ Fite–Faraco staining in tissue is preferable over Ziehl–Neelsen with a higher sensitivity (77% versus 59.3%, P < 0.05).¹⁰ Multidrug therapy combined with corticosteroid treatment was effective in most cases, in line with the WHO guideline for leprosy and first-line SS treatment.^6,9 Corticosteroids may suppress the inflammatory immune response to M. leprae antigens in this variant. Furthermore, thalidomide was used as maintenance therapy to prevent ENL recurrences, even in refractory cases, due to its anti–tumor necrosis factor-α activity.¹¹

In countries with a low prevalence of leprosy, this atypical variant can create a diagnostic challenge, resulting in inaccurate diagnosis, transmission, and untimely treatment. It is crucial to increase awareness of this atypical variation to ensure prompt identification and appropriate therapy in potentially treatable cases. The detections of cardinal signs and bacilli are imperative for the correct diagnosis of leprosy, emphasizing the importance of medical history inquiry, peripheral neural examination, and acid-fast staining.

Note: Supplemental material appears at www.ajtmh.org.