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Review Article
ARTICLE IN PRESS
doi:
10.25259/IJDVL_909_19

Lucio’s phenomenon: A systematic literature review of definition, clinical features, histopathogenesis and management

Department of Medical Clinics, Division of Dermatology, Ribeirão Preto Medical School, University of São Paulo, Brazil
Department of Surgery and Anatomy, Division of Plastic Surgery, Ribeirão Preto Medical School, University of São Paulo, Brazil
Department of Stomatology, Public Oral Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
Corresponding author: Prof. Marco Andrey Cipriani Frade, Department of Medical Clinics, Division of Dermatology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. mandrey@fmrp.usp.br
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Frade MA, Coltro PS, Bernardes-Filho F, Horácio GS, Neto AA, da Silva VZ, et al. Lucio’s phenomenon: A systematic literature review of definition, clinical features, histopathogenesis and management. Indian J Dermatol Venereol Leprol, doi: 10.25259/IJDVL_909_19

Abstract

Leprosy is a chronic disease with clinical presentations according to the immunologic spectrum. Lepromatous form is the most advanced, with the highest transmissibility and risk of causing disabilities. Lucio’s phenomenon is a rare manifestation among lepromatous patients with a rapid and severe evolution and high mortality. It is difficult to differentiate from ulcerative/necrotic erythema nodosum leprosum and has no consensus on how it should be treated. This article is a qualitative review of the literature after the introduction of multidrug therapy, aiming to bring consensus related to the clinical, laboratory and histopathological diagnostic criteria of the disease and its management.

Keywords

Erythema nodosum leprosum
leprosy
Lucio phenomenon
Mycobacterium leprae

Introduction

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, or less commonly by Mycobacterium lepromatosis, an acid-fast bacillus (AFB), which multiplies slowly and has an incubation period of about five years.1,2 The disease primarily affects the peripheral cutaneous nerves, skin, mucosa of the upper respiratory tract and the eyes.3 Leprosy is curable, and treatment provided in the early stages averts physical disability.1,3,4

The number of patients treated for leprosy (the registered prevalence) has declined steadily over the last three decades.5 However, the number of new cases detected each year has shown a much smaller, although variable decline in different countries.5,6 Worldwide, the three countries with the highest burden – India, Brazil and Indonesia – accounted for 80.2% of the new case load globally in 2017. Brazil contributed 92.3% of new leprosy cases in the Americas region.7

Leprosy reactions are immunological episodes of acute or subacute inflammation, characterized by cutaneous and systemic involvement, disrupting the usual chronic course and clinical stability of the patients.3,8 Physical disabilities, deformities and morbidity are caused mainly by these episodes.3 Leprosy reactions can occur before, during or after the end of treatment and can be classified clinically and histopathologically into different variants: reversal reaction (Type I), erythema nodosum leprosum (Type II)3,8 and Lucio’s phenomenon.9

Lucio’s phenomenon is a type of reaction usually observed in untreated or inadequately treated diffuse forms of lepromatous leprosy and is a life-threatening medical emergency. It is always related to advanced forms of leprosy and consequently has a high bacillary load. However, according to Bernardes Filho et al., its diagnosis is difficult, especially in non-endemic areas which leads to delay in identifying the disease and loss of treatment time.10 In addition, the resulting severe deformities and disabilities lead to high morbidity and/or mortality.

The objective of this study was to do a qualitative systematic review of literature to arrive at a consensus on its definition, clinical features, diagnosis, treatment and outcomes.

Methods

Search strategy

A search of PubMed, ScienceDirect, EMBASE and SciELO databases was performed in April 2018, to identify eligible articles for the review. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart to facilitate a qualitative review of the literature and formed the basis for inclusion or exclusion of the articles.

Eligibility criteria

Studies describing clinical cases (case reports, letters and case series) published from 1981, after the start of multidrug therapy (MDT) by the World Health Organization (WHO), and those considering the clinical, diagnostic, therapeutic and evolutionary aspects of LP were included in this analysis. We included articles in English, Portuguese, Spanish, French and German, using the keywords “Lucio phenomenon” and “Lucio’s phenomenon.” Articles in which the clinical and diagnostic definitions of LP were not clearly characterized, were excluded from the review.

Study selection

Potentially relevant studies were selected from each database, and duplicates were excluded from the study. We selected, retrieved and reviewed 63 full-text articles. Disagreements on the final inclusion of a study were resolved through consensus between two reviewers (MACF and FBF). Finally, only 39 studies were selected as 24 publications did not meet the inclusion criteria for this review [Figure 1].11-49

Figure 1:: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram

Data extraction

A table was created to summarize the findings from the selected articles which included: authors, year of publication, number of cases described, sex, age, country of the patients, clinical features and disability grading (considering 0, 1 or 2 for hands, feet and eyes evaluations by the WHO guideline), bacilloscopy of slit skin smear, start of Lucio’s phenomenon (pre-, during or post-treatment), clinical diagnosis and histopathology patterns, laboratory tests, antileprosy drugs, treatment of leprosy reactions, antiplatelet and anticoagulant agents, systemic antibiotics, surgical treatments and outcomes [Tables 1 and 2].7

Table 1:: Demographic, clinical and laboratorial characteristics and outcome of patients
Reference n Sex Age Clinical form Bacilloscopy of SSS Start of LP (Pre, During or Pos) PGL-I antibody titer PCR of tissue for Mycobacterium leprae Outcome
10 1 M 60 LL 6+ Pre NR NR Most of the ulcers healed slowly, leaving depigmented atrophic scars
11 2 F 64 LL 5+ Pre Positive Positive General condition and skin lesions improved; antileprosy drugs will be continued for 2 years
12 3 F 20 LL NR During NR NR MDT planned to be given for 24 months
13 4 M 65 LL 6+ Pre NR NR The patient was followed up for 2 months; initially, he showed improvement but was later lost to follow-up
14 5 M 38 DLL 4+ Pre NR NR The ulcers healed slowly with depigmented scars after 10 weeks
15 6 F 28 LL NR Pre NR NR MDT was prescribed for 12 months, but as after this period, biopsies of infiltrated skin on left knee and right elbow still disclosed +/6+granular and well-preserved bacilli, MDT was prescribed for 1 year more
16 7 M 65 DLL 6+ Pre NR NR MRSA septicemia and died on the 16th day of hospitalization
17 8 M 53 LL 2+ Pre NR NR Regression of the ulcers within 2 months
18 9 F 29 LL 6+ During NR NR The ulcers started regressing over the following 2weeks and healed completely in 4–6weeks with scarring. MDT was continued until smears were negative
19 10 F 69 LL NR Pre NR NR After 4weeks of inpatient treatment, the patient was discharged and the actual leprosy therapy with dapsone and rifampicin continued
19 11 M 64 LL NR Pre NR NR The patient died due to sepsis 17 days after admission
20 12 M 76 LL NR Pre NR NR NR
21 13 M 65 DLL 5+ During (abandon) NR NR The patient died from an undetermined cause
22 14 M 37 LL 6+ Pre NR NR Death
23 15 F 31 LL 6+ Pre NR NR Improvement of skin lesions 45days after the start of treatment
24 16 M 49 LL Positive Pre NR NR NR
25 17 M 64 LL 4+ Pre NR NR Satisfactory response to treatment with resolution of secondary local sepsis and visible clinical recovery was also seen with the onset of healing of ulcers due to Lucio’s phenomenon
26 18 F 76 DLL 6+ Pre NR Positive At a 2-month follow-up the patient was still under MDT without side effects
27 19 F 22 LL 3+ During (irregular MDT) NR NR NR
28 20 M 52 NR Positive Pre NR NR Died
28 21 F 57 NR Positive Pre NR NR Died of sepsis
28 22 M 74 NR Positive Pre NR NR Died
28 23 F 59 NR Positive Pre NR NR Died of sepsis
28 24 M 71 NR 3+ Pre NR NR Alive
29 25 M 63 LL 5+ Pre NR NR Marked improvement in the cutaneous signs and symptoms after 1 month
30 26 F 24 LL Positive Pre NR Positive NR
31 27 M 32 LL NR Pre NR Positive NR
31 28 F 50 DLL NR Pre NR Positive The patient was cured at Carville; she died in 1998 at the age of 85
32 29 M 61 LL NR During (irregular MDT) NR NR The patient was discharged after 15days of hospitalization with significant improvement demonstrated both clinically and in laboratory tests. Outpatient clinic follow-up was done at 30, 90 and 120 days post hospital discharge monitoring and returned to the original Basic Health Unit using only MDT, following the multibacillary scheme and without any sign or symptom of reaction recidivation
33 30 M 13 DLL Positive Pre NR NR NR
34 31 F 23 LL 4+ Pre NR NR She was discharged well 7weeks later
34 32 M 34 LL 2+ Pre NR NR Lesions healed after a further 2–4 months, leaving atrophic scars
34 33 M 45 LL 3+ Pre NR NR He succumbed to sepsis 20days after first presentation
35 34 M 32 LL 5+ Pre NR NR The patient recovered very well and now, after more than 1year of specific drugs, he is in a very good health
36 35 M 51 DLL 0 Pos NR NR Outcome was favorable after 1 month of treatment
37 36 F 34 LL NR Pos NR NR The patient subsequently developed pulmonary thromboembolism which culminated in death
38 37 F 33 LL NR Pre NR NR Died at the 35th day of admission because of severe sepsis
39 38 M 54 LL NR Pre NR NR NR
40 39 M 61 LL 5+ Pre NR NR The patient died 2weeks after hospital admission (sepsis, shock, disseminated intravascular coagulopathy and renal and respiratory failure)
40 40 M 72 LL 5+ Pre NR NR Died approximately 2 months after admission (sepsis, renal impairment from fluid loss, disseminated intravascular coagulopathy and shock)
41 41 F 37 DLL 3+ Pre Positive Positive After 2 months of hospitalization and medical management with antiretrovirals, he was discharged due to favorable clinical evolution and improvement of HIV viral load
42 42 F 43 LL Positive Pre NR NR Died of sepsis
43 43 F 27 LL 1+ Pre NR NR The gestation developed to term for a normal childbirth, without concurrent disease. The newborn was of appropriate weight for gestational age and without malformations
44 44 M 30 LL 6+ Pre NR NR He was discharged with the advice to continue MB MDT for 2 years under monthly follow-up
45 45 F 86 DLL NR Pre NR Positive Died at home 3 months later of unknown cause
46 46 M 53 DLL NR Pre Positive Positive Died of presumed septic shock
46 47 M 31 DLL NR Pre NR Positive Died
47 48 M 71 LL NR Pre NR NR The patient died due to sepsis 7 days after admission
48 49 F 17 NR NR Pre Positive NR NR

LL: Lepromatous leprosy, DLL: Diffuse LL, LP: Lucio’s phenomenon, MB: Multibacillary, MDT: Multi drug therapy, NR: Not reported, SSS: Slit-skin smear, PGL-I: Phenolic glycolipid-I, PCR: Polymerase chain reaction, MRSA: Methicillin-resistant Staphylococcus aureus

Table 2:: Clinical manifestations and histopathology of patients
Reference n Clinical diagnosis (pattern) Histopathology
Skin Madarosis Nodule Systemic symptoms Glove-and-stocking anesthesia Nerves Epidermis, dermis, and/or subcutaneous fat Grenz zone AFB in endothelial walls Capillary thrombosis
10 1 Multiple stellate purpuric patches, angular infarcts and gangrene, few with overlying hemorrhagic bullae and deep jagged necrotic ulcers, purpuric patches Yes No Fever Yes Symmetrically thickened peripheral nerves Diffuse infiltration of solid staining and granular bacilli in epidermis and dermis, including endothelial cells. Dense neutrophilic and lymphocytic infiltrate NR Yes Yes
11 2 Painful erythematous macules, papules, nodules and multiple necrotic crusts; atrophic scars of old lesions Yes Yes Fever Yes The great auricular, ulnar, radial cutaneous and superficial peroneal nerves were slightly enlarged Papillary dermal oedema, vascular proliferation and multiple granulomas in dermis and subcutaneous fat. The noncaseous granulomas had infiltration of foamy macrophages and neutrophils NR Yes Yes
12 3 Multiple elevated plaque to nodule-like tender rashes, necrosis NR Yes Fever NR Thickening of both common peroneal and right ulnar nerves Unremarkable epidermis, foam cells with numerous lepra bacilli in dermis NR Yes Yes
13 4 Multiple punched-out ulcers of various sizes; margins of ulcers varied from round to irregular in shape; scarring and atrophy were noted over healed ulcers Yes No No Yes Moderate thickening of the ulnar, radial and common peroneal nerves Ischemic necrosis in the epidermis with varying degrees of atrophy and loss of rete ridges. The dermis showed foamy histiocytes containing fragmented bacilli with necrotizing vasculitis of vessels in the dermis NR NR NR
14 5 Multiple hemorrhagic bullae, purpuric macules, scattered angular purpuric macules, large deep irregular ulcers with angulated margins NR No No Yes Peripheral nerves were symmetrically thickened and nontender Atrophic epidermis. Necrotizing leukocytoclastic vasculitis of papillary dermal vessels with thrombosis, numerous AFB in macrophages and macrophage granulomas extending up to subcutis Yes NR Yes
15 6 Diffuse infiltration of the skin, more pronounced on the face, elbows, and knees and irregular and purpuric maculae, some covered by hemorrhagic vesicles and hematic crusts Yes Yes No NR Ulnar and tibial painful nerve thickening Normal epidermis. Patchy and nodular perivascular, periadnexial, and perineural inflammatory infiltrate of vacuolated histiocytes, lymphocytes and plasma cells; and some neutrophils in the dermis and extending to hypodermis NR Yes Yes
16 7 Dark, irregular-shaped, bizarre, erythematous, purpuric spots and angulated ulcers, multiple deep ulcers covered with a blackish eschar, superficial atrophic scars of old, healed lesions, face was diffusely infiltrated Yes No Fever Yes Bilaterally, the ulnar, radial, lateral popliteal, posterior tibial and great auricular nerves were moderately thickened Ulcerated epidermis and dermis. Infiltrate of foamy macrophages NR Yes Yes
17 8 Erythematopurpuric, irregularly-limited spots appeared, hemorrhagic blisters and resulting necrotic ulcers Yes No No Yes NR NR NR Yes Yes
18 9 Multiple deep ulcers, atrophic scars Yes No Fever Yes Bilaterally, the ulnar, radial, lateral popliteal, posterior tibial and great auricular nerves were moderately enlarged Ulcerated epidermis and dermis along with foamy macrophages, ischemic necrotizing vasculitis, fibrinoid necrosis and new vessel formation. Clumps of AFB periadnexally, perivascularly, and within macrophages and endothelial cells NR Yes Yes
19 10 Disseminated polygonal necrotic foci and some mummified areas Yes No No NR Peripheral nerves were not thickened Necrosis of the upper dermis. Inflammatory infiltrate around multiple vascular walls with concomitant degeneration NR Yes Yes
19 11 Disseminated polygonal purpura, necrosis, saddle nose Yes No No NR Retroauricular nerves on the left were thickened Necrosis; infiltrates of epithelioid cells, lymphocytes, plasma cells and neutrophils NR Yes Yes
20 12 Necrotizing lesions with large polygonal scars NR No No NR NR NR NR Yes Yes
21 13 Purpuric macules, dysesthesias, necrosis No Fever NR NR Moderate infiltrate of foam cells which followed the linear paths of the blood vessels and nerves, in some areas that had occlusive vasculopathy and neutrophilic nuclear dust. Fite Faraco staining: positive for Mycobacterium lepraein the foam cells, interstitial cells, and endothelial cells NR Yes Yes
22 14 Multiple irregular dark violaceous purpura with angular, ragged margins and scabs Yes Yes Fever NR NR Atrophic epidermis with an intact epidermis Yes Yes Yes
23 15 Shallow polygonal ulcers with fibrinonecrotic base and irregular erythematous edges, bilateral necrosis on the ear, elbows, buttocks and toes, left ankle revealed tendon exposure NR No Fever NR NR Superficial and deep inflammatory perivascular lymphohistiocytic infiltrate, with Virchow’s cells NR Yes Yes
24 16 Ulcerations, hypopigmented macules, leonine facies Yes Yes Fever NR NR Epidermal necrosis NR Yes Yes
25 17 Necrosis NR No Fever NR Bilateral thickening of the ulnar nerves Focal necrosis. Foamy macrophages within the dermis NR Yes Yes
26 18 Polymorphous necrotic-haemorrhagic macules with irregular shapes, angulated or ‘stellar’; the collapse of the nasal pyramid, atrophy of both auricular lobes, diffuse infiltration of the skin of the trunk, atrophy of both thenar and hypothenar eminences of both hands, with flexion of the proximal interphalangeal joints and claw fingers of both hands; blue discoloration of the right big and second toe with distal gangrene Yes No Fever Yes Superficial peripheral nerves did not appear enlarged or painful on palpation Epidermis was necrotic. Perineural and periadnexal infiltrate with foamy macrophages NR Yes Yes
27 19 Ulcers, necrosis Yes No NR Yes Superficial cutaneous nerves were thickened NR NR NR NR
28 20 Palpably nodular purple-reddish lesions (nonpainful); diffuse infiltrate in the face; vesicles, blisters and necrosis Yes Yes Fever NR NR Polymorphonuclear infiltrate with plasmocytes, eosinophils, lymphocytes and fibrinoid necrosis NR NR NR
28 21 Plaques and nodules (nonpainful, nontender); pustules and ulcers Yes Yes Fever NR NR Necrotizing vasculitis (polymorphonuclear infiltrate with foamy histiocytes, plasmocytes, eosinophils and lymphocytes in the dermis and hypodermis and fibrinoid necrosis in the vessel wall NR NR NR
28 22 Necrotic ulcers in both hands Yes No Fever NR NR Necrotizing vasculitis NR NR NR
28 23 Necrotic ulcer lesions, erythematous-violaceous plaques in both arms and legs Yes No Fever NR NR Necrotizing vasculitis NR NR NR
28 24 Macular and atrophic scarring skin lesions on the ear lobule and both lower extremities with alteration of thermalgesic sensitivity on these lesions Yes No Fever NR NR Vasculitis septal and lobulillar hypodermitis NR NR NR
29 25 Infiltrated face, besides ulceronecrotic geometrically shaped lesions Yes No No NR Bilaterally thickened fibular nerves, which were painless to palpation Ulcerated epidermis. Dense histiocitary infiltrate with peri-adnexal and interstitial distribution; the presence of vascular fibrinoid necrosis with neutrophilic infiltrate and associated edema NR Yes Yes
30 26 Multiple nodules, hemorrhagic crusts, necrotic crusts with surrounding areas of irregularly-shaped purpura on swollen legs Yes Yes No NR NR Epithelial necrosis with re-epithelization, subjacent neutrophils, fibrin and occlusion of superficial dermal vessels. Diffuse granulomatous dermatitis without panniculitis and presence of plasma cells, lymphocytes and foamy histiocytes, many of them with globi NR Yes Yes
31 27 Crops of painful, tender and erythematous macules and papules spread over the body Yes Yes Fever No No, however, the patient complained of paraesthesias and dysesthesias in both forearms Abundant vacuolated histiocytes within parafollicular areas and sinuses; Fite stain demonstrated innumerable AFB NR NR NR
31 28 Flat infiltrative, confluent, deeply livid, sharply outlined and in variable sizes and shapes; left earlobe was indurated, the forehead subcutaneous tissue was swollen and the sclerae and conjunctivae were injected Yes No Fever NR NR Foci of necrosis in the dermis and epidermis, vasculitis and lymphohistiocytic infiltration of the appendages. A Fite stain further revealed AFB in histiocytes in the dermis and subcutaneous tissue, around nerves and arteries, and in the endothelial cells of blood vessels NR Yes Yes
32 29 Livedoid maculae and painful, polymorphic ecchymotic maculae, some of them topped by whole and tense blisters with hyaline content. There were infiltrated ulcerated plaques, with irregular outlines and ill-defined borders, in addition to small erythematous subcutaneous nodules. Most of the lesions presented an ulcerated surface covered by scarce granulation tissue, purulent fibrin material, sometimes hemorrhagic and honeycolored crusts NR Yes Fever NR NR Extensive areas of necrosis and suppuration in the dermis and subcutaneous regions, with thrombosed blood vessels in their midst. By means of Fite Faraco staining were detected AARB in the neighborhood of these vessels, within their walls, invading endothelial cells and the vascular lumen, besides focal areas of histiocyte proliferation, with ample xanthomatous cytoplasm NR Yes Yes
33 30 Numerous, nonpalpable, thread-like and blanchable blood vessels; face was “swollen and puffy,” “diffuse central facial edema;” ear lobes were enlarged; hands and fingers, as well as his feet and toes, were described as having a nontender, nonpitting edema; toes had a “red-purplish discolouration” Yes No No NR NR Heavy infiltrate of macrophages in the dermis and subcutis. AFB were numerous NR Yes Yes
34 31 Confluent, sharply marginated, purpuric patches, bullae, gangrenous and ulcerated; multiple, irregularly shaped, angulated, purpuric macules; face and ears were diffusely infiltrated No No Fever NR NR Extensive necrotizing leukocytoclastic vasculitis and numerous foamy histiocytes with globi of AFB in the dermis and subcutis NR NR NR
34 32 Diffusely infiltrated waxy skin, flattened nasal bridge. Both ears were grossly enlarged with hemorrhagic blisters. There were widely disseminated, bizarrely shaped, purpuric macules and patches of varying sizes affecting all four limbs and the lower half of the trunk Yes No Fever NR Thickened ulnar nerves Multiple perivascular and periadnexal, poor to moderately formed granulomata in the dermis and subcutis, composed of a few foci of epithelioid histiocytes, abundant foamy macrophages, lymphocytes and occasional plasma cells. Wade–Fite stain showed numerous masses of AFB in macrophages, endothelial walls and sweat glands NR Yes No
34 33 Progressive gangrene affecting all four limbs; collapsed nasal bridge; multiple, bizarrely shaped, purplish papules and plaques; necrotic ulcers; scrotal skin was also gangrenous Yes No No NR NR Endothelial proliferations, as well as interstitial, perivascular and periadnexal infiltrates of foamy macrophages, with globi of AFB admixed with acute inflammatory cells and prominent leukocytoclasia in both the dermis and subcutis NR NR NR
35 34 Cutaneous ulcerations, purpuric erythematous cutaneous lesions, diffusely infiltrated “myedematous” xerotic skin Yes No Fever NR Bilateral swelling of ulnar and radial nerves Necrotizing vasculitis of dermal vessels with AFB in endothelial cells NR Yes Yes
36 35 Inflammatory livedo, several infiltrating maculo-papular lesions and painful erythemato-pupuric lesions Yes No No NR NR Epidermic necrosis with aspects of leukocytoclastic vasculitis NR NR NR
37 36 Diffuse skin infiltration, saddle nose, necrotic, dark, irregular-shaped lesions Yes No No NR NR Epidermal necrosis; intense macrophagic infiltration in the adipose tissue NR Yes Yes
38 37 Leonine face, extensive ecchymotic patches in association with deep ulcerative lesions Yes No Fever NR NR Atrophic epidermis with focal necrosis, swollen endothelial cells with fibrinoid necrosis and a mixed inflammatory infiltrate with nuclear dusts NR Yes Yes
39 38 Multiple superficial non-healing ulcers with hyposthetic margin, large thick nose and ears giving appearance of somewhat Leonine face NR No Fever NR NR NR NR NR NR
40 39 Deep and irregular ulcers, areas of purpura and a few bullae NR No No NR NR Foamy macrophages and occasional neutrophils in the edematous dermis. There was leukocytoclastic vasculitis, and AFB were seen with the modified Fite stain. The direct immunofluorescence showed IgM, C3, and C1q in the walls of superficial and deep dermal blood vessels NR Yes Yes
40 40 Deep necrotic irregular ulcers, purpura and earlobes and gangrene of the toes Yes No No NR NR Dense infiltrate of neutrophils with lymphocytes NR NR NR
41 41 Skin ulcers with burning pain associated with local oedema and serous-hematic and purulent discharge Yes No Fever Yes Thickening and pain on palpation of the auricular, ulnar, median, radial, posterior tibial and common fibular nerves NR NR NR NR
42 42 Skin ulcers, necrosis, livedo Yes No No NR NR Infiltrate of histiocytes and polymorphonuclear cells, numerous intact and fragmented AFB, isolated and in globi NR NR NR
43 43 Infiltrated facies, edema and extensive erythema in the members, with disseminated and confluent erythematous-purpuric lesions, topped by blisters with well-defined borders, some with ulcerated and necrotic areas Yes No No NR NR Leukocytoclastic vasculitis with fibrinoid necrosis, foamy histiocytes occupying the lobular portion of the hypodermis and presence of numerous granular bacilli determined by Fite Faraco. This pattern is compatible with Virchow’s leprosy and Lucio’s leprosy phenomenon NR NR NR
44 44 Ulceration of the skin, swelling of the feet, erythematous acral lesions, triangular and bizarre purpuric and necrotic lesions, necrosis of pinnae and nasolabial folds, diffuse infiltration of the face Yes No No Yes Thickening of the right radial cutaneous and both ulnar nerves Necrotizing vasculitis of the small vessels in the upper dermis and endothelial proliferation of medium-sized vessel in the mid dermis; periappendageal and perivascular lymphohistiocytic infiltrate containing foamy macrophages; The infiltrate extended up to the subcutaneous fat NR Yes Yes
45 45 Purpuric appearance, with necrosis and ulceration in some of the areas, leading to sloughing in acral sites such as fingers and toes Yes No No NR NR Vasculitis with thrombosis and perivascular and periadnexial lymphocytic infiltrates as well as numerous AFB NR Yes Yes
46 46 Multiple, tender, well demarcated, purpuric skin lesions with scabs on all 4 extremities Yes No Fever NR NR Necrosis, vasculitis and innumerable AFB; nerve invasion, vasculitis and panniculitis with AFB invasion that caused skin ulceration and massive AFB burden(globi) in internal organs NR Yes Yes
46 47 Extensive skin necrosis evidenced by ulceration and gray to black discoloration NR No Fever NR NR Invasion of nerves and subcutis (deeply located) by numerous AFB-laden macrophages diagnosed LL, and vasculitis with endothelial proliferation and AFB infiltration NR Yes Yes
47 48 Ulcers, necrosi Yes No No NR NR Necrosis; AFB positive Yes Yes Yes
48 49 Facial malar flush, deep ulcerative lesions in both pretibial areas and palpable purpuric lesions NR No No NR NR Prominent dermal vascular changes with endothelial proliferation leading to luminal narrowing. Asparse to moderate inflammatory infiltrate consisting mainly of round cells with a polymorphonuclear admixture, in some areas, was present. Inflammatory cells were found primarily around and only occasionally in the wall of the vessels. Thrombosis and fibrinoid necrosis were absent. Dense aggregates of AFB were readily revealed after Ziehl-Nielsen staining in endothelial cells of even normal appearing vessels. In some places of one of the skin biopsies small aggregates of foamy histiocytes containing AFB were observed NR Yes No

NR: Not reported, AFB: Acid-fast bacilli, AARB: Alcohol-acid resistant bacilli, AFB: acid-fast bacillus

Results

The 39 articles included in this review report 49 patients, of whom 29 were men and 20 were women. The patients’ ages ranged from 13 to 86 years, with an average of 48.27 years. The cases of LP described were from 17 countries, including: Brazil (12), India (9), Argentina (5), Mexico (4), China (3), Malaysia (3), United States (3), and one each from Colombia, Ecuador, Greece, Iran, Spain, Peru, Polynesia, South Korea, Sri Lanka and Tunisia. As shown in Figure 2, of the 12 Brazilian LP cases, four were from São Paulo state, two from Rio de Janeiro state, and one each from Amazonas, Espírito Santo, Mato Grosso, Paraná, Rio Grande do Sul states and the Federal district. The three patients reported in the United States (US) were originally from Mexico and had been residing in the US for 3, 7 and 10 years, respectively. Among the three patients described in Malaysia, 2 came from Indonesia and had lived in Malaysia for 2 and 3 years, respectively. The LP case reported in Spain was of a patient from Paraguay who had been living in Spain for two years.

Figure 2:: Distribution of LP cases reported in the literature in Brazil and around the world. (Plotted using Google Maps)

Among the included cases, while one and two patients were described as having Grade 1 and Grade 2 physical disabilities, respectively, there were no descriptions for the other 46 cases. While there was no reference to the bacilloscopy in 16 patients, it was available in 33 patients. The slit skin smear was described as negative in one patient, positive in eight cases (with no report of the bacterial index) and a bacterial index of 1+, 2+, 3+ 4+, 5+ and 6+ in 1, 2, 4, 3, 6 and 8 patients, respectively.

Forty two (85.7%) patients were diagnosed with Lucio’s phenomenon without a previous leprosy diagnosis. Five patients (10.2%) presented with it during the treatment for leprosy, of which three had a history of irregular treatment. Two (4.1%) patients had it after the end of the leprosy treatment, of which one had a negative bacterial index, while it was not described for the other patient.

Clinically, all the patients reviewed had skin necrosis, irregular skin ulcers, erythematopurpuric macules and diffuse skin infiltration. While livedo was seen in three patients, eyelashes and eyebrows were absent in 37 (75.5%), lepromas were seen in 7 (14.3%) and 27 (55.1%) of them had a fever. Thickened peripheral nerves were described in 18 (36.7%) patients and 11 (22.4%) had a glove and stocking pattern of sensory impairment.

The histopathology of the cases revealed necrosis of the epidermis in 21 (42.8%), superficial and deep lymphohistiocytic inflammatory infiltrate in 42 (85.7%), solid AFB singly and in globi in the macrophages in 16 (32.6%), vessels occluded by a thrombus in 31 (63.3%) and macrophagic infiltrate in the wall and/or AFB in the wall of the skin vessels in 32 cases (65.3%).

Only 4 (8.2%) cases were positive for phenolic glycolipid-I antibody titration, while the other reports did not mention it. The polymerase chain reaction of the tissue revealed Mycobacteria in 9 (18.4%) patients, M. leprae in 5 (10.2%) and 4 (8.2%) showed the presence of M. lepromatosis. All four reported cases of M. lepromatosis were from Mexico, with one living in Minnesota for ten years and the other in Texas for seven years. While 31 patients (63.3%) had anemia with hemoglobin levels ranging from 5 to 11 g/dL (average: 9.1 g/dL), there was no information regarding the hemoglobin levels in eight cases. Leukocytosis was reported in 16 patients (32.6%) with leukocyte counts ranging from 11,230 to 69,000 cells/mm3 (mean: 26,648 cells/mm3), while nine patients (18.4%) had counts in the normal range, four (8.2%) had leukopenia and 20 (40.8%) cases did not report the white blood cell counts. Erythrocyte sedimentation rate and/or C-reactive protein levels were increased in 25 (51%) patients. IgM anti-cardiolipin was positive in four cases, negative in two and not described in 43 (87.7%) cases. Bone marrow examination was performed in three patients, of which two were positive for AFB.

Among 49 cases reported, only six patients used standard MDT exclusively, to treat Lucio’s phenomenon, of which three (50%) died; two by sepsis and one from an undetermined cause. Thirty two (65.3%) patients were given steroids as anti-inflammatory treatment with different outcomes. When this steroid treatment (n = 32) was given along with bactericidal drugs (MDT, ofloxacin and/or clarithromycin; n = 25), 17 patients (68%) survived, while eight (32%) died. When given along with bacteriostatic drugs (dapsone and/or clofazimine; n = 4), only one (25%) patient survived while three (75%) died. Besides the standard adult treatment regimen for MB leprosy, use of ten alternative drug schemes (substitute schemes) was reported [Table 3].

Table 3:: Anti-leprosy drug schemes and number of reported cases according the literature review
Anti-leprosy drug schemes Number of cases Death outcome
MDT 25 7
MDT+OFL 3 1
MDT without DDS and with OFL 1 0
DDS+CLF 3 2
DDS+RFP 1 1
DDS 1 1
(RFP+DDS) 4 years+DDS monotherapy 1 0
(RFP + DDS + CLZ)/day 4 1
(RFP + OFL + MIN + CLA)/day 1 0
RFP/m + DDS/day 1 0
(RFP + DDS + CLF + OFL)/day 1 1

MDT: Multidrug therapy; OFL: Ofloxacin; DDS: Dapsone; CLF: Clofazimine; RFP: Rifampicin; MIN: Minocycline; CLA: Clarithromycin

Fifteen patients used systemic antibiotics for sepsis, 14 (93.3%) with bactericidal antileprosy drugs and 10 (66.7%) with steroids. Nine (60%) of these patients survived, all using bactericidal antileprosy drugs, while seven (46.7%) cases survived in the steroid group. Five (33.3%) patients died, four (80%) by sepsis (three using bactericidal antileprosy drugs and one steroid exclusively) while one died of pulmonary thromboembolism.

Nine (18.4%) cases were prescribed thalidomide and eight (88.9%) steroids. Only two (4.1%) patients had used acetylsalicylic acid and, two (4.1%), pentoxifylline.

Among the 49 cases reported, debridement was performed in five patients and one of them underwent skin grafting.

Overall, improvement in the general condition and skin lesions was reported in 23 (46.9%) patients. Eighteen (36.7%) patients died, 11 due to sepsis, one due to pulmonary thromboembolism and six from unknown causes. The outcomes for eight cases were not reported.

Discussion

Despite the high number of patients with leprosy in the world, Lucio’s phenomenon is seen mostly in untreated patients and rarely reported.11-14 It is restricted to particular geographic areas of South and Central Americas and rarely reported from other parts of the world such as Africa and Asia. It may not be easily recognized, even in endemic countries which leads to delay in diagnosis and loss of treatment time.10,12,15 Several previous reports show how leprosy has been neglected, as only a few reported cases of Lucio’s phenomenon had a previous diagnosis of leprosy.

In our view, Lucio’s phenomenon is defined as a specific kind of leprosy reaction manifested by severe necrotizing lesions that can occur in Lucio–Latapi leprosy and other forms of lepromatous leprosy. The initial pathogenesis begins in the vascular endothelium, since the M. leprae parasitizes here, leading to the occlusion of deep-vein plexus veins and subcutaneous tissue, progressing to a cutaneous hemorrhagic infarction.16-18

Clinically, many authors related that Lucio’s phenomenon can resemble the necrotic variant of erythema nodosum leprosum,20,21,22,50 though there are certain differentiating features. It is characterized by a transient or persistent, blotchy, reddish-blue to purple and net-like cyanotic pattern with a burning sensation. These macular areas are sharply delineated and have a characteristic center which turns purpuric and necrotic leaving stellar atrophic scars [Figures 3 and 4].22-49 In our experience, Lucio’s phenomenon is characterized by erythematous-violaceous macular and slightly infiltrated plaques on the skin, which subsequently lead to central necrosis and ulceration, affecting mainly the limbs but also the trunk and face in the severe cases, without significant systemic involvement initially. Erythema nodosum leprosum, on the other hand, is marked by painful, erythematous tender plaques or nodules that may be superficial or deep-seated with high fever and malaise. It may also present as edema of the face, hands and feet, iritis, episcleritis, arthritis, arthralgia, dactylitis, lymphadenopathy, organomegaly and orchitis, all of which are rare or totally absent in Lucio’s phenomenon.15,16

Figure 3:: Diffuse erythematous-purpuric and ulceronecrotic lesions over the lower limbs
Figure 4:: Diffuse polymorphous necrotic-hemorrhagic lesions with irregular shapes over upper limbs and trunk

Histopathologically, Lucio’s phenomenon is characterized by a large number of AFB aggregates in the vascular endothelium, areas of fibrinoid necrosis,18 leukocytoclastic vasculitis50 and ischemic epidermal necrosis [Figures 5 and 6].18,22 Acute erythema nodosum leprosum, on the other hand, is marked by a polymorphonuclear leukocyte inflammatory infiltrate in the deeper layers of the dermis and subcutis, within preexisting lepromatous lesions, often associated with vasculitis. Edema of the dermis is another frequent finding.16 Lucio’s phenomenon presents less neutrophil infiltration compared to erythema nodosum leprosum and confirmed colonization of endothelial cells by solid-staining AFB [Figure 7]. Involvement of bone marrow and lymph nodes has been rarely described.19,32

Figure 5:: Neutrophilic inflammatory infiltrate with the presence of lymphocytes and vacuolated histiocytes with areas of vascular wall aggression (vasculitis) and thrombi (H and E, ×50)
Figure 6:: Presence of moderate bacillary load in xanthomatous histiocytes of the inflammatory infiltrate and vascular wall involvement (Fite Faraco stain, ×400)
Figure 7:: Diagrammatic illustration showing the differences between Lucio’s phenomenon and erythema nodosum leprosum respectively. a - A large number of acid-fast bacilli aggregate in the vascular endothelium, areas of fibrinoid necrosis, leukocytoclastic vasculitis and ischemic epidermal necrosis b - Polymorphonuclear leukocyte inflammatory infiltrate in the deeper layers of the dermis and subcutis, often associated with vasculitis

On correlating the clinical and histopathological findings, we corroborate the findings of Pursley and Jacobson, that in Lucio’s phenomenon, ulceration is the rule, general symptoms are scarce or nonexistent and in histopathology, there is endothelial proliferation, thrombosis, ischemic necrosis and a discrete mononuclear infiltrate along with the infiltrate of lepromatous leprosy, while in erythema nodosum leprosum, ulceration is rare, systemic signs and symptoms are common, and there are only a few bacilli present.51

Our literature review corroborates previous reports indicating that Lucio’s phenomenon and late diagnosis of leprosy are associated with madarosis, generalized skin infiltration, a high degree of disabilities and several signs and symptoms of systemic inflammation. Lucio’s phenomenon is an acute reactional clinical episode of leprosy, considering the high number of patients with anemia, leukocytosis, an acute increase in systemic markers of inflammation associated with devastating cutaneous necrosis, sepsis and the consequent high risk of death. Recent reports5,6 on the disparity between the official data and the actual incidence of leprosy highlight the hidden endemic nature of leprosy in many parts of the world,1,52,53 reports that should alert us in relation to underdiagnosis of leprosy around the world and to the possibility of the disease load increasing, and consequently in the number of Lucio’s phenomenon cases. In fact, only the early diagnosis and proper management of the leprosy patients can reduce the high morbidity and mortality of Lucio’s phenomenon, which are as worrying as the spread of infection epidemiologically, considering the high bacillary load of these lepromatous leprosy patients.

According to the reviewed literature, we would highlight that there is no consensus about the treatment of Lucio’s phenomenon. In addition to specific MDT, steroids, anticoagulants, systemic antibiotics, surgical debridements and skin grafting were described with variable outcomes. In summary, regarding treatment, three points deserve to be emphasized: the use of multibacillary MDT due to the patients’ high bacillary load, the use of immunosuppressant and anticoagulants due to vascular aggression and necrosis, and the care of multiple cutaneous ulcers and consequent risk of infection and sepsis.

Limitations

The major limitation of our study is the low number of case reports reviewed which is due to the low incidence of Lucio’s phenomenon and difficulty in its diagnosis.

Conclusion

There are only a few articles on Lucio’s phenomenon, most of them being case reports. Clinically, it is characterized by crops of wine–red colored irregular macules with a characteristic center, turning purpuric, and then necrotic, leaving behind stellate atrophic scars after healing. In general, it is associated with clinical signs of advanced leprosy such as diffuse skin infiltration and madarosis. Furthermore, it is characterized by a high bacterial index and histopathologically by the presence of AFB in the vascular endothelium associated with thrombosis and/or leukocytoclastic vasculitis. Although there is no consensus, most reports suggest that the treatment of Lucio’s phenomenon should use bactericidal antileprosy drugs (MDT or alternatives schemes) and systemic steroids. All should be aware of the risk of sepsis, which should be treated immediately if it occurs.

Acknowledgment

The authors thank the dermatopathologist Bernard Kawa Kac for illustration number seven of this review.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

The financial support was provided by the Center of National Reference in Sanitary Dermatology focusing on Leprosy of Ribeirão Preto Clinical Hospital; MS/FAEPA-FMRP-USP (749145/2010, 767202/2011).

Conflicts of interest

There are no conflicts of interest.

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