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

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

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

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Figure 1:

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

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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.

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Figure 2:

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

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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].

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

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Figure 3:

Diffuse erythematous-purpuric and ulceronecrotic lesions over the lower limbs

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Figure 4:

Diffuse polymorphous necrotic-hemorrhagic lesions with irregular shapes over upper limbs and trunk

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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

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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)

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Figure 6:

Presence of moderate bacillary load in xanthomatous histiocytes of the inflammatory infiltrate and vascular wall involvement (Fite Faraco stain, ×400)

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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

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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 reports^5,6 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.

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.