How can a lepra reaction be diagnosed in a patient receiving multidrug therapy for leprosy, including diagnostic criteria and an algorithm, and how can it be differentiated from dapsone hypersensitivity syndrome and from progression to multibacillary disease?

Diagnosing Lepra Reactions in Leprosy Patients on Multidrug Therapy

Lepra reactions are diagnosed primarily by clinical criteria including the timing of symptom onset, specific cutaneous patterns, and systemic features, with Type 1 reactions occurring within weeks to months after starting treatment and presenting with increased erythema and swelling of existing lesions, while Type 2 reactions manifest as new tender nodules (erythema nodosum leprosum).

Diagnostic Criteria for Type 1 (Reversal) Reactions

Clinical Features:

• Increased erythema, edema, and tenderness of pre-existing leprosy lesions occurring during or after initiation of multidrug therapy 1
• Acute neuritis with nerve pain, tenderness, and new sensory or motor deficits 1
• Timing: Typically develops within weeks to several months after starting treatment, though can occur before treatment 1
• Constitutional symptoms are usually mild or absent in Type 1 reactions 1

Diagnostic Criteria for Type 2 Reactions (Erythema Nodosum Leprosum)

Clinical Features:

• New crops of tender, erythematous nodules on the face, arms, and legs that were not present before 2
• Systemic symptoms: Fever, malaise, arthralgia, and constitutional upset 2
• Atypical presentations may include bullous lesions, necrotic ulcers, or urticarial plaques 2
• Timing: Occurs in over 50% of lepromatous leprosy patients, typically during treatment 2

Critical Differentiation: Lepra Reaction vs. Dapsone Hypersensitivity Syndrome

Dapsone Hypersensitivity Syndrome Diagnostic Criteria:

Timing is the most critical distinguishing feature:

• Onset 2-8 weeks after starting dapsone (mean 29.82 days, range 14-49 days) 3, 4
• Dapsone hypersensitivity syndrome characteristically begins 1-4 weeks into therapy 5

Clinical Triad (must have all three):

• Fever (present in 100% of cases) 3
• Generalized lymphadenopathy (present in 80.8% of cases) 3
• Exfoliative dermatitis or widespread maculopapular rash (most common cutaneous manifestation) 3, 6

Additional Features:

• Hepatitis with jaundice (84.6% have elevated bilirubin) 3, 6
• Hepatosplenomegaly (73% have hepatomegaly) 3, 6
• Facial and peripheral edema 3, 6
• Mucosal involvement (oral erosions, conjunctivitis) 6
• Laboratory findings: Elevated liver enzymes (100%), leukocytosis (69.2%), anemia (46.2%), eosinophilia (15.4%) 3

Key Differentiating Features:

Feature	Type 1 Lepra Reaction	Type 2 Lepra Reaction	Dapsone Hypersensitivity Syndrome
Timing	Weeks to months after MDT	During treatment	2-8 weeks after starting dapsone [3]
Skin lesions	Increased erythema of existing lesions [1]	New tender nodules [2]	Generalized exfoliative dermatitis or maculopapular rash [3]
Fever	Mild or absent [1]	Present [2]	Always present [3]
Lymphadenopathy	Absent	May be present	Generalized (80.8%) [3]
Hepatitis/Jaundice	Absent	Absent	Present (84.6%) [3]
Mucosal involvement	Absent	Absent	Common (oral erosions, conjunctivitis) [6]

Differentiation from Progression to Multibacillary Disease

Progression to multibacillary leprosy is NOT an acute event:

• Progression represents a gradual shift in immune response over months to years, not an acute reaction 1
• New lesions appear slowly with increasing bacterial load, without acute inflammation 1
• No systemic symptoms such as fever, malaise, or acute neuritis 1
• Skin smears show increasing bacterial index over time, whereas lepra reactions occur with stable or decreasing bacterial loads during treatment 1

Diagnostic Algorithm

Step 1: Establish Timeline

• Document exact date of MDT initiation and date of symptom onset 3
• If symptoms begin 2-8 weeks after starting dapsone, dapsone hypersensitivity syndrome is the primary concern 3, 4

Step 2: Assess Skin Lesion Pattern

• Worsening of pre-existing lesions → Type 1 reaction 1
• New tender nodules → Type 2 reaction 2
• Generalized exfoliative dermatitis or widespread maculopapular rash → Dapsone hypersensitivity syndrome 3

Step 3: Check for Systemic Features

• Fever + generalized lymphadenopathy + hepatitis → Dapsone hypersensitivity syndrome until proven otherwise 3, 6
• Fever + new nodules without hepatitis → Type 2 reaction 2
• Acute neuritis without systemic symptoms → Type 1 reaction 1

Step 4: Laboratory Evaluation

• Complete blood count: Leukocytosis and eosinophilia suggest dapsone hypersensitivity syndrome 3
• Liver function tests: Elevated transaminases and bilirubin strongly suggest dapsone hypersensitivity syndrome 3, 6
• Methemoglobin level: Elevated in dapsone toxicity 5, 7

Step 5: Immediate Management Decision

• If dapsone hypersensitivity syndrome is suspected, immediately discontinue dapsone and do not rechallenge 6, 3
• Continue leprosy treatment with clofazimine and rifampicin only 6
• If Type 1 or Type 2 reaction is diagnosed, continue multidrug therapy while treating the reaction 1, 2

Critical Pitfalls to Avoid

Do not confuse Type 1 reaction with dapsone hypersensitivity syndrome:

• Both can occur during the same timeframe after starting MDT 4
• The presence of hepatitis, generalized lymphadenopathy, and mucosal involvement distinguishes dapsone hypersensitivity syndrome 3, 6
• A case report documented concurrent Type 1 reaction and dapsone hypersensitivity syndrome, requiring careful clinical assessment 4

Do not rechallenge with dapsone if hypersensitivity syndrome is diagnosed:

• Dapsone hypersensitivity syndrome has a mortality rate of 11.5% due to hepatic failure 3
• Patients who survive can be safely treated with alternative regimens (clofazimine + rifampicin) 6

Monitor for severe complications:

• Dapsone hypersensitivity syndrome can progress to exfoliative dermatitis, shock, acute renal failure, pancytopenia, and sepsis 6
• Early recognition and dapsone discontinuation are essential to prevent mortality 3