Therapeutic paradox: Mycobacterium indicus pranii (MIP) vaccine-induced erythema nodosum necroticans and acute foot drop

Dear Editor,

Immunomodulating agents offer a broad spectrum of therapeutic benefits, addressing conditions from bacterial infections to malignancies. The Mycobacterium Indicus Pranii (MIP) vaccine is one such immunomodulating agent developed in India for use in leprosy. It aids leprosy treatment by boosting bacillary clearance, accelerating clinical recovery, and inducing lepromin conversion in anergic cases.

A 49-year-old man with a 2-year history of fever and evanescent nodular skin lesions presented to our department. On slit skin smear, his bacteriological index (BI) was 6+ and morphological index (MI), 20%. He was diagnosed as a case of borderline lepromatous Hansen’s disease (BLHD) with chronic recurrent Erythema Nodosum Leprosum (ENL) after biopsy. His BI was 6+ on histopathology. Patient was treated with multibacillary multidrug therapy (MB-MDT) and 200 mg thalidomide with good control of the ENL lesions.

Because of persistent high BI (5+) and MI(15%), he was administered 0.1 mL (0.5 × 10⁹ cells) of the MIP vaccine in both deltoids 4 months later, to improve bacterial clearance. Three days after the first dose, he developed high-grade fever, arthritis, ulcerative lesions on his extremities and trunk, and weakness of his right foot. Examination revealed ulcerated plaques with yellowish-black crusting over all limbs and trunk, with no signs of neuritis. Right-sided foot drop was present [Medical Research Council (MRC) grade -3] [Figures 1a and b]. Differentials considered were erythema nodosum necroticans (ENN), Lucio phenomenon, and vasculitis.

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Figure 1a:

Plaques with thick yellowish crusting and focal ulcerations on the left upper and lower limbs.

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Figure 1b:

Right foot drop is evident by weakened dorsiflexion as compared to the left side.

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Laboratory investigations revealed haemoglobin values of 8.2 g/dL, total leukocyte count of 15,200/mm³ (neutrophils 80%, lymphocytes 14%), SGOT/PT levels at 11/168 IU/L, and a serum alkaline phosphatase of 931 IU/L. Blood cultures were sterile, but pus culture grew Pseudomonas aeruginosa. Histopathology of the ulcerated plaque revealed a dense inflammatory infiltrate predominantly composed of plasma cells and lymphocytes with scattered foamy histiocytes around blood vessels and adnexal structures. The deep dermis and subcutis showed foci of necrosis, while medium-sized arteries exhibited intimal swelling, transmural lymphohistiocytic inflammation and bacilli within the vessel wall (BIG-5+) [Figures 2a and b]. The prominence of plasma cells was in keeping with histological features of chronic ENL, consistent with the biopsy being performed more than 72 hours after the onset of the reaction, as described by Chatterjee et al.¹ Drug resistance testing was negative, and genotyping revealed the presence of M. leprae. Pre-vaccination nerve conduction studies (NCS) showed absent bilateral sural sensory nerve action potentials, while post-vaccination studies revealed newly absent right posterior tibial and bilateral common peroneal compound muscle action potentials, consistent with vaccine-induced reactive motor neuropathy. The final diagnosis of vaccine-induced ENN with acute foot drop was supported by clinical chronology, NCS findings, and a Naranjo score of 4, indicating a possible adverse drug reaction.²

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Figure 2a:

Section shows skin with small vessel vasculitis and surrounding necrosis (bold arrows), deep dermal necrosis (asterisk) and a large subcutaneous arteriole with transmural inflammation (thin arrow). (Haematoxylin & eosin, 40x).

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Figure 2b:

Section shows a large subcutaneous arteriole with transmural inflammation (arrow). (Haematoxylin & eosin, 100x).

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Based on the pus culture sensitivity reports, antibiotic therapy was escalated from intravenous ceftriaxone to piperacillin-tazobactam after 72 hours. The patient was initiated on low-dose oral prednisolone (20 mg) with MB-MDT. Thalidomide was discontinued due to the emergence of motor neuropathy. After 10 days, the prednisolone dose was escalated to 1 mg/kg/day and subsequently tapered by 10 mg per month over a period of 8 months. The patient showed significant improvement in cutaneous lesions and the associated foot drop (MRC grade -4). Owing to the neurological complications, the MIP vaccine was discontinued to mitigate any future risks. At 14 months of MB-MDT, BI remains 2+ and MI, 0%. A repeat biopsy is scheduled at the end of the 2-year treatment period.

A study by De Sarkar et al.³ found that individuals receiving the MIP vaccine along with MDT experienced a higher incidence of Type 1 Reactions (T1R: 30% vs. 10%) but a lower incidence of Type 2 reactions (T2R: 15% vs. 25%) and reaction-associated neuritis (10% vs. 20%) compared to those on MDT alone. Our case is consistent with the prior report by Kothari et al, where MIP vaccination triggered T2R in a patient with high bacillary load and prior ENL history, likely due to enhanced bacillary clearance leading to excess antigen release and immune complex formation.⁴

ENL has also been reported following the Indian Cancer Research Institute (ICRC) vaccine, influenza vaccines, and the COVID-19 vaccine.⁵ A case of ENL with foot-drop has been reported with COVID-19 vaccination.⁶ However, to the best of our knowledge, the development of ENN with acute foot drop following administration of the MIP vaccine has not been reported.

While MIP vaccination can influence immune response patterns, severe reactions are uncommon. Our case underscores the need for high vigilance for this rare but severe complications.