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A CASE OF SEPTIC SHOCK ERYTHEMA NODOSUM LEPROSUM Vinodkumar Radhakrishnan(1), G.Vasumathi(1), A.Ramalingam(1),S.M.Sujatha(1) Abstract Hansens Disease is one of the common treatable dermato-neurologic manifestations of a chronic granulomatous infectious disease. ENL or Type 2 Lepra reaction is an immune complex hypersensitivity phenomenon occurring in patients with polar or borderline lepromatous leprosy. It affects skin, peripheral nerves & mucous membranes. It follows initiation or completion of leprosy treatment in 90% of cases but can rarely precede treatment. This case describes a Lepra Reaction presenting with septic shock as a first manifestation even before treatment initiation. Patients may present with ENL as their first manifestation of leprosy which predominantly presents as crops of painful erythematous nodules and in severe cases it presents with fever, uveitis, arthritis, hypotension and tachycardia which mimics septic shock and can be lifethreatening. This case illustrates the importance of diagnosing an immune reaction in the setting of leprosy and clinical suspicion and recognition of this syndrome is critical to instituting appropriate therapy at early stage to prevent damaging effects. KEY WORDS Hansens disease, Lepra Reaction, Erythema Nodosum Leprosum (ENL), Septic Shock. INTRODUCTION: Lepra Reactions are immunological phenomenon caused by acid fast bacilli affecting skin peripheral nerves and mucous membranes. It can occur before during or after completion of MDT for Leprosy. This case describes a lepra Reaction presenting with systemic manifestation before treatment initiation in the form of septic shock as a first manifestation. Patients may present present with ENL initially seen as crops of painful erythematous nodules and in severe cases it presents with fever, uveitis, arthritis, hypotension and tachycardia which mimics septic shock and can be lifethreatening. This case illustrates the importance of diagnosing an immune reaction in the setting of leprosy and clinical suspicion and recognition of this syndrome is critical to instituting appropriate therapy at early stage to prevent damaging effects. CASE REPORT : We had a 24 yrs female admitted in our emergency departement with high grade fever and myalgia for 2 weeks and she was dyspnoeic in a critically ill state. She also had history of headache and vomiting. Her past medical history was insignificant except for history suggestive of allergic skin rashes. She was drowsy but oriented, febrile, dehydrated. BP – 80/60 mm/hg PR – 120/min regular RR – 24 /min .Her systemic examination was unremarkable including eyes and Vol 2 | Issue 3 | July- September | 2015 Stanley Medical Journal joints. She had multiple small irregular erythematous maculo-papular & nodular eruptions and infiltrated plaques. They were non itchy and tender seen on her face, trunk, abdomen, back and limbs. Multiple chronic atrophic patches were seen over both leg and forearm. Genitals, palm and sole were normal. She had diffuse hair loss but peripheral nerves had no thickening. Inv: CBC: HB 11.6 gm% Total counts – 21,000 cells/cu.mm P 80 L15 E2 M3% PLT 2.9 lakhs. RFT: WNL, LFT: T.B – 0.8, T.P-6.9, Alb-4.3 g/dl, SGOT-62, SGPT-92, ALP-127 CXR: NAD; ECG: Sinus Tachycardia CRP: Positive 13 mg/L ESR: 43 mm at first hour - both raised. Problems: Fever / maculopaular skin lesions? Acute on chronic / Sespis / Septic shock. She was treated with iv crystalloids, Inotropes, antibiotics, PPI, anti-pyretics, antihistamines and skin emollients. During further stay her fever spiked intermittently. Skin lesions worsened (figure 1 and 2) and she started to have severe knee joint pain s/o Arthritis. It was managed with NSAIDS. In view of persistent fever Antibiotic escalated. Pt still had spikes of Fever, BP Improved. She started to have an acute onset of visual blurring in right eye assoc with watering and discomfort. Right eye: - AC flares cells+ broken synechia - ant capsule involved Visual 1. Department of General Medicine, Stanley Medical College 15 Vol 2 | Issue 3 | July-September | 2015 Stanley Medical Journal Figure 1 : Multiple erythematous maculo-papular eruptions and infiltrated plaques Figure 2: Painful erythematous nodules is a predominant feature of ENL SKIN LESIONS acuity 3/60 – 6/36. Impression: Acute Iridocyclitis (figure 3). Hence started on Ciprofloxacin and cyclosporin eye drops. We have a patient who presented to us with FEVER – unresolved with antibiotics - SKIN LESION WORSENING + ARTHRITIS + UVEITIS. All septic workup turned out to be negative. What is left? Hansen’s had to be ruled out. Hence we proceeded with a SSS smear which turned out be POSITIVE for acid fast bacilli and bacillary index varied 3+ to 4+ at different sites. (Figure 4) . OTHER Investigations done: Finally the skin biopsy done showed epidermal thinning and atrophy. Rete-ridges were lost while in dermis the subepidermal free zone of Unna (grenz zone) was spared; plenty of neutrophils in the dermis with Virchow Cells (macrophages) VACUOLATED FOAMY CYTOPLASM (figure 5) seen - feature classical of LEPROMATOUS LEPROSY. ECHO: Normal No vegetations. ASO/ ANA/ RF : Negative CPK : 46 IU/L — FLP & Thyroid profile – normal limits; DIFFERENTIAL DIAGNOSIS: (TABLE 1) BIOPSY REPORT: Considering the clinical manifestations in our patient Table 1: Maculo papular Skin Rash in patients with fever and uveitis. CTD /vasculitis: Viral infections: cannot be ruled out ANA/RF : negative. Pulse - normal Cutaneous Drug Reactions: old skin lesions worsening. Peripheral Smear: inc Neutrophils. HIV: negative Syphilis – palms & soles spared VDRL negative, HBsAg Anti HCV Negative EM/TEN/SJS/TSS Tuberculosis/verrucosa cutis : Mucosal sites are normal. No blisters. Mantoux - negative, Sputum AFB & C/S : negative Gram negative sepsis: Sero Negative Arthritis: All cultures sterile, Lepto/ WIDAL/ QBC/ MPMF/Dengue Xray knee /pelvis with Both Hip and LS spine : Normal : Negative no other associated symptoms Uveitis with Skin lesions Sarcoid /TB: Serum calcium -normal, Xray Chest : NAD , No hilar Adenopathy 16 Diabetes : RBS normal Behcets : No oral /genital ulcers IBD :No symptoms of Altered bowel habits , Stool for ova cyst : Negative , USG abdomen : NAD deformity. Two types of reactions1 are recognised: Reversal Reaction (RR)-TYPE 1 and Erythema Nodosum Leprosum (ENL) – TYPE 2. Together they may affect 30–50% of all MB leprosy patients2. Figure 3 : Iridocyclitis FINAL DIAGNOSIS: Hence with her dramatic inflammatory presentation final diagnosis was established as LEPROMATOUS LEPROSY IN TYPE 2 LEPRA REACTION – Erythema nodosum leprosum (ARTHRITIS +UVEITIS + SEVERE SKIN ERUPTIONS) possibly VIRAL EXANTHEMA precipitating ENL. TREATMENT: Hence she was started on MB-MDT regimen and Steroids and she showed dramatic clinical improvement and discharged. Her follow up over the next four months was also uneventful. DISCUSSION: Hansens Disease is one of the common treatable dermato-neurologic manifestations of a chronic granulomatous infectious disease. Because M. leprae infects peripheral nerves, the inflammation associated with reactions is a medical emergency. Severe nerve injury may develop rapidly, with subsequent loss of sensation, paralysis and Figure 4 : SLIT SKIN SMEAR Multiple pink coloured Acid fast solid staining rods in groups on a background of neutrophils Reversal Reaction: Occurrence of either or both of the following in a patient with leprosy (mostly borderline forms) namely increased inflammation of skin lesions, inflammation of nerves (manifesting as new motor/ sensory impairment, nerve pain or tenderness) may show increased function loss, and sometimes acral edema. T1R could occur before, during or after treatment with multi drug therapy (MDT). The majority (about 50%) of reactions occur during treatment with MDT but approximately 25% of patients present with a type 1 reaction at the time of diagnosis. Approximately 30% of patients with borderline leprosy go on to develop T1R at some point during their illness3. ENL or type II reaction is an immunological phenomenon with the involvement of both the humoral and cell mediated immune responses to Mycobacterium Leprae with elevated levels of TNF alpha4. ENL may occur following initiation of leprosy treatment in 90% of cases but can rarely precede4 or even follow completion of treatment as in our patient. It can occur as a single acute episode, but frequently develops into a chronic condition with recurrent episodes5. Immune responses causing ENL are triggered by high loads of fragmented bacilli in skin tissue6. ENL usually occurs in leprosy patients classified as lepromatous (LL) or borderline lepromatous leprosy BL (Ridley-Jopling), comprising the multi-bacillary (MB) patient group, as defined by WHO. There is occurrence of crops of tender erythematous subcutaneous nodules often in the face or extensor surfaces of Figure 5 : SKIN BIOPSY Vol 2 | Issue 3 | July- September | 2015 Stanley Medical Journal 17 Vol 2 | Issue 3 | July-September | 2015 Stanley Medical Journal 18 the limbs as a predominant feature. There may be associated systemic illness like fever, malaise, weight loss, peripheral oedema, arthralgia / arthritis, bone pain7. Severe ENL reaction is often recurrent and chronic and may vary in its presentation like multiple ulcerating pustular nodules, or neuritis. Recurrence is the rule rather than the exception. Involvement of other organs (e.g. eyes, testes, lymph nodes and joints) sometimes arthritis occurs, or lymphadenitis, orchitis may be encountered as well as iridocyclitis and glaucoma which can lead to blindness. Hypotension and tachycardia can occur which may mimic septic shock and it can be life-threatening7, 8. General principles of Management: Systemic corticosteroids are the first line of treatment for 12 weeks accompanied with MDT regimen9. Management with corticosteroids: If still on anti-leprosy treatment, continue the standard course with MDT. Use adequate doses of analgesics to control fever and pain. Use standard course of prednisolone in dosage per day not exceeding 1 mg/Kg body weight. Management with clofazimine and corticosteroids is indicated in cases with severe ENL who are not responding satisfactorily to treatment with corticosteroids or where the risk of toxicity with corticosteroids is high. Start clofazimine 100 mg three times a day for maximum of 12 weeks. Complete the standard course of prednisolone. Taper the dose of clofazimine to 100 mg twice a day for 12 weeks and then 100 mg once a day for 12-24 weeks. If the MDT treatment is already completed there is no need to restart MDT. It takes about 4-6 weeks for clofazimine to take full effect in controlling ENL. Other drug claimed to be useful in ENL is pentoxifylline10, 11 alone or in combination with clofazimine/prednisolone. Due to the well-known teratogenic side effects World Health Organisation does not support the use of thalidomide in the management of ENL. Cyclosporine has been used with mixed results12. Azathioprine and methotrexate have been used in combination with prednisolone for treatment of Type 2 reactions and may offer a steroid sparing regimen for treatment 13. In our patient Lepra reaction (ENL) presented as a first manifestation of Leprosy associated with septic shock14. Further she had no classical features of leprosy like hypoanesthetic patches, peripheral nerve thickening, sensory symptoms or trophic ulcers which makes this case unique. This case mainly illustrates the importance of diagnosing an immune reaction in the setting of leprosy. Unusual presentation of leprosy should be clinically suspected and recognized as it is critical for instituting appropriate therapy at early stage to prevent damaging effects. Hence increased awareness may avoid delay in diagnosis. REFERENCES: 1. WHO Expert Committee on Leprosy (2010: Geneva, Switzerland).Global leprosy situation, 2010. Weekly epidemiological record 85: 337–348. 2. Scollard DM et al. The continuing challenge of leprosy. Clinical Microbiology Reviews, 2006, 19:338–381. 3. Leinhardt C, Fine PEM. Type 1 reaction, neuritis and disability in leprosy: What is the current epidemiological situation? Leprosy Review 1994; 65: 9 - 33 4. Pocaterra L, Jain S, Reddy R et al. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 2006; 74: 868-7 5. Myerson M. Erythema Nodosum Leprosum. International Journal of Dermatology, Vol. 35, June 1996. 6. Wemambu SNC, Turk JL, Waters MFR, Rees RJW (1969) Erythema nodosum leprosum: a clinical manifestation of the arthus phenomenon. The Lancet 294: 933–935. 7. A Systematic Review on the Epidemiological Data of Erythema Nodosum Leprosum, a Type 2 Leprosy Reaction. Carlijn G. N. Voorend, Erik B. Post*The Royal Tropical Institute (KIT Health), Amsterdam, The Netherlands 8. Van Veen NH, Lockwood DN, Van Brakel WH, Ramirez Jr J, Richardus JH (2009) Interventions for erythema nodosum leprosum. A Cochrane review. Lepr Rev 80: 355–372 9. Welsh O et al. A new therapeutic approach to type II leprosy reaction. International J. Dermatology, 1999,38: 931-933. 10. Nery JA et al. The use of pentoxifylline in the treatment of type 2 reactional episodes in leprosy. Indian J. Leprosy, 2000, 72 (4): 457-467. 11. Moreira AL et al Comparison of pentoxifylline, thalidomide and prednisone in the treatment of ENL. International Journal of Leprosy and Other Mycobacterial Diseases, 1998, 66:61–65. 12. Mascarell L, Truffa-Bachi P. New aspects of cyclosporin A mode of action: from gene silencing to gene upregulation. Mini Reviews in Medicinal Chemistry, 2003, 3:205–214. 13. Mahajan VK, Sharma NL, Sharma A. Pulse dexamethasone, oral steroids and azathioprine in the management of erythema nodosum leprosum. Leprosy Review, 2003, 74:171–174. 14. Type 2 Lepra Reaction as a Cause of Pyrexia of Unknown Origin KV Vinod Et al JAPI •April 2012 • Vol 1. 60 ACKNOWLEDGEMENT: We are thankful to The Department of Dermatology, Stanley Medical College Hospital Chennai – 600 001 for helping us in Skin Biopsy.