1. Poster produced by Faculty & Curriculum Support (FACS), Georgetown University School of Medicine 1. Data on file. Alexion Pharmaceuticals, Inc; 2. Loirat C, Frémeaux-Bacchi V. Orphanet J Rare Dis 2011;6:60-90; 3. Campistol JM et al. Nefrologia 2013;33:27-45; 4. Caprioli J et al. Blood 2006;108:1267-79; 5. Noris M, Remuzzi G. N Engl J Med 2009;361:1676-87; 6. Neuhaus TJ et al. Arch Dis Child 1997;76:518-21; 7. Ohanian M et al. Clin Pharmacol 2011;3:5-12; 8. Sellier-Leclerc AL et al. J Am Soc Nephrol 2007;18:2392-400; 9. Loirat C et al. Pediatr Nephrol 2008;23:1957-72; 10. Noris M et al. J Am Soc Nephrol 2005;16:1177-83; 11. Benz K, Amann K. Curr Opin Nephrol Hypertens 2010;19:242-7; 12. Al-Akash SI. Pediatr Nephrol 2011;26:613-9; 13. Dragon-Durey M-A et al. J Am Soc Nephrol 2010;21:2180-7; 14. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844-59; 15. Bitzan M et al. Semin Thromb Hemost 2010;36:594-610; 16. Scully M et al. Br J Haematol 2012;158:323-35; 17. Zuber J et al. Nat Rev Nephrol 2012;8:643-57; 18. Barbot J et al. Br J Haematol 2001;113:649-51 Rickettsia Induced Atypical Haemolytic Uremic Syndrome Mohamed El-Naggari 1,2, Anas Alwogud Abdelmogheth 2, Dana Al Nabhani 1, Zakaria Al Muharrmi 3, Ibtisam El Nour 1. Abstract Sultan Qaboos University Hospital; Pediatric Nephrology (1), Pediatric Intensive Care. (2) Sultan Qaboos University; Microbiology Department. (2) Muscat; Sultanate Of Oman. Corresponding Author: mnaggari@yahoo.com ; mnaggari@squ.edu.om. Introduction Discussion Conclusions References 1.Sallée M, Daniel L, Piercecchi MD, Jaubert D, Fremeaux-Bacchi V, Berland Y, Burtey S. Myocardial infarction is a complication of factor H-associated atypical HUS. Nephrol Dial Transplant 2010; 25(6): 2028-32. 2.Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108:1267-79. 3.Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5: 1844- 59. 4.Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011; 6: 60-90. 5.Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol 2009; 9: 729-40. 6.Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T. Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 673-81. 7.Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012; 8: 643-57. Case Report aHUS is a genetic, devastating life threatening disease that may cause sudden death vital organ damage, (1) with 65% may require permanent renal dialysis. (2) It is a complement mediated Thrombotic Micro Angiopathy (TMA) with a clinical characteristic of thrombocytopenia, evidence of microangiopathic haemolysis and organ impairment or damage. (3) Pathogenesis of aHUS is chronic uncontrolled complement activation which can be triggered by infection, autoimmune, surgery and pregnancy. (4) Rickettsial diseases are characterized by the triad of high fever, headache and general malaise, and skin rash. An 11 years old boy presented with one week history of itchy maculopapular urticarial rash over the thighs, Scattered nodular like erythematous lesions over the arms (figure 1-A) and petechial rash over the dorsum of both feet (figure 1-B). This rash associated with high grade fever reached 39.5 degree, headache and generalized body pain and joint swelling. Systemic examination revealed hepatomegaly (3cm below costal margin), splenomegaly (3cm below costal margin), generalized body tenderness, bilateral knee and ankle joint swelling some restriction of movement, mainly in flexion with partial extension. Stable and normal vital signs except fever which was persistent, high grade with partial response to antipyretic medication. Initial investigations showed mild proteinuria (24 hrs. protein 700 mg/dl), microscopic haematuria (1+), normal Complete Blood Count (CBC), normal coagulation profile, high CRP 125, high ESR 58 mm/hr, persistent unexplained low sodium 128 mmol/L, low chloride 89 mmol/L, very high Creatinine Kinase 781 U/L, serum albumin 29 g/L, normal renal function, normal complement level, elevated ALT 190 IU/L and elevated AST 250 U/L. Initial radiological assessment was completely normal including Gallium scan. Several combination of antibiotics were used with no response and persistent fever for 35 days. All investigation of autoimmune causes including vasculitis (ANA weak +ve, Anti Ds DNA –ve, ANCA weak +ve, Anti MMPO -ve, Anti PR3 –ve, normal skin biopsy), immune deficiency, malignancy (bone marrow aspirate) and pyrexia of unknown origin were negative including all cultures except persistent high inflammatory markers. Fundus examination showed pre-retinal cheesy white infiltrates extending up to macula, obscuring the vessels with no hemorrhage (Fig 2-A). The differential diagnosis of ophthalmological finding were secondary leukemia, infection and immune related vasculitis. Finally, Proteus OX2 (titre 80), OX K (titre 80) came positive which is suggestive of Rocky mountain spotted fever with context of the clinical presentation (figure 4). Doxycline started with marked improvement of fever. Suddenly, the patient had a catastrophic deterioration in the form of acute renal failure (reduction of eGFR from 110 down to 20 ml/min/1.73m2) with severe reduction in UOP <0.7 ml/kg/hour, thrombocytopenia, microangiopathic hemolytic anemia (Figure 2-A), high LDH, generalized convulsions, progressive heavy proteinuria (prot./Cr. ratio 453 mg/mmol), disturbed level of consciousness that required mechanical ventilation, shock with two inotropic support, bluish dusky coloration of fingers. Urgent renal biopsy was suggestive of TMA (Figure 4-A, 4-B). Five session of double volume plasma exchange was done with no response. Eculizumab loading started after meningococcal vaccination and antibiotics prophylaxis as per protocol, with good response after third dose. The response were in the improvement of laboratory findings as shown in (figure 3). Clinically, there was improvement in ventilatory parameters that weaned gradually till extubation. The patient needed renal replacement therapy in the form of Continuos venous Haemo-Diafiltration (CVVHD) then regular haemodialysis. Meanwhile, ADAMTS13 and genetic tests came to be normal which confirms the diagnosis of aHUS. We planned to continue the patient on maintenance therapy of Eculizumab. aHUS is a genetic, devastating life threatening disease that may cause sudden death, vital organ damage, with 65% may require permanent renal dialysis. It is a complement mediated Thrombotic Micro Angiopathy (TMA) with a clinical characteristic of thrombocytopenia, evidence of microangiopathic haemolysis and organ impairment or damage. We are reporting an 11 years old boy presented with itchy maculopapular urticarial rash and Scattered nodular like erythematous lesions. This rash associated with high grade fever reached 39.5 degree, headache, generalized body pain, joint swelling, and hepato-spleenomegaly. Several combination of antibiotics were used with no response and persistent fever for 35 days. All investigation of autoimmune causes including vasculitis, immune deficiency, malignancy and pyrexia of unknown origin were negative except persistent high inflammatory markers. Fundus examination showed pre-retinal cheesy white infiltrates extending up to macula. Finally, Proteus OX 2, OX K came positive which is suggestive if Rocky mountain spotted fever with context of the clinical presentation. Doxycline started with improvement of fever. Suddenly, the patient deteriorated in the form of acute renal failure, microangiopathic hemolytic anemia, thrombocytopenia, high LDH, generalized convulsions. Renal biopsy was suggestive of TMA. Plasma exchange done with no response. Meanwhile, ADAMTS13 and genetic tests came to be normal with diagnosis of aHUS. Eculizumab started with good response after third dose of loading then started on maintenance therapy. All parameter normalized including LDH, Platelet and schistocytes count. patient progressed to end stage renal failure and dialysis dependent. High clinical suspicion of aHUS is required in all patients presenting with TMA. Eculizumab is the drug of choice with a plan to continue for at least 1 year hoping of regain of renal function. Rickettsia infection is considered the triggering factor for aHUS. High clinical suspicion of aHUS is required in all patients presenting with TMA. Eculizumab is the drug of choice with a plan to continue for at least 1 year hoping of regain of renal function. Advancements in aHUS treatment options warrant, early diagnosis and intervention. Rickettsia infection is considered the triggering agent for aHUS in our patient. Fig. (2-B): Red cell morphology shows approximately 5-10% schistocytes. leukocytosis with a striking leukoerythroblastic blood picture. Fig. (2-A): pre-retinal cheesy white infiltrates extending up to macula, obscuring vessels, no sheathing of vessels, no hemorrhages Fig. (1-A): Scattered nodular like-erythematous lesions over the arms medially Fig. (1-B): Petchial / purpuric rash over the dorsum of both feet. Fig. (4-A): Renal biopsy showed thrombi within the glomeruler capillary loops (arrows). Fig. (4-B): Renal biopsy showed thrombi within the arterioles (arrow) with ischemic collapse of glomeruler tuft. Fig. (3): The laboratory response to different modalities of management; PlasmaPharesis, Steroids. Eculizumab, Haemodialysis and Continous Veno Venous Haemo-Diafiltration (CVVHD) aHUS is a permanent, ongoing disease of systemic, complement mediated TMA which is due to genetic deficiency of complement regulators. (3) The complement system is a vital component of the natural (innate) protective immune system. It is always on to allow rapid immune response. Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation. Factors that amplify complement activation are infection, autoimmune disease, surgery and pregnancy. (5) Most genetic mutations of complements inhibitors have been discovered in the past 20 years, but 30–50% of patients with aHUS have no identifiable genetic mutation. (3) So, detection of genetic mutation is not required for diagnosis of aHUS. Clinical presentation of aHUS can be similar to other systemic TMAs (3) Historical treatment did not require differential diagnosis between aHUS, TTP, and STEC-HUS historically grouped as TTP / HUS (3,6) aHUS is a rare disease, leading to lack of clinical suspicion. (3,6) Zuber et al, (6,7) recommends trail of plasma exchange/ infusion for 5 days, then assess the response in the form of normalizing LDH, platelet count and reduction therapy of serum creatinine by 25%. At that point, we should consider alternative as Eculizumab. In our patient, we started Eculizumab after treatment with PE for 5 days with no improvement (figure 3). Eculizumab is humanized anti-C5 antibody. It is considered the first and only approved therapy for atypical aHUS. Eculizumab binds with high affinity to C5, blocking the terminal complement C5a and C5b-9 formation. It is recommended that eculizumab treatment be continued for the patient’s lifetime, unless the discontinuation of Eculizumab is clinically indicated. (7) Therefore, we recommend to continue on therapy for 1 year with good monitoring of TMA signs, and life long treatment should be offered to the patient.