Leptospirosis Hantavirus Nephropathy


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Dr Loh Chek Loong
Hospital Kuala Lumpur

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Leptospirosis Hantavirus Nephropathy

  1. 1. Leptospirosis Nephropathy
  2. 2. Leptospirosis <ul><li>Leptospirosis is a bacterial zoonotic infection caused by a spirochete, L.interrogans </li></ul><ul><li>Synonyms for the disease include Weil's disease, Swineherd's disease, rice-field fever, cane-cutter fever, swamp fever, mud fever, hemorrhagic jaundice, Stuttgart disease, and Canicola fever </li></ul>
  3. 3. <ul><li>A tropical environment with a heavy rainfall, high humidity and wet soil are good media for growth </li></ul><ul><li>Although Leptospirosis is usually encountered in warm-climate and developing regions but is also reported in European countries and in the USA </li></ul><ul><li>Grows well in neutral or alkaline environment </li></ul><ul><li>Rodent (or rats) with their alkaline urine are rich reservoirs </li></ul>
  4. 4. <ul><li>Renal involvement is a prominent feature of both mild and severe forms of this re-emerging but frequently ignored infectious disease </li></ul><ul><li>Subclinical infection, and even the anicteric febrile disease, are self-limiting forms and thus carry an excellent prognosis </li></ul><ul><li>However, 10-60% of leptospirosis infections may induce acute renal failure (ARF) and are associated with significant morbidity and mortality </li></ul>
  5. 5. <ul><li>Risk factors for infection include </li></ul><ul><ul><li>Occupational exposure </li></ul></ul><ul><ul><li>Recreational activities </li></ul></ul><ul><ul><li>Household exposure </li></ul></ul><ul><ul><li>Other </li></ul></ul>
  6. 6. Presentations <ul><li>Hypotension (MAP<70 mmHg), representing moderate to severe disease, is noted in 60% of people with leptospirosis </li></ul><ul><li>A patient with leptospirosis can be fully conscious despite the presence of hypotension, but can rapidly develop ARF and lung complications, and die within 5–6 h of admission to the hospital </li></ul><ul><li>‘ leptospirosis triad’ was coined to describe a syndrome of hypotension, ARF and pulmonary complications that occurs in 20% of patients with this disease. Pulmonary complications, which include pulmonary edema, acute respiratory distress syndrome, pulmonary hemorrhage and pneumonitis, are less common in normotensive patients than in hypotensive patients (Niwattayakul K et al. (2002) Ren Fail 24: 297–305) </li></ul>
  7. 8. Lancet Infectious Disease Vol 3,Dec 2003
  8. 9. A retrospective 5-year study in Moldova of acute renal failure due to leptospirosis: 58 cases and a review of the literature Nephrol Dial Transplant (2003) 18: 1128–1134
  9. 10. Severity of disease related to platelets? Peces R, Escalada P, Gorostidi M, Alvarez J. Fracaso renal agudo en la leptospirosis. Nefrologı´a 1992; 12 [Suppl 4]: 182–187
  10. 12. <ul><li>Incidences of ARF varies between 10-60% in case series reports </li></ul><ul><li>Renal failure is hypercatabolic a/w cholestatic jaundice </li></ul><ul><li>Hyperbilirubinamic renal failure represents a severe form of renal failure often with oliga-anuric </li></ul><ul><li>Neurological symptoms are related with uremia </li></ul><ul><li>(Nephropathy in Leptospirosis, Visith S., J Postgrad Med 2005;51;184-188) </li></ul>
  11. 13. Pathology <ul><li>Broad spectrum of renal pathology changes </li></ul><ul><li>Interstitial nephritis is the first to occur and is present even in patients with normal renal function </li></ul><ul><li>The pathogenesis of renal lesions includes bacterial invasion, toxicity of bacterial products, effects of proinflammatory cytokines and mediators, and hemodynamic alterations </li></ul>
  12. 14. <ul><li>Tubulointerstitial nephritis is the main manifestation of acute renal failure </li></ul><ul><li>Interstitial odema and cellular infiltrates in the tubulo interstitial area </li></ul><ul><li>Changes can be reversible if treatment is instituted early </li></ul><ul><li>Leptospiral renal dysfunction is thought to originate from leptospiral endotoxin </li></ul><ul><li>Leptospiral endotoxin induces an increase in TNF α </li></ul>
  13. 15. Leptospirosis Renal Disease, Yang et al, NDT 2001; 16 (S5), 73-77
  14. 16. <ul><li>Glomerular changes are not significant </li></ul><ul><li>Mesangial proliferative GN seen (Sitprija V, Evans H. The kidney in human leptospirosis. Am J Med 1970;49:780-8. ) </li></ul><ul><li>Vasculitis with focal haemorrhages seen early. Tubular atrophy and necrosis may also be seen in leptospirosis renal failure </li></ul><ul><li>(Arean VM. The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil's disease). Am J Pathol 1962;40:393-423. ) </li></ul>
  15. 17. Diagnosis <ul><li>High index of suspicion </li></ul><ul><li>The definitive diagnostic test is the recovery of leptospires from clinical specimens, either by culture, which is insensitive and slow, by immunohistochemical staining, or by showing the presence of leptospiral DNA by PCR. </li></ul>
  16. 18. <ul><li>Leptospires can be isolated from blood and CSF samples during the first 7–10 days of illness </li></ul><ul><li>Urine during the 2nd and 3rd week of illness </li></ul><ul><li>Slow growth and only can be reported as negative after 6-8 weeks </li></ul><ul><li>(Levett PN. Usefulness of serologic analysis as a predictor of the infecting serovar in patients with severe leptospirosis. Clin Infect Dis 2003; 36: 447–52) </li></ul>
  17. 19. Serology <ul><li>Gold standard is MAT (microscopic agglutination test) </li></ul><ul><li>The standard criterion for a positive MAT are a fourfold increase in antibody titre, or a conversion from seronegativity to a titre of 1/100 or above </li></ul><ul><li>Requires certain expertise </li></ul><ul><li>ELISA is then used as preliminary screening </li></ul>
  18. 20. Fluid administration <ul><li>Decreased response to fluids similar to sepsis patients </li></ul><ul><li>Systemic vasodilation is seen with elevated plasma aldosterone and ADH (Barsoum et Tropical Nephrology In Diseases of Kidney and Urinary Tract. Lippincott Williams and Wilkins 2001, pg 2301) </li></ul><ul><li>Cautious treatment with fluid to avoid iatrogenic pulmonary odema. Small dose of dopamine may improve hypotension and increase urine output (Losuwanrak K, Potential use of dopamine in leptospirosis, Int Med of Thailand 2003:19:180-184) </li></ul>
  19. 21. Treatment <ul><li>In the case series reported from Hawaii from 1974–1998, no significant difference was seen between use and non-use of antibiotics and duration of illness (Vinetz JM. A Mountain out of a molehill: do we treat acute leptospirosis, and if so, with what? Clin Infect Dis 2003; 36: 1514–15.) </li></ul><ul><li>Edwards et all Penicillin therapy in icteric leptospirosis. Am J Trop Med Hyg 1988; 39: 388–90 reported no difference in treated and untreated patients in regards to normalization of biochemical parameters, fever or mortality </li></ul>
  20. 22. Reports favouring treatment <ul><li>RCT showed treatment with doxycylline and penicillin shortened duration of fever and prevented leptospiral shedding in urine (McClain et al,Ann Intern Med 1984 May;100(5):696-8 Watt G et,Lancet 1988 Feb 27;1(8583):433-5) </li></ul><ul><li>Ceftriaxone, cefotaxime were also shown to be effective in Thailand (Panaphut T, Clin Infect Dis 2003 Jun 15;36(12):1507-13;Suputtamongkol Y,Clin Infect Dis 2004 Nov 15;39(10):1417-24. </li></ul>
  21. 23. Treatment of renal failure <ul><li>PD is still done in rural places and is seldom complicated with bleeding (Sitprija V, Leptospiral nephropathy. Semin Nephrol 2003;23:42-8) </li></ul><ul><li>Plasmapheresis or blood exchange offers good results in patients with hyperbilirubinaemic renal failure with a total serum bilirubin above 425 mmol/L (Sitprija V, Renal failure and hyperbilirubinaemia in leptospirosis: Treatment with exchange transfusion. Med J Aust 1973;1:171-2.  Pecchini F, Borghi M, et al . Acute renal failure from leptospirosis: New trends of treatment . Clin Nephrol 1982;18:164. Pochanugool C, Hyperbilirubinemic renal failure in tropical disease: Treatment with exchange transfusion. J Med Assoc Thai 1978;61:75-7.Tse KC, et al . Potential benefit of plasma exchange in treatment of severe icteric leptospirosis complicated by acute renal failure. Clin Diagn Lab Immunol 2002;9:482-4.) </li></ul>
  22. 24. <ul><li>In patients with severe leptospirosis with multiple organ failure, continuous venovenous haemofiltration (CVVH) or plasmapheresis has been shown to improve systemic and renal haemodynamics and clinical condition (Siriwanij T, Haemodynamics in leptospirosis: Effects of plasmapheresis and continuous venovenous haemofiltration. Nephrology 2005;10:1-6 ) </li></ul>
  23. 25. Copyright ©2007 American Society of Nephrology Andrade, L. et al. Clin J Am Soc Nephrol 2007;2:739-744 Figure 1. (A) Door-to-dialysis time (from intensive care unit admission to the initiation of dialysis); (B) mean serum urea during the dialysis treatment period 739-744, 2007
  24. 26. Copyright ©2007 American Society of Nephrology Andrade, L. et al. Clin J Am Soc Nephrol 2007;2:739-744 Figure 2. Mortality according to treatment group 739-744, 2007
  25. 27. Prognosis <ul><li>Prognosis of renal failure in leptospirosis is usually favourable unless complicated by multiple organ involvement </li></ul><ul><li>Pulmonary complications, hyperbilirubinaemia, oligo-anuria, diarrhoea, hyperkalaemia, old age and associated infection or underlying diseases carry bad prognosis with mortality ranging from 12% to 36% (Leptospirosis in northeastern Thailand : Hypotens Comp Pub Health 2002;33:155-60Risk factors for death and changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg 1999;61:630-4. . Acute lung injury in leptospirosis: Clinical and laboratory features outcome, and factors associated with mortality. Clin Infect Dis 1999;29:1561-3. Epidemiology of leptospirosis in New Caledonia (South Pacific): A one-year survey. Eur J Epidemiol 1997;13:161-7. Epidemic leptospirosis associated with pulmonary hemorrhage-Nicaragua. 1995. J Infect Dis 1998;178:1457-63 </li></ul><ul><li>ARF in presence of failure of two or more organ-systems carries an unfavourable prognosis. (A retrospective 5 - year study in Moldova of acute renal failure due to leptospirosis: 58 cases and a review of the literature. Nephrol Dial Transplant 2003;18:1128-34 ) </li></ul>
  26. 28. A retrospective 5-year study in Moldova of acute renal failure due to leptospirosis: 58 cases and a review of the literature Nephrol Dial Transplant (2003) 18: 1128–1134
  27. 29. Hantavirus
  28. 30. Historical Perspective <ul><li>Korean War – 3000 UN soldiers approaching mortality of 10% (“Korean Hemorrhagic Fever”) </li></ul><ul><li>Thought to be a new disease </li></ul><ul><li>Only in 1978, was this group of virus known as hantavirus identified (Lee HW, Lee PW, Johnson KM: Isolation of the etiologic agent of Korean hemorrhagic fever. J Infect Dis 137: 298–308, 1978 ) </li></ul><ul><li>Old disease re-emerged </li></ul><ul><li>American civil war in 1862 and 1863 </li></ul><ul><li>World War I </li></ul><ul><li>Known as ‘trench’ nephritis </li></ul>
  29. 31. <ul><li>The genus comprises a few types of virus with each giving rise to different presentations </li></ul><ul><li>Clinical syndromes caused by hantaviruses have also been known as epidemic hemorrhagic fever, hemorrhagic nephrosonephritis, Songo fever, Korean hemorrhagic fever, and nephropathia epidemica </li></ul><ul><li>Now collectively referred to by the World Health Organization as &quot;hemorrhagic fever with renal syndrome&quot; (HFRS) </li></ul>
  30. 32. Epidemiology <ul><li>Hantavirus infection is acquired by inhalation of aerosolized virus containing particles, or contact with urine, secretions or feces of infected rodents </li></ul><ul><li>The rodent vectors differ for each viral species but include mice, voles, shrews, and rats </li></ul><ul><li>Many cases have been reported in Europe and Asia, including Scandinavia, the Balkans, and Korea. In addition, the 1999 war in the Balkans was associated with a resurgence of cases, most of which resulted from the exposure of soldiers to rodents in the field </li></ul>
  31. 33. Biology <ul><li>The genus Hantavirus is roughly composed of two main groups: Old World and New World hantaviruses. </li></ul><ul><li>HFRS in humans is caused by pathogenic Old World hantaviruses that include Amur virus, Seoul virus, and HTNV </li></ul><ul><li>Mortality can be up till 15% </li></ul><ul><li>Puumala virus (PUUV) is the main hantavirus species in Europe and induces Nephropathia epidemica (NE), a milder variant of HFRS, with mortality rates of 0.1% (Hantaviruses: Immunology, treatment, and prevention. Viral Immunol 17: 481–497, 2004Hantavirus infections in Europe. Lancet Infect Dis 3: 653–661, 2003) </li></ul>
  32. 35. Nephropathia Epidemica (NE) <ul><li>a sudden onset with high fever, headache, backache, and abdominal pain </li></ul><ul><li>Transient thrombocytopenia </li></ul><ul><li>conjunctival hemorrhages, palatine petechiae, and a truncal petechial rash after 3 or 4 d is possible </li></ul><ul><li>Hemorrhages are accompanied by oliguria, azotemia, proteinuria, and hematuria </li></ul><ul><li>Within 3 d, the rash disappears and the patients develop polyuria. The convalescent phase extends over several weeks, and sequelae are rare. </li></ul><ul><li>Severe courses of NE with acute renal failure and lethal outcome range between 0.1 and 1% (Infectious diseases; Viral diseases. In: The Merck Manual of Diagnosis and Therapy , 17th Ed., Indianapolis, Wiley Publishers, 2005 ) </li></ul>
  33. 36. HFRS <ul><li>Incubation period of HFRS is 7 to 36 d </li></ul><ul><li>Only 10 to 15% of cases have a severe course, with lethality rates between 6 to 15%. </li></ul><ul><li>Characterized by systemic involvement of capillaries and venules. It induces various hemorrhagic manifestations and circulation disorders. </li></ul><ul><li>Renal involvement is characterized by acute renal failure as a result of interstitial hemorrhage and interstitial infiltrates </li></ul>
  34. 37. 5 clinical phases of HFRS <ul><li>Febrile, hypotensive, oliguric, diuretic, and convalescent </li></ul><ul><li>Initial onset resembles NE </li></ul><ul><li>Visual symptoms may be prominent (photophobia, visual impairment, conjunctival haemorrhages) </li></ul><ul><li>The urinary sediment reveals hematuria and atypical gross proteinuria (in some cases >3 g/24 h) </li></ul><ul><li>Hypotensive phase ranges 3 to 6 d after onset of fever </li></ul><ul><li>A wide range of renal conditions, including acute tubulointerstitial nephritis, necrotizing glomerulonephritis, and IgA nephropathy. </li></ul><ul><li>The oliguric phase starts at approximately day 8, and hemorrhagic manifestations become more prominent. The diuretic phase starts at approximately day 11, and the convalescent phase lasts approximately 3 wk to 6 mo. </li></ul>
  35. 38. Hantavirus Pulmonary Syndrome <ul><li>Flu-like symptoms </li></ul><ul><li>Acute non cardiac pulmonary oedema and hypotension within 2-15d </li></ul><ul><li>Bilateral infiltrates develop rapidly, sometimes associated with pleural effusions. Neutrophilic leukocytosis, hemoconcentration, hrombocytopenia, and circulating immunoblasts are observed </li></ul><ul><li>ARF is a result of shock and respiratory failure </li></ul>
  36. 40. Renal prognosis <ul><li>Most patients generally return to baseline glomerular filtration rate (GFR) following an episode of acute renal failure related to hantavirus infection </li></ul><ul><li>Long-term sequelae were perhaps best illustrated in observational studies five and ten years after Puumala virus-induced nephropathy. At five years, affected patients had a higher GFR, more proteinuria, and higher blood pressure compared with healthy controls; however, hyperfiltration and proteinuria resolved by ten years. (Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis. Miettinen MH et alKidney Int. 2006 Jun;69(11):2043-8 Renal function and blood pressure five years after puumala virus-induced nephropathy. - Makela S, et alKidney Int 2000 Oct;58(4):1711-8) </li></ul>
  37. 41. Pathology <ul><li>Immunohistology analysis of hantavirus-infected renal tissue reveals interstitial infiltrates with immune cells and interstitial hemorrhage </li></ul><ul><li>The most common histopathologic lesion are acute tubulointerstitial nephritis </li></ul><ul><li>Intertubular capillaries are congested, and the interstitium is broadened by edema, indicative of a generalized capillary damage. </li></ul><ul><li>Occasionally, glomerular pathology, e.g. , hypercellularity and expansion of the mesangium, are observed, and this is probably the underlying cause of gross proteinuria. Tubular, interstitial, and glomerular histologic damage are associated with the clinical severity of renal failure </li></ul>
  38. 42. <ul><li>Focal mononuclear interstitial infiltration, capillary congestion, and interstitial hemorrhage at the corticomedullary junction. </li></ul><ul><li>Normal glomeruli. Focal interstitial edema with a mild mononuclear infiltrate and prominent endothelial cells of peritubular capillaries. Magnification, x100 in A, Masson trichrome stain; x160 in B, PAS stain. </li></ul>
  39. 43. Kidney International, Vol. 48 (1995), Pp. 887—902
  40. 44. Kidney International, Vol. 48 (1995), Pp. 887—902
  41. 45. Diagnosis <ul><li>Diagnosis is made on a basis of clinical and laboratory findings </li></ul><ul><li>The diagnosis of hantavirus infection can be confirmed with serologic tests. By the time symptoms are evident, patients usually have antiviral antibodies of the IgM class, and most also have IgG antibodies </li></ul><ul><li>The diagnosis of kidney disease in HFRS is based upon the typical clinical and laboratory manifestations (proteinuria, hematuria, elevated serum creatinine), in conjunction with the serological evidence of a recent hantavirus infection </li></ul>
  42. 46. Therapy <ul><li>There are no specific antiviral therapies for hantavirus </li></ul><ul><li>The treatment of patients with HFRS or HPS is restricted to supportive procedures to keep under control the symptoms, which may be life-threatening </li></ul><ul><li>One prospective double-blinded study of 242 patients with serologically proven infection found that intravenous ribavirin therapy resulted in a reduction in mortality, other studies did not confirm these benefits (Huggins JW, et al. : Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis 164: 1119–1127, 1991 ) </li></ul><ul><li>Supportive therapy on ARF as indicated </li></ul>
  43. 47. Prevention <ul><li>Vaccine has been developed in Korea and has shown high titers of IgG in the initial few months. However, the antibodies reduce rapidly after that (Cho HW, Howard CR: Antibody responses in humans to an inactivated hantavirus vaccine (Hantavax). Vaccine 17: 2569–2575, 1999 Cho HW, Howard CR, Lee HW: Review of an inactivated vaccine against hantavirus es. Intervirology 45: 328–333, 2002 Hjelle B: Vaccines against hantavirus es. Expert Rev Vaccines 1: 373–384, 2002 Park K, Kim CS, Moon KT: Protective effectiveness of hantavirus vaccine. Emerg Infect Dis 10: 2218–2220, 2004) </li></ul>
  44. 48. LS vs HV Acute renal failure caused by leptospirosis and Hantavirus infection in an urban hospital European Journal of Internal Medicine 13 (2002) 264–268
  45. 49. LS vs HV Acute renal failure caused by leptospirosis and Hantavirus infection in an urban hospital European Journal of Internal Medicine 13 (2002) 264–268
  46. 50. Mis-diagnosis of Hantavirus <ul><li>Clement J, Hinrichsen S, Crescente J et al. Hantavirus -induced hemorrhagic fever with renal syndrome (HFRS) has to be considered in the differential diagnosis of leptospirosis-suspected cases in the New and the Old World. Am J Trop Med Hyg 1999; 61: 316–317 </li></ul>