Adverse reactions to antituberculosis agents


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Adverse reactions to antituberculosis agents

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Adverse reactions to antituberculosis agents

  1. 1. Boonthorn 14 Aug 2009
  2. 2. Outline <ul><li>Definition </li></ul><ul><li>Epidemiology </li></ul><ul><li>Principal of drug metabolism </li></ul><ul><li>Immune system of the liver </li></ul><ul><li>Pathogenesis </li></ul><ul><li>Diagnostic approach </li></ul><ul><li>In vitro test </li></ul><ul><li>In vivo test </li></ul>
  3. 3. Definition of drug allergic liver injury <ul><li>DILI devided into : </li></ul><ul><ul><li>Predictable (type A reaction ) or dose-dependent </li></ul></ul><ul><ul><ul><li>Effect of the reactive metabolites ( free radicals or reactive oxygen ) after phase I biotransformation </li></ul></ul></ul><ul><ul><li>Unpredictable or idiosyncratic (type B reaction ) </li></ul></ul><ul><ul><ul><li>Immune idiosyncrasy (shortened delay on rechallenge ) </li></ul></ul></ul><ul><ul><ul><li>eg. halothane </li></ul></ul></ul><ul><ul><ul><li>Metabolic idiosyncrasy ( no decrease in delay on rechallenge) eg. isoniazid </li></ul></ul></ul><ul><ul><li>Type C reaction (chronic dose-time dependent exposure) </li></ul></ul><ul><ul><li>Type D ( delayed ) reaction </li></ul></ul><ul><ul><li>Type E (withdrawal ) reaction </li></ul></ul>Drug hypersensitivity. KARGER
  4. 4. DILI based on liver test abnormalities <ul><li>Liver injury deined by increase >2 times of ULN of ALT or conjugated bilirubin or combined increase of AST,AP and total bilirubin </li></ul><ul><ul><li>Acute hepatocellular injury (ALT>ULN or ALT/AP>5) Most common </li></ul></ul><ul><li>Acute cholestatic liver injury (AP>2 times or ALT/AP<2) </li></ul><ul><ul><li>Acute cholestatic hepatitis (second most common ) resemble acute biliary obstruction </li></ul></ul><ul><ul><li>Pure cholestasis : pruritis ,jaundice </li></ul></ul><ul><li>Mixed hepatocellular and cholestasis ( ALT/AP 2-5 ) frequently associated with immunoallergic manifestation </li></ul>Drug hypersensitivity. KARGER
  5. 5. Epidemiology Tubercle and Lung Disease
  6. 6. Tubercle and Lung Disease
  7. 7. Most common in first 9 weeks Largely due to PZA Majority within 4 weeks Tubercle and Lung Disease
  8. 8. MJAFI 2006; 62 : 45-49 chronic HBV infection on ATT (9/24, 37.5%) patients given ATT who had no evidence of HBV infection (13/128,10.2%)
  9. 9. Pak J Med Sci January - March 2007 Vol. 23 No. 1 33-38
  10. 10. Risk Factors of Antituberculosis Drugs-Induced Hepatotoxicity in Thai patient S. Krittiyanunt et al./Thai J. Pharm. Sci. 26 (3-4): 121-128 (2002) retrospective-analytical research , collected between 1998 and 2000
  11. 11. S. Krittiyanunt et al./Thai J. Pharm. Sci. 26 (3-4): 121-128 (2002)
  12. 12. Studied MHC class II alleles and clinical risk factors for the development of hepatotoxicity in 346 North Indian pts. with TB. 56 patients developed drug-induced hepatotoxicity (DIH group), whereas the remaining 290 patients did not (non-DIH group). Sharma, Balamurugan, Saha, et al. : Hepatotoxicity and Antituberculosis Chemotherapy
  13. 13. Breen, Miller, Gorsuch, et al
  14. 14. International Union Against Tuberculosis and Lung Disease 2003
  15. 15. <ul><li>1. Ageing. changes in drug metabolism and excretion </li></ul><ul><li>2. Malnutrition. reduction in hepatocyte glutathione. little neutralisation of the toxic metabolites originating from drug acetylation.hypoalbuminaemia , causes increase in the plasma free fraction of drugs, thus increasing the risk of drug-induced toxicity. </li></ul><ul><li>3. Pregnancy. fatty liver with hypoalbuminaemia </li></ul><ul><li>4. Liver or kidney dysfunction. Anti-TB drugs can cause liver or kidney toxicity; consequently, special caution should be exercised when administering such substances to patients with impaired function of these organs </li></ul>International Union Against Tuberculosis and Lung Disease 2003
  16. 16. . 5. Treatment with other drugs. cytochrome P450 has been frequently associated with production of hepatotoxic reactive metabolites 6. Disseminated or advanced TB. consequence of malnutrition or liver deterioration attributable to the disease itself. 7. Patients previously subjected to antituberculous therapy. increased risk of damage attributable to rifampicin, which in turn is associated with hypersensitivity reactions that lead to the release of immune complexes. 8. Atopy. linked to the existence of other cases of adverse anti-TB drug reactions in family members; thus, the clinical history of the patient should be carefully evaluated before treatment is started. 9. Sex. Women are at a comparatively greater risk of developing druginduced liver reactions. 10. HIV infection. risk of such reactions increases with the degree of host immunosuppression. International Union Against Tuberculosis and Lung Disease 2003
  17. 17. Principle of drug metabolism HEPATOLOGY, Vol. 37, No. 4, 2003 Journal compilation © 2006 Asian Pacific Society of Respirology
  18. 18. Drug-Induced Direct Hepatotoxicity <ul><li>direct action of drug, or reactive metabolite of a drug, against hepatocytes. </li></ul><ul><li>Classically used to examine acetaminophen </li></ul><ul><li>produce centrilobular hepatic necrosis, which may lead to acute liver failure </li></ul><ul><li>metabolite, N-acetylp-benzoquinoneimine (NAPQI) </li></ul><ul><li>depletes glutathione and initiates covalent binding to cellular proteins </li></ul><ul><li>lead to the disruption of calcium homeostasis, mitochondrial dysfunction, and oxidative stress and may eventually culminate in cellular damage and death. </li></ul>The AAPS Journal 2006; 8 (1) Article 6
  19. 19. Immune system of liver <ul><li>KC play essential role in </li></ul><ul><ul><li>phagocytosis and removal of pathogens </li></ul></ul><ul><ul><li>produce cytokines and other mediators, including prostanoids, nitric oxide, and reactive oxygen intermediates </li></ul></ul><ul><ul><li>promoting and regulating hepatic inflammation </li></ul></ul><ul><ul><li>modulating the phenotype of other cells in the liver eg. NK and NKT cells </li></ul></ul><ul><ul><li>major population of antigen-presenting cells (APCs) within the liver </li></ul></ul><ul><ul><li>balance between induction of immunity and tolerance within the liver </li></ul></ul>The AAPS Journal 2006; 8 (1) Article 6
  20. 20. Immune system of liver <ul><li>NK and NKT cells </li></ul><ul><ul><li>~50% of intrahepatic leukocytes. </li></ul></ul><ul><ul><li>act as a fi rst line of defense against pathogens and invading tumor cells </li></ul></ul><ul><ul><li>Cytotoxic capacity against other cells </li></ul></ul><ul><ul><li>Enhanced by IL-12 and IL-18, produced by activated KC. </li></ul></ul><ul><ul><li>produce high levels of T helper (Th) 1 and Th2 cytokines upon stimulation (IFN- γ or IL-4 ) </li></ul></ul>The AAPS Journal 2006; 8 (1) Article 6
  21. 21. Immune system of liver <ul><li>Adaptive immune responses favor induction of immunological tolerance rather than immunity. supported by </li></ul><ul><li>(1) dietary antigens derived from the GI tract are tolerized in liver </li></ul><ul><li>(2) allogeneic liver organ transplants are accepted across MHC barriers </li></ul><ul><li>(3) preexposure to donor cells through the portal vein of recipient animals increased their acceptance of solid tissue allografts </li></ul><ul><li>(4) preexposure of soluble antigens via the portal vein leads to systemic immune tolerance </li></ul>The AAPS Journal 2006; 8 (1) Article 6
  22. 22. Mechanisms for liver-induced tolerance <ul><li>apoptosis of activated T cells </li></ul><ul><ul><li>elephant ’ s graveyard ” for activated T cells. Studies using T-cell receptor transgenic models have demonstrated that following antigen exposure, activated T cells undergo apoptosis after transient accumulation within the liver </li></ul></ul><ul><li>immune deviation </li></ul><ul><ul><li>Th2 cytokine production is preferentially maintained </li></ul></ul><ul><ul><li>LSEC are capable of selectively suppressing IFN- γ -producing Th1 cells while promoting outgrowth of IL-4-expressing Th2 cells </li></ul></ul><ul><li>active suppression of T cell activation </li></ul><ul><ul><li>Naïve T cells,normally encounter APCs in lymphoid tissues, could be primed directly by LSEC and/or KC within the liver </li></ul></ul><ul><ul><li>LSEC are presenting antigen to T cells, LSEC-activate d CD4 + or CD8 + T cells fail to differentiate into Th1 cells or cytotoxic effector cells </li></ul></ul>The AAPS Journal 2006; 8 (1) Article 6
  23. 23. Role of Innate Immunity in DILI <ul><li>In acetaminophen overdose </li></ul><ul><ul><li>NAPQI-induced hepatocyte damage lead to activation of innate immune cel ls </li></ul></ul><ul><ul><ul><li>stimulating hepatic infiltration of inflammatory cells.produce inflammatory mediators, cytokines, chemokines, and ROSand RNS nitrogen species ,IFN- γ , Fas, or Fas ligand,causing liver damage </li></ul></ul></ul><ul><ul><ul><li>represent major source of hepatoprotective factors,in transgenic mice deficient in IL-10,IL-6, or COX-2 are more susceptible to liver injury </li></ul></ul></ul><ul><ul><ul><li>Depletion of NK and NKT cells protected mice from liver injury </li></ul></ul></ul><ul><ul><ul><li>KC activation release TNF- α , IL-12 and IL-18 (activate NK,NKT CELL) , IL-10 and IL-6 (protective role) </li></ul></ul></ul><ul><ul><ul><li>Role of these cell remains controversial </li></ul></ul></ul>The AAPS Journal 2006; 8 (1) Article 6
  24. 24. Mechanisms of Drug-Induced Liver Injury The AAPS Journal 2006; 8 (1) Article 6
  25. 25. Role of Adaptive Immune Response in DILI <ul><li>hapten hypothesis </li></ul><ul><ul><li>drugs, or metabolites , act as haptens and covalently bind to endogenous proteins to form immunogenic drug-protein adducts. elicit either antibody or cytotoxic T-cell responses </li></ul></ul><ul><li>p-i concept </li></ul><ul><ul><li>drugs can bind to T-cell receptors, mimicking a ligand and its receptor interaction, and cause T-cell activation in an MHC-dependent fashion </li></ul></ul><ul><li>difficult to directly prove the pathogenic role of the adaptive immune system in DILI, because of the lack of animal models </li></ul>
  26. 26. W.J. Pichler / Immunol Allergy Clin N Am 24 (2004) 373–397
  27. 27. W.J. Pichler / Immunol Allergy Clin N Am 24 (2004) 373–397 p-i concept
  28. 28. DANGER HYPOTHESIS <ul><li>immune system does not directly differentiate self and non-self, and it only responds to a foreign antigen if the antigen is associated with a danger signal </li></ul><ul><li>“ immune system is more concerned with damage than with foreignness, and is called into action by alarm signals from injured tissues, rather than by the recognition of non-self” </li></ul><ul><li>driving force of the immune system is need to detect and protect against danger. Intracellular stress and cell death caused by a reactive metabolite are likely to be danger signals in DILI </li></ul>Liver Immunology:Principles and Practice
  29. 29. Liver Immunology:Principles and Practice model of the immune mechanisms of idiosyncratic DILI
  30. 30. Diagnosis:a practical approach <ul><li>Step 1:exclusion of other cause of liver injury </li></ul><ul><ul><li>Serologies for viral and autoimmune hepatitis </li></ul></ul><ul><ul><li>Abdominal ultrasonography </li></ul></ul><ul><ul><li>Confounders eg.hypotension,sepsis,heart failure,use of TPN </li></ul></ul><ul><ul><li>Concomitant disease (affect outcome negatively ) eg.HIV,alcoholism,DM,obesity </li></ul></ul><ul><li>Step 2:identification of clinical signature </li></ul>Clin Liver Dis 10 (2006) 207–217
  31. 31. Step 2:identification of clinical signature <ul><li>Pattern of liver test abnormality </li></ul>hepatocellular jaundice : worst prognosis, > 10% chanceof progressing to acute liver failure , may result in liver transplantat ion or death cholestatic pattern may present resembling acute biliary obstruction or chronically with jaundice or pruritus. usually resolve slowly after drug withdrawal Clin Liver Dis 10 (2006) 207–217
  32. 32. Clin Liver Dis 10 (2006) 207–217
  33. 33. <ul><ul><li>Latency period </li></ul></ul><ul><ul><li>short (hours to days) : acetaminophen </li></ul></ul><ul><ul><li>intermediate or delayed (1–8 wks): sulindac,phenytoin </li></ul></ul><ul><ul><li>long (1–12 months): isoniazid , troglitazone </li></ul></ul><ul><ul><li>Some antibiotics (eg, amoxicillin/clavulanate, erythromycin, and trovafloxacin) : symptoms and jaundice 3 to 4 weeks after cessation of therapy. </li></ul></ul>Clin Liver Dis 10 (2006) 207–217
  34. 34. <ul><ul><li>Feature of immune hypersensitivity </li></ul></ul><ul><ul><li>fevers, skin rash, and peripheral eosinophilia </li></ul></ul><ul><ul><li>SJS and TEN </li></ul></ul><ul><ul><li>Hematologic abn. Eg. granulocytopenia, thrombocytopenia,or hemolytic anemia </li></ul></ul>Clin Liver Dis 10 (2006) 207–217
  35. 35. <ul><ul><li>Course after drug withdrawal (dechallenge) </li></ul></ul><ul><ul><li>cholestatic reactions tend to subside more slowly than hepatocellular reactions </li></ul></ul><ul><ul><li>liver test abnormalities sometimes lasting for more than a year </li></ul></ul><ul><ul><li>Overall, in the nonfulminant situation, improvement after cessation can be viewed as consistent with DILI. </li></ul></ul>Clin Liver Dis 10 (2006) 207–217
  36. 36. Recommendations for the use of ATT in cirrhosis Meta analysis Incidence of clinical hepatitis : INH (0.6%),INH wihtout R (1.6%),rifam without INH (1.1%),INH with rifam (2.5%) British study :INH (0.3%),Rifam (1.4%),PZA (1.25%) Hepatitis per mo. :PZA>Rifam (3 times),>INH (5 times) A meta-analysis. Chest 1991;99:465–71. Thorax 1994;45:403–8.
  37. 37. <ul><li>Role of liver test monitoring </li></ul><ul><li>Monitoring of ATT therapy (either isoniazid alone in patients older than 35 years or any regimen containing either isoniazid or pyrazinamide) </li></ul><ul><li>Role of steroids in the treatment of drug-induced liver injury </li></ul><ul><ul><li>insufficient data to support or refute use of steroids individually for each case </li></ul></ul><ul><ul><li>severe hepatitis (jaundice and coagulopathy) do not improve rapidly within 3 - 4 days after cessation of drug, and if concomitant features support allergy (rash, eosinophilia), trial of steroids (prednisone,40–60 mg) for 1 week followed by a rapid taper </li></ul></ul>Clin Liver Dis 10 (2006) 207–217
  38. 38. Lymphocytic Transformation test
  39. 39. DETECTION OF HYPERSENSITIVITY TO DRUGS BY LYMPHOCYTE CULTURES IN DRUG-INDUCED ALLERGIC HEPATITIS antituberculosis drugs (streptomycin: 7,INH: 5, PAS: 3, ethionamide :2, rifampicin: 1) Positive responses : 15 cases ( MI test ) and 49 cases ( lymphocyte transformation ) Clinical symptoms : cutaneous eruption (60%), fever (69 %) itching (73%),eosinophilia (50%) were seen in more than half of the patients . Gastroenterologia Japonica Vol. 10, No. 4.--1975--
  40. 40. Gastroenterologia Japonica Vol. 10, No. 4.--1975--
  41. 41. Lymphocyte transformation studies in drug hypersensitivity CMA JOURNAL/MAY 5, 1979/VOL. 120 8 pts. with INH -induced hepatitis, liver biopsy ( negative for H B sAg ) and rapid resolution of jaundice , abnormal LFT upon withdrawal of the drug 3 patients with MP rashes following INH therapy were assessed by LTT with INH . Substantial lymphocyte stimulation was demonstrated for 9/11 patients 19 control subjects - 8 pts(INH without adverse effects ), 6 healthy individuals and 5 patients who had recently discontinued isoniazid .
  42. 42. Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury Gut 1997; 41: 534–540
  43. 43. Gut 1997; 41: 534–540 25(26%) 53(56%) clinical markers (rash,arthralgia,eosinophilia) absent about 70% pts. with demonstrable T cell reactivity to drugs challenges
  44. 44. Drug lymphocyte stimulation test in diagnosis of adverse reactions to anti-tuberculosis drugs <ul><li>prospective study </li></ul><ul><li>436 pts. with TB were admitted for treatment between January 2002 and August 2007 </li></ul><ul><li>DLST ,DPT </li></ul><ul><li>tested drugs : INH, RIF,EMB,PZA </li></ul><ul><li>69 (15.8%) had adverse drug reactions to anti-TB drugs </li></ul><ul><li>sensitivity of DLST was 14.9% for all drugs (INH: 14.3%, RIF: 13.6%, EMB: 14.3%, PZA: 0%). </li></ul><ul><li>DLST offers little contribution to the detection of causative agents in patients with adverse anti-TB drug reactions </li></ul>Suzuki Y., et al . Chest.
  45. 45. Lymphocyte transformation test for evaluation of adverse effects of anti TB drug <ul><li>15 pts. With INH and RIF </li></ul><ul><li>Control 21pts. ( 7 exposed,14 never been exposed anti TB ) </li></ul><ul><li>4/15 of hepatotoxic only positive with RIF , 3/15 with INH </li></ul><ul><li>8/15 negative </li></ul><ul><li>In healthy control with previous contact :INH positive 2 , INH +RIF 1 </li></ul><ul><li>Control without former contact : negative </li></ul><ul><li>LTT can be useful for identifying the drug responsible for immunological side effects </li></ul>Eur med res.1999 Feb 25 ;4(2) 67-71
  46. 46. Patch test
  47. 47. Hypersensitivity syndrome from isonizid <ul><li>34 yrs. Old woman with pulmonary TB Rx with INH, RIF,PZA ,after 2 mo. Developed severe pruritic urticariform cutaneous eruption </li></ul><ul><li>PZA discontinued because RX completed </li></ul><ul><li>1 wk later worsening eruption,fever,icterus ,lymphadenopathy,hepatomegaly .eosinophilia (8%)ALT 1459,ANA neg,high LDH=> second line </li></ul><ul><li>1yr later LTT to INH,RIF,PZA neg </li></ul><ul><li>Epicutaneous test with 1%RIF in vaseline (neg),10%PZA in alc.(neg),1% INH in NSS (strongly pos after 48,96hrs.) , 10 controls (neg) </li></ul>Allergy S4 ,1999/1004-1013
  48. 48. Hypersensitivity syndrome from INH with positive patch test <ul><li>68 yrs. Man in 1995 Dx :TB ,Rx:INH,RIF,PZA </li></ul><ul><li>2 yrs. Later ,recurrent TB Rx:INH,RIF,EMB </li></ul><ul><li>1 mo. Later develop fever, asthenia,facial edema,pancytopenia,increase liver enz.=>stop anti TB </li></ul><ul><li>10 d later he was asymptomatic </li></ul><ul><li>Patch test with RIF,EMB,INH (50%pet) </li></ul><ul><li>Positive(+++D2) only to INH ,10 healthy control (neg) </li></ul><ul><li>DPT with RIF ,EMB were negative </li></ul>Contact dermatitis. 2001,45,306
  49. 49. Delayed type hypersensitivity reaction to EMB and INH <ul><li>24 yrs, woman started with INH,RIF,EMB </li></ul><ul><li>2 wks. Later itchy,desquamative,erythrematous,papular rash </li></ul><ul><li>5 d after drug withdrawal =>progress </li></ul><ul><li>Rx:topical fluticasone,oral cetrizine => improved </li></ul><ul><li>After subsided ,patch test were perform with INH,RIF,EMB (crutch and moistened with water) </li></ul><ul><li>Positive with EMB,INH at D3 </li></ul><ul><li>10 healthy control were negative at D2,3 </li></ul>Contact dermatitis 2002:46:359
  50. 50. Rifampicin allergy confirmed by ID test,but with negative patch test <ul><li>45 yrs. Woman with peritoneal TB </li></ul><ul><li>Start with INH,RIF,EMB,PZA </li></ul><ul><li>7.5 wks. Develop MP rash ,fever, chill , joint pain=>stop drug => improved </li></ul><ul><li>Patch test with INH,RIF,EMB,PZA (30%pet)were neg </li></ul><ul><li>Skin prick test with 1% INH and RIF,30% EMB and PZA were neg </li></ul><ul><li>IDT 0.1% RIF 10mm. </li></ul><ul><li>Reinstated with INH,EMB,PZA,strep=> no eruption </li></ul>Contac dermatitis,2001.45.108
  51. 51. DRESS induced by ATT <ul><li>29 yrs. Female on celecoxib and antituberculosis drug </li></ul><ul><li>1 mo. Developed DRESS </li></ul><ul><li>Patch test were positive for celecoxib and EMB </li></ul>J Korean Med Sci 2008; 23: 521-5
  52. 52. Conclusion <ul><li>DILI : type A or B , hepatocellular or cholestatic </li></ul><ul><li>Risk factor of ATT: age , sex ,malnutrition ,liver and kidney dysfunction , concomitant with HBV and HIV </li></ul><ul><li>Drug metabolism in liver </li></ul><ul><li>Tolerance VS immunity </li></ul><ul><li>Hapten, p-i concept , danger hypothesis </li></ul><ul><li>Diagnostic approach </li></ul><ul><li>Invtro and in vivo test </li></ul>
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