Infections in Organ Transplantation and Neutropenia

1. Infections in Organ Transplantation and Neutropenia Dr. Brian O’Connell

2. Content 1. Introduction 2. Infections among asplenic patients 3. Infections among solid organ transplant recipients 4. Infections among patients with neutropenia

3. Introduction • Infection: result of an imbalance between host defences and virulence of the infecting organism • Immunocompromised: deficits in the body’s natural defence mechanisms that predispose to infection • Infection remains a significant cause of morbidity and mortality in this group of patients

4. Host defences and associated pathogens

5. Classification of Pathogens • Primary pathogens: • May cause disease in normal host e.g. group A streptococci, M. tuberculosis. • Sometime pathogens: • Organisms that sometimes cause disease in normal hosts • Opportunist pathogens: • Organisms that virtually never cause disease in normal hosts • Latent pathogens: • Organisms that infect the normal host and are controlled but may recrudesce when immunocompromised eg. Toxoplasma gondii, Herpes simplex, Pneumocystsis carinii.

6. Examples of opportunistic pathogens • Coagulase-negative staphylococci • Skin organism • Commonest cause of bacteraemia in neutropenic patients in this hospital • Pseudomonas aeruginosa • Colonises gut and may cause • bacteraemia with a high mortality And a necrotising skin condition • Aspergillus species • thousands of spores inhaled everyday • Mortality of at least 65% when causes invasive disease • Mycobacterium avium-intracellulare • Environmental organism • Systemic infection in HIV

7. 1. Infections among asplenic patients • Major lymphoid organ harbouring a significant amount of total immunoglobulin producing B-lymphocytes • Mononuclear cells in splenic sinusoid phagocytose circulating bacteria, especially unopsonised organisms • Spleen - main production site for opsonising antibodies • Predisposed to infections caused by capsulate bacteria e.g. Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis • Also malaria and babesiosis (intra-erythrocytic parasites)

8. Overwhelming post-splenectomy infection (OPSI) or post-splenectomy sepsis • Significant increase (up to 600 fold) in risk of serious infection • Dramatic presentation • Lifetime risk • Increased risk with younger patient • Underlying disease • Time since splenectomy • Presentation: • Short prodrome, fever, chills, sometimes diarrhoea • Rapid progression • Mortality: 50-70% despite maximal supportive care and appropriate antimicrobial therapy

9. Interval from splenectomy to postsplenectomy sepsis (data from: Holdsworth Br J Surg 1991; 78: 1031-38)

10. Prevention/Management • Immunisation • S. pneumoniae (23 valent) • H. influenzae type b • N. meningitidis group C • Annual influenza vaccine • meningococcus group A if travelling to an endemic area (i.e. Africa, India, Nepal, Pakistan, Saudi Arabia) • Penicillin prophylaxis • Lifelong • Penicillin 333-666 mg BD or Erythromycin 250 mg BD, if penicillin allergic

11. Patient awareness • Patients developing signs of infection should be advised to seek medical attention urgently • Patients should be provided with amoxycillin and advised to take 1 gm if symptoms develop and medical attention is likely to be delayed • advised of the risks of travelling to areas where malaria is endemic - severe malaria may occur despite antimalarial prophylaxis • Medic-alert bracelet

12. 2. Infections among solid organ transplant recipients • Early infections (<60 days) tend to be related to surgical procedure • Late infections tend to be related to net state of immunosuppression and environmental exposure Type of transplant • In general, kidney and heart transplant have less infective complications than liver and lung or heart/lung transplantation

13. Factors that contribute to infection after transplantation • Ill recipient • Colonised with virulent and possibly resistant organisms • Already receiving immunosuppressive drugs • Prior latent infection e.g. Pneumocystis, CMV, TB • Damaged organ • Donor transmitted infections • Surgical operation, ITU stay • Immunosuppression • Immunosuppressive element of some infections e.g. CMV, hepatitis C virus

14. Donor transmitted infection • Viral • HIV, Hepatitis B, C • Bacterial • More common in lung transplantation than other solid organ transplants • Protozoal • Toxoplasmosis

15. Bacterial and parasitic infections in solid organ transplant recipients

16. Rubin NEJM 1998; 324: 1741

17. Onset of episodes of infection post liver transplantation No. of episodes of infection Time post transplantation (days)

18. Approach to fever in organ transplant recipient • Despite immunosuppressive therapy most patients with infection develop fever • Note pneumocystis may present with dry cough and dyspnoea • Cryptococcal meningitis may present with headache only • History, physical exam and take relevant specimens, perform CXR • Antibiotics may be withheld if patient appears well

19. Prevention • Pre-transplant screening for latent infection • CMV, Toxoplasmosis • Remove foci of infection • Antibiotic prophylaxis • For surgery • sometimes for donor transmitted infection e.g. lung transplantation • Long-term e.g CMV, pneumocystis, toxoplasmosis

20. 4. Infections among patients with neutropenia

21. Introduction • Patients with neutropenia are at significant increased risk of infection • Related to depth of neutropenia • Mainly bacterial infections and less commonly fungal infection • Do not present with signs of inflammation • Infected neutropenic patients nearly always have fever • Require prompt (within 1 hour) antimicrobial therapy

22. Causes of fever among neutropenic patients

23. Risk factors for bacteraemic infection in cancer patients • depth of neutropenia • <1.0 x 109/l • <0.5 x 109/l • <0.1 x 109/l • duration of neutropenia • mucosal damage e.g. HSV, chemotherapy induced mucositis • right atrial catheters • cellular immune defects • defects of phagocyte function • factors relating to the virulence of colonising organisms

24. Episodes of severe infection related to number of circulatingneutrophils Neutrophil count (10 9/L) Bodey Ann Inter Med 1966. 64:328-44

25. Sources of bacteraemic infection Hickman catheter

27. Bacterial translocation • M-cells in Peyer’s patches • phagocytose bacteria Mesenteric Lymph Node (MLN) Thoracic Duct Systemic Circulation

28. Oropharyngeal mucositis

29. Spectrum of organisms causing blood-steam infection • Bacterial infections • Gram positive • Coagulase negative staphylococci • Viridans streptococci • Enterococci • Gram-negative • Enterobacteriaceae • E. coli • Non-fermentative GNB • P. aeruginosa • Fungal Infections • Candida species

30. Single organism bacteraemias in EORTC trials of febrile neutropenia

31. Possible reasons for change in spectrum of organisms from Gram-negative to Gram-positive • More severe oral mucositis • More frequent use of indwelling catheters • Selective pressure of antimicrobials – in particular cephalosporins and quinolones • Quinolone prophylaxis

32. Empiric antimicrobial therapy • absence of clinical signs of inflammation • Historical high mortality due to Gram-negative bacteraemia • 90% in 1962 • 20% in 1978 • <10% 2000 • concept of empiric antimicrobial therapy Temperature > 38.50 C x 2 or >390 C x 1 Clinical examination, take blood cultures and commence broad-spectrum antibiotic therapy

33. Which antibiotics? Principles: • Controversial • Bactericidal • broad-spectrum with activity against Pseudomonas aeruginosa • non-toxic • choice depends upon institutional spectrum of infections, susceptibility pattern of infecting micro-organisms, individual clinical situation, cost and toxicity

34. Established therapeutic regimens 1) Anti-pseudomonal B-lactam + aminoglycoside 2) Double B-lactam combination 3) Monotherapy with either ceftazidime, cefipime, meropenem or piperacillin-tazobactam 4) Any of the above regimens + vancomycin/teicoplanin

35. Despiteextensive clinical studies sincethe 1970s, no singleempirical therapeutic regimen forthe initial treatment offebrile patients with neutropeniacan be recommended • choice depends upon institutional spectrum of infections, susceptibility pattern of infecting micro-organisms and individual clinical situation

36. Oral antimicrobial therapy for febrile neutropenia • may be considered for patients: • who haveno focus of bacterialinfection or • Patients who do not have symptoms andsigns suggesting systemic infection(e.g., rigors, hypotension) otherthan fever

37. IDSA Guidelines: CID 2002; 34: 730-751

38. Prophylaxis against bacterial infections • Oral quinolones are used in many centres for prophylaxis of bacterial infection • Reuter et al. CID 2005;15: 1087-93 • 2 periods: • 1 year with levofloxacin prophylaxis • Without prophylaxis • Stopped prematurely because of increased Gram-negative bacteraemia and increased mortality • Cullen et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. NEJM 2005; 353: 988-998. • Randomised, double blind trial • 500mg levofloxacin od (784) v. placebo 781 • Primary outcome – no. of febrile episodes • In levofloxacin group: • less febrile episodes (P<0.001) • less hospitalisations (P=0.004)

39. Fungal Infections

40. Risk groups and incidence • autopsy data shows that up to 25% of neutropenic patients with leukaemia have evidence of fungal infection • allogeneic BMT • 85 autopsies - 26% had fungal infection • Risk depends upon: • depth and duration of neutropenia • GVHD • age • positive CMV serology (Milliken 1990 RID, 12,S374)

41. Empiric treatment of fever of unknown origin • administration of amphotericin B has become standard practice • (Piizzo Am J Med 1982; 72: 101; EORTC Am J Med 1989; 86: 668) • controversy about when to start • dose is uncertain • will not prevent emergence of IFI

42. Fungal Pathogens 1. Candida species • C. albicans • C. parapsilosis • C. glabrata • C. tropicalis • C. krusei • changing epidemiology • increasing use of azoles • increasing use of central intravascular catheters

43. Clinical Syndromes • Mucocutaneous disease • Localised disease • Invasive disease • acute disseminated candidiasis • line-related candidaemia • chronic disseminated candidiasis/hepatosplanic candidiasis

44. Chronic disseminated candidiasis/hepatosplenic candidiasis

45. 2. Aspergillus species A. fumigatus, A. flavus Clinical Syndromes • invasive pulmonary aspergillosis (IPA) • focal or diffuse • sinus disease • cutaneous disease

47. Epidemiology and Risk Factors • associated with building works • early (neutropenia >21 days) • late (associated with GVHD) Diagnosis • histological • culture • CT • PCR • antigen detection

49. Halo sign

50. 3. Mucormycosis • Rhizopus, Absidia, Rhizomucor, Cunninghamella • associated with prolonged neutropenia Clinical Syndromes • rhinocerebral, pulmonary, cutaneous, disseminated • characterised by fever and necrosis Diagnosis • biopsy - histology and microbiology