Infections in Organ Transplantation and Neutropenia

1
Infections in Organ Transplantation and
Neutropenia
Dr. Brian OConnell
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 bodys
  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
Type of deficit Deficit Examples Organisms
Local Breach of physical defences IV catheter, urinary catheter, surgical wound, tracheal intubation Bacteria, Candida.
Generalised Deficits of cell-mediated immunity Humoral immunity Phagocytic defenses a)Organ transplant, AIDS b) Chronic lymphocytic leukaemia, Myeloma, asplenia c) ALL, AML, Cytotoxic chemotherapy a) Intracellular, viruses, parasites, Listeria, Salmonella Capsulate bacteria Coliforms, Pseudomonas, Aspergillus.
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 (lt60 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
Organ transplanted First 2 weeks Early Late
Kidney Wound infection UTI UTI Listeria monocytogenes, Toxoplasmosis, Pneumocystis, Cryptococcus neoformans, Nocardia spp.
Liver Intra-abdominal, Bacteraemia, Pneumonia Pulmonary aspergillosis, Cholangitis. Listeria monocytogenes, Toxoplasmosis, Pneumocystis, Cryptococcus neoformans, Nocardia spp.
Heart/lung Mediastinitis, Empyema, pneumonia Pulmonary aspergillosis, Listeria monocytogenes, Toxoplasmosis, Pneumocystis, Cryptococcus neoformans, Nocardia spp.
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
• lt1.0 x 109/l
• lt0.5 x 109/l
• lt0.1 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
circulating neutrophils
Neutrophil count (10 9/L)
Bodey Ann Inter Med 1966. 64328-44
25
Sources of bacteraemic infection
Hickman catheter
26
(No Transcript)
27
Bacterial translocation
M-cells in Peyers 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
• lt10 2000
• concept of empiric antimicrobial therapy
• Temperature gt 38.50 C x 2 or gt390 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

• Despite extensive clinical studies since the
  1970s, no single empirical therapeutic regimen
  for the initial treatment of febrile patients
  with neutropenia can 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 have no focus of bacterial infection
• or
• Patients who do not have symptoms and signs
  suggesting systemic infection (e.g., rigors,
  hypotension) other than 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 200515 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 (Plt0.001)
• less hospitalisations (P0.004)

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

46
(No Transcript)
47

• Epidemiology and Risk Factors
• associated with building works
• early (neutropenia gt21 days)
• late (associated with GVHD)
• Diagnosis
• histological
• culture
• CT
• PCR
• antigen detection

48
(No Transcript)
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

51
Rhinocerebral mucormycosis
52
Histological appearance of mucormycosis
53
Mucor species
54
Lactophenol cotton blue stain of Rhizopus species
55
4. Other pathogenic fungi

• Fusarium spp.
• Alternaria spp.
• Pseudallescheria boydii
• Trichosporon spp.
• Malassezia furfur

56
Disseminiated Fusarium infection