Transcript Infections in Organ Transplantation and Neutropenia1

Infections in Organ
Transplantation and
Neutropenia
Dr. Brian O’Connell
Content
1. Introduction
2. Infections among asplenic patients
3.
Infections among solid organ transplant
recipients
4. Infections among patients with neutropenia
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
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:
a)
cell-mediated
immunity
a)
a)
Humoral
immunity
Phagocytic
defenses
a)Organ transplant, AIDS a) Intracellular, viruses,
parasites, Listeria,
Salmonella
b) Chronic lymphocytic
leukaemia, Myeloma,
asplenia
c) ALL, AML, Cytotoxic
chemotherapy
b)
Capsulate bacteria
c)
Coliforms,
Pseudomonas,
Aspergillus.
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.
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
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)
► 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
Interval from splenectomy to postsplenectomy sepsis
(data from: Holdsworth Br J Surg 1991; 78: 1031-38)
Cumulative % of PSS
120
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Years following splenectomy
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
►
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
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
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
Donor transmitted infection
► Viral
 HIV, Hepatitis B, C
► Bacterial
 More common in lung transplantation than other solid organ
transplants
► Protozoal
 Toxoplasmosis
Bacterial and parasitic infections in solid organ
transplant recipients
Organ
transplanted
First 2 weeks
Early
Late
Kidney
Wound
infection
UTI
UTI
Liver
Intraabdominal,
Bacteraemia,
Pneumonia
Pulmonary
aspergillosis,
Cholangitis.
Listeria
monocytogenes,
Toxoplasmosis,
Pneumocystis,
Cryptococcus
neoformans,
Nocardia spp.
Heart/lung
Mediastinitis,
Empyema,
pneumonia
Pulmonary
aspergillosis,
Rubin NEJM 1998; 324: 1741
Onset of episodes of infection post liver
transplantation
25
Blood
20
Bile
15
Peritoneal
Pleural
10
No. of
episodes
of infection 5
Time post transplantation (days)
>1
00
>9
0
80
+
70
+
60
+
50
+
40
+
30
+
6<
10
11
<1
5
16
<2
0
21
<2
5
25
<3
0
05
0
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
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
4. Infections among patients
with neutropenia
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
Causes of fever among neutropenic patients
Clinically
documented
infections 17%
Unexplained
fever 39%
Microbiologically
documented
infections 44%
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
►
Infectious episodes (%)
Episodes of severe infection related to
number of circulating neutrophils
50
45
40
35
30
25
20
15
10
5
0
<0.1
01-0.5
0.5-1
Neutrophil count (10 9/L)
Bodey Ann Inter Med 1966. 64:328-44
>1
Sources of bacteraemic infection
Hickman
catheter
Bacterial translocation
M-cells in Peyer’s patches
phagocytose bacteria
Mesenteric Lymph Node (MLN)
Thoracic Duct
Systemic Circulation
Oropharyngeal mucositis
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
%
Single organism bacteraemias in EORTC
trials of febrile neutropenia
Gram (-)
Gram (+)
20
18
16
14
12
10
8
6
4
2
0
I
II
III
IV
V
VIII
IX
X
XIV
(1973- (1978- (1980- (1983- (1986- (1988- (1991- (1993- (199778)
80)
83)
86)
88)
90)
92)
94)
00)
EORTC Trials
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
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
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
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
►
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
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
IDSA Guidelines: CID 2002; 34: 730-751
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)
Fungal Infections
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:
(Milliken 1990 RID, 12,S374)
►depth and duration of neutropenia
►GVHD
►age
►positive CMV serology
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
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
Clinical Syndromes
Mucocutaneous disease
• Localised disease
•
•
Invasive disease
►acute disseminated candidiasis
►line-related candidaemia
►chronic disseminated
candidiasis/hepatosplanic candidiasis
Chronic disseminated candidiasis/hepatosplenic
candidiasis
2. Aspergillus species
A. fumigatus, A. flavus
Clinical Syndromes
•
•
•
invasive pulmonary aspergillosis (IPA)
►focal or diffuse
sinus disease
cutaneous disease
Epidemiology and Risk Factors



associated with building works
early (neutropenia >21 days)
late (associated with GVHD)
Diagnosis





histological
culture
CT
PCR
antigen detection
Halo sign
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
Rhinocerebral mucormycosis
Histological appearance of mucormycosis
Mucor species
Lactophenol cotton blue stain of Rhizopus species
4. Other pathogenic fungi





Fusarium spp.
Alternaria spp.
Pseudallescheria boydii
Trichosporon spp.
Malassezia furfur
Disseminiated Fusarium infection