Infections in Organ Infections in Organ Transplantation and Transplantation and

NeutropeniaNeutropenia

Dr. Brian O’Connell

ContentContent

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

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) Humoral immunity

a) Phagocytic defenses

a)Organ transplant, AIDS

b) Chronic lymphocytic leukaemia, Myeloma, asplenia

c) ALL, AML, Cytotoxic chemotherapy

a) Intracellular, viruses, parasites, Listeria, Salmonella

b) Capsulate bacteria

c) Coliforms, Pseudomonas, Aspergillus.

Host defences and associated 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.

Classification of Pathogens

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

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Years following splenectomy

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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 Listeria monocytogenes,

Toxoplasmosis,

Pneumocystis,

Cryptococcus neoformans,

Nocardia spp.

Liver Intra-abdominal,

Bacteraemia,

Pneumonia

Pulmonary aspergillosis,

Cholangitis.

Heart/lung Mediastinitis,

Empyema,

pneumonia

Pulmonary aspergillosis,

Rubin NEJM 1998; 324: 1741

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Onset of episodes of infection post liver

transplantation

No. of

episodes

of infection

Time post transplantation (days)

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 4. Infections among patients with neutropeniawith 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

Episodes of severe infection related to Episodes of severe infection related to number of circulatingnumber of circulating neutrophilsneutrophils

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Neutrophil count (10 9/L)Bodey Ann Inter Med 1966. 64:328-44

Hickman catheter

Sources of bacteraemic infection

Bacterial translocation

Mesenteric Lymph Node (MLN)

Thoracic Duct

Systemic Circulation

M-cells in Peyer’s patches

phagocytose bacteria

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 Single organism bacteraemias in EORTC trials of febrile neutropeniatrials of febrile neutropenia

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I(1973-

78)

II(1978-

80)

III(1980-

83)

IV(1983-

86)

V(1986-

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VIII(1988-

90)

IX(1991-

92)

X(1993-

94)

XIV(1997-

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EORTC Trials

%

Gram (-)

Gram (+)

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 InfectionsFungal Infections

• 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

Risk groups and incidence

(Milliken 1990 RID, 12,S374)

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

Empiric treatment of fever of unknown origin

Fungal Pathogens1. 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

A. fumigatus, A. flavus

Clinical Syndromes• invasive pulmonary aspergillosis (IPA)

►focal or diffuse• sinus disease• cutaneous disease

2. Aspergillus species

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

Rhizopus, Absidia, Rhizomucor, Cunninghamella associated with prolonged neutropenia

Clinical Syndromes rhinocerebral, pulmonary, cutaneous, disseminated characterised by fever and necrosis

Diagnosis biopsy - histology and microbiology

3. Mucormycosis

Rhinocerebral mucormycosis

Histological appearance of mucormycosis

Mucor species

Lactophenol cotton blue stain of Rhizopus species

Fusarium sppFusarium spp.. AlternariaAlternaria spp. spp. Pseudallescheria boydiiPseudallescheria boydii TrichosporonTrichosporon spp. spp. Malassezia furfurMalassezia furfur

4. Other pathogenic fungi

Disseminiated Fusarium infection