Transcript Infections complicating transplantation

Infections in the
immunocompromised: with particular
reference to Haematological
malignancy patients
Aims & Objectives
• To give overview of the types of
immunodeficiency and associated infections
• Describe clinical presentations of
opportunistic infections with emphasis on
Haematological patients
• List preventative measures employed in
transplantation
Romani et al 2004
Rare inherited immunodeficiency
states
• Di George syndrome, SCID associated with T cell defects
(PCP, CMV, mycobacteria)
• Hypogammaglobulinaemia: B cell defects ( pyogenic
infections)
• Phagocyte disorders: Chronic granulomatous disorder
(Staph aureus, fungal infections)
• Complement deficiency states (encapsulated bacteria)
Acquired immunodeficiency states
• Primary: AIDS,
hypogammaglobulinaemia
• Secondary: to immunosuppression eg,
transplantation
Immunocompromised Hosts
Leukaemia therapy
Bone marr. transplant
Myelofibrosis
Cyclophosphamide
Alcoholism
Chr Gr Disease
Leukaemia
Lymphoma
Transplant
AIDS
Steroids
Cyclosporin A
Staph epidermidis
E coli, klebsiella
Pseudomonas
Enterococci
Candida
Herpes
Tuberculosis
Legionella
Nocardia
Cryptococcus
Pneumocystis
CLL
Myeloma
Splenectomy
Complement def
Late transplant
Pneumococcus
Neisseria
Mycoplasma
Enteroviruses
Giardia
Categories of transplant patients
• Bone marrow/ stem cell transplants
• Solid organ transplants
-kidney
-liver
-heart/ heart-lung
• Other tissue transplants
Bone marrow and stem cell transplantation:
why does infection occur?
• The underlying disease itself may result in a high risk of
infection eg, leukaemia, aplasia
• Prior to the transplant the patient needs to be
immunosuppressed
• There follows a prolonged period of immunocompromise
• Graft versus host disease and therapeutic
immunosuppression may increase the risk further
• General support measures may be complicated by infection
eg, indwelling catheters
Risk periods for infection after
transplantation
• Neutropenic phase: generally lasts 3 weeks
• 1-3 months: acute immunosuppression
• 4-12 months chronic immunosuppression
Factors increasing risk of
infection during neutropenia
• Lack of circulating and tissue neutrophils to
phagocytose invading bacteria and fungi
• Mucositis due to chemotherapy/irradiation causing
breach in mucosal barriers
• Indwelling catheter providing portal of entry for
skin organisms
• Broad spectrum antibiotics reducing colonization
resistance
Infections complicating the
neutropenic period
• Bacteraemia: gram negative and gram positive
• Herpes mucositis: herpes simplex virus
• Invasive mycosis: Candida and Aspergillus
Clinical presentations of these
infections
• Febrile neutropenia: fever greater than 380C
for 2 hours or longer.
• There may be rigors, drop in blood pressure,
septic shock
• Herpes: mouth ulceration which may be
complicated by bacteraemia by oral bacteria
• Candida sepsis; Aspergillus lung infiltrates
Approaches to treatment at this
stage
• Initial empirical therapy with a broad spectrum of
intravenous antibiotics
• Clinical trials (EORTC studies suggest either beta
lactam + aminoglycoside or cephalosporin or
carbapenem) support this approach
• Failure of fever to resolve by 5 days prompts
initiating empirical antifungal therapy eg:
amphotericin B
• Herpes mucositis treated with acyclovir
Algorythm for therapy of febrile
neutropenia
Broad spectrum antibiotics
eg tazocin +gentamicin
No reponse in 2-3 days?
Change to 2nd line
Eg ceftazidime +teicoplanin
No response by 5-7 days?
Change to antifungal
Eg: amphotericin B
Blood culture pathogens that we
commonly isolate during neutropenia
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Coagulase negative staphylococci
Enterobacteria
Ps aeruginosa
Corynebacteria (JK coryneforms significant)
“oddies”: Stenotrophomonas maltophilia,
environmental bacteria
• Candida
Further infectious complications:
days 30-100
• Pneumonia: “interstitial”
• Bacterial sepsis with prolonged neutropenia
• Fungaemia, dissemination, chronic hepatic
candidiasis
• Reactivation of latent viruses eg, CMV, BK
THE IMPORTANCE OF
PNEUMONIA
• A major killer in both developed and
developing countries
• Accounts for more deaths than other
infectious diseases
• Mortality rates vary but can be as high as
25%
• A major cause of death in children in
developing countries
• Incidence here (?) 2-5/1000 population
TYPES OF COMMUNITY ACQUIRED
PNEUMONIA
• In a previously healthy individual
• Here the infection may have been acquired
by droplet spread from another
• Alternatively, in patients with underlying
diseases endogenous colonizing bacteria
may be the cause
• These are more likely to be resistant to firstline antibiotics
MICROBIOLOGICAL CAUSES (%) OF
COMMUNITY ACQUIRED PNEUMONIA FROM
HOSPITAL BASED STUDIES (N=3,000)
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No cause found
Pneumococcus
Influenza virus
Legionella spp*.
Haem. Influenzae
Other viruses
Psittacosis/Q fever
Gram neg. bacilli
Staph aureus*
CAP
Severe CAP
36
25
8
7
5
5
33
27
2.3
17
5
8
3
2
2.7
2
2
5
TYPICAL GRAM APPEARANCE OF
Strep pneumoniae IN SPUTUM
GRAM POSITIVE CHAINS
DIPLOCOCCI
Streptococcus pneumoniae
(pneumococcus)
• A gram positive coccus that grows in short
chains
• Alpha haemolytic on blood agar
• Identified by its susceptibility to optochin
• Polysaccharide capsule confers
pathogenicity-at least 80 serotypes
• There are multivalent vaccines for
prevention of pneumococcal disease
SOME COMPLICATIONS OF
PNEUMOCOCCAL SEPSIS
• Bacteraemia (10%+)
• Empyema (1%)
• Meningitis (<0.5%)
• Mortality rates of 10-25%
• Splenectomy or asplenia a major
risk factor
Pneumococcal vaccine is
recommended for:
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Age >65 years
Underlying chronic lung disease
Asplenia
Alcoholism
Diabetes mellitus
Chronic renal failure
HIV infection
VIRUSES THAT CAUSE COMMUNTIY
ACQUIRED PNEUMONIA
INFLUENZA
OTHER VIRAL CAUSES
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Respiratory syncytial virus (RSV)
Parainfluenza viruses
Enteroviruses
(Cytomegalovirus)
Principal causes of interstitial pneumonia
(immunocompromised)
• Cytomegalovirus
• Pneumocystis carinii
• Respiratory viruses
-RSV
-Parainfluenza
-Infleunza
Legionnaires’ disease
• A severe pneumonia due to Legionella
pneumophila
• Can be community or hospital acquired
• Organism is acquired from environmental
sources eg, humidified air conditioning,
showers
• Usually attacks debilitated individuals
RISK FACTORS
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Male sex
Advanced age
Cigarette smokers
Alcoholism
Chronic lung disease
Immmunosuppression, malignancy
ACID ALCOHOL FAST RODS
SUGGESTING TUBERCULOSIS
PNEUMONIA IN THE
IMMUNOCOMPROMISED HOST
• Cause depends on the underlying
immunodeficiency
• More likely to present as a diffuse
interstitial pneumonia
• Treatment often empirical as establishing
the cause is often difficult
MAJOR CAUSES OF PNEUMONIA IN
IMMUNOCOMPROMISED
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Pneumocystis jirovecii (carinii)
Cytomegalovirus
Other respiratory viruses
Tuberculosis
Fungi
How we investigate undiagnosed
pneumonia
o CT scan
o Bronchoalveolar lavage
-culture for bacteria, fungi
-immunofl. For PCP
-culture for viruses
o Transbronchial biopsy
o Legionella urinary antigen
o Look for evidence of CMV infection
Approach to treatment….
o Cover the most likely pathogens with high
mortality: PCP, fungi, broad spectrum
antibiotics
o Adjust according to changing clinical
picture and investigation findings
Late complications:
days 100-12 months
o Usually associated with ongoing
immunosuppression for GVHD
o Infections with capsulate bacteria a major
risk eg, pneumococcus
o Reactivation of varicella zoster virus not
uncommon
o Other opportunistic infections occur as in
chronic immunosuppression
Infections complicating solid
organ transplantation
• Early infections complicate the surgical
procedure eg, wound infection, post-op
pneumonia
• After 1 month the risk of opportunistic
infections increases and correlates with the
level of immunosuppression
• Infections are more often due to
“intracellular” pathogens
Some examples of opportunistic
pathogens in organ tr. recipients
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Legionella pneumophila (pneumonia)
Nocardia asteroides (pneumonia, dissem.)
Listeria monocytogenes (meningitis)
Myco.tuberculosis (pneumonia, dissem.)
Pneumocystis jirovecii (pneumonia)
Crypto. neoformans (meningitis)
Aspergillus fumigatus (pneum. Dissem.)
Toxoplasma gondii (pneum. Encephalitis)
Viral infections complicating
organ transplantation
o Cytomegalovirus pneumonia, disseminated
infection, retinitis
o HSV oropharyngeal or oesophageal infection,
disseminated, encephalitis
o VZV rash, disseminated
o EBV pulmonary, hepatic disease, lymphoma
o Others: papilloma virus, HHV 6, resp viruses
Strategies to protect the
immunocompromised
Identify the patient and perform a
risk assessment
• Most common groups are patients with
acquired immunocompromise due to
underlying disease and its treatment
• A good example is acute leukaemia
• This may be treated by either chemotherapy
or stem cell transplant
A risk assessment in an acute leukaemic
patient:undergoing remission induction
chemotherapy
• They may have infection on presentation ,
therefore full clinical examination
• Neutropenia will last for c. 3 weeks
therefore antibacterial prophylaxis is
appropriate
• Antifungal prophylaxis controversial
• Antiviral prophylaxis for HSV reactivation
Do prophylactic antibiotics
work?
• There have been many trials that have
shown benefit from antibiotic prophylaxis
• The concept adopted is selective depletion
of gut flora leaving the colonization
resistance intact
• Ciprofloxacin widely used for this purpose
• Antifungals eg, fluconazole reduce mucosal
infections due to candida
Additional approaches
• Protective environment: single room
isolation
• Care of indwelling catheter
• General avoidance of risks after chemo
completed
Protecting the stem cell
transplant patient
• Allogeneic transplant carries a higher risk
than autologous
• More prolonged period of
immunosuppression
• Greater risk of airborne fungal infection and
CMV
Protective measures for the SCT
patient
• Protected environment: positive pressure HEPA
filtered room
• Antibiotic and antifungal prophylaxis
• HSV prophylaxis (acyclovir)
• Measures to prevent CMV infection: screened
blood products, ganciclovir
• Cotrimoxazole prophylaxis on engraftment for P
jirovecii prevention
• Penicillin prophylaxis in chronic GVHD
• Vaccination: ‘killed’ vaccines
General measures to prevent
infection
• Avoid contact with respiratory infections
• Physiotherapy with bacterial chest
infections
• Avoid live vaccines
• Irradiate blood
• Use CMV seronegative blood
• Promptly treat infections
Splenectomy/hyposplenism carries an
increased risk of overwhelming sepsis
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Sickle cell disease
Coeliac disease
GVHD
ITP
Splenic irradiation
Surgical removal
Causes of infection after
splenectomy
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Strep pneumoniae
H influenzae
Meningococcus
Salmonella spp
Capnocytophaga canimorsus (dog bites)
Babesia microti (tick borne or transfusion)
Plasmodium malaria
Preventive measures
• Delay elective splenectomy
• Vaccinate before splenectomy
• Vaccinate with: pneumococcal;
meningococcal; H influenzae
• Penicillin prophylaxis (children main
benefit)
• Early empirical therapy
• Alert bracelet