Transcript Outline • Overview • General features of selected infections – Bacterial infections – Fungal infections • Candida • Aspergillus – Viral infections • Herpes viruses • Respiratory viruses • Other—HHV6,

Outline
• Overview
• General features of selected infections
– Bacterial infections
– Fungal infections
• Candida
• Aspergillus
– Viral infections
• Herpes viruses
• Respiratory viruses
• Other—HHV6, adenovirus, BK
– Other infection complications:
• CAMPATH (B/T cell depletion) increased association with
EBV-related PTLD
Post-Transplant Infections Now Exceed
Acute Rejection as Cause for Hospitalization:
A Report of the NAPRTCS
Vikas R. Dharnidharka,Donald M. Stablein,William E. Harmon
Am J Transplant 4(3):384-389, 2004
Infectious Diseases & Transplantation
• Direct consequences of microbial invasion
– Pneumonia
– Wound infection
– Abscess
• Indirect consequences of local and systemic
cytokine, growth factor and chemokine release
in response to such invasion
– Immunosuppressing effect leading to other OI
– Role in the pathogenesis of allograft injury
– Role in development of malignancies
Risk Factors
• Net state of immunosuppression
– Dose, duration, temporal sequence of immunosuppressive drugs
– Presence or absence of leucopaenia
– Breaches to the mucocutaneous barriers
– Devitalised tissue
– Metabolic factors – caloric malnutrition, uraemia, hyperglycaemia
– Presence of immunomodulating viruses – CMV, EBV, HCV, HBV,
HIV
• Epidemiologic exposures
• Consequences of invasive procedures
FACTORS THAT INCREASE THE RISK OF INFECTION
Host related
• Older age (>40yrs)
• AML/AA, non 1st CR malignancy
• Immunomodulating viruses
(CMV,HIV,HHV6/7 )
• Organ dysfxn (mucositis,liver & renal dysfxn)
• Concomitant immunosuppressive disease
Environment related
• Colonization with virulent pathogens (Staphy
aureus, Pseudomonas, Candida spp )
• Heavy exposure to contaminated
environment (water,food,inanimate objects,air)
Treatment related
• Prolonged neutropenia (>10days)
• CD4 cytopenia (<200)
• Allogeniec BMT/PBSCT ( MUD, T cell depleted,
GVHD II-IV, myeloablative conditioning regimen )
• Autologous BMT/PBSCT if CD34 < 2 x 106/kg
• Prior therapy with purine analogues (Fludarabine)
and high dose steroids ( > 1mg/kg for >2wks )
Hematology 1999
The Timeline of Post-Transplant Infections
Nosocomial
Technical
OI, relapsed, residual activation
of latent infection
Community
acquired
Transplant
<4 weeks
1-6 months
>6-12months
MRSA, candida,
Aspergillus, aspiration,
CRI, C.difficile, VRE
HSV, CMV, EBV,
HBV, HCV, TB, PCP
BKV, Listeria, Nocardia,
Toxoplasmosis, Strongyloides
CAP, Aspergillus,
CMV colitis, UTI
Nosocomial pathogens,
Donor-derived recipient
colonisers
Period of most intensive IS
Common to rare
Important aspects of SCT
•
Conditioning therapy:
– myeloablative vs. non-myeloablative (GVHD encouraged, less neutropenia, and
infections predominate LATE)
– mucosal damage; risk of bacteremia
– DXT effects: single dose (increased risk of pancreatitis, parotitis) vs. fractionated;
virtually all develop diarrhea; severe mucositis
•
Infusion of stem cells: autologous vs. allogeneic (HLA match important);
increased risk of GVHD with allogeneic and longer engraftment/neutropenia
•
Source of stem cells: peripheral blood (faster engraftment but more GVHD)
vs. marrow vs. cord blood (longer engraftment but less GVHD)
•
Infection risks:
– Periods of immune impairment
• Neutropenia (early during engraftment)
• T cell (late)
• Hypogammaglobulinemia (early to late)
– GVHD and therapy
– Intravascular lines
Pre-engraftment days 0-30
*Neutropenic pathogens
*Gingivostomatitis
*Venoocclusive disease
Post-engraftment days 30-100
*Opportunistic infections
*CMV
*Adenovirus
*GVHD
Late post-transplantation >100 days
*Herpes zoster
*Encapsulated organisms assoc with GVHD
Figure 311-1 Phases of predictable opportunistic infections among HSCT recipients. Immune defects predisposing to infection are bordered by color (neutropenia = pink,
lymphopenia = blue, and hypogammaglobulinemia = green). Barrier defects predisposing to infection are shaded in color (mucosal breakdown = yellow, skin breakdown
= silver). Contribution of defects to infections occurring with high incidence are designated by border color (for immune defects) and/or shading (for barrier defects).
(Adapted from Van Burik J-AH, Freifeld AG. Infection in the severely imunocompromised host. In: Abeloff MD, Armitage JO, Niederhuber JE, et al, eds. Clinical Oncology.
3rd ed. Philadelphia: Churchill Livingstone; 2004:942.)
Downloaded from: Principles and Practice of Infectious Diseases
Non-infectious entities in SCT
•
•
•
•
Hemorrhagic cystitis from cyclophosphamide
DXT induced diarrhea
ATG and fevers, chills, arthralgias
Venooclusive disease—painful hepatomegaly,
elevated LFTs; complicated by jaundice, ascites,
MSOF; 5-10% mortality
• GVHD—skin, GI tract, lungs
• Pneumonitis/diffuse alveolar hemorrhage from
drugs, DXT, GVHD
Bacterial infections
• Mucositis related-early after BMT
• Neutropenia: ANC <500; risk dependent on severity and duration of
neutropenia
• Sites of infection in neutropenic fever:
–
–
–
–
–
–
–
Mouth/pharynx
Respiratory tract
Skin/soft tissue
Perineal region
Urinary tract
Sinuses
GI tract
25%
25%
15%
10%
5%
5%
5%
Neutropenic enterocolitis (Typhlitis)
• Presentation :Fever, RLQ tenderness, diarrhea,
bleeding
• Etiology :Polymicrobial including Pseudomonas
aeruginosa and Clostridium septicum
• CT scan: cecal inflammation, bowel wall thickening,
mesenteric stranding, intraluminal air
• Treatment principles :
Broad spectrum antibiotics
Rest the bowel
Early TPN
Surgery for surgical indications
Specific bacterial pathogens in neutropenic host
• In addition to the usual MRSA, Enteric flora, Anaerobes:
• Nocardia sps –g+AFcb;pneumonia, lung abcess;usually sensitive
to TMP-SMX, quinolone & macrolide are ineffective.
• Rhodococcus equi—g+cb, present in soil/water; pneumonia, lung
abscess, empyema, bacteraemia; salmon pink colonies in 4-7days;
treat with 2 abx
(vanco,quinolone,carbapenems,rifampicin,tetracycline); PCN
resistant.
• Corynebacterium jeikium– colonizes skin, catheter related
bacteremia - vancomycin drug of choice
Puthucheary SD, Sangkar V, Hafeez A, Karunakaran R, Raja NS, Hassan HH. Rhodococcus equi – an
emerging human pathogen in immunocompromised host : a report of four cases from Malaysia. Southeast Asian
J Trop Med Public Health,2006 Jan; 37(1): 157-161
Bacterial infections
• Intravascular-catheter related
– Throughout transplant, prolonged indwelling lines
• Coagulase negative staph
• Corynebacteria
• Mycobacteria
• Encapsulated organisms (GVHD and therapy)
– Strep pneumo with severe, rapid sepsis (?flushing )
Fungal Infections in Transplantation
Organ
Incidence
Aspergillus
mortality
Candida
mortality
Kidney
0-20%
20-100%
23-71%
Liver
5-40%
50-100%
6-77%
Heart
5-20%
78%
27%
50-94%
40-80%
Allogeneic SCT 5-30%
IFI in SOT – US 25 center survey
IFI type
IFI cases
(% total)
Fatality(%)
Median days
to diagnosis
Candidiasis
Aspergillosis
Zygomycosis
Cryptococcosis
Endemic mycoses
Others
56
21
1
7
5
10
29
45
-
107
172
280
386
-
Pappas ICAAC 2003
Candida biotypes isolated from clinical specimens
in Malaysia
Candida spp
C albicans
C parapsilosis
C tropicalis
C glabrata
C krusei
Others
KP Ng et al. Mycopathologica 1999
N (%)
493 (44.2)
290 (26.0)
198 (17.7)
107 (9.6)
14 (1.25)
12 (1.04)
Fungal infections
• Candida—endogenous or exogenous source;
disseminated candidiasis as neutropenia
resolves**
• Filamentous fungi
–
–
–
–
Aspergillus
Fusarium
Zygomycetes
Other moulds
• ? Pneumocystic carinii pneumonia
• Other endemic fungi
– Coccidiomycosis, Histoplasmosis NOT COMMON but
is seen.
Hepatosplenic Candidiasis
• Typically does NOT present
during neutropenia
• Clinical presentation secondary
to inflammatory response—
granulomatous inflammation
• After engraftment: ab pain, increased LFTs, fever, ?leg/flank
pain
• Differential: other fungi, bacteria, lymphoma
• Radiographic changes may get worse before improving
• C. albicans most common
– Treatment varies ( ? Sensitivity pattern and clinical virulence
is considered )
Mucosal lesions
• Candida, HSV, and cytotoxic drugs
• Candidal lesions can be
– Pseudomembranous or erythematous
• Diagnosis by scraping and culture
Invasive Aspergillosis
• Increased over last decade
• Occurs during neutropenia or later
• Presentation: fever (can be blunted),
cough, SOB, hemoptysis
• Pneumonia, disseminated disease to skin,
abdominal organs, CNS
Aspergillosis
Necrotic skin lesion
Invasive pulmonary aspergillosis:
Classic findings nodules and cavities
CNS lesion
Halo sign on chest CT
Early diagnosis and treatment Aspergillosis
• Pulmonary infiltrates within 96 hrs: better
outcome
• Early CT scan chest in 37 patients
– neutropenia and pulmonary infiltrates
– decreased mean days to diagnosis: 7 to 1.9
– antifungals plus resection in 43%: mortality 28%
Aisner et al, Ann Intern Med, 1977
Caillot et al, J Clin Oncol, 1997
Diagnosis of invasive fungal infection(IFI)
• High index of suspicion
• Low threshold for imaging
Diagnosis IFI: Imaging
• CT scan: aspergillosis
– halo sign: early while neutropenic
– air crescent sign: later on neutrophil
recovery
– sensitivity 72% , specificity 100%
Blum et al, Chest,1994
Diagnosis IFI: blood culture
• 30% positive with disseminated
candidiasis
• Rarely positive with moulds except
S prolificans, Fusarium
Diagnosis IFI: respiratory culture
• Respiratory tract cultures for Aspergillus
– predictive value for invasive infection depends
on setting
– neutropenic post allo BMT 96%, SOT 60%
• But bronchoalveolar lavage negative in
50% cases
IFI Diagnosis: biopsy
• Tissue biopsy: culture and histopathology
– gold standard but not always attainable
– culture low yield
– advantage: exclude other pathology, infections,
identify species, perform susceptibility testing
IA Diagnosis: Can we do better?
• Potentially decrease mortality by earlier
treatment
• Save unnecessary antifungal cost and toxicity
• Focus aggressive antifungal therapy to those
who most need it-risk prognosticate
Galactomannan antigen in IA
• ELISA (Sanofi Pasteur Diagnostics)@2003FDA
• Detects galactomannan (cell wall) using rat MoAb
• Threshold for detection 1ng/ml serum & specific for Aspergillus only
• Sn 60-90% ; Sp 80-90% with PPV 88% and NPV 98% in leukaemic
and post Allo SCT individuals.
Laboratory Problems :
Interlab variability
Anti-aspergillus antibodies
False pos with antibiotics
Cross reactivity
False neg with lesions that are
not angioinvasive
Maertens, et al. Blood 2001:97;1604-1610
Questions of utility :
In non-neutropenic individuals
Patient on mould active agents
children
Aspergillus PCR
• Not standardised
• Nested PCR
o most sensitive
o detects 1-10 CFU/ml
o detects all species
o not automated
• Real time PCR
o more convenient,
o less prone to contamination
o but less sensitive by factor of 10.
Medical Mycology:
The Last 50 Years
# of drugs
14
12
10
8
6
4
5-FC
2
0
1950
1960
1970
L-AmB
ABCD
ABLC
Terbinafine
Itraconazole
Fluconazole
Ketoconazole
Miconazole
1980
1990
2000
Pneumocystis Pneumonia
• Common late after BMT
– Steroids, T cell depletion
– Can occur earlier in patients who receive steroids in prior
regimens
• Prophylaxis at least 6 months(or longer) in patients with chronic
GVHD
– Twice weekly bactrim most effective
– Dapsone, aerosolized pentamidine less effective
• Diagnosis later than with AIDS
– Mortality >50% if presenting late
Viral infections
• Almost ANY virus can
cause severe illness in the
immunocompromised host
• Episodic infections
• Latent infections that may
reactivate
• Reactivation occurs in
seropositive patients vs.
primary infection in
seronegative (reduced with
leucodepleted blood
products-frequency of 2%)
Latent Virus
Seroprevalence
CMV
45-90%
EBV
>90%
HHV-6
>90%
HSV
50-90%
VZV
>90%
BK
>90%
H1N1
?
Epidemiology of Cytomegalovirus
• Infection- common, disease less (usually late)
• Dependent on serostatus and prevention strategy
• In patients without prevention:
Transplant type
CMV infection
CMV disease
Allogeneic SCT
R+/D+orR-/D+
R-/D-
70%
15-25%
3-5%
35-40%
10%
1-3%
Autologous SCT
R+
R-
25-40%
3-5%
5-7%
1-3%
CMV Infection
– seroconversion - anti-CMV IgM antibodies
– fourfold increase in anti-CMV IgG titers
– detection of CMV antigens in infected cells
– detection of CMV-DNAemia by molecular
techniques; and/or isolation of the virus by
culture of the throat, buffy coat, or urine
CMV Disease
• Clinical signs and symptoms
– Fever, leucopenia
– Organ involvement - hepatitis, pneumonitis,
pancreatitis, colitis, meningoencephalitis,
myocarditis, chorioretinitis
• 1-4 months after transplantation when
prophylaxis is not used or 1-4 months after
discontinuation of prophylaxis
• Risk of reactivation increased in seropositive
recipients
CMV Disease
• Viremia
• Pneumonia-indolent, dry cough,
mild hypoxemia, fever with rapid
progression to failure;
interstitial pneumonitis
• GI disease
– Esophagitis, colitis
• Encephalitis, retinitis—LESS FREQUENT
Diagnosis
• Serology
– Fourfold increase in IgG titer or a markedly positive IgM titer
– Limited value for diagnosis of active infection especially during
intense immunosuppression
– Significant Ab rise often too late, IgM may remain negative
• Culture
– Isolation of CMV by culture of urine, buffy coat, throat, BAL
– Rapid shell-vial culture technique - fluorescence tagged
monoclonal antibody used to detect CMV antigen expressed
early in viral replication
– Less sensitive, time consuming
• Detection of CMV in culture indicates the presence of the
virus but does not confirm active CMV disease
• CMV viruria may persist for years
Diagnosis
• CMV antigenemia assays
– rapid detection via tagged monoclonal antibodies specific to the
pp65 lower matrix protein in PBMC
– sensitivity 89%, specificity of 93%
– antigenaemia parallels period of symptoms
• PCR, qPCR, DNA hybridization
– sensitivity, specificity >80%
– diagnose active infection 1-3 weeks before conventional tools
CMV antigenaemia detection or DNA/RNAemia (especially
qPCR) methods of choice for diagnosing and monitoring
active CMV infection( weekly )
CMV Prevention and Therapy
• Prevention
– Prophylaxis and early therapy
• Induction GCV (bid) for 2 weeks then maintenance qd until
day 100
• Valganciclovir safe and effective
• Common complication is neutropenia; use GCSF with ANC
<1000
• Therapy
– Pneumonia
• Ganciclovir + CMV-Ig or IVIG
• Alternatives: foscarnet, cidofovir
– GI
• Ganciclovir
HSV infection/reactivation
• Reactivation is common
– >70% in seropositive
without prophylaxis
• ACV now common for prophylaxis usually for 30 days
• ACV resistance—a growing problem
– Incidence 5-10% among allogeneic SCT
– Increased with URD txp, GVHD, haploidentical txp
– Decreased among patients treated with GCV for CMV
VZV after HSCT
• Reactivation may be accompanied by severe skin lesions,
disseminated disease
– Multidermatomal lesions
– Encephalitis
– Hepatitis—ab pain, transaminitis
late after BMT
– DIC
– Can have disseminated disease WITHOUT skin lesions
• Acyclovir prophylaxis effective in decreasing reactivation but
at risk after discontinuation
– VZV seropositive
– Severe GVHD
HHV-6 after SCT
• HHV-6 seroprevalence >95% by age 2
– Early reactivation in 38-60% SCT recipients (mostly type B)
– Clinical correlates: rash, BM suppression, delayed platelet
engraftment, idiopathic pneumonitis
• Best association with meningoencephalitis
– Nonspecific presentation, primarily confusion
– Autopsy with white matter edema and inflammation
– Risk factors: URD, anti-T-cell immunotherapy
• Diagnosis by CSF PCR
• ACV-resistant
• Treatment: ganciclovir, foscarnet, cidofovir
BK virus
• Cause of hemorrhagic cystitis
• Incidence in allogeneic >>> autologous
– Cofactors: GVHD, steroids
• Definitive diagnosis difficult as
asymptomatic shedding common
• Therapy: supportive, ? Cidofovir which is
most active in vitro but renal toxicities
Episodic Viral infections after SCT
• Exposure determines risk
• Time after SCT: no effect
• Immunosuppression
impacts severity of illness
• Key: infection control
practices can limit
morbidity/mortality
– Isolation procedures
– Vaccination of HCW for flu
– Symptomatic surveillance
Virus
Attack rate
RSV
5-15%
Parainfluenza
5-10%
Influenza
<5%
Adenovirus
<5%
Rhinovirus/hMPV
<5%
Measles
<1%
Parasitic infections
• Toxoplasmosis
– Almost always reactivation and not primary
infection
– Occurs in 2-7% in those who are seropositive
– Clinical manifestations: fever, encephalitis,
pneumonitis, myocarditis