Infections in HSCT
Meng Yao Lu
Department of Pediatrics
National Taiwan University Hospital
October 17, 2009
HSCT patients . . .
Highly susceptible to infectionsprimary diagnosischemotherapy and anti-GVHD medicinespancytopenia indwelling cathetersmucosal and skin breakdownparenteral nutritionbroad spectrum antibiotics
Infections in transplant . . .
prolonged fever in >90%
50% have documented infections bacterial >> fungal > viral
infectious mortality of 4%-33%
bacterial and fungal infections predominate in the first post-transplant month
after 100 days, viral and encapsulated bacterial infections predominate
risk depends on type of transplant allogeneic unrelated >> allogeneic related > autologous
Three Periods of susceptibility . . .early recovery or “pre-engraftment” first several weeks after transplant related to neutropenia, chemotherapy induced mucositis and
CVL placement
mid-recovery or “early post-engraftment” second and third months after transplant related to acute GVHD, decreased cellular immunity
secondary to GVHD, immunosuppressive therapy and viral infections (e.g. CMV) and indwelling CVLs
late recovery interval beyond three months after transplant related to decreased cellular immunity secondary to chronic
GVHD, nonspecific suppressor cells due to chronic GVHD, reduced opsonization, decreased reticuloendothelial function, immunoglobulin G subclass deficiencies
PreventionConscientious hand washing
meticulous oral hygiene
low bacterial diet fruits & fresh salads --> aerobic GN rodspepper --> Aspergillus
HEPA filtration
decontaminationnot universally practiced
Laminar Air Flow (LAF) rooms
Surveillance cultures
Timeline of Infections
Common sites of infection . . .
blood (40.1%)GI tract (12.7%)skin (12.7%)upper respiratory tract (11.7%)lung (10.7%)urinary tract (6.8%)hepatobiliary system (1.6%)central nervous system (1.6%)eye (0.7%)
Blood. November 1995, Ochs et al.
The common bacteria . . .Gram positives GP bacteremia rates now
exceed GN rates enter via central lines,
skin and occasionally via GI tract
Staph epidermidis Staph aureus enterococcus α hemolytic strep Corynebacterium spp.
Gram negatives the most virulent and a
frequent cause of morbidity & mortality
enter via mucosa/GI tract, damaged skin, or central lines
Eschericia coli Klebsiella spp. P. aeruginosa Pseudomonas Enterobacter Acinetobacter Proteus Serratia
Antibacterial Therapy . . .Pre-Transplant Prophylaxis no longer routinely implemented at all transplant centers included oral nonabsorbable agents (e.g. Vancomycin, Gentamicin,
neomycin, colistin and polymyxin B) use of anti-PCP therapy is universal for all centers
Empiric Treatment prompt administration of broad spectrum coverage begin usually with third-generation cephalosporin or broad-spectrum
penicillin, add aminoglycoside with septic picture reevaluate if fever persists (> 3 days) and no + cultures
Specific Therapy tailor to identification and sensitivity panels may await confirmation of S. epidermidis infection with repeat cultures
The common fungi . . .
Candida sp. granulocytopenia cell-mediated immunity reactivation or
colonization TPN with high CHO broad spectrum
antibiotics resistance to prophylaxis
Aspergillus sp. granulocytopenia hi-grade GVHD broad spectrum
antibiotics dusty building
renovation hospital environment reactivation or
colonization life style corticosteroids
Aspergillus . . .
inhalation of spores
colonization of the Sino-pulmonary tree
invasion and dissemination
lack of specific diagnostic test
mortality approaches 90% with invasion
Epidemiology of Aspergillosis in HSCT Recipients
Bimodal Distribution Neutropenic phase
Depth Duration
Post engraftment phase GvHD Steroid use CSA/Tacrolimus Mucosal disruption CMV disease
Aspergillosis : Clinical Manifestations
Pneumonia Pleuritic pain Cough Hemoptysis
Sinusitis Nasal congestion Eschars Epistaxis Palatal hemierythema Disseminated infection (CNS)
Antifungal Therapy . . .Prophylaxis Polyenes (nystatin) Amphotericin B
broad spectrum extensive potential
toxicities Azoles
intravenous versus oral
Echinocandins Caspofungin Micafungin
Treatment Amphotericin B
0.5-1.5 mg/kg/day IV systemic greatly increased
toxicities, especially with concurrent CYA
Azoles Voriconazole
Echinocandins Caspofungin Micafungin
The common viruses . . .Herpesviruses CMV- associated with high rates of mortality EBV - PTLD HSV- 70-80% of transplant pts. are seropositive VZV- 20-50% of transplant pts. develop zoster
Epstein-Barr virus (EBV) 0.5% of allogeneic BMT recipients develop EBV-LPS
HHV6
Respiratory Viruses RSV, parainfluenza viruses, rhinovirus and influenza A & B
Enteroviruses adenovirus, coxsackie virus and rotavirus
Antiviral Therapy . . .Prophylaxis CMV
CMV-neg. blood pdts ganciclovir
HSV Acyclovir
VZV usually unnecessary
Treatment CMV
Ganciclovir Foscarnet Cidofovir immunoglobulin
HSV hi-dose acyclovir foscarnet
VZV hi-dose acyclovir
EBV donor lymphocytes
HSV 1 & 2 infection
Predominantly during neutropenia and within day 30 of HSCT
Mucocutaneous (oral/genital), esophageal, disseminated
Routine prophylaxis use of acyclovir
Resistance is uncommon
CMV infection
CMV infection remains as an important cause of morbidity and mortality in children undergoing HSCT.
Treatment StrategiesProphylactic therapyPre-emptive therapy after periodic
surveillance
0.0
0.2
0.4
0.6
0.8
1.0
3 4 5 6 7
Log viral load (genomes/ml)
Pro
bab
ilit
y o
f d
isease
Cope et al (1997) J Infect Dis 176: 1484-90
Suppression of CMV reduces disease probability
Risk factor Transplant type and
conditioning
Peak incidence Day+ 45-60 days
MUD > MRD > autograft
BMT > PBSCT ?
Conditioning Myeloablative> non-myeloablative < 100 days Myeloablative=non-myeloablative at 1 year
T cell depletion In vivo (ATG, Campath) Ex vivo (CD34 selection)
Interventions to control CMV
Primary infection
Latency
Reactivation ( +ve pp65 or PCR)
Disease
Prophylaxis
Pre-emptive therapy
CMV NaivePrevent infectionCMV Neg Donor, Leokodepletion
CMV viral load and pre-emptive antiviral therapy
Therapeutic approaches to control CMV replication
Prophylaxis Universal or targeted Eliminates direct and
indirect effects of CMV
Subset of patients remain at risk of late CMV infection/disease after cessation of prophylaxis
Pre-emptive therapy Targets individuals
based on their virologic markers
Minimises drug exposure
Patients may require more than one treatment
May not eliminate the indirect effects of CMV
Forum debate (2001) Rev Med Virol 11:73-86
CMV viral load and pre-emptive antiviral therapy
Preemptive treatment : highly effective
Detection
= pp65 antigenemia assay
= pp67 mRNA assay :sensitive but seldom use
= DNA detection methods
= Quantitative real-time PCR assays
EBV associated Post-Transplant Lmyphoproliferative Disorder
EBV PTLD
Therapy for EBV PTLD
Decrease immunosuppression
Rituximab
Antiviral agent
Donor-derived EBV-specific CTLs
Chemotherapy
Herpes Zooster/Varicella
Primary vs reactivated
High mortality rate in disseminated infection High dose acyclovir
Prevention Acyclovir prophylaxis VZIG within 96h of exposure Immunization of seronegative household
membersw Contact and respiratory precautions
Immunoglobulins
No role in Autologous transplant recipients
Allogeneic recipients: 400-500 mg/kg weekly from day 7 to day 100+
Reported effects: decrease bacterial sepsis decrease CMV disease decrease interstitial pneumonitis decrease acute GVHD decrease bacterial infections decreased mortality
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