Infections in HSCT

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

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Log viral load (genomes/ml)

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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