Fungal Infections § Yeasts are fungi that grow as single cells (eg. Candida, Cryptococcus) § Moulds grow as multicellular filaments called hyphae (e.g. Aspergillus, fusarium. Zygomycetes)
Causes of invasive fungal infections § 95-97% are due to candida § C. albicans (majority) § C. tropicalis § C. glabrata § C. parapsilosis § C. krusei § The remaining are due to other non-candida yeasts § Trichosporon § Cryptococcus § Blastoscizomyces § Effective anti-candida agents have contributed to a changing spectrum § Significant reduction in candida infections § Aspergillus increased § Fusarium, scedosporium, zygomycetes – environmental § Trichoderma, paecilomyces, scopulariopsis – dermatiacious
Risk factors § Yeast infections (most due to candida species) § Usually acquired from patient’s GI or mucocutaneous flora § Mostly occur during neutropenic phase after intensive chemo or conditioning § Risk factors § Heavy colonisation § Disruption of mucocutaneous membranes § Reduced phagocytic cell function § Lack of effective antifungal therapy in blood stream § Mould infections (mainly aspergillus) § Usually aquired from inhalation of airborne spores § 2 at risk populations § Neutropenic patients § HSCT recipients with GvHD
Antifungal agents Polyene § Amphotericin B (50mg = £100 = £400/day for an adult dose) § Nephrotoxicity 20-66% § Concurrent therapy with CsA or tacrolimus, aminoglycosides etc § Baseline decreased renal function § Better with liposomal preparations
Azoles § Fluconazole § Narrow spectrum (little activity against Aspergillus) § Good toxicity profile, few drug interactions § Often used as prophylaxis § Itraconazole § Broader spectrum of activity than fluconazole (includes activity against aspergillus and dermatophytes) § Numerous interactions esp. with vincristine (increased risk of neurotoxicity) and CsA – care needed in transplant patients § Unpredictable bioavailability § Poor tolerability § Voriconazole (200mg = £77) § Good activity against yeasts (fungistatic), moulds (fungicidal) and common dermatophytes § 96% bioavailability § Possibly superior to amphotericin in invasive aspergillosis (70 v 57% survival advantage in one study) § May also be useful for salvage treatment in refractory invasive candidiasis (56% response rate) – has efficacy in fluconazole resistant candida § Zygomycetes are intrinsically resistant § Posaconazole § Only available as oral preparation § Efficacy against zygomycetes (in contrast to voriconazole)
Echinocandins § Caspofungin § Good activity against candida (fungicidal) § Greater activity than amphotericin or fluconazole § At least as effective as ambisome in treating invasive candidiasis § Aspergillus (fungistatic) and variable efficacy § However has efficacy as salvage therapy in invasive aspergillosis (45% response) § Highly active against Pneumocystis carinii § Not active against Histoplasma, Cryptococcus neoformans, Trichosporon, Fusarium or any Zygomycetes. § Insufficient bioavailability for oral use and must be given IV § Few clinically relevant interactions - 20% reduction in tacrolimus levels
Combination therapy § Encouraging results but expensive and toxic § Ambisone and flucytosine combination therapy more effective than ambisone alone in the treatment of Cryptococcus § Caspofungin and voriconizole more effective than voriconazole alone in patients with invasive aspergillosis refractory to ambisone – higher 3 month survival.
Prophylaxis § Which agent? § Fluconazole is the most common agent, only covers yeasts § Increasing use of extended mould active azoles § Concern for invasive mould infections § Itraconazole, voriconazole, posiconazole § Prophylactic voriconazole is currently under investigation in allo HSCT § Randomised trials comparing itraconazole/ fluconazole with oral posiconazole have demonstrated efficacy of posiconazole (8 v 2% invasive fungal infection / 22 v 16% mortality) [Cornley et al., NEJM 2007] § When to treat? § Should be initiated at same time as cytotoxics § Concerns re interactions esp. with vincristine have led to it being given after cytotoxics § Should be continued until risk over § May be extended in patients with GvHD requiring prolonged immunosupression
Pre-emptive antifungal therapy § Evidence of invasive fungal infection based upon a surrogate marker, eg. Antigen or genomic detection test, but without clinical evidence of disease § HRCT can detect up to 60% pulmonary lesions in PUO when CXR normal § Early detection is associated with better outcomes § German study § Fluconazole prophylaxis, started either pre-emptive or empirical ambisome § Serial serum PCR fungal DNA detection studies § Documented IFI were similar § 30 day mortality was reduced by 67% in the pre-emptive group § Needs validation in larger randomised trials
§ Galactomannin § Polysaccharide cell wall component – ELISA detects Aspergillus GM antigen § Angioinvasion assumed to be necessary for test to be positive § Sensitivity 90% / Specificity 98% reported in stem cell transplant recipients § Thought to be less in other groups (50-100% sensitivity / 92-100% specificity) § False positives possibly due to translocation of GM from food (increased with mucositis, GVHD, cytotoxic chemotherapy) § Test may need to be repeated twice if positive due to possible lack of reproducibility
§ Fungal DNA PCR § Less sensitive than GM (50-70%) § Specificity reported 63-100%
Empirical antifungal therapy § Antifungal therapy in the setting of persistent fever (5-7 days)despite broad spectrum anti-bacterial therapy, with no clinical, radiological, microbiological tests suggestive of fungal infection § 56-82% of HSCT patients receive empirical antifungal therapy § 2-15% have proven IFI § Fluconazole v. amphotericin § Trials have shown that fluconazole was as effective, but these patients included patients not on fluconazole prophylaxis and at low risk of IA and other IFIs. § Itraconazole v. amphotericin § As effective § Advantage of oral preparation, allowing earlier hospital discharge § Voriconazole v. ambisome § No inferiority demonstrated § Amphotericin v. ambisome § No inferiority, ambisome showed reduced toxicity § Caspofungin v. ambisome § No inferiority and better toxicity
Directed antifungal therapy § Invasive candidiasis § Amphotericin B is superior to fluconazole, despite the renal toxicity § Voriconazole is a safe and effective alternative to amphotericin B § Caspofungin, an echinocandin has shown favourable results in comparison to amphotericin B § Caspofungin or voriconazole can be used for fluconazole resistant spp. That have not responded to amphotericin or who are intolerant § Invasive aspergillosis § Either amphotericin or voriconazole § Itraconazole has been recommended as maintenance and secondary prophylaxis of IA, but not for primary treatment of IA or IC § Caspofugin or itraconazole can be used if refractory patients
BCSH Guidelines § Epidemiology § Shift from systemic candidiasis to invasive aspergillosis § Within SC , shift from albicans to non-albicans spp § Induction chemo for AML has same risk of IFI as allogeneic transplants § Diagnosis § Should be confirmed when possible § Diagnostic records should be kept up to date to allow recognition of changes in pathogens § Suggestive clinical features warrant early and thorough investigation to support early use of antifungals § Negative blood culture, does not exclude invasive candida. If clinical suspicion, encourage biopsy § Suitable specimens include aspirated fluid (incl. BAL) or a biopsy for cytology, histology and culture. Microscopic findings or growth from any normally sterile tissue warrants antifungals § Routine screening for galactomannin by sandwich ELISA may assist early diagnosis if results interpreted in context of other evidence § CSF should be specifically stained for fungi, esp Cryptococcus § All yeast isolates should have speciation and susceptibility testing § Radiology § All units treating at risk patients, need immediated acces to CT and mycological diagnostic methods § If suspected, early CT scan more likely to show the predictive halo sign § HRCT § If suspected and supportive CT signs (halo, air crescent sign, cavitation) should have antifungals § Inconclusive clinical or micro evidence and non-specific CT signs, should have repeat scan within 7 days § If sinus suspected, axial and coronal CT of sinuses should be performed – if suspicous, urgent ENT assessment with surgical debridement and antifungals § Therapy § Empirical use of antifungals for unresponsive fevers should be discouraged § When empirical use unavoidable, seek evidence from CT and mycological tests § In empirical treatment, preferable to minimise toxicity. Lowest rates of toxicity are for caspofungin followed by ambisome. They had similar efficacy § If CT / mycological testing negative, empirical therapy may be unnecessary § If proven CNS IFI, voriconazole has best CNS penetration § Combination therapy should be discouraged § Prophylaxis § Antifungal prophylaxis not recommended for autos § Antifungal prophylaxis is recommended for allos and induction AML § Prophylaxis of IFI for high risk patients – itraconazole or posaconazole. Both are superior to fluconazole. No data to justify use of voriconazole § Itraconazole, posaconazole may be equally effective, but not yet proven in RCT § Azoles should be avoided when there is a risk of serious drug interactions (eg. Vincristine). Intermittent ambisome preferred § Loading dose 800mg/ d capsules for 7 days or 400mg /d iv for 2 days to acieve steady state and then daily dose of 400mg/ d orall solution or 200mg /d iv. § Trough levels of 500ng /ml § Levels should be measured weekly § Secondary prophylaxis may be effective for those with prior proven IFI § Duration of prophylaxis unclear; in acute leuks until neut >0.5 § Azoles need not be stopped when starting iv systemic antifungals § Surgery § Should be considered for respectable pulmonary aspergillus § Growth Factors § No evidence to support them as prophylaxis or supportive
§ T-cell mediated immune suppression
Herpes viruses § Primary and reactivation infections § Viral latency can be detected by serological screening § Antiviral therapy used prophylactically and for treatment § Acyclovir (prodrug – valacyclovir) § Penciclovir (prodrug – famciclovir) § Ganciclovir (produrg – valganciclovir) § Foscarnet § Cidofovir
§ Herpes simplex virus § Haem patients, almost entirely reactivation § Occurs early after therapy and frequently recurs with future treatment § Mucocutaneous may present with atypical appearance and be confused with candida § More invasive, heal slowly, prolonged viral shedding, and may disseminate § Acyclovir resistance is uncommon § Foscarnet or cidofovir for double resistant strains § Acyclovir prophylaxis is effective § Allos § Autos and acute leukaemia induction § T-cell depleting therapy § Previous HSV during treatment
§ Varicella zoster virus § Chicken pox (primary) and herpes zoster (reactivation) § Primary infection can be very severe, and patients at risk should be counselled regarding avoidance of exposure and early treatment § Hepatic or GI VZV, difficult to diagnose and significant mortality § Treatment – acyc, valacyc, famcic § No evidence for IVIG or steroids § Guidelines don’t support routine prophylaxis, based on evidence that disease occurs after prophylaxis discontinued
§ Cytomegalovirus § Pneumonia, enteritis, encephalitis, retinitis, hepatitis, cholangitis, cystitis, nephritis, sinusitis, marrow suppression § T-cell function is paramount in control of CMV § No effective antiviral prophylaxis § Hope for marabivir § Treatment – ganciclovir, foscarnet or cidofovir § IVIG may be helpful in CMV interstitial pneumonia § Ganciclovir resistance is well recognised § Early pre-emptive treatment is based, hence routine PCR monitoring § Late CMV infection after HSCT – CMV specific T-cell dysfunction § Active GvHD § High dose steroids § Low CD4 § Previous CMV treatment § DLI
§ Human herpes virus 6 § B variant most commonly associated with disease in immunocompomised § CNS dysfunction, hypothyroidism and delayed platelet engraftment § Quantitative real time PCR § Treatment – foscarnet, gancyclovir
§ Adenovirus § Primary infection is via respiratory or oral-faecal route § Reactivation in immunocompromised patients § Viraemia, pneumonia, hepatitis, GI disease, cystitis, nephritis, conjunctivitis § Quantitative PCR § Treatment – cidofovir and IV immunoglobulin (oral immunoglobulin if severe colitis)
§ BK virus § Haemorrhagic cystitis and renal impairment § PCR for blood and urine § Treatment is supportive with hyperhydration and platelet support § Antiviral treatment inadequate § Bladder instilled cidofivir
Respiratory viruses § RSV, parainfluenza and influenza A and B § Transmitted by air borne droplets and hand contact § RSV and influenza are winter viruses § Parainfluenza most prevalent during the summer § Diagnosis – RT-PCR for viral RNA from NPA § Influenza A and B § Neuraminidase inhibitor – osetamivir (tamiflu) § RSV § Nebulised ribavarin
Human Metapneumovirus § Newly discovered RNA paramyxovirus § May be an important cause of idiopathic pneumonia in transplant patients
Hepatitis B § Reactivation is a common complication in HBsAg or HBcAb positive patients undergoing immunosuppressive treatment § HBsAg – chronic, inactive carrier § HBcAb – resolved Hep B § Prophylactic therapy with nucleoside analogues (lamivudine) reduces incidence and morbidity of HBV reactivation § HBsAg positive patients should begin prophylactic therapy before chemo and continue for at least 3 months at the end § HBsAg negative patients should receive either prophylaxis or close monitoring § HBV vaccination is recommended for all HBsAg negative recipients prior to HSCT
Hepatitis C § Common in stem cell recipients (5-70%) § Ongoing or previous infection is not a CI to HSCT § Increased susceptibility to VOD, GVHD, but doesn’t appear to impact 5-10 year survival § Fibrosis progesses more rapidly and is the third leading cause of late death § Selected long term survivors should be considered for anti-viral therapy § Pegylated interferon and ribavarin can be safely given to patients who have been off immunosupression for more than 6 months with no GVHD or myelosupression |
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