Haemato-oncology‎ > ‎

Fungal and Viral infections

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


§        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



§        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)



§        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.




§        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



Viral infections


§        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