HOMO SAPIENS DISEASES - FUNGI / METAZOA GROUP
(see also Physiology of Fungi, Antimicrobials for Eukaryal organisms and fungal toxins sections)

Table of contents :

  • Generalities on fungal infections
  • Fungi/Metazoa incertae sedis
  • Fungi
    		•
  • Zygomycota
  • Microsporidia
  • stramenopiles
  • Web resources
    		•

    Generalities on fungal infections :

  • Fungi/Metazoa incertae sedis
  • Fungi
  • stramenopiles
  • the Transportation Security Administration, who supposedly monitors US airports, "strongly" suggests that passengers remove their shoes while passing through the lines in American airports. The penalty for not doing so is an intimidating delay in which a total body scan for such contraband as glasses frames and wrist watches is conducted, whereupon you still are required to remove your shoes and to stand around on unkempt airport carpets while your shoes are X-rayed! If you do as "suggested," you must march 10 to 15 feet either barefoot or in stocking feet to a point where one's shoes may be reclaimed. This is evidently because a demented
    • passenger attempted to ignite his shoes with either matches or a cigarette lighter, already prohibited. Unless I am terribly mistaken, one's flora are being mixed with that of several hundreds of thousand of passengers who have passed through the same lines. The floors are rarely cleaned (evidently) and never disinfected. Has
    simple hygiene been forfeited in the US in the name of "security?" When the TSA finally answered a query, they told me that OSHA had approved the cross contamination of hundreds of thousands of feet. The CDC, NIH, WHO, or state or local health departments were not consulted. National Security indeed. Though a disgusting and unaesthetic procedure, the people at highest risk must obviously be airport security staff. Studies documenting increased risk of dermatophytes and/or tinea pedis, and increased risk of respiratory tract symptoms like asthma or allergic alveolitis, is clearly highly needed
    Invasive fungal infections (IFIs) are continuing threats to patients with hematologic malignancies. Factors associated with greater susceptibility for IFIs include: Definitions of IFIs in patients with cancer and recipients of HSCT :
    Category, type of infection Description
    Proven invasive fungal infections
         Deep tissue infections
              Moldsa Histopathologic or cytopathologic examination showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage (either microscopically or unequivocally by imaging); or positive culture result for a sample obtained by sterile procedure from normally sterile and clinically or radiologically abnormal site consistent with infection, excluding urine and mucous membranes
              Yeastsa Histopathologic or cytopathologic examination showing yeast cells (Candida species may also show pseudohyphae or true hyphae) from specimens of needle aspiration or biopsy excluding mucous membranes; or positive culture result on sample obtained by sterile procedure from normally sterile and clinically or radiologically abnormal site consistent with infection, excluding urine, sinuses, and mucous membranes; or microscopy (India ink, mucicarmine stain) or antigen positivityb for Cryptococcus species in CSF
         Fungemia
              Moldsa Blood culture that yields fungi, excluding Aspergillus species and Penicillium species other than Penicillium marneffei, accompanied by temporally related clinical signs and symptoms compatible with relevant organism
              Yeastsa Blood culture that yields Candida species and other yeasts in patients with temporally related clinical signs and symptoms compatible with relevant organism
         Endemic fungal infectionsc
              Systemic or confined to lungs Must be proven by culture from site affected, in host with symptoms attributed to fungal infection; if culture results are negative or unattainable, histopathologic or direct microscopic demonstration of appropriate morphological forms is considered adequate for dimorphic fungi (Blastomyces, Coccidioides and Paracoccidioides species) having truly distinctive appearance; Histoplasma capsulatum variant capsulatum may resemble Candida glabrata
              Disseminated May be established by positive blood culture result or positive result for urine or serum antigen by means of RIAref
    Probable invasive fungal infections At least 1 host factor criterion; and 1 microbiological criterion; and 1 major (or 2 minor) clinical criteria from abnormal site consistent with infection
    Possibled invasive fungal infections At least 1 host factor criterion; and 1 microbiological or 1 major (or 2 minor) clinical criteria from abnormal site consistent with infection
  • a : append identification at genus or species level from culture, if available.
  • b : false-positive cryptococcal antigen reactions due to infection with Trichosporon beigelii, infection with Stomatococcus mucilaginosis, circulating rheumatoid factor, and concomitant malignancy may occur and should be eliminated if positive antigen test is only positive result in this category.
  • c : histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis.
  • d : this category is not recommended for use in clinical trials of antifungal agents but might be considered for studies of empirical treatment, epidemiological studies, and studies of health economics.

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    Candida and Aspergillus are the major fungal pathogens that cause infection. New antifungal agents have been developed and new fungal diagnostics are now licensed. It is hoped that incorporation of these new tools into antifungal strategies will result in improved outcomes.

    Combination therapy : few controlled trials of combination therapy have been performed, despite this approach being evaluated in numerous in vitro and animal model studies. Combination antifungal therapy (amphotericin B + flucytosine) is well established for cryptococcal meningitis. In a recent trial, the combination of fluconazole and amphotericin B was compared to fluconazole in high doses (800 mg/day) as therapy for candidemiaref: overall, the response rate was higher and time to bloodstream clearance was shorter in the group receiving the combination. This advantage was offset by greater nephrotoxicity in the combination arm. Despite considerable interest in this concept, there are no controlled trials for aspergillosis. Although several case series suggest benefitref1, ref2, the majority of Aspergillus cases in which combination therapy was evaluated were only "possible" infections. There are pitfalls with the use of combination therapy including potential antagonism, greater toxicity, and costref1, ref2. Thus, controlled trials are clearly needed.
    Adjunctive measures : for catheter-related candidemia, removal of a central venous catheter, if possible, should be strongly consideredref. More rapid clearance of fungemia with catheter removal has been seen in several studies. For Aspergillus infections, consideration should be given for surgical excision of infarcted tissue, especially if the patient faces additional antineoplastic therapy. The role of cytokines such as myeloid growth factors and interferon gamma are supported by preclinical data, but there is a paucity of clinical trial data. Similarly, the use of granulocyte transfusions for neutropenic patients not responding to antimicrobial therapy is intuitively sensible, but this strategy is not without complications, is difficult to implement, and lacks convincing clinical data.
    Duration of therapy : the duration of therapy has not been defined in clinical trials but generally lasts for several weeks to months. Prophylaxis : fluconazole, itraconazole, and low doses of amphotericin B have been shown in randomized trials to be effective as prophylaxis. More recently, micafungin has also been shown to be effective as prophylaxis (Van Burik J-A, Ratanatharathorn V, Lipton J, et al. Randomized, double-blind trial of micafungin versus fluconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplant. In: Program and abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego). [Abstract M1238]. Washington, DC: American Society for Microbiology, 2002). In general, from meta-analyses of randomized trial data, the benefit appears to be meaningful when the risk of IFI is at least 15% in the patient group treatedref. Most of the antifungal benefit seen in clinical trials has been in the prevention of Candida infection. Trials of itraconazole during neutropenia have been mostly conducted in patient groups at low risk for aspergillosis, and thus no clear benefit against aspergillosis has been shown. A recent meta-analysisref showed that itraconazole given in oral solution at adequate doses (at least 400 mg/day) was associated with fewer Aspergillus infections. 2 randomized trials of prolonged prophylaxis comparing itraconazole to fluconazole after allogeneic HSCT provide an unclear message: although an anti-Aspergillus benefit for itraconazole was suggested (but not definitely shown), issues of excess toxicity were also raisedref1, ref2. High rates of recurrence of IFI occur if the once-infected patient is subjected to subsequent antineoplastic treatment cycles or undergoes hematopoietic stem cell transplantation, and thus "secondary" prophylaxis or chronic maintenance is necessary until the underlying disease is controlled and the full treatment course is completed. Several published case series indicate that hematopoietic stem cell transplantation can be successfully performed in patients given secondary prophylaxisref. After completion of therapy the patient should be observed to monitor for possible exacerbation.
    Empirical therapy for neutropenic patients with persistent fever : early trials demonstrated that rates of IFIs were 15–30% in neutropenic patients with fever persisting 4–7 days despite antibiotics; fungal morbidity could be reduced by empirical amphotericin B. Subsequent trials with lipid formulations of amphotericin B, itraconazole, voriconazole and caspofungin have been performed. In each study, the test agent was compared with either amphotericin B or liposomal amphotericin B. Since all patients had an active agent, the rates of IFIs in both groups were anticipated to be small and thus a surrogate endpoint of "success" was used as the primary endpoint. Success was judged by defervescence, resolution of an IFI if found at baseline, absence of breakthrough IFI, survival to neutrophil recovery, and no toxicity that necessitated withdrawal of study drug. None of these agents were found to be superior to amphotericin B in the primary endpoint and, in one case, voriconazole failed to meet its protocol-specified non-inferiority bounds. However, a strong trend in favor of itraconazole was noted for the primary endpoint of success (P = 0.055), and differences in secondary endpoints, in terms of rates of breakthrough IFIs (in favor of voriconazole over liposomal amphotericin B) and response of baseline IFIs (in favor of caspofungin over liposomal amphotericin B), were noted in these various trialsref. Considerable differences in toxicity were demonstrated with the various agents. Indeed, tolerability should be considered in the choice of a specific agent for a given patient.
    What the future holds : several studies indicate early treatment is key in determining the outcome of IFI treatment. Conventional diagnostic methods are either too slow or fraught with considerable imprecision, and use of invasive procedures is not practical for many patients with aspergillosis. Two rapid diagnostic tests using serum have been licensed. The serum galactomannan assay, testing for a constituent of Aspergillus cell wall released into blood early during the course of invasive Aspergillus infection, has been found to have sensitivity and specificity both exceeding 80% (US Food and Drug Administration [FDA] package insert). This assay used twice weekly detected two-thirds of Aspergillus infections in advance of conventional diagnostic testingref. This assay clearly has promise. However, concerns as to its performance in children, non-neutropenic patients, patients receiving anti-mould antifungal prophylaxis, and in patients with antibody have been raisedref. Recent reports indicate that false-positive test results can often occur in patients receiving piperacillin-tazobactamref. More recently, another serum assay, the glucan assay, detecting a cell wall constituent in a wide range of fungal pathogens (rather than limited to only Aspergillus), has received FDA approval. It was found to have high levels of sensitivity and specificityref. The development of PCR assays also appears promising, and one trial showed that sampling of serum twice weekly accurately identified patients with IFIref, often earlier than known using conventional diagnostic criteria. It is hoped that such assays can assist the clinician to better distinguish febrile patients with fungal infections from those who are febrile but not infected. Further experience is needed for all of these assays to determine if and how these assays can assist us in making diagnoses more accurately, earlier, and allow the targeting of antifungal therapy to replace empirical trials in patients suspected of infection. Ultimately, successful resolution of any IFI is dependent on restoration of the compromised host defenses that led to susceptibility for infection in the first place. Indeed, it can be argued that without immune recovery no IFI can be adequately or durably controlled. There has been substantial progress in our understanding of how host immune responses interact with fungal pathogensref. These insights are leading to new therapeutic strategies. Cytokines such as IL-12 show promise as adjunctive therapy in preclinical studies. Efforts to enhance Th1 immune responses (or decrease polarization to Th2 responses) also offer promise from preclinical studies. Infusions of common myeloid progenitors provide protection against lethal infection in animal modelsref. New fungal molecular structures are being identified that may prove to be novel targets for antifungal drugs or can elucidate crucial cellular receptors, such as the TLRs, that can be exploited. Vaccine strategies using dendritic cells pulsed with fungal antigens are also under developmentref1, ref2.
  • Web resources
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