Fungal Infections


blood cell counts are often low or normal with little inflammation.29,30 Immune reconstitution inflammatory syndrome (IRIS) is a major concern among persons with cryptococcosis who are beginning ART. Within the first three months of ART, approximately 30 % of HIV-infected persons experience IRIS, a large proportion of which may be due to Cryptococcus.31–33


Two scenarios can give rise to IRIS in


HIV-positive populations: 1) subclinical infections become unmasked by a reconstituted immune response to viable organisms that persist due to an ineffective immune response, and 2) antigens of dead organisms from a recently treated infection persist and become the target of a reconstituted immune response that resembles a relapse of the infection although cultures are negative.32


The factors associated


with development of IRIS are thus a CD4 T cell count <100 cells/µl at commencement of ART34,35


anti-cryptococcal antifungal therapy,31,33,36


and a rapid introduction of ART following resulting in high organism


loads and the presence of a substantial concentration of antigen from viable or nonviable organisms. A similar phenomenon has been observed in organ transplant patients.37


Both situations likely


arise from dysregulated, protective immune responses mounted by pathogen-specific T cells against a foreign entity.32,38


Corticosteroid therapy may effectively treat IRIS-associated cryptococcal meningitis.39 Laboratory Diagnosis


Diagnosis of cryptococcal infection is made by conventional methods (culture and direct microscopy), or methods based on detection of antigen.


Conventional Methods – Culture or Direct Microscopy Cryptococcus can be cultured on most primary fungal isolation media within 48 to 72 hours. Observation of encapsulated yeast cells in an India ink or mucicarmine preparation which outline the polysaccharide capsule, is suggestive of Cryptococcus neoformans or gattii. Direct examination of CSF using India ink can be highly specific, although it is dependent on technician experience. Sensitivity of India ink stain depends on the fungal burden in CSF (70–90 % in AIDS patients with high fungal burden).


Culture confirmation is based on the organism’s ability to produce urease and phenol oxidase on specialised media, on carbon assimilation profile and ability to grow at 37 °C, or on sequence identification of isolated DNA. Sensitivity ranges from 50–80 %, depending on the source of the clinical isolate.16,40


Cryptococcal Antigen Detection Methods: Latex Agglutination Test and Enzyme Immunoassay


Commercially available LATs or EIAs, used for detection of the capsular polysaccharide antigens of Cryptococcus in body fluids (CSF, sera, urine), are highly sensitive (>90 %) and specific (>90 %).40 Cryptococcal antigen detection is a reliable, simple and rapid method for diagnosis of cryptococcal disease and is subject to less interpretation by the user than India ink staining. These tests also require only moderate laboratory infrastructure, making them potentially feasible diagnostic options in many central and provincial laboratories in less economically-developed countries.


Treatment


Currently, the recommended primary antifungal therapy regimen consists of a combination of induction therapy with amphotericin B deoxycholate (0.7 mg/kg/day intravenously) and flucytosine (100 mg/kg/day orally) for at least two weeks, followed by consolidation


84


For elevated intracranial pressure, defined as ≥25 cm H2O, initial normalisation of intracranial pressure (to ≤20 cm H2O), as well as daily lumbar punctures in persons with persistently elevated CSF


pressure are recommended until pressure is stabilised for more than two days.41


A temporary drain may be necessary in those individuals requiring repeated daily lumbar punctures.


The success of treatment, particularly those treated with fluconazole monotherapy, may be influenced by the development of antifungal resistance. Although currently there is no clear consensus on whether MIC values can predict response to therapy in cryptococcal infections, and MIC breakpoint guidelines are not yet available for Cryptococcus, in some studies patients with relapse have demonstrated high frequencies of Cryptococcus isolates with elevated MICs.36


Although


decreased susceptibility to fluconazole has also been observed in Cambodian CSF isolates,45


other reports have demonstrated that


prevalence of cryptococcal isolates with elevated MICs to fluconazole is low and not increasing.46,47,48


Future surveillance programmes are


needed, particularly in areas where use of prophylactic fluconazole usage is common, in order to understand if broader fluconazole use has changed antifungal susceptibility patterns.


Epidemiology Non-HIV-infected


Cryptococcosis is one of the most common invasive fungal infections among solid organ transplant recipients. Surveillance conducted between 2001 and 2006 by The Transplant-Associated Infection Surveillance Network (TRANSNET), a consortium of 23 US transplant centres, documented 8 % of invasive fungal infections occurring among solid organ transplants as cryptococcosis.49


The overall


incidence of cryptococcosis in solid organ transplant patients was approximately 0.2 %.50


Cryptococcosis in solid organ transplant


recipients makes up 20–60 % of non-HIV associated cryptococcosis in the US,51–53


and 17.4 % in France;54 mortality is often >40 %.3,51,55


Cryptococcal meningitis is also a well known complication of other conditions that result in cell-mediated immune dysfunction, including glucocorticoid treatment, haematological malignancy and sarcoidosis. A retrospective study conducted in Thailand studying cases occurring during 1987–2003 found that 65 % of patients without HIV had underlying disease, including receipt of immunosuppressive drugs, systemic lupus erythematosus, malignancy and diabetes mellitus.56


In EUROPEAN INFECTIOUS DISEASE


therapy with fluconazole (400 mg/day orally) for a minimum of eight weeks.41


However, in many less developed countries, flucytosine is not widely available and amphotericin B monotherapy, administered for four to six weeks, is acceptable in these areas. Alternatively, amphotericin B can be given with fluconazole (800 mg/day orally) for two weeks, followed by fluconazole (800 mg/day orally) for a minimum of eight weeks. In other resource-limited settings, fluconazole is often the only antifungal drug available for treatment of cryptococcal meningitis.42–44 When fluconazole alone is used, doses of ≥800 mg/day are recommended (≥1,200 mg/day preferred), for a period of 10–12 weeks.41


For HIV-infected persons, maintenance therapy with fluconazole (200 mg/day) is advised after primary therapy to prevent relapse. Maintenance therapy discontinuation can be considered in asymptomatic patients who have restored immune function, as measured by a CD4 count >100 cells/µl with ART, and with an undetectable or very low HIV viral load.41


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92