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Invasive aspergillosis is characterized by two different types of angioinvasion. During pulmonary aspergillosis, hyphae are initially outside of the pulmonary vasculature and they invade the endothelial cell lining of the blood vessels by passing from the abluminal to the luminal surface. Some of these hyphal fragments can break off and circulate in the bloodstream. In severely immunocompromised hosts, these blood-borne hyphal fragments adhere to the luminal surface of the endothelial cells and they penetrate the endothelial cell lining of the vasculature by passing from the luminal to the abluminal surface. We have set up in vitro models of luminal and abluminal endothelial cell invasion by Aspergillus fumigatus. Luminal invasion by hyphae results in both endothelial cell damage and stimulation of tissue factor expression. Abluminal invasion causes less endothelial cell damage than luminal invasion, but greater induction of endothelial cells genes encoding cytokines, leukocyte adhesion molecules and tissue factor. These differences in the endothelial cell response to luminal versus abluminal infection may indicate significant differences in the pathogenesis of hematogenously disseminated versus locally invasive versus aspergillosis.

Background: Travelers to malarious areas are at risk of acquiring malaria; however, with chemoprophylaxis and prompt, effective therapy, serious complications of infection are generally preventable. In June 2002, we investigated a report of a cluster of malaria cases among US university staff and students who visited Ghana and were reportedly adherent to appropriate malaria chemoprophylaxis., Methods: We administered a questionnaire to all participants and collected blood specimens for malaria serological examinations from those reporting malaria infection diagnosed by blood smear in Ghana., Results: Of the 33 participants, 25 completed the questionnaire. Twenty-four took a Centers for Disease Control and Prevention-recommended chemoprophylactic drug; 14 (56%) of 25 reported complete adherence to therapy. Twenty (80%) of 25 subjects reported symptoms consistent with possible malaria. Six of these persons reported a microscopic diagnosis of malaria and were treated in Ghana. Serological examination for malaria was performed using blood samples obtained from 5 of these participants; the results for all were negative, suggesting that incorrect diagnoses of malaria were made., Conclusions: Misdiagnosis of malaria made while a person is abroad may not only lead to erroneous reports of drug resistance, but it could also result in unnecessary administration of antimalarial treatment. Health care providers and public health authorities must critically evaluate reports of chemoprophylactic failures and disseminate accurate information to travelers.

Infections due to Candida species are the most common of the fungal infections. Candida species produce a broad range of infections, ranging from nonlife-threatening mucocutaneous illnesses to invasive process that may involve virtually any organ. Such a broad range of infections requires an equally broad range of diagnostic and therapeutic strategies. This document summarizes current knowledge about treatment of multiple forms of candidiasis and is the guideline of the Infectious Diseases Society of America (IDSA) for the treatment of candidiasis. Throughout this document, treatment recommendations are scored according to the standard scoring scheme used in other IDSA guidelines to illustrate the strength of the underlying data. The document covers 4 major topical areas. The role of the microbiology laboratory. To a greater extent than for other fungi, treatment of candidiasis can now be guided by in vitro susceptibility testing. The guidelines review the available information supporting current testing procedures and interpretive breakpoints and place these data into clinical context. Susceptibility testing is most helpful in dealing with infection due to non-albicans species of Candida. In this setting, especially if the patient has been treated previously with an azole antifungal agent, the possibility of microbiological resistance must be considered. Treatment of invasive candidiasis. In addition to acute hematogenous candidiasis, the guidelines review strategies for treatment of 15 other forms of invasive candidiasis. Extensive data from randomized trials are really available only for therapy of acute hematogenous candidiasis in the nonneutropenic adult. Choice of therapy for other forms of candidiasis is based on case series and anecdotal reports. In general, both amphotericin B and the azoles have a role to play in treatment. Choice of therapy is guided by weighing the greater activity of amphotericin B for some non-albicans species (e.g., Candida krusei) against the lesser toxicity and ease of administration of the azole antifungal agents. Flucytosine has activity against many isolates of Candida but is not often used. Treatment of mucocutaneous candidiasis. Therapy for mucosal infections is dominated by the azole antifungal agents. These drugs may be used topically or systemically and have been proven safe and efficacious. A significant problem with mucosal disease is the propensity for a small proportion of patients to suffer repeated relapses. In some situations, the explanation for such a relapse is obvious (e.g., relapsing oropharyngeal candidiasis in an individual with advanced and uncontrolled HIV infection), but in other patients the cause is cryptic (e.g., relapsing vaginitis in a healthy woman). Rational strategies for these situations are discussed in the guidelines and must consider the possibility of induction of resistance over time. Prevention of invasive candidiasis. Prophylactic strategies are useful if the risk of a target disease is sharply elevated in a readily identified group of patients. Selected patient groups undergoing therapy that produces prolonged neutropenia (e.g., some bone-marrow transplant recipients) or who receive a solid-organ transplant (e.g., some liver transplant recipients) have a sufficient risk of invasive candidiasis to warrant prophylaxis.

The interactions of host cells and fungi during infection represent a complex interplay. Although T helper 1 (Th1)-mediated immunity is primarily responsible for acquired resistance to Paracoccidioides brasiliensis, studies have demonstrated that polymorphonuclear neutrophils play a critical role in providing an early resistance to this organism. One study has shown that the invasiveness of Candida albicans requires adherence, particularly to endothelial cells, which in turn are stimulated to express various cell-markers and pro-inflammatory cytokines as part of a proactive resistance to invasion. Somewhat in contrast to infection with C. albicans, it has been shown that the capsular glucuronoxylomannan of Cryptococcus neoformans causes the shedding of host-cell adherence molecules (L-selectins) needed for the migration of host-inflammatory cells to sites of infection and likely explains, in part, the reduced host inflammatory response to this organism. Resistance to aspergillosis is often associated with the immune status of the host. In one set of studies, it has been demonstrated that lymphocytes have little direct effect on the organism, but that antigen-presenting dendritic cells stimulate the production of Th1 cytokines, suggesting a positive role for the dendritic cell in host-response. Similarly, another study has shown that among the regulatory cytokine networks that Th2-associated cytokines (e.g., interleukin-10) likely play a detrimental role in the resistance of the host to Aspergillus fumigatus.

Because of the rapidly increasing incidence of serious candidal infections, a consensus conference of 22 investigators from the United States, Europe, and Japan was held to discuss strategies for the prevention and treatment of deep-organ infections caused by Candida species. Commonly asked questions concerning the management of candidal infections were selected for discussion by the participating investigators. Possible answers to the questions were developed by the investigators, who then voted anonymously for their preferences. In certain instances, unanimity or a strong consensus was the result. In all cases, the full spectrum of responses was recorded and is presented in this report. The forms of candidal infection addressed included candidemia, candiduria, hepatosplenic candidiasis (chronic systemic candidiasis), candidal endophthalmitis, and candidal peritonitis. Prevention and treatment strategies were considered for patients who have undergone surgery, for neutropenic and nonneutropenic patients, and for patients who have undergone bone marrow and solid organ transplantation. The therapeutic roles of amphotericin B (standard and lipid formulations) and the azoles were considered.

The incidence of candidal infections in patients with cancer is increasing, and drug-resistant fungi are being isolated more frequently. Diagnosis of hematogenously disseminated candidiasis remains difficult. Characteristic clinical presentations, such as endophthalmitis and chronic hematogenously disseminated candidiasis, are inconstant and may not develop until after neutrophil recovery. Blood cultures are insensitive for detecting candidemia. Growth of Candida species in even one blood culture is strongly suggestive of hematogenously disseminated candidiasis. Serological tests to diagnose this disease remain experimental. Whenever feasible, central venous catheters should be removed from patients with candidemia. Amphotericin B is the treatment of choice for acute and chronic hematogenously disseminated candidiasis. The roles of azoles and liposomal amphotericin B in treating these diseases are currently undefined. Prophylactic use of antifungal agents decreases the incidence of documented fungal infections in neutropenic patients but does not improve overall survival and may increase the likelihood of infections by resistant fungi.

Endothelial cells activated with interferon-gamma (IFN-gamma) have been shown to inhibit the replication of Toxoplasma gondii. To determine if this cytokine protects endothelial cells from damage by Candida albicans, human umbilical vein endothelial cells were pretreated with IFN-gamma and infected with C. albicans; endothelial cell damage was measured by the release of 51Cr. Pretreatment with IFN-gamma decreased the extent of endothelial cell injury caused by C. albicans by up to 100% +/- 8.2%. This diminution of endothelial cell damage was confirmed by scanning electron microscopy. The degree of protection was dependent on the concentration of IFN-gamma, with maximum protection occurring at 13 units/mL. Higher concentrations of IFN-gamma were toxic to the endothelial cells. Pretreating the endothelial cells with this cytokine had no effect on candidal germination and growth, suggesting that IFN-gamma stimulates endothelial cells to become resistant to or inhibit the action of candidal virulence factors.

The increasing incidence of nosocomial candidal infections is a pivotal problem for patients who do not have neutropenia. In contrast with previous principles, candidemia--even in nonneutropenic patients--should be treated with systemic antifungal agents except in rare circumstances. Amphotericin B remains the agent of choice for treatment of hematogenously disseminated candidiasis and for candidemia, although the optimal dosage and duration of this therapy are poorly defined. Therapy with fluconazole is an alternative for patients who are intolerant to amphotericin B; the efficacy of fluconazole compared with that of amphotericin B in hematogenous candidal infections is unknown but is currently being evaluated. Removal of prosthetic devices that are infected with Candida is necessary in nearly all instances to cure the infection. Similarly, removal of an indwelling catheter whose use is associated with candidemia, as opposed to leaving the catheter in place during antifungal therapy, may increase survival rates of patients and lower their rates of complication. Antifungal prophylaxis may be useful for patients who are undergoing transplantation of an organ.

The response of human umbilical vein endothelial cells to invasion by Candida species was examined in vitro. Live Candida albicans caused significant endothelial release of eicosanoids, mainly prostaglandins. Since prostaglandin I2 (PGI2) is an important prostaglandin produced by endothelial cells, factors influencing its release were studied. The ability of different strains and species of Candida to induce endothelial PGI2 release was closely related to their capacity to injure the endothelium (r = .99). C. albicans was the only species tested that either stimulated PGI2 release or damaged the endothelial cells; only this organism possessed detectable phospholipase activity. Candida glabrata and Candida tropicalis had no phospholipase activity and neither increased PGI2 release nor caused significant endothelial damage. Close proximity with germinated C. albicans was required for endothelial injury and PGI2 release. The ability of C. albicans to stimulate endothelial cells may have important implications in regulating neutrophil activities against organisms that interact with endothelial cells.

Success in elucidating the pathogenesis of certain bacterial infections through studies of bacterial adherence to host cells has stimulated interest in parallel investigations of fungal adherence. Fungal adherence differs from bacterial adherence, especially when fungal coadherence (adherence of fungal cells to each other) is a factor. Using human umbilical vein endothelial cells cultured in a living monolayer in microtiter plates, we developed an ELISA to study adherence of Candida albicans to endothelial cells in the absence of yeast coadherence. A rabbit antibody to Candida detected the adherent Candida, and an alkaline phosphatase-conjugated antibody to rabbit IgG was the developing antibody. A linear relationship between the log of the optical density and the log of the number of adherent organisms was seen for wells containing 3 X 10(4)-1 X 10(6) organisms (r = .923- .965). In addition to measuring adherence of living Candida to living target cells and avoiding Candida coadherence, this assay makes it possible to investigate adherence limited to lumenal surfaces, conserves reagents, and facilitates the testing of large numbers of potential adherence modifiers.