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      Determinants of Disease Presentation and Outcome during Cryptococcosis: The CryptoA/D Study

      1 , * , 2 , 3 , 1 , 4 , the French Cryptococcosis Study Group

      PLoS Medicine

      Public Library of Science

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          Cryptococcosis is a life-threatening opportunistic fungal infection in both HIV-positive and -negative patients. Information on clinical presentation and therapeutic guidelines, derived mostly from clinical trials performed before introduction of highly active antiretroviral therapy in patients with cryptococcal meningoencephalitis, is missing data on extrameningeal involvement and infections by serotype D as opposed to serotype A of Cryptococcus neoformans.

          Methods and Findings

          The prospective multicenter study CryptoA/D was designed in France (1997–2001) to analyse the factors influencing clinical presentation and outcome without the bias of inclusion into therapeutic trials. Of the 230 patients enrolled, 177 (77%) were HIV-positive, 50 (22%) were female, and 161 (72.5%) were infected with serotype A. Based on culture results at baseline, cryptococcosis was more severe in men, in HIV-positive patients, and in patients infected with serotype A. Factors independently associated with mycological failure at week 2 independent of HIV status were initial dissemination (OR, 2.4 [95% confidence interval (CI), 1.2–4.9]), high (>1:512) serum antigen titre (OR, 2.6 [1.3–5.4]), and lack of flucytosine during induction therapy (OR, 3.8 [1.9–7.8]). The three-month survival was shorter in patients with abnormal neurology or brain imaging at baseline, and in those with haematological malignancy.


          Thus sex, HIV status, and infecting serotype are major determinants of presentation and outcome during cryptococcosis. We propose a modification of current guidelines for the initial management of cryptococcosis based on systematic fungal burden evaluation.


          Françoise Dromer and colleagues report that sex, HIV status, and infecting serotype are major determinants of cryptococcosis presentation and outcome.

          Editors' Summary


          For people with a healthy immune system, athletes' foot may be the only fungal infection they ever have. But individuals whose immune system has been damaged by infection with HIV or who are immune-suppressed after organ transplantation or cancer chemotherapy can develop cryptococcosis. This is a life-threatening infection caused by Cryptococcus neoformans, a fungus found in bird droppings that enters the human body through the lungs. The initial infection can go unnoticed, although a pneumonia-like disease sometimes develops. However, if the fungus spreads (disseminates) around the body it can cause other symptoms. The commonest of these is cryptococcal meningitis, a swelling of the membrane around the brain that can cause a stiff neck, headaches, and neurological symptoms such as palsies. For anyone with cryptococcal meningitis or severe pneumonia the current treatment guidelines recommend a two-week induction therapy with the antifungal drugs amphotericin B and flucytosine, followed by fluconazole for ten weeks.

          Why Was This Study Done?

          Even when these guidelines are followed, cryptococcosis kills some people. The guidelines are based on data from clinical trials of antifungal drugs in HIV-positive patients done before there were effective treatments for HIV infections. Patients without meningitis and those with very severe disease were excluded from these trials. Also, it is known that two variants of C. neoformans cause cryptococcosis: variety grubii (also known as serotype A) and variety neoformans (serotype D). There is very little information about the impact of patient-related factors (such as sex, age, and HIV status) or the variety of C. neoformans on clinical presentation (the symptoms patients have when they first visit a doctor), therapeutic management, or disease outcomes in the real world; this information is needed to improve the treatment guidelines. In this nationwide study across France, the researchers have asked what factors influence clinical presentation and outcomes in HIV-positive and HIV-negative patients with cryptococcosis, and whether infections with the two varieties of C. neoformans behave similarly.

          What Did the Researchers Do and Find?

          Patients were enrolled in the study when their first episode of cryptococcosis was confirmed by growing C. neoformans from blood, urine, or cerebrospinal fluid. Information was collected about their initial symptoms, which body sites were infected with fungus (their mycological status), and their treatment. Clinical and mycological data were also collected at two weeks and three months, and the blood levels of cryptococcal secreted molecules were measured to provide a “serum antigen titer,” a measure of fungal load. The researchers found that cryptococcosis was more severe at presentation in men, in HIV-positive patients, and in patients infected with C. neoformans variety grubii. Patients whose treatment failed at two weeks (judged by the continued presence of C. neoformans in culture of their body fluids) tended to have disseminated disease at presentation, to have high serum antigen titers, and not to have been given flucytosine during the initial round of therapy. Finally, three-month survival was worse in patients with abnormal neurology or brain imaging at the start of the study, or those with hematological malignancies (cancers that affect immune system cells).

          What Do These Findings Mean?

          These findings provide new information on what determines the clinical presentation and outcome in patients with cryptococcosis. Because the study was done in France, these results will only apply to other countries where C. neoformans causes cryptococcosis—in some countries C. gattii can cause the disease. In addition, not all of the cryptococcosis cases that occurred in France during the study period were enrolled in the study, so it is possible that the infection might have had different characteristics in the missing patients. Nevertheless, the results of this study suggest that more patients would benefit from a two-week induction therapy with amphotericin B and flucytosine than currently recommended. This treatment, write the researchers, should be given to all patients with a high serum antigen titer, fungus in the blood, or initial infection at two separate body sites (in addition to those with cryptococcal meningitis or severe pneumonia for whom it is currently recommended). They also suggest that the fungal burden should be routinely determined in all patients so that their treatment can be adjusted if necessary.

          Additional Information.

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040021

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          Most cited references 54

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          Do multiple outcome measures require p-value adjustment?

           Ronald Feise (2002)
          Background Readers may question the interpretation of findings in clinical trials when multiple outcome measures are used without adjustment of the p-value. This question arises because of the increased risk of Type I errors (findings of false "significance") when multiple simultaneous hypotheses are tested at set p-values. The primary aim of this study was to estimate the need to make appropriate p-value adjustments in clinical trials to compensate for a possible increased risk in committing Type I errors when multiple outcome measures are used. Discussion The classicists believe that the chance of finding at least one test statistically significant due to chance and incorrectly declaring a difference increases as the number of comparisons increases. The rationalists have the following objections to that theory: 1) P-value adjustments are calculated based on how many tests are to be considered, and that number has been defined arbitrarily and variably; 2) P-value adjustments reduce the chance of making type I errors, but they increase the chance of making type II errors or needing to increase the sample size. Summary Readers should balance a study's statistical significance with the magnitude of effect, the quality of the study and with findings from other studies. Researchers facing multiple outcome measures might want to either select a primary outcome measure or use a global assessment measure, rather than adjusting the p-value.
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            1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.

            CDC has revised the classification system for HIV infection to emphasize the clinical importance of the CD4+ T-lymphocyte count in the categorization of HIV-related clinical conditions. This classification system replaces the system published by CDC in 1986 (1) and is primarily intended for use in public health practice. Consistent with the 1993 revised classification system, CDC has also expanded the AIDS surveillance case definition to include all HIV-infected persons who have < 200 CD4+ T-lymphocytes/microL, or a CD4+ T-lymphocyte percentage of total lymphocytes of < 14. This expansion includes the addition of three clinical conditions--pulmonary tuberculosis, recurrent pneumonia, and invasive cervical cancer--and retains the 23 clinical conditions in the AIDS surveillance case definition published in 1987 (2); it is to be used by all states for AIDS case reporting effective January 1, 1993.
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              Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans.

              Although Cryptococcus neoformans and cryptococcosis have existed for several millennia, a century has passed since the discovery of this encapsulated yeast and its devastating disease. With the advent of the AIDS pandemic, cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality and a frequently life-threatening opportunistic mycosis among patients with AIDS. Both basic and clinical research have accelerated in the 1990s, and this review attempts to highlight some of these advances. The discussion covers recent findings, current concepts, controversies, and unresolved issues related to the ecology and genetics of C. neoformans; the surface structure of the yeast; and the mechanisms of host defense. Regarding cell-mediated immunity, CD4+ T cells are crucial for successful resistance, but CD8+ T cells may also participate significantly in the cytokine-mediated activation of anticryptococcal effector cells. In addition to cell-mediated immunity, monoclonal antibodies to the major capsular polysaccharide, the glucuronoxylomannan, offer some protection in murine models of cryptococcosis. Clinical concepts are presented that relate to the distinctive features of cryptococcosis in patients with AIDS and the diagnosis, treatment, and prevention of cryptococcosis in AIDS patients.

                Author and article information

                Role: Academic Editor
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                February 2007
                6 February 2007
                : 4
                : 2
                [1 ] Unité de Mycologie Moléculaire, Centre National de Référence Mycologie et Antifongiques, CNRS URA3042, Institut Pasteur, Paris, France
                [2 ] Institut Bergonié, Centre Régional de Lutte Contre le Cancer du Sud-Ouest, Bordeaux, France
                [3 ] Université Paris V, Hôpital Cochin, Service de Médecine Interne, CIC Vaccinologie Cochin–Pasteur, Paris, France
                [4 ] Université Paris V–Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Paris, France
                Duke University Medical Center, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: dromer@ 123456pasteur.fr
                06-PLME-RA-0445R3 plme-04-02-02
                Copyright: © 2007 Dromer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Research Article
                Infectious Diseases
                Infectious Diseases
                Public Health and Epidemiology
                Infectious Diseases
                HIV Infection/AIDS
                Custom metadata
                Dromer F, Mathoulin-Pélissier S, Launay O, Lortholary O, French Cryptococcus Study Group (2007) Determinants of disease presentation and outcome during cryptococcosis: The CryptoA/D study. PLoS Med 4(2): e21. doi: 10.1371/journal.pmed.0040021



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