Cost Effectiveness of Cryptococcal Antigen Screening as a Strategy to Prevent HIV-Associated Cryptococcal Meningitis in South Africa

Objectives

Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM.

Design

Cost-effectiveness analysis.

Methods

Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART.

Results

The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495).

Conclusions

CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.     

Cryptococcal meningoencephalitis.

A patient was admitted to hospital with an apparent psychiatric disturbance. When she became stuporous the cerebrospinal fluid was cultured but proved sterile. The latex test showed that serum was positive for cryptococcal antigens, and cryptococcal meningoencephalitis was diagnosed. Amphotericin B was given but when she developed a toxic reaction it was replaced by flucytosine. She responded well to flucytosine alone and no side effects appeared on continued treatment. Cryptococcal meningitis may present as a psychiatric disturbance, and serological tests are invaluable aids to diagnosis.     

Cryptococcal meningitis with malaria

Cryptococcal meningitis is an uncommon infection globally, including Nigeria. This systemic fungal infection often is associated with immunodeficiency. The most common causes of meningitis in Nigeria in the 2–3 year age group are the malaria parasites and bacteria. The concomittant infections ofCryptococcal neoformans andPlasmodium falciparum are uncommon. We present here the report of a case of fatal cryptococcal meningitis with malaria infection in a 2 year old child from Nigeria (one of the malaria endemic regions of the world). This case emphasizes the importance of doing a combination of fungal and bacterial cultures as well as looking for malarial parasites in the determination of etiological agents of meningitis in any hospital in Africa. We suggest that cerebrospinal fluid from meningitis cases must be cultured using Sabouraud dextrose agar and any growth on the agar must be examined using Indian ink.     

系统性红斑狼疮合并隐球菌脑膜炎1例

1临床资料 患者女,42岁。因“反复关节痛、口腔溃疡4年,头痛10d”于2008年1月急诊入院,患者4a前因反复关节痛、口腔溃疡,当地医院查自身抗体：ANA（＋）,nRNP／Sm、SSA、组蛋白均阳性。血常规中白细胞2．4×10^9／L,红细胞3．42×10^12／L,血红蛋白73g/L。诊断为系统性红斑狼疮,给予强的松40mg／d口服1个月后病情好转,3a内逐渐将强的松减量为10mg／d维持已1a。     

隐球菌形态学变化及其致病机制

致病真菌在与宿主相互作用过程中可能发生形态学变化,如菌丝形成.这种形态学变化有利于病原菌适应不同的外界环境,使其在宿主体内生存.外有荚膜包裹的隐球菌是隐球菌病的致病真菌.该菌可通过孢子吸人方式侵入宿主体内,其后又能通过增加自身荚膜厚度和形成巨大菌体来抵抗和逃避宿主的免疫防御功能.对隐球菌形态学变化意义的理解,有助于了解该病的致病机制,从而推动临床诊治发展.     

Cryptococcal dermotropism in the rhesus monkey

An unexpected result was obtained from the intravenous injection ofCryptococcus neoformans into rhesus monkeys. We had sought to develop pulmonary lesions, but instead cutaneous lesions occurred.Each of seven monkeys received five millionCryptococcus neoformans cells intravenously. On the ninth to fifteenth day an acneform cutaneous eruption and nodular sub-cutaneous swellings appeared in all the monkeys and disappeared spontaneously by about the thirtieth day. Biopsies on the ninth day showed free cryptococcal cells with polymorphonuclear response. Biopsy on the twenty-second day showed persistent abscesses with a surrounding shell of giant cells containing shrunken and partially digested cryptococcal organisms. Chest x-rays on the fifteenth day showed no pulmonary lesions. None of the monkeys died spontaneously. When they were sacrificed between the 37th and 102nd day, the lungs were devoid, both grossly and microscopically, or cryptococcal lesions. However, a fulminating cryptococcosis of the right bulbus oculi was found on one monkey and a minute cryptococcal granuloma in the brain of another. Skin testing with cryptococcin was negative before the experimental injection, but became positive at three weeks. Reinjection ofC. neoformans i.v. in one of the monkeys resulted in a second crop of dermal lesions, though of smaller extent and of shorter duration.The 39.5° C temperature of the rhesus monkey may be a factor in the paucity of pulmonary lesions and the development of cutaneous ones.Aided by Grant AI 08454, Department of Health, Education and Welfare, U.S. Public Health Service. Presented at the Annual Meeting of the American Society for Microbiology, Minneapolis, Minn., May 2–7, 1971.     

Cryptococcal lymphadenitis in a dog.

We describe a case of canine crytococcosis, the clinical symptoms were: feverish syndrome, vomiting and diarrhoeas and bilateral lymphadenitis in superficial lymph nodes. Microbiology and histopathology study of popliteal lymph node biopsy demonstrated the presence of round yeasts of some 3 microm of diameter, which we identified as Cryptococcus neoformans. Thirty months after suspending the medication the dog returned to the surgery; the dog was very thin and it had nervous symptoms; the owners decided it upon euthanasia. After carrying out the necropsy we take samples for their microbiology and histopathology study, both techniques detect to C. neoformans in marrow, CNS tissue and lymph nodes.     

慢性粒细胞性白血病并发新生隐球菌性脑膜脑炎1例

慢性粒细胞性白血病并发新生隐球菌性脑膜脑炎临床较少见,作者在临床工作中诊治本病患者1例,取得了满意疗效,报告如下:1资料与方法1.1临床资料患者女,29岁,因反复腹泻3年,头晕、乏力、左前臂斑片状淤斑2d于2004年7月3日就诊外院血液科。查血常规:白细胞28.37×109/L,中性幼稚细     

Cryptococcal Interactions with the Host Immune System

Opportunistic pathogens have become of increasing medical importance over the last decade due to the AIDS pandemic. Not only is cryptococcosis the fourth-most-common fatal infectious disease in sub-Saharan Africa, but also Cryptococcus is an emerging pathogen of immunocompetent individuals. The interaction between Cryptococcus and the host''s immune system is a major determinant for the outcome of disease. Despite initial infection in early childhood with Cryptococcus neoformans and frequent exposure to C. neoformans within the environment, immunocompetent individuals are generally able to contain the fungus or maintain the yeast in a latent state. However, immune deficiencies lead to disseminating infections that are uniformly fatal without rapid clinical intervention. This review will discuss the innate and adaptive immune responses to Cryptococcus and cryptococcal strategies to evade the host''s defense mechanisms. It will also address the importance of these strategies in pathogenesis and the potential of immunotherapy in cryptococcosis treatment.The basidiomycetous yeast genus Cryptococcus includes the two medically important pathogens C. neoformans and C. gattii. These two species are further divided into C. neoformans serotypes A (C. neoformans var. grubii), D (C. neoformans var. neoformans), and A/D and C. gattii serotypes B and C (formerly C. neoformans var. gattii) based on differential antibody recognition of the polysaccharide capsule (135). The two pathogenic species show different geographical distributions. C. neoformans is globally distributed and has been isolated from various natural sources, with particularly high concentrations occurring in avian guano, rotting vegetables, and soil. In contrast, C. gattii is geographically restricted to tropical and subtropical regions, with the notable exception of British Columbia. In tropical and subtropical regions, it has been found to be associated with the eucalyptus species Eucalyptus camaldulensis, Eucalyptus tereticornis, Eucalyptus rudis, and Eucalyptus gomphocephala (64, 172). C. neoformans causes mainly opportunistic infections in immunocompromised patients with underlying conditions, such as HIV, leukemia, and other cancers, or in those taking corticosteroid medication (135). Serotype A is responsible for the majority of cryptococcosis cases in immunocompromised hosts (135). In contrast, C. gattii affects mainly immunocompetent individuals. The recent and spreading cryptococcosis outbreak in healthy individuals in British Columbia has highlighted the potential of C. gattii to act as an emerging pathogen (84, 85, 121). In addition, other non-C. neoformans/non-C. gattii species, such as Cryptococcus laurentii and Cryptococcus albidus, have recently started to emerge as potential human pathogens (83).Cryptococcal infection can be asymptomatic, chronic, or acute. Typically, an initial pulmonary infection can spread systemically, with a particular predilection for the central nervous system. Pulmonary infections are in most cases asymptomatic. However, they can involve coughing, pleuritic chest pain, fever, dyspnoea, weight loss, and malaise. Pneumonia and acute respiratory distress syndrome have been reported mainly for immunocompromised patients (17, 141). Cryptococcosis of the central nervous system is life threatening and presents as meningitis or meningoencephalitis, with symptoms such as headache, increased intracranial pressure, fever, lethargy, coma, personality changes, and memory loss. Less common are secondary infections of the skin, lungs, prostate, and eye (135). A recent publication estimated 957,900 cases of cryptococcal meningitis resulting in 624,700 deaths globally each year (150). It is the leading cause of death in HIV-infected individuals, with an incidence of 30% and a mortality of 30 to 60%. The mortality rate in transplant patients is even higher (20 to 100%) (Centers for Disease Control and Prevention) (135).The dramatic course of Cryptococcus infections in immunocompromised individuals shows the importance of an intact immune response to the pathogen. This review will consider both the host''s innate and adaptive immune responses to C. neoformans and C. gattii together with the pathogens'' strategy to undermine these defense mechanisms and how current knowledge might be applied to improve anticryptococcal therapy.     

Cryptococcal capsular polysaccharide clearance in nonimmune mice

Clearance of cryptococcal polysaccharide (CP) from tissues and body fluids of nonimmune mice was studied. Mice were injected intravenously one time only with one mg of purified CP, and serum, urine and tissues were obtained from each animal at various intervals for a period of 84 days. Tissue extracts, serum and urine were tested for CP content by enzyme-linked immunosorbent assay (ELISA) and latex agglutination. High concentrations of CP were detected by both assays one-half hour after injection in blood (serum), liver, spleen, kidney and lung (extracts). The duration of ELISA detectable CP was longest (70 days) in liver and spleen and shortest (14 days) in lung extract. By 14 days after injection, concentration of CP in the blood fell below that found in the liver and spleen. CP remained detectable (titers 32–64) after all other extracts became negative. These results indicate that CP is stored in tissues (binding mechanism and site unknown), and that the liver and spleen possess greater storage capacity than other tissues. Antibody (IgM) to CP appeared in low titer on the 14th day and thereafter.     

Cryptococcal Meningitis in Patients with Autoimmune Hemolytic Anemia

To summarize the epidemiology, clinical features, treatment, and outcome of cryptococcal meningitis (CM) in autoimmune hemolytic anemia (AIHA) patients and to provide a reference for the prevention and control of AIHA complicated with CM, we evaluated five cases of CM in patients with AIHA treated in our hospital from 2003 to 2013 and eight related foreign cases. All of the clinical isolates were Cryptococcus neoformans var. grubii and grouped into the VNI genotype and serotype A. The clinical features exhibit significant features. Headache, nausea, and fever are common symptoms of AIHA complicated with CM. The early clinical manifestations lack specificity, which may lead to delayed diagnosis and treatment. Long-term use of prednisone (≥15 mg day^?1), poor control of anemia, and splenectomy are risk factors for AIHA complicated with cryptococcal infection. The combination of intravenous amphotericin B and oral 5-fluorocytosine remains the preferred treatment for AIHA complicated with CM.     

Treatment of Cryptococcal Meningitis in KwaZulu-Natal,South Africa

Background

Cryptococcal meningitis (CM) remains a leading cause of death for HIV-infected individuals in sub-Saharan Africa. Improved treatment strategies are needed if individuals are to benefit from the increasing availability of antiretroviral therapy. We investigated the factors associated with mortality in routine care in KwaZulu-Natal, South Africa.

Methodology/Principal Findings

A prospective year long, single-center, consecutive case series of individuals diagnosed with cryptococcal meningitis 190 patients were diagnosed with culture positive cryptococcal meningitis, of whom 186 were included in the study. 52/186 (28.0%) patients died within 14 days of diagnosis and 60/186 (32.3%) had died by day 28. In multivariable cox regression analysis, focal neurology (aHR 11 95%C.I. 3.08–39.3, P<0.001), diastolic blood pressure <60 mmHg (aHR 2.37 95%C.I. 1.11–5.04, P = 0.025), concurrent treatment for tuberculosis (aHR 2.11 95%C.I. 1.02–4.35, P = 0.044) and use of fluconazole monotherapy (aHR 3.69 95% C.I. 1.74–7.85, P<0.001) were associated with increased mortality at 14 and 28 days.

Conclusions

Even in a setting where amphotericin B is available, mortality from cryptococcal meningitis in this setting is high, particularly in the immediate period after diagnosis. This highlights the still unmet need not only for earlier diagnosis of HIV and timely access to treatment of opportunistic infections, but for better treatment strategies of cryptococcal meningitis.