Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 µmol/liter (95% CI, 30 to 45 µmol/liter) by day 7 and by 49 µmol/liter (95% CI, 35 to 64µmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 µmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Resource utilisation and cost of ambulatory HIV care in a regional HIV centre in Ireland: a micro-costing study.

BACKGROUND: It is anticipated that demands on ambulatory HIV services will increase in coming years as a consequence of the increased life expectancy of HIV patients on highly active anti-retroviral therapy (HAART). Accurate cost data are needed to enable evidence based policy decisions be made about new models of service delivery, new technologies and new medications. METHODS: A micro-costing study was carried out in an HIV outpatient clinic in a single regional centre in the south of Ireland. The costs of individual appointment types were estimated based on staff grade and time. Hospital resources used by HIV patients who attended the ambulatory care service in 2012 were identified and extracted from existing hospital systems. Associations between patient characteristics and costs per patient month, in 2012 euros, were examined using univariate and multivariate analyses. RESULTS: The average cost of providing ambulatory HIV care was found to be €973 (95% confidence interval €938-€1008) per patient month in 2012. Sensitivity analysis, varying the base-case staff time estimates by 20% and diagnostic testing costs by 60%, estimated the average cost to vary from a low of €927 per patient month to a high of €1019 per patient month. The vast majority of costs were due to the cost of HAART. Women were found to have significantly higher HAART costs per patient month while patients over 50 years of age had significantly lower HAART costs using multivariate analysis. CONCLUSIONS: This study provides the estimated cost of ambulatory care in a regional HIV centre in Ireland. These data are valuable for planning services at a local level, and the identification of patient factors, such as age and gender, associated with resource use is of interest both nationally and internationally for the long-term planning of HIV care provision.

Determinants of mortality in a combined cohort of 501 patients with HIV-associated Cryptococcal meningitis: implications for improving outcomes.

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes. METHODS: Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality. RESULTS: Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART). CONCLUSIONS: CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.

New insights in the prevention, diagnosis, and treatment of cryptococcal meningitis.

Cryptococcal meningitis (CM) remains a major cause of morbidity and mortality among immunocompromised patients, especially in areas of high HIV prevalence, although it can also cause disease in the apparently immunocompetent. Improving the management of HIV-associated CM is important to ensure that patients can survive to benefit from increasing access to ART. In this review we focus on recent advances in prevention, diagnosis, and treatment of CM.

Impact of Long COVID on health and quality of life.

Background: The aim of this study was to measure the impact of post-acute sequelae of COVID-19 (PASC) on quality of life, mental health, ability to work and return to baseline health in an Irish cohort. Methods: We invited individuals with symptoms of COVID-19 lasting more than 14 days to participate in an anonymous online questionnaire. Basic demographic data and self-reported symptoms were recorded. Internationally validated instruments including the patient health questionnaire somatic, anxiety and depressive symptom scales (PHQ-SADS), the Patient Health Questionnaire-15 (PHQ-15) and Chadler fatigue scale (CFQ) were used. Results: We analysed responses from 988 participants with self-reported confirmed (diagnostic/antibody positive; 81%) or suspected (diagnostic/antibody negative or untested; 9%) COVID-19. The majority of respondents were female (88%), white (98%), with a median age of 43.0 (range 15 - 88 years old) and a median BMI of 26.0 (range 16 - 60). At the time of completing this survey, 89% of respondents reported that they have not returned to their pre-COVID-19 level of health. The median number of symptoms reported was 8 (range 0 to 33 symptoms), with a median duration of 12 months (range 1 to 20 months) since time of acute infection. A high proportion of PASC patients reported that they have a moderate or severe limitation in their ability to carry out their usual activities, 38% report their ability to work is severely limited and 33% report a moderate, or higher, level of anxiety or depression. Conclusion: The results of this survey of an Irish cohort with PASC are in line with reports from other settings, and we confirm that patients with PASC reported prolonged, multi-system symptoms which can significantly impact quality of life, affect ability to work and cause significant disability. Dedicated multidisciplinary, cross specialty supports are required to improve outcomes of this patient group.

Capnocytophaga canimorsus meningitis and bacteraemia without a dog bite in an immunocompetent individual.

We describe the case of an immunocompetent 75-year-old man with Capnocytophaga canimorsus bacteraemia and meningitis. C. canimorsus is commonly found in the oral flora of dogs with human infection typically occurring following a bite. Unusually, while our patient was a dog owner, there was no history of bite nor scratch mark. Admission blood cultures flagged positive for Gram-negative bacilli, but prolonged molecular analysis was required before C. canimorsus was isolated in blood and cerebrospinal fluid. There is a high mortality rate in invasive infection, and in our patient's case, antibiotic therapy was commenced prior to laboratory confirmation with our patient making a complete recovery. This case highlights the importance of including C. canimorsus in the differential diagnosis of unwell patients who keep dogs, even without a bite. This case occurred amid heightened awareness of COVID-19, which may represent predisposition for zoonoses during social isolation and increased human-pet contact.

Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi.

BACKGROUND: Cryptococcal meningitis is a major cause of human immunodeficiency virus (HIV)-associated morbidity and mortality in Africa. Improved oral treatment regimens are needed because amphotericin B is neither available nor feasible in many centers. Fluconazole at a dosage of 1200 mg per day is more fungicidal than at a dosage of 800 mg per day, but mortality rates remain unacceptably high. Therefore, we examined the effect of adding oral flucytosine to fluconazole. METHODS: From 13 February through 2 December 2008, HIV-seropositive, antiretroviral-naive patients experiencing their first episode of cryptococcal meningitis were randomized to receive (1) 14 days of fluconazole (1200 mg per day) alone or (2) in combination with flucytosine (100 mg/kg per day) followed by fluconazole (800 mg per day), with both groups undergoing 10 weeks of follow-up. The primary end point was early fungicidal activity, derived from quantitative cerebrospinal fluid cultures on days 1, 3, 7, and 14. Secondary end points were safety and 2- and 10-week mortality. RESULTS: Forty-one patients were analyzed. Baseline mental status, cryptococcal burden, opening pressure, CD4(+) cell count, and HIV load were similar between groups. Combination therapy was more fungicidal than fluconazole alone (mean early fungicidal activity +/- standard deviation -0.28 +/- 0.17 log colony-forming units [CFU]/mL per day vs -0.11 +/- 0.09 log CFU/mL per day; P < .001). The combination arm had fewer deaths by 2 weeks (10% vs 37%) and 10 weeks (43% vs 58%). More patients had grade III or IV neutropenia with combination therapy (5 vs 1, within the first 2 weeks; P = .20), but there was no increase in infection-related adverse events. CONCLUSIONS: The results suggest that optimal oral treatment for cryptococcal meningitis is high-dose fluconazole with flucytosine. Efforts are needed to increase availability of flucytosine in Africa. Clinical trials registration. isrctn.org Identifier: ISRCTN02725351.

Management of cryptococcal meningitis in sub-saharan Africa.

Cryptococcal meningitis (CM) is a common form of meningitis in sub-Saharan Africa due to the high prevalence of HIV/AIDS. This report outlines the management of CM with a focus on resource-limited settings. Sections covered include epidemiology and diagnosis, pharmacotherapy, management of complications, timing of antiretrovirals, and primary and secondary prevention of CM. Emphasis has been given to recent articles and landmark trials, and opinion is given from the authors' own experiences.

Disseminated cryptococcal infection initially presenting as cryptococcal cellulitis in an HIV-negative patient on long-term steroids.

Cryptococcosis is an invasive fungal infection caused by encapsulated yeasts of the Cryptococcus species. Inoculation usually occurs by inhalation through the respiratory tract, where it can then spread haematogenously to various sites, such as the central nervous system or the skin, in susceptible patients. We present the case of a 68-year-old male patient on long-term steroids who presented with a right upper limb cellulitis not responding to antibiotics. This was subsequently diagnosed as cryptococcal cellulitis on an urgent skin biopsy. Wound swabs and blood cultures, which were initially negative, were repeated and confirmed the presence of disseminated cryptococcal disease. The patient's neighbours kept racing pigeons and this was hypothesised as a potential source of infection.

Utilisation patterns and cost of hospital care for people living with HIV in Ireland in 2012: a single-centre study.

Data on the pattern and cost of health service use by HIV patients are required for evaluations of the cost-effectiveness of new drugs and technologies as well as being essential for service planning. The aim of this study was to identify the utilisation patterns and cost of hospital care for HIV patients in a single centre in Ireland in 2012. Data on the frequency and non-drug costs of all hospital resources used by HIV patients were extracted from a hospital activity-based costing system. Cost data were analysed using a generalised linear model. A total of 328 patients, 3672 patient months, were included in this study. Patients had a mean of 4.4 scheduled infectious disease outpatient appointments per patient year; 37% of patients also used another outpatient service, 15% in-patient services, 4% day-case service and 18% emergency department services in 2012. Patients with very advanced HIV disease continue to incur a disproportionate amount of the total cost of providing care. This study provides baseline utilisation and cost data for use of both infectious-disease and non-infectious disease hospital services and will be useful for service planning in light of the likely increases in resource demands.

Autoantibodies to CD59, CD55, CD46 or CD35 are not associated with atypical haemolytic uraemic syndrome (aHUS).

Autoantibody formation against Factor H (FH) is found in 7-10% of patients who are diagnosed with atypical haemolytic uraemic syndrome (aHUS). These autoantibodies predominately target the C-terminal cell binding recognition domain of FH and are associated with absence of FHR1. Additional autoantibodies have also been identified in association with aHUS, for example autoantibodies to Factor I. Based on this, and that there are genetic mutations in other complement regulators and activators associated with aHUS, we hypothesised that other complement regulator proteins, particularly surface bound regulators in the kidney, might be the target for autoantibody formation in aHUS. Therefore, we assayed serum derived from 89 patients in the Newcastle aHUS cohort for the presence of autoantibodies to CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF), CD35 (complement receptor type 1, CR1; TP10) and CD59. We also assayed 100 healthy blood donors to establish the normal levels of reactivity towards these proteins in the general population. Recombinant proteins CD46 and CD55 (purified from Escherichia coli) as well as soluble CR1 (CD35) and oligomeric C4BP-CD59 (purified from eukaryotic cell media) were used in ELISA to detect high responders. False positive results were established though Western blot and flow cytometric analysis. After excluding false positive responders to bacterial proteins in the CD46 and CD55 preparations, and responses to blood group antigens in CD35, we found no significant level of patient serum IgG reactivity with CD46, CD55, CD35 or CD59 above that detected in the normal population. These results suggest that membrane anchored complement regulators are not a target for autoantibody generation in aHUS.

A phase II randomized controlled trial adding oral flucytosine to high-dose fluconazole, with short-course amphotericin B, for cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis in Africa is associated with up to 70% mortality at 3 months and 500 000 deaths annually. We examined strategies to improve on fluconazole (FLU) monotherapy: addition of flucytosine (5-FC) and/or addition of short-course amphotericin B (AmB). METHODS: In step 1, previously reported, patients were randomized to receive FLU 1200 mg per day with or without 5-FC 100 mg/kg per day for 14 days. In step 2, 43 patients were similarly randomized, with addition of AmB 1 mg/kg per day for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. RESULTS: Forty patients (25% with Glasgow Coma Scale <15) were analyzed. EFA for the triple combination arm was greater than that for AmB-FLU: -0.50 ±â€Š0.15 log CFU/day vs. -0.38 ±â€Š0.19 log colony forming units per day (P=0.03); and greater than that for step 1 with FLU-5-FC (-0.28 ±â€Š0.17) or FLU alone (-0.11 ±â€Š0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, P = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, P = 0.1). CONCLUSION: Addition of 5-FC and short-course AmB to high-dose FLU significantly enhanced EFA and may be associated with favorable trends in survival. Both these strategies should be tested in a larger phase III study.

Chronic symptomatic hypocalcaemia - difficulties in diagnosis and treatment in rural Africa.

We describe a case of an African woman who had been misdiagnosed with peripheral neuropathy secondary to antiretroviral therapy. After clinical examination and laboratory investigation, an alternative diagnosis was made - chronic symptomatic hypocalcaemia secondary to hypoparathyroidism as a consequence of thyroid surgery approximately 30 years previously. We discuss the challenges faced by patients in areas with limited resources for the diagnosis and/or treatment of metabolic conditions such as this.