HIV and fungal priority pathogens.

The burden of invasive fungal infections associated with opportunistic fungal pathogens is a persistent challenge, particularly among people with advanced HIV disease. In October, 2022, WHO published the Fungal Priority Pathogens List (FPPL)-the first global effort to systematically prioritise fungal pathogens. Of the 19 pathogens in the WHO FPPL, four opportunistic pathogens in particular cause invasive diseases in people living with HIV: Cryptococcus neoformans, Histoplasma spp, Pneumocystis jirovecii, and Talaromyces marneffei. These four fungal pathogens are major causes of illness and death in people with advanced HIV and overwhelmingly affect those in low-income and middle-income countries. Access to diagnostics, improved surveillance, targeted support for innovation, and an enhanced public health focus on these diseases are needed in the effort to reduce HIV-associated deaths.

A cost comparison of amikacin therapy with bedaquiline, for drug-resistant tuberculosis in the UK.

OBJECTIVES: Prioritisation of oral bedaquiline over the injectable agents in the treatment of multidrug-resistant Tuberculosis (MDR-TB) in the World Health Organisations (WHO) 2019 guidelines prompted this UK analysis of cost implications. The objective was to estimate the costs of amikacin versus bedaquiline in MDR TB treatment regimens using a historical cohort where the injectable agents were the standard of care. METHODS: This was a retrospective study using a known cohort of UK patients treated with an injectable agent, with data available on resource use, costs for the use of amikacin were compared with those for bedaquiline, based on recommended monitoring for bedaquiline. RESULTS: The estimated cost of treatment per patient had mean (sd) of £27,236 (4952) for the observed injectable group, £30,264 (3392) and 36,309 (3901) for the 6 and 8 month amikacin groups, and £31,760 (2092) for the bedaquiline group. The cost in the bedaquiline group was £30,772 (1855) with a 10% reduction and £27,079 (1234) with a 33% reduction in-patient stay. CONCLUSIONS: In most scenarios, bedaquiline is close to cost neutral compared with injectable therapy, especially if, as expected, some reduction in duration of admission is possible as a result of bedaquiline's more rapid culture conversion.

XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing.

OBJECTIVES: We describe the first published cluster of extensively drug resistant Tuberculosis (XDR-TB) in the UK and show how early whole genome sequencing (WGS) of Mtb can assist in case management and contact investigations. METHODS: We describe the contact tracing investigation undertaken after the presentation of an adult with XDR-TB. Active cases were treated with an XDR-TB drug regimen and contacts underwent a programme of follow-up for 2 years. All isolates of Mycobacterium tuberculosis (Mtb) were assessed early using whole genome sequencing (WGS) as well as routine drug susceptibility testing (DST). RESULTS: Thirty-three contacts were screened. In the first year one confirmed and one probable case were identified through contact tracing. A further possible case was identified through epidemiological links. Two confirmed cases were identified through WGS 2 years later. Twenty-five (80%) contacts without evidence of tuberculosis were adherent to 1 year of follow-up and 14 (45%) were adherent to 2 years of follow-up. WGS of Mtb was used to guide drug choices, rapidly identify transmission events, and alter public health management. CONCLUSION: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.

Immunity to hepatitis A in people born and raised in endemic areas.

BACKGROUND: Hepatitis A is the most common vaccine-preventable disease in international travelers. Many individuals born and raised in hepatitis A endemic areas are likely to be immune to hepatitis A. Unnecessary hepatitis A immunization could be avoided by taking into account prior exposure to hepatitis A and judicious use of serotesting prior to immunization. METHODS: Patients born and raised in countries of high prevalence of hepatitis A who were seen for pretravel consultation and who had hepatitis antibody measured were eligible. Data were collected about country of birth and length of residence there before emigration, length of time till departure on current trip, current age, and hepatitis A antibody result. RESULTS: Patients ranged from 12 to 74 years of age and were from 27 countries. Their pretravel visit occurred from 4 to more than 90 days prior to departure. Ninety-five percent (122 of 129) of patients were immune to hepatitis A, including 100% (83 of 83) of those who resided in their country of origin until at least aged 20. Most patients were seen for pretravel consultation less than 28 days prior to departure. CONCLUSION: Individuals born and raised until aged 20 in hepatitis A endemic countries are likely to be immune to hepatitis A. Serotesting is most helpful in assessing immunity to hepatitis A in those under 20 years of age.

Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis.

BACKGROUND: Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM. METHODS: We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro. RESULTS: Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally. CONCLUSIONS: Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.