Background

Cryptococcal meningitis (CM) is one of the most common causes of AIDS-related mortality worldwide, accounting for 33%-63% of all cases of adult meningitis in sub-Saharan Africa and >500 000 deaths annually. In sub-Saharan Africa, the World Health Organization recommends routinely screening AIDS patients with a CD4 count ≤100 cells/µL for cryptococcal infection. In the United States, there are no recommendations for routine screening. We aimed to determine the prevalence of cryptococcal infection and outcomes of those infected among people living with advanced AIDS in the United States, to inform updates in the prevention and management of CM.

Methods

Using stored sera from participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study from 1986 to 2012, we screened 1872 specimens with CD4 T-cell counts ≤100 cells/µL for cryptococcal antigen (CrAg) using the CrAg lateral flow assay.

Results

The overall prevalence of CrAg positivity within the study population was 2.9% (95% confidence interval, .2%-3.8%). Results from multivariable analysis revealed that a previous diagnosis with CM and a CD4 count ≤50 cells/µL were significantly associated with CrAg positivity. Participants who were CrAg positive had significantly shorter survival (2.8 years) than those who were CrAg negative (3.8 years; P = .03).

Conclusions

The prevalence of cryptococcal infection among advanced AIDS patients in the United States was high and above the published cost-effectiveness threshold for routine screening. We recommend routine CrAg screening among human immunodeficiency virus-infected patients with a CD4 count ≤100 cells/µL to detect and treat early infection.

Cryptococcal meningitis (CM) is one of the leading opportunistic infections associated with human immunodeficiency virus (HIV) infection. The worldwide burden of CM among persons living with HIV/acquired immunodeficiency syndrome (AIDS) was estimated in 2009 to be 957,900 cases, with approximately 624,700 deaths annually. The high burden of CM globally comes despite the fact that cryptococcal antigen (CrAg) is detectable weeks before the onset of symptoms, allowing screening for cryptococcal infection and early treatment to prevent CM and CM-related mortality (2). However, few studies have been conducted in the United States to assess the prevalence of cryptococcal infection. To quantify the prevalence of undiagnosed cryptococcal infection in HIV-infected persons in the United States during 1986-2012, stored sera from 1,872 participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study with CD4 T-cell counts <100 cells/µL were screened for CrAg, using the CrAg Lateral Flow Assay (LFA) (Immy, Inc.). This report describes the results of that analysis, which indicated the overall prevalence of CrAg positivity in this population to be 2.9% (95% confidence interval [CI] = 2.2%-3.7%).

In 2012, the U.S. Defense Threat Reduction Agency Joint Science and Technology Office initiated a program to develop novel point-of-need diagnostic devices for surveillance of emerging infectious diseases including dengue, malaria, plague, and melioidosis. Prior to distribution of devices to observe their correct use among community members in Iquitos, Peru, and Phnom Penh, Cambodia, research was conducted to: 1) assess acceptability of use, including the motivation to use a rapid diagnostic test (RDT) before or instead of seeking care at a health facility, 2) explore comprehension of RDT use instructions, and 3) examine possible strategies for large scale RDT distribution and use at each site. In February 2014, 9 focus group discussions (FGD) with community members and 5 FGD with health professionals were conducted in Iquitos, and 9 FGD with community members and 9 in-depth interviews with health professionals in Phnom Penh. In both places, participants agreed to use the device themselves (involving finger prick) or could identify someone who could do so in their home or neighborhood. The main incentive to RDT use in both sites was the ability for device results to be used for care facilitation (post confirmatory tests), specifically reduced wait times to be seen or obtain a diagnosis. Comprehension of RDT use instructions was assessed in Iquitos by asking some participants to apply the device to research team members; after watching a short video, most steps were done correctly. In Phnom Penh, participants were asked to describe each step after reading the instructions; they struggled with comprehension. Health professionals' main concerns in both sites were their community's ability to accurately use the test, handle complicated instructions, and safety (i.e., disposal of lancets). Health system structure and ability to use home diagnostic devices varied in the two disease endemic sites, with substantial challenges in each, suggesting the need for different strategies for RDT large scale community use, and illustrating the value of formative research before deployment of novel technologies.

In 2012, the U.S. Defense Threat Reduction Agency Joint Science and Technology Office initiated a program to develop novel point-of-need diagnostic devices for surveillance of emerging infectious diseases including dengue, malaria, plague, and melioidosis. Prior to distribution of devices to observe their correct use among community members in Iquitos, Peru, and Phnom Penh, Cambodia, research was conducted to: 1) assess acceptability of use, including the motivation to use a rapid diagnostic test (RDT) before or instead of seeking care at a health facility, 2) explore comprehension of RDT use instructions, and 3) examine possible strategies for large scale RDT distribution and use at each site. In February 2014, 9 focus group discussions (FGD) with community members and 5 FGD with health professionals were conducted in Iquitos, and 9 FGD with community members and 9 in-depth interviews with health professionals in Phnom Penh. In both places, participants agreed to use the device themselves (involving finger prick) or could identify someone who could do so in their home or neighborhood. The main incentive to RDT use in both sites was the ability for device results to be used for care facilitation (post confirmatory tests), specifically reduced wait times to be seen or obtain a diagnosis. Comprehension of RDT use instructions was assessed in Iquitos by asking some participants to apply the device to research team members; after watching a short video, most steps were done correctly. In Phnom Penh, participants were asked to describe each step after reading the instructions; they struggled with comprehension. Health professionals' main concerns in both sites were their community's ability to accurately use the test, handle complicated instructions, and safety (i.e., disposal of lancets). Health system structure and ability to use home diagnostic devices varied in the two disease endemic sites, with substantial challenges in each, suggesting the need for different strategies for RDT large scale community use, and illustrating the value of formative research before deployment of novel technologies.

Rapid diagnostic tests (RDTs) have the potential to identify infectious diseases quickly, minimize disease transmission, and could complement and improve surveillance and control of infectious and vector-borne diseases during outbreaks. The U.S. Defense Threat Reduction Agency's Joint Science and Technology Office (DTRA-JSTO) program set out to develop novel point-of-need RDTs for infectious diseases and deploy them for home use with no training. The aim of this formative study was to address two questions: 1) could community members in Iquitos, Peru and Phnom Penh, Cambodia competently use RDTs of different levels of complexity at home with visually based instructions provided, and 2) if an RDT were provided at no cost, would it be used at home if family members displayed febrile symptoms? Test kits with written and video (Peru only) instructions were provided to community members (Peru [n = 202]; Cambodia [n = 50]) or community health workers (Cambodia [n = 45]), and trained observers evaluated the competency level for each of the several steps required to successfully operate one of two multiplex RDTs on themselves or other consenting participant (i.e., family member). In Iquitos, >80% of residents were able to perform 11/12 steps and 7/15 steps for the two- and five-pathogen test, respectively. Competency in Phnom Penh never reached 80% for any of the 12 or 15 steps for either test; the percentage of participants able to perform a step ranged from 26-76% and 23-72%, for the two- and five-pathogen tests, respectively. Commercially available NS1 dengue rapid tests were distributed, at no cost, to households with confirmed exposure to dengue or Zika virus; of 14 febrile cases reported, six used the provided RDT. Our findings support the need for further implementation research on the appropriate level of instructions or training needed for diverse devices in different settings, as well as how to best integrate RDTs into existing local public health and disease surveillance programs at a large scale.