Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases, Santa Clara Valley Medical Center
SOURCE: Clark EH, Marquez C, Whitman JD, Bern C. Screening for Chagas disease should be included in entry-to-care testing for at-risk people with human immunodeficiency virus (HIV-1) living in the United States. Clin Infect Dis 2022;75:901-906.
These authors argue for routine Chagas screening of human immunodeficiency virus (HIV)-infected persons living in the United States who are at risk for this infection. Many persons living with HIV are immigrants from Latin American countries, or were born to women from Latin American countries, and may be at risk for Trypanosoma cruzi infection. Approximately 1% to 4% of individuals from Central and South American countries may harbor lifelong infection. While many remain asymptomatic, approximately 24,000 acute cases of Chagas disease occur annually around the world. Newer guidelines recommend screening for T. cruzi infection in those at risk, especially blood and organ donors, but do not include specific recommendations for HIV-infected persons.
HIV-infected persons with more advanced HIV infection are at risk for more severe central nervous system (CNS) manifestations of Chagas disease, often with CNS mass lesions, with or without meningoencephalitis. Six cases of CNS T. cruzi reactivation in persons with advanced HIV infection were reviewed. T. cruzi localized more often to the white matter of the brain, in contrast to toxoplasmosis, which more often localizes to the cortex or the basal ganglia. But the two infections often are radiographically indistinguishable, and CNS Chagas may readily be mistaken for toxoplasmosis. Once CNS infection occurs, it is nearly always fatal (70% to 100%) or results in permanent disability. Of the six CNS cases reported from 1992-2018, three patients were from El Salvador, two were from Honduras, and one was from Mexico. Four of the patients died within days to weeks of their presentation. Myocarditis is the second most common manifestation of T. cruzi infection in HIV-infected persons (10% to 23% of cases), resulting in conduction defects and chronic cardiomyopathy. Rarely, reactivation T. cruzi infection can result in gastrointestinal manifestations, skin lesions, peritonitis, or cervicitis.
The authors recommend that routine screening for T. cruzi be included with the other standard entry-to-care screening testing for HIV-infected persons at risk for Chagas, and that “catch-up” testing be performed for those currently in care, as follows:
• born in or lived for at least six months in endemic countries of Latin America;
• born to a woman who was born in or lived for at least six months in an endemic country of Latin America;
• born to a woman with confirmed T. cruzi infection;
• have a history of bite or exposure to feces of triatome vectors.
Per the 2018 Pan American Health Organization (PAHO)/World Health Organization (WHO) guidelines on testing and treatment, the “gold standard” for testing includes the use of two serological tests with antigens that detect different antibodies against T. cruzi (enzyme-linked immunoassay [ELISA], hemagglutination inhibition assay [HAI], or indirect immunofluorescence [IIF]). Further screening with a third test (the “tie-breaker”) should be performed if these results are discordant.
In my experience, positive screening serology for T. cruzi can be quite anxiety provoking and confusing for individuals, who must wait for the results of one or two additional confirmatory tests. Commercial laboratories offer only one serologic test, and confirmatory testing must be sent to the Centers for Disease Control and Prevention Parasitic Diseases reference laboratory. Making additional testing available at clinical laboratories and state laboratories would be helpful, and automatic reflex testing to a second type of serologic test would be appropriate.
SOURCE: Stuck L, van Haaster AC, Kapata-Chanda P, et al. How “subclinical” is subclinical tuberculosis? An analysis of national prevention survey data from Zambia. Clin Infect Dis 2022;75:842-848.
Many screening tools for identifying cases of pulmonary tuberculosis (TB) focus on the presence of cough for two weeks or longer, along with other possible symptoms, but many patients present with insidious complaints such as weight loss or chest pain without cough. A recent patient of mine presented with three weeks of chest pain alone and was repeatedly treated with non-steroidals for a “pulled muscle.” In my experience, the lack of cough, or at least the lack of persistent cough, leads clinicians down the wrong path, and TB is not considered in the differential. Such patients often are referred to as “subclinical TB,” although they nonetheless may be infectious.
Presenting symptoms were assessed in a group of 257 patients with confirmed pulmonary TB in Zambia, all of whom had positive sputum cultures or GeneXPERT MTB/RIF testing. The average age was 42.1 years, 56.4% were male, and 14% were human immunodeficiency virus (HIV)-infected (although 49% declined HIV testing). Presenting symptoms of any duration (in decreasing order of frequency) included cough (71.6%), chest pain (65%), weight loss (49%), fever (40.9%), and night sweats (35.4%). Only 12.5% of these patients presented with all five symptoms, and 8.9% reported none of them.
Of the 257 patients, 40.5% did not have cough for two or more weeks, and 28.4% had no cough at all. Of the 73 patients with no cough, chest pain and night sweats occurred in six (8.2%), and chest pain and fever occurred in five (6.8%). One-third of these patients with “subclinical” TB without cough or cough for less than two weeks had symptoms for at least one month, and 9.6% had symptoms for at least three months.
Therefore, the authors caution against the use of clinical queries that focus on the presence of cough for two or more weeks, which could lead to delays in the diagnosis of nearly half of pulmonary TB cases.
SOURCE: Kempker RR, Smith AGC, Avaliani T, et al. Cycloserine and linezolid for tuberculosis meningitis: Pharmacokinetic evidence of potential usefulness. Clin Infect Dis 2022;75:682-689.
These authors conducted a prospective pharmacokinetic (PK) survey of serial serum and cerebrospinal fluid (CSF) samples in 17 patients treated for tuberculosis (TB) meningitis in Tbilisi, Georgia, from 2019-2020. All of the patients were hospitalized and, per standard of care, CSF samples were obtained to monitor clinical response at days 7, 14, and 28 of treatment, and then monthly thereafter while they remained hospitalized (up to 112 days). CSF was collected between two and six hours post dosing and compared with paired serum levels. Analysis was performed by mass spectrometry.
All 17 patients received linezolid, five received cycloserine, five received clofazimine, four received delamanid, and two received bedaquiline. This resulted in a total of 69 matching serum and CSF samples for patients taking linezolid; 22 CSF and 21 matching serum samples in patients taking cycloserine; 24 CSF and 23 matching serum samples in patients receiving clofazimine; 19 matching CSF and serum samples in patients receiving delamanid; and 12 CSF and 11 matching serum samples in patients receiving bedaquiline.
Both linezolid and cycloserine achieved meaningful concentrations in CSF and may prove to be useful candidates for the treatment of TB meningitis. Among the 17 patients receiving linezolid, the CSF/serum ratio at two hours and six hours was 0.25 and 0.59, respectively. About 68% of the CSF samples yielded concentrations > 1 mcg/mL, including 93% of the samples at six hours. Co-administration of regular dose rifampin did not affect serum or CSF concentrations. CSF cycloserine concentrations in the five patients receiving this agent were very high — the median CSF concentrations were ~15 mcg/mL at both two and six hours. Cycloserine CSF/serum ratios were 0.52 at two hours and 0.66 at six hours.
Unfortunately, despite adequate serum concentrations detected at all time points, none of the CSF specimens yielded detectable amounts of bedaquiline, clofazimine, or delamanid. All three drugs are highly protein bound (bedaquiline 99.9%, delaminid 99.5%, and clofazimine > 85%), and all three are fairly large-sized molecules, making CNS penetration difficult. Both delamanid and clofazimine are highly lipophilic, and it is conceivable that both may penetrate brain tissue without diffusion into the CSF. An important question remains how relevant the concentrations of drugs such as these in CSF might be to the treatment of TB meningitis.
