Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells - United States, 2023.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

Cost of Tuberculosis Therapy Directly Observed on Video for Health Departments and Patients in New York City; San Francisco, California; and Rhode Island (2017-2018).

Objectives. To assess costs of video and traditional in-person directly observed therapy (DOT) for tuberculosis (TB) treatment to health departments and patients in New York City, Rhode Island, and San Francisco, California.Methods. We collected health department costs for video DOT (VDOT; live and recorded), and in-person DOT (field- and clinic-based). Time-motion surveys estimated provider time and cost. A separate survey collected patient costs. We used a regression model to estimate cost by DOT type.Results. Between August 2017 and June 2018, 343 DOT sessions were captured from 225 patients; 87 completed a survey. Patient costs were lowest for VDOT live ($1.01) and highest for clinic DOT ($34.53). The societal (health department + patient) costs of VDOT live and recorded ($6.65 and $12.64, respectively) were less than field and clinic DOT ($21.40 and $46.11, respectively). VDOT recorded health department cost was not statistically different from field DOT cost in Rhode Island.Conclusions. Among the 4 different modalities, both types of VDOT were associated with lower societal costs when compared with traditional forms of DOT.Public Health Implications. VDOT was associated with lower costs from the societal perspective and may reduce public health costs when TB incidence is high.

Newly Exerted T Cell Pressures on Mutated Epitopes following Transmission Help Maintain Consensus HIV-1 Sequences.

CD8+ T cells are important for HIV-1 virus control, but are also a major contributing factor that drives HIV-1 virus sequence evolution. Although HIV-1 cytotoxic T cell (CTL) escape mutations are a common aspect during HIV-1 infection, less is known about the importance of T cell pressure in reversing HIV-1 virus back to a consensus sequences. In this study we aimed to assess the frequency with which reversion of transmitted mutations in T cell epitopes were associated with T cell responses to the mutation. This study included 14 HIV-1 transmission pairs consisting of a 'source' (virus-donor) and a 'recipient' (newly infected individual). Non-consensus B sequence amino acids (mutations) in T cell epitopes in HIV-1 gag regions p17, p24, p2 and p7 were identified in each pair and transmission of mutations to the recipient was verified with population viral sequencing. Longitudinal analyses of the recipient's viral sequence were used to identify whether reversion of mutations back to the consensus B sequence occurred. Autologous 12-mer peptides overlapping by 11 were synthesized, representing the sequence region surrounding each reversion and longitudinal analysis of T cell responses to source-derived mutated and reverted epitopes were assessed. We demonstrated that mutations in the source were frequently transmitted to the new host and on an average 17 percent of mutated epitopes reverted to consensus sequence in the recipient. T cell responses to these mutated epitopes were detected in 7 of the 14 recipients in whom reversion occurred. Overall, these findings indicate that transmitted non-consensus B epitopes are frequently immunogenic in HLA-mismatched recipients and new T cell pressures to T cell escape mutations following transmission play a significant role in maintaining consensus HIV-1 sequences.

Differential expression of CD96 surface molecule represents CD8⁺ T cells with dissimilar effector function during HIV-1 infection.

During HIV-1 infection, immune dysregulation and aberrant lymphocyte functions are well-established characteristics. Cell surface molecules are important for immunological functions and changes in expression can affect lymphocyte effector functions, thereby contributing to pathogenesis and disease progression. In this study we have focused on CD96, a member of the IgG superfamily receptors that have generated increasing recent interest due to their adhesive and co-stimulatory functions in addition to immunoregulatory capacity. CD96 is expressed by both T and NK cells. Although the function of CD96 is not completely elucidated, it has been shown to have adhesive functions and enhance cytotoxicity. Interestingly, CD96 may also have inhibitory functions due to its immunoreceptor tyrosine-based inhibitory motif (ITIM). The clinical significance of CD96 is still comparatively limited although it has been associated with chronic Hepatitis B infection and disease progression. CD96 has not previously been studied in the context of HIV-1 infection, but due to its potential importance in immune regulation and relevance to chronic disease, we examined CD96 expression in relation to HIV-1 pathogenesis. In a cross-sectional analysis, we investigated the CD8(+) T cell expression of CD96 in cohorts of untreated HIV-1 infected adults with high viral loads (non-controllers) and low viral loads ("elite" controllers). We demonstrated that elite controllers have significantly higher CD96 mean fluorescence intensity on CD8(+) T cells compared to HIV-1 non-controllers and CD96 expression was positively associated with CD4(+) T cell counts. Functional assessment showed that CD8(+) T cells lacking CD96 expression represented a population that produced both perforin and IFN-γ following stimulation. Furthermore, CD96 expression on CD8(+) T cells was decreased in presence of lipopolysaccharide in vitro. Overall, these findings indicate that down-regulation of CD96 is an important aspect of HIV-1 pathogenesis and differential expression is related to cell effector functions and HIV-1 disease course.

Associations between antibodies to a panel of Plasmodium falciparum specific antigens and response to sub-optimal antimalarial therapy in Kampala, Uganda.

BACKGROUND: Antibodies are important in the control of blood stage Plasmodium falciparum infection. It is unclear which antibody responses are responsible for, or even associated with protection, partly due to confounding by heterogeneous exposure. Assessment of response to partially effective antimalarial therapy, which requires the host to assist in clearing parasites, offers an opportunity to measure protection independent of exposure. METHODS: A cohort of children aged 1-10 years in Kampala, Uganda were treated with amodiaquine+sulfadoxine-pyrimethamine for uncomplicated malaria. Serum samples from the time of malaria diagnosis and 14 days later were analyzed for total IgG to 8 P. falciparum antigens using a quantitative indirect ELISA. Associations between antibody levels and risk of treatment failure were estimated using Cox proportional hazard regression. RESULTS: Higher levels of antibodies to apical membrane antigen 1 (AMA-1), but to none of the other 7 antigens were significantly associated with protection against treatment failure (HR 0.57 per 10-fold increase in antibody level, CI 0.41-0.79, p = 0.001). Protection increased consistently across the entire range of antibody levels. CONCLUSIONS: Measurement of antibody levels to AMA-1 at the time of malaria may offer a quantitative biomarker of blood stage immunity to P. falciparum, a tool which is currently lacking.

Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity.

Sema4D, also known as CD100, is a constitutively expressed immune semaphorin on T cells and NK cells. CD100 has important immune regulatory functions that improve antigen-specific priming by antigen-presenting cells, and can also act as a costimulatory molecule on T cells. We investigated the consequence of HIV-1 infection on CD100 expression by T cells, and whether CD100 expression signifies functionally competent effector cells. CD100 expression on T cells from healthy individuals was compared with HIV-1-infected subjects including elite controllers, noncontrollers, and patients receiving antiretroviral therapy. The frequency and fluorescence intensity of CD100 on CD8(+) and CD4(+) T cells were decreased during HIV-1 infection. Furthermore, the absolute number of CD100-expressing CD8(+) T cells was positively associated with the magnitude of HIV-1-specific T-cell responses. CD8(+) T cells lacking CD100 expression were functionally impaired and present in increased numbers in HIV-1-infected individuals. The number of CD100(-)CD8(+) T cells positively correlated with T-cell immunosenescence, immune activation, and viral load. Loss of CD100 expression appears to result from direct antigen stimulation, as in vitro cytokine exposure and viral replication did not significantly impact CD100 expression. These data suggest that loss of CD100 expression probably plays an important role in dysfunctional immunity in HIV-1 infection.

A resident-led quality improvement initiative to improve obesity screening.

Instruction on quality improvement (QI) methods is required as part of residency education; however, there is limited evidence regarding whether internal medicine residents can improve patient care using these methods. Because obesity screening is not done routinely in clinical practice, residents aimed to improve screening using QI techniques. Residents streamlined body mass index (BMI) documentation, created educational materials about obesity, and launched an obesity screening QI initiative in a residency clinic. Residents designed plan-do-study-act cycles focused on increasing awareness and maintaining improvements in screening over a 1-year period. Documentation rates were collected at baseline, 2 weeks, 6 months, and 1 year post-intervention. At 1 year, obesity treatment rates also were collected. BMI documentation rates after 1 year were higher than baseline (43% vs 4%, P < .0001). In obese patients, BMI documentation was associated with lifestyle counseling (34% vs 14%, P < .01). An internal medicine resident-led QI project targeting obesity can improve screening.

Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial.

OBJECTIVE: To evaluate whether interleukin (IL)-2 in patients with chronic HIV infection can maintain CD4 T cell counts during 6 months of HAART interruption. DESIGN: Prospective, randomized, controlled, open-label phase II noninferiority trial comparing IL-2 with HAART interruption or continuous HAART. METHODS: Forty-one IL-2-experienced (three or more prior cycles) HIV-1-infected adults with CD4 cell count at least 500 cells/microl were randomized in the ratio 2: 1 to interrupted (I = 27) or continuous (C = 14) HAART for 6 months following an initial IL-2 cycle. Subsequent IL-2 cycles were triggered by CD4 T cell counts less than 90% of baseline. Immune, metabolic, and quality of life indices were compared (Mann-Whitney and Fisher's exact tests), defining noninferiority as a percentage difference (C- I) in treatment success (CD4 T cells > or =90% of baseline at 6 months) with a 95% confidence interval (CI) lower limit greater than -20%. RESULTS: Demographic and immune parameters were similar between the groups at baseline. Median CD4 T cell count, HIV viral load, and treatment success differed significantly at 6 months (I: 866 cells/microl, 39,389 copies/ml, 48.1%; C: 1246 cells/microl, <50 copies/ml, 92.3%; P < or = 0.001). Group I was inferior to C (% difference = -44.2%; 95% CI: -64.2%, -11.2%; P = 0.013). Minor statistically significant differences in HgbA1c and energy level occurred at 6 months (I > C). Following HAART interruption, single cases of acute retroviral syndrome, secondary syphilis, non-Hodgkin's lymphoma, and Kaposi's sarcoma recurrence were observed. CONCLUSION: IL-2 alone was inferior to IL-2 with HAART in maintaining baseline CD4 T cell counts. HAART interruption had a small impact on metabolic parameters and quality of life.

Interruption of antiretroviral therapy blunts but does not abrogate CD4 T-cell responses to interleukin-2 administration in HIV infected patients.

BACKGROUND: Intermittent administration of interleukin (IL)-2 to HIV infected patients leads to CD4 T-cell expansions that are associated with decreased CD4 T-cell turnover. IL-2 is under evaluation in antiretroviral therapy (ART) interruption studies, but it is unclear how the emergence of viremia may affect CD4 expansions. METHODS: CD4 T-cell responses were evaluated in 27 HIV infected patients on long-term intermittent IL-2 therapy who underwent ART interruption immediately after an IL-2 cycle ('IL-2/off') and compared with responses from a previous IL-2 cycle while on continuous ART ('IL-2/on'). Immunophenotypic analysis, including intracellular Ki67 staining, of cryopreserved peripheral blood mononuclear cells was performed. RESULTS: CD4 T-cell increases, in naive and central memory CD4 T-cell subsets, were observed in the IL-2/on (106 and 327 cells/microl, respectively) and IL-2/off (84 and 184 cells/microl, respectively) cycles 1 month following IL-2 administration. These increases were greater during the IL-2/on cycle (P = 0.05, P = 0.01, respectively). In both cycles, the change in CD4 T-cell count correlated with the change in CD4/CD25 T cells. In the IL-2/off cycle, the change in the proportion of CD4 T cells expressing Ki67 was associated with both the changes in viral load (r = 0.64, P = 0.001) and the changes in CD4 T cells (r = -0.56, P = 0.01). CONCLUSIONS: IL-2 administration followed by ART interruption led to significant, although blunted, CD4 T-cell increases. IL-2 induced CD4 T-cell increases in the setting of emergent viremia were associated with decreased CD4 T-cell activation that counteracted the viremia-induced increases in CD4 T-cell activation.