Salivary Cathelicidin (LL-37) in Children and Adolescents Living with HIV.

Introduction: Human cathelicidin LL-37 is a salivary antimicrobial peptide (AMP) with broad-spectrum activity against oral diseases, but few studies have assessed its role in children and adolescents living with HIV (CALHIV). We assessed salivary LL-37 levels and correlates in a long-term cohort of Kenyan CALHIV followed since antiretroviral therapy (ART) initiation. Methods: Saliva was collected from 76 CALHIV who were recruited from two ongoing pediatric HIV studies in Nairobi, Kenya. Oral examinations documenting oral manifestations of HIV, dental caries, and gingivitis were completed. Additional variables included age, sex, HIV treatment (initial ART regimen) and disease parameters, caregivers' demographics, and oral pathologies were conducted. Data were statistically analyzed using the independent T test on the log-transformed LL-37. Results: At the oral exam visit, the mean age of participants was 13.3 years (±SD = 3.4), and the median CD4 count was 954 cells/mm3. Mean salivary cathelicidin values of the cohort were 23.7 ± 21.1 ng/mL. Children with permanent dentition at time of oral examination, and children who initiated ART at ≥2 years old had higher mean LL-37 concentrations compared to those with mixed dentition and those who initiated ART <2 years old (p = 0.0042, 0.0373, respectively). LL-37 levels were not found to differ by initial type of ART regimen, CD4 count, or oral disease. Conclusion: Further research and longitudinal studies are necessary to evaluate and improve the innate immunity of CALHIV in Kenya.

"When they are all grown, I will tell them": Experience and perceptions of parental self-disclosure of HIV status to children in Nairobi, Kenya.

BACKGROUND: There is mixed evidence on the influence of self-disclosure of one's HIV status on mental health, health behaviours and clinical outcomes. We studied the patterns of self-disclosure among parents living with HIV, and factors that influence parental disclosure. METHODS: This mixed-methods study was among adults in HIV care participating in a study assessing the uptake of pediatric index-case testing. They completed a survey to provide demographic and HIV-related health information, and assess self-disclosure to partners, children and others. We ran generalized linear models to determine factors associated with disclosure and reported prevalence ratios (PR). Eighteen participants also participated in in-depth interviews to explore perceived barriers and facilitators of self-disclosure to one's child. A content analysis approach was used to analyze interview transcripts. RESULTS: Of 493 caregivers, 238 (48%) had a child ≥ 6 years old who could potentially be disclosed to about their parent's HIV status. Of 238 participants, 205 (86%) were female, median age was 35 years, and 132 (55%) were in a stable relationship. Among those in a stable relationship, 96 (73%) knew their partner's HIV status, with 79 (60%) reporting that their partner was living with HIV. Caregivers had known their HIV status for a median 2 years, and the median age of their oldest child was 11 years old. Older caregiver age and older first born child's age were each associated with 10% higher likelihood of having disclosed to a child (PR: 1.10 [1.06-1.13] and PR: 1.10 [1.06-1.15], per year of age, respectively). The child's age or perceived maturity and fear of causing anxiety to the child inhibited disclosure. Child's sexual activity was a motivator for disclosure, as well as the belief that disclosing was the "right thing to do". Caregivers advocated for peer and counseling support to gain insight on appropriate ways to disclose their status. CONCLUSIONS: Child's age is a key consideration for parents to disclose their own HIV status to their children. While parents were open to disclosing their HIV status to their children, there is a need to address barriers including anticipated stigma, and fear that disclosure will cause distress to their children.

Predictors of intact HIV DNA levels among children in Kenya.

OBJECTIVE: We determined predictors of both intact (estimate of replication-competent) and total (intact and defective) HIV DNA in the reservoir among children with HIV. DESIGN: HIV DNA in the reservoir was quantified longitudinally in children who initiated antiretroviral therapy (ART) at less than 1 year of age using a novel cross-subtype intact proviral DNA assay that measures both intact and total proviruses. Quantitative PCR was used to measure pre-ART cytomegalovirus (CMV) viral load. Linear mixed effects models were used to determine predictors of intact and total HIV DNA levels (log 10 copies/million). RESULTS: Among 65 children, median age at ART initiation was 5 months and median follow-up was 5.2 years; 86% of children had CMV viremia pre-ART. Lower pre-ART CD4 + percentage [adjusted relative risk (aRR): 0.87, 95% confidence intervals (95% CI): 0.79-0.97; P  = 0.009] and higher HIV RNA (aRR: 1.21, 95% CI: 1.06-1.39; P  = 0.004) predicted higher levels of total HIV DNA during ART. Pre-ART CD4 + percentage (aRR: 0.76, 95% CI: 0.65-0.89; P < 0.001), CMV viral load (aRR: 1.16, 95% CI: 1.01-1.34; P  = 0.041), and first-line protease inhibitor-based regimens compared with nonnucleoside reverse transcriptase-based regimens (aRR: 1.36, 95% CI: 1.04-1.77; P  = 0.025) predicted higher levels of intact HIV DNA. CONCLUSION: Pre-ART immunosuppression, first-line ART regimen, and CMV viral load may influence establishment and sustainment of intact HIV DNA in the reservoir.

The effect of antiretroviral therapy initiation on vitamin D levels and four oral diseases among Kenyan children and adolescents living with HIV.

OBJECTIVES: The impact of antiretroviral treatment (ART) on the occurrence of oral diseases among children and adolescents living with HIV (CALHIV) is poorly understood. The aim of this study was to determine the effect of ART timing on vitamin D levels and the prevalence of four oral diseases (dry mouth, dental caries, enamel hypoplasia, and non-herpes oral ulcer) among Kenyan CALHIV from two pediatric HIV cohorts. METHODS: This nested cross-sectional study was conducted at the Kenyatta National Hospital, Nairobi, Kenya. CALHIV, 51 with early-ART initiated at <12 months of age and 27 with late-ART initiated between 18 months-12 years of age, were included. Demographics, HIV diagnosis, baseline CD4 and HIV RNA viral load data were extracted from the primary study databases. Community Oral Health Officers performed oral health examinations following standardized training. RESULTS: Among 78 CALHIV in the study, median age at the time of the oral examination was 11.4 years old and median ART duration at the time of oral examination was 11 years (IQR: 10.1, 13.4). Mean serum vitamin D level was significantly higher among the early-ART group than the late-ART group (29.5 versus 22.4 ng/mL, p = 0.0002). Children who received early-ART had a 70% reduction in risk of inadequate vitamin D level (<20 ng/mL), compared to those who received late-ART (p = 0.02). Although both groups had similar prevalence of oral diseases overall (early-ART 82.4%; late-ART 85.2%; p = 0.2), there was a trend for higher prevalence of dry mouth (p = 0.1) and dental caries (p = 0.1) in the early versus late ART groups. The prevalence of the four oral diseases was not associated with vitamin D levels (p = 0.583). CONCLUSIONS: After >10 years of ART, CALHIV with early-ART initiation had higher serum vitamin D levels compared to the late-ART group. The four oral diseases were not significantly associated with timing of ART initiation or serum vitamin D concentrations in this cohort. There was a trend for higher prevalence of dry mouth and dental caries in the early-ART group, probably as side-effects of ART.

Pediatric HIV Pre-test Informational Video is Associated with Higher Knowledge Scores Compared to Counselor-Delivered Information.

Video-based pre-test information is used in high resource settings to increase HIV testing coverage but remains untested in resource-limited settings. We conducted formative and evaluative focus group discussions with healthcare workers (HCWs) and caregivers of children in Kenya to develop and refine a pediatric HIV pre-test informational video. We then assessed HIV knowledge among caregivers sequentially enrolled in one of three pre-test information groups: (1) individual HCW-led (N = 50), (2) individual video-based (N = 50), and (3) group video-based (N = 50) sessions. A brief video incorporating information on national pediatric testing, modes of HIV transmission, and dramatized testimonials of caregivers who tested children was produced in three languages. Compared to individual HCW-led sessions (mean: 7.2/9; standard deviation [SD]: 1.3), both the group video-based (mean: 7.7; SD: 0.9) and individual video-based (mean: 7.6; SD: 0.9) sessions had higher mean knowledge scores. Video-based pre-test information could enhance existing pediatric HIV testing services.

Brief Report: Pediatric Saliva-Based HIV Testing: Health care Worker and Caregiver Acceptability.

BACKGROUND: Pediatric HIV testing remains suboptimal. The OraQuick test [saliva-based test (SBT)] is validated in pediatric populations ≥18 months. Understanding caregiver and health care worker (HCW) acceptability of pediatric SBT is critical for implementation. METHODS: A trained qualitative interviewer conducted 8 focus group discussions (FGDs): 4 with HCWs and 4 with caregivers of children seeking health services in western Kenya. FGDs explored acceptability of pediatric SBT and home- and facility-based SBT use. Two reviewers conducted consensus coding and thematic analyses of transcripts using Dedoose. RESULTS: Most HCWs but few caregivers had heard of SBT. Before seeing SBT instructions, both had concerns about potential HIV transmission through saliva, which were mostly alleviated after kit demonstration. Noted benefits of SBT included usability and avoiding finger pricks. Benefits of facility-based pediatric SBT included shorter client waiting and service time, higher testing coverage, and access to HCWs, while noted challenges included ensuring confidentiality. Benefits of caregivers using home-based SBT included convenience, privacy, decreased travel costs, increased testing, easier administration, and child comfort. Perceived challenges included not receiving counseling, disagreements with partners, child neglect, and negative emotional response to a positive test result. Overall, HCWs felt that SBT could be used for pediatric HIV testing but saw limited utility for caregivers performing SBT without an HCW present. Caregivers saw utility in home-based SBT but wanted easy access to counseling in case of a positive test result. CONCLUSIONS: SBT was generally acceptable to HCWs and caregivers and is a promising strategy to expand testing coverage.

Home-based HIV Testing for Children: A Useful Complement for Caregivers with More Children, Who are Male, and with an HIV Negative Partner.

Expanding index and family-based testing (HBT) is a priority for identifying children living with HIV. Our study characterizes predictors that drive testing location choice for children of parents living with HIV. Kenyan adults living with HIV were offered a choice of HBT or clinic-based testing (CBT) for any of their children (0-12 years) of unknown HIV status. Multilevel generalized linear models were used to identify correlates of choosing HBT or CBT for children and testing all versus some children within a family, including caregiver demographics, HIV history, social support, cost, and child demographics and HIV prevention history. Among 244 caregivers living with HIV and their children of unknown HIV status, most (72%) caregivers tested children using CBT. In multivariate analysis, female caregivers [aRR 0.52 (95% CI 0.34-0.80)] were less likely to choose HBT than male caregivers. Caregivers with more children requiring testing [aRR 1.23 (95% CI 1.05-1.44)] were more likely to choose HBT than those with fewer children requiring testing. In subgroup univariate analysis, female caregivers with a known HIV negative spouse were significantly more likely to choose HBT over CBT than those with a known HIV positive spouse [RR 2.57 (95% CI 1.28-5.14), p = 0.008], no association was found for male caregivers. Child demographics and clinical history was not associated with study outcomes. Caregiver-specific factors were more influential than child-specific factors in caregiver choice of pediatric HIV testing location. Home-based testing may be preferable to families with higher child care needs and may encourage pediatric HIV testing if offered as an alternative to clinic testing.

Financial Incentives for Pediatric HIV Testing (FIT): Caregiver Insights on Incentive Mechanisms, Focus Populations, and Acceptability for Programmatic Scale Up.

Children living with HIV experience gaps in HIV testing globally; scaling up evidence-based testing strategies is critical for preventing HIV-related mortality. Financial incentives (FI) were recently demonstrated to increase uptake of pediatric HIV testing. As part of this qualitative follow-up study to the FIT trial (NCT03049917) conducted in Kenya, 54 caregivers participated in individual interviews. Interview transcripts were analyzed to identify considerations for scaling up FI for pediatric testing. Caregivers reported that FI function by directly offsetting costs or nudging caregivers to take action sooner. Caregivers found FI to be feasible and acceptable for broader programmatic implementation, and supported use for a variety of populations. Some concerns were raised about unintended consequences of FI, including caregivers bringing ineligible children to collect incentives and fears about the impact on linkage to care and retention if caregivers become dependent on FI.

Caregivers' report of HIV-associated oral manifestations among HIV-unexposed, exposed, and infected Kenyan children.

BACKGROUND: Few oral health studies have been conducted in HIV-exposed uninfected children, who, like their HIV-infected peers, have altered immunity and perinatal drug exposures. AIM: To compare caregiver' self-report of oral diseases, hygiene practices and utilization of routine dental care, between HIV-infected (HIV), HIV-exposed uninfected (HEU), and HIV-unexposed uninfected (HUU) children in Kenya. DESIGN: This nested cross-sectional study was conducted at the Kenyatta National Hospital, Nairobi, Kenya. Caregivers of 196 children (104 HIV-infected, 55 HEU, and 37 HUU) participated in this study. Using a validated questionnaire from the WHO and photographs of HIV-related oral lesions, we collected data on oral diseases and oral health practices. RESULTS: Caregivers of HIV-infected children reported at least one oral disease in their children (42%; HEU [27%]; HUU [17%; P = .008]). Oral candidiasis was the most common disease reported (HIV-infected [24%], HEU [5.5%], and HUU [2.8%; P < .05]). Baseline CD4% was associated with oral candidiasis (OR = 0.93, 95% CI: 0.88-0.98). Only 16% of children had ever visited a dentist, and most initiated brushing after 3 years of age (83%). Nearly all (98%) caregivers desired a follow-up oral examination. CONCLUSIONS: HIV infection/exposure and low CD4% were associated with increased odds of oral diseases. Most caregivers desired a follow-up oral examination for their children.

Association Between Cytomegalovirus and Epstein-Barr Virus Viremia And Human Immunodeficiency Virus DNA Levels in the Reservoir of Kenyan Infants Receiving Antiretroviral Therapy.

Identifying determinants of human immunodeficiency virus (HIV) reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) coinfections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA-suppressed Kenyan children starting antiretroviral therapy before 7 months of age. Earlier acquisition of CMV and EBV and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of antiretroviral therapy, independent of HIV RNA levels over time. These data suggest that delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation.

Mixed cytomegalovirus genotypes in HIV-positive mothers show compartmentalization and distinct patterns of transmission to infants.

Cytomegalovirus (CMV) is the commonest cause of congenital infection and particularly so among infants born to HIV-infected women. Studies of congenital CMV infection (cCMVi) pathogenesis are complicated by the presence of multiple infecting maternal CMV strains, especially in HIV-positive women, and the large, recombinant CMV genome. Using newly developed tools to reconstruct CMV haplotypes, we demonstrate anatomic CMV compartmentalization in five HIV-infected mothers and identify the possibility of congenitally transmitted genotypes in three of their infants. A single CMV strain was transmitted in each congenitally infected case, and all were closely related to those that predominate in the cognate maternal cervix. Compared to non-transmitted strains, these congenitally transmitted CMV strains showed statistically significant similarities in 19 genes associated with tissue tropism and immunomodulation. In all infants, incident superinfections with distinct strains from breast milk were captured during follow-up. The results represent potentially important new insights into the virologic determinants of early CMV infection.

Home- and Clinic-Based Pediatric HIV Index Case Testing in Kenya: Uptake, HIV Prevalence, Linkage to Care, and Missed Opportunities.

INTRODUCTION: Gaps in HIV testing of children persist, particularly among older children born before the expansion of the prevention of mother-to-child transmission of HIV programs. METHODS: The Counseling and Testing for Children at Home study evaluated an index-case pediatric HIV testing approach. Caregivers receiving HIV care at 7 health facilities in Kenya (index cases), who had children of unknown HIV status aged 0-12 years, were offered the choice of clinic-based testing (CBT) or home-based testing (HBT). Testing uptake and HIV prevalence were compared between groups choosing HBT and CBT; linkage to care, missed opportunities, and predictors of HIV-positive diagnosis were identified. RESULTS: Among 493 caregivers, 70% completed HIV testing for ≥1 child. Most caregivers who tested children chose CBT (266/347, 77%), with 103 (30%) agreeing to same-day testing of an untested accompanying child. Overall HIV prevalence among 521 tested children was 5.8% (CBT 6.8% vs HBT 2.4%; P = 0.07). Within 1 month of diagnosis, 88% of 30 HIV-positive children had linked to care, and 54% had started antiretroviral treatment. For 851 children eligible for testing, the most common reason for having an unknown HIV status was that the child's mother was not tested for HIV or had tested HIV negative during pregnancy (82%). CONCLUSION: Testing uptake and HIV prevalence were moderate with nonsignificant differences between HBT and CBT. Standardized offer to test children accompanying caregivers is feasible to scale-up with little additional investment. Linkage to care for HIV-positive children was suboptimal. Lack of peripartum maternal testing contributed to gaps in pediatric testing.

Training Exposure and Self-Rated Competence among HIV Care Providers Working with Adolescents in Kenya.

Lack of health care worker (HCW) training is a barrier to implementing youth-friendly services. We examined training coverage and self-reported competence, defined as knowledge, abilities, and attitudes, of HCWs caring for adolescents living with HIV (ALWH) in Kenya. Surveys were conducted with 24 managers and 142 HCWs. Competence measures were guided by expert input and Kalamazoo II Consensus items. Health care workers had a median of 3 (interquartile range [IQR]: 1-6) years of experience working with ALWH, and 40.1% reported exposure to any ALWH training. Median overall competence was 78.1% (IQR: 68.8-84.4). In multivariable linear regression analyses, more years caring for ALWH and any prior training in adolescent HIV care were associated with significantly higher self-rated competence. Training coverage for adolescent HIV care remains suboptimal. Targeting HCWs with less work experience and training exposure may be a useful and efficient approach to improve quality of youth-friendly HIV services.

Brief Report: Use of the Consolidated Framework for Implementation Research (CFIR) to Characterize Health Care Workers' Perspectives on Financial Incentives to Increase Pediatric HIV Testing.

BACKGROUND: A prior randomized control trial showed financial incentives increase HIV testing rates for children of unknown HIV status. Translating evidence-based interventions such as these to scale requires an implementation science approach. METHODS: A qualitative study evaluating health care providers' perceptions of barriers and facilitators of a previously completed financial incentives intervention for pediatric HIV testing was conducted at health care facilities in Kisumu, Kenya. Six focus group discussions with 52 providers explored determinants of acceptability, feasibility, and sustainability of financial incentive scale-up for pediatric HIV testing using the Consolidated Framework for Implementation Research to inform question guides and thematic analysis. RESULTS: Providers found the use of financial incentive interventions for pediatric HIV testing to be highly acceptable. First, providers believed financial incentives had a relative advantage over existing strategies, because they overcame cost barriers and provided additional motivation to test; however, concerns about how financial incentives would be implemented influenced perceptions of feasibility and sustainability. Second, providers expressed concern that already overburdened staff and high costs of financial incentive programs would limit sustainability. Third, providers feared that financial incentives may negatively affect further care because of expectations of repeated financial support and program manipulation. CONCLUSIONS: Providers viewed financial incentives as an acceptable intervention to scale programmatically to increase uptake of pediatric testing. To ensure feasibility and sustainability of financial incentives in pediatric HIV testing programs, it will be important to clearly define target populations, manage expectations of continued financial support, and establish systems to track testing.

Brief Report: Diagnostic Accuracy of Oral Mucosal Transudate Tests Compared with Blood-Based Rapid Tests for HIV Among Children Aged 18 Months to 18 Years in Kenya and Zimbabwe.

BACKGROUND: Gaps persist in HIV testing for children who were not tested in prevention of mother-to-child HIV transmission programs. Oral mucosal transudate (OMT) rapid HIV tests have been shown to be highly sensitive in adults, but their performance has not been established in children. METHODS: Antiretroviral therapy-naive children aged 18 months to 18 years in Kenya and Zimbabwe were tested for HIV using rapid OraQuick ADVANCE Rapid HIV-1/2 Antibody test on oral fluids (OMT) and blood-based rapid diagnostic testing (BBT). BBT followed Kenyan and Zimbabwean national algorithms. Sensitivity and specificity were calculated using the national algorithms as the reference standard. RESULTS: A total of 1776 children were enrolled; median age was 7.3 years (interquartile range: 4.7-11.6). Among 71 children positive by BBT, all 71 were positive by OMT (sensitivity: 100% [97.5% confidence interval (CI): 94.9% to 100%]). Among the 1705 children negative by BBT, 1703 were negative by OMT (specificity: 99.9% [95% CI: 99.6% to 100.0%]). Due to discrepant BBT and OMT results, 2 children who initially tested BBT-negative and OMT-positive were subsequently confirmed positive within 1 week by further tests. Excluding these 2 children, the sensitivity and specificity of OMT compared with those of BBT were each 100% (97.5% CI: 94.9% to 100% and 99.8% to 100%, respectively). CONCLUSIONS: Compared to national algorithms, OMT did not miss any HIV-positive children. These data suggest that OMTs are valid in this age range. Future research should explore the acceptability and uptake of OMT by caregivers and health workers to increase pediatric HIV testing coverage.

Influence and involvement of support people in adolescent and young adult HIV testing.

HIV incidence and mortality are high among adolescents and young adults (AYA) in sub-Saharan Africa, but testing rates are low. Understanding how support people (SP), such as peers, partners, or parents, influence AYA may improve HIV testing uptake. AYA aged 14-24 seeking HIV testing at a referral hospital in Nairobi, Kenya completed a post-test survey assessing the role of SP. Among 1062 AYA, median age was 21. Overall, 12% reported their decision to test was influenced by a parent, 20% by a partner, and 22% by a peer. Young adults (20-24 years old) were more likely than adolescents (14-19 years old) to be influenced to test by partners (23% vs. 12%, p < .001), and less likely by parents (6.6% vs. 27%, p < .001), healthcare workers (11% vs. 16%, p < .05), or counselors (9.4% vs. 19%, p < .001). Half of AYA were accompanied for testing (9.9% with parent, 10% partner, 23% peer, 4.3% others, and 2.1% multiple types). Young adults were more likely than adolescents to present alone (58% vs. 32%, p < .001) or with a partner (12% vs. 6.7%, p < .05), and less likely with a parent (1.6% vs. 31%, p < .001). Similar proportions of adolescents and young adults came with a peer or in a group. Correlates of presenting with SP included: younger age (aRR = 1.55 [95%CI = 1.30-1.85]), female sex (aRR = 1.45 [95%CI = 1.21-1.73]), and school enrollment (aRR = 1.41 [95%CI = 1.05-1.88]). SP play an important role in AYAs' HIV testing and varies with age. Leveraging SP may promote uptake of HIV testing and subsequent linkage care for AYA.

Financial Incentives to Increase Uptake of Pediatric HIV Testing (FIT): study protocol for a randomised controlled trial in Kenya.

INTRODUCTION: Index case testing (ICT) to identify HIV-infected children is efficient but has suboptimal uptake. Financial incentives (FI) have overcome financial barriers in other populations by offsetting direct and indirect costs. A pilot study found FI to be feasible for motivating paediatric ICT among HIV-infected female caregivers. This randomised trial will determine the effectiveness of FI to increase uptake of paediatric ICT. METHODS AND ANALYSIS: The Financial Incentives to Increase Uptake of Pediatric HIV Testing trial is a five-arm, unblinded, randomised controlled trial that determines whether FI increases timely uptake of paediatric ICT. The trial will be conducted in multiple public health facilities in western Kenya. Each HIV-infected adult enrolled in HIV care will be screened for eligibility: primary caregiver to one or more children of unknown HIV status aged 0-12 years. Eligible caregivers will be individually randomised at the time of recruitment in equal 1:1:1:1:1 allocation to one of five arms (US$0 (control), US$1.25, US$2.50, US$5.00 and US$10.00). The trial aims to randomise 800 caregivers. Incentives will be disbursed at the time of child HIV testing using mobile money transfer or cash. Arms will be compared in terms of the proportion of adults who complete testing for at least one child within 2 months of randomisation and time to testing. A cost-effectiveness analysis of FI for paediatric ICT will also be conducted. ETHICS AND DISSEMINATION: This study was reviewed and approved by the University of Washington Institutional Review Board and the Kenyatta National Hospital Ethics and Research Committee. Trial results will be disseminated to healthcare workers at study sites, regional and national policymakers, and with patient populations at study sites (regardless of enrolment in the trial). Randomised trials of caregiver-child FI interventions pose unique study design, ethical and operational challenges, detailed here as a resource for future investigations. TRIAL REGISTRATION NUMBER: NCT03049917; Pre-results.

The Potential Harm of Cytomegalovirus Infection in Immunocompetent Critically Ill Children.

Cytomegalovirus (CMV) is a ubiquitous infection that causes disease in congenitally infected children and immunocompromised patients. Although nearly all CMV infections remain latent and asymptomatic in immunologically normal individuals, numerous studies have found that systemic viral reactivation is common in immunocompetent critically ill adults, as measured by detection of CMV in the blood (viremia). Furthermore, CMV viremia is strongly correlated with adverse outcomes in the adult intensive care unit (ICU), including prolonged stay, duration of mechanical ventilation, and death. Increasing evidence, including from a randomized clinical trial of antiviral treatment, suggests that these effects of CMV may be causal. Therefore, interventions targeting CMV might improve outcomes in adult ICU patients. CMV may have an even greater impact on critically ill children, particularly in low and middle income countries (LMIC), where CMV is regularly acquired in early childhood, and where inpatient morbidity and mortality are inordinately high. However, to date, there are few data regarding the clinical relevance of CMV infection or viremia in immunocompetent critically ill children. We propose that CMV infection should be studied as a potential modifiable cause of disease in critically ill children, and that these studies be conducted in LMIC. Below, we briefly review the role of CMV in immunologically normal critically ill adults and children, outline age-dependent differences in CMV infection that may influence ICU outcomes, and describe an agenda for future research.