Digital technologies in the public-health response to COVID-19.

Digital technologies are being harnessed to support the public-health response to COVID-19 worldwide, including population surveillance, case identification, contact tracing and evaluation of interventions on the basis of mobility data and communication with the public. These rapid responses leverage billions of mobile phones, large online datasets, connected devices, relatively low-cost computing resources and advances in machine learning and natural language processing. This Review aims to capture the breadth of digital innovations for the public-health response to COVID-19 worldwide and their limitations, and barriers to their implementation, including legal, ethical and privacy barriers, as well as organizational and workforce barriers. The future of public health is likely to become increasingly digital, and we review the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases.

Towards an ultra-rapid smartphone- connected test for infectious diseases.

The development is reported of an ultra-rapid, point-of-care diagnostic device which harnesses surface acoustic wave (SAW) biochips, to detect HIV in a finger prick of blood within 10 seconds (sample-in-result-out). The disposable quartz biochip, based on microelectronic components found in every consumer smartphone, is extremely fast because no complex labelling, amplification or wash steps are needed. A pocket-sized control box reads out the SAW signal and displays results electronically. High analytical sensitivity and specificity are found with model and real patient blood samples. The findings presented here open up the potential of consumer electronics to cut lengthy test waiting times, giving patients on the spot access to potentially life-saving treatment and supporting more timely public health interventions to prevent disease transmission.

Correction: Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.

[This corrects the article DOI: 10.1371/journal.pone.0163722.].

Correction: Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006299.].

Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

Cytomegalovirus in pregnancy and the neonate.

Congenital cytomegalovirus (CMV) remains a leading cause of disability in children. Understanding the pathogenesis of infection from the mother via the placenta to the neonate is crucial if we are to produce new interventions and provide supportive mechanisms to improve the outcome of congenitally infected children. In recent years, some major goals have been achieved, including the diagnosis of primary maternal CMV infection in pregnant women by using the anti-CMV IgG avidity test and the diagnosis and prognosis of foetal CMV infection by using polymerase chain reaction real-time tests to detect and quantify the virus in amniotic fluid. This review summarises recent advances in our understanding and highlights where challenges remain, especially in vaccine development and anti-viral therapy of the pregnant woman and the neonate. Currently, no therapeutic options during pregnancy are available except those undergoing clinical trials, whereas valganciclovir treatment is recommended for congenitally infected neonates with moderately to severely symptomatic disease.

Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.

BACKGROUND: To help decide when to start and when to stop pre-emptive therapy for cytomegalovirus infection, we conducted two open-label randomized controlled trials in renal, liver and bone marrow transplant recipients in a single centre where pre-emptive therapy is indicated if viraemia exceeds 3000 genomes/ml (2520 IU/ml) of whole blood. METHODS: Patients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml was randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B). For both parts, the primary endpoint was the occurrence of a separate episode of viraemia requiring treatment because it was greater than 3000 genomes/ml. RESULTS: In Part A, the primary endpoint was not significantly different between the two arms; 18/32 (56%) in the monitor arm had viraemia greater than 3000 genomes/ml compared to 10/27 (37%) in the immediate treatment arm (p = 0.193). However, the time to developing an episode of viraemia greater than 3000 genomes/ml was significantly delayed among those randomized to immediate treatment (p = 0.022). In Part B, the primary endpoint was not significantly different between the two arms; 19/55 (35%) in the less than 200 genomes/ml arm subsequently had viraemia greater than 3000 genomes/ml compared to 23/51 (45%) among those randomized to stop treatment in the less than 3000 genomes/ml arm (p = 0.322). However, the duration of antiviral treatment was significantly shorter (p = 0.0012) in those randomized to stop treatment when viraemia was less than 3000 genomes/ml. DISCUSSION: The results illustrate that patients have continuing risks for CMV infection with limited time available for intervention. We see no need to alter current rules for stopping or starting pre-emptive therapy.

CMV infected or not CMV infected: that is the question.

Cytomegalovirus (CMV) infection is widespread in the human population. Normally, in adolescents and adults, prior exposure to CMV can readily be determined by IgG assays. However, in individuals where antibody production is impaired, such as patients with common variable immunodeficiency disease or in the very young where maternal antibodies are present, diagnosis of CMV infection is problematic using such assays. In this issue of the European Journal of Immunology, a study by Sester and colleagues [Eur J Immunol 2013. 43: 1099-1108] using CD4(+) T-cell immunity as a marker of infection clearly differentiates young children with prior exposure to CMV from those who only have passive maternal antibody. This information will quickly find application in the pretransplant screening of young children for CMV infection and help with the stratification of these children to identify those who are truly CMV negative and are therefore at risk for future CMV infection and disease if receiving an organ from a CMV-positive donor as discussed in this Commentary.

The "silent" global burden of congenital cytomegalovirus.

Human cytomegalovirus (CMV) is a leading cause of congenital infections worldwide. In the developed world, following the virtual elimination of circulating rubella, it is the commonest nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. The seroprevalence of CMV in adults and the incidence of congenital CMV infection are highest in developing countries (1 to 5% of births) and are most likely driven by nonprimary maternal infections. However, reliable estimates of prevalence and outcome from developing countries are not available. This is largely due to the dogma that maternal preexisting seroimmunity virtually eliminates the risk for sequelae. However, recent data demonstrating similar rates of sequelae, especially hearing loss, following primary and nonprimary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Although a significant proportion of congenital CMV infections are attributable to maternal primary infection in well-resourced settings, the absence of specific interventions for seronegative mothers and uncertainty about fetal prognosis have discouraged routine maternal antibody screening. Despite these challenges, encouraging results from prototype vaccines have been reported, and the first randomized phase III trials of prenatal interventions and prolonged postnatal antiviral therapy are under way. Successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population. In this review, we highlight the global epidemiology of congenital CMV and the implications of growing knowledge in areas of prevention, diagnosis, prognosis, and management for both low (50 to 70%)- and high (>70%)-seroprevalence settings.

Acute cytomegalovirus infection is associated with increased frequencies of activated and apoptosis-vulnerable T cells in HIV-1-infected infants.

Cytomegalovirus (CMV) coinfection is associated with infant HIV-1 disease progression and mortality. In a cohort of Kenyan HIV-infected infants, the frequencies of activated (CD38(+) HLA-DR(+)) and apoptosis-vulnerable (CD95(+) Bcl-2(-)) CD4(+) and CD8(+) T cells increased substantially during acute CMV infection. The frequency of activated CD4(+) T cells was strongly associated with both concurrent CMV coinfection (P = 0.001) and HIV-1 viral load (P = 0.05). The frequency of apoptosis-vulnerable cells was also associated with CMV coinfection in the CD4 (P = 0.02) and CD8 (P < 0.001) T cell subsets. Similar observations were made in HIV-exposed uninfected infants. CMV-induced increases in T cell activation and apoptosis may contribute to the rapid disease progression in coinfected infants.

Differential decay kinetics of human cytomegalovirus glycoprotein B genotypes following antiviral chemotherapy.

BACKGROUND: The impact of different cytomegalovirus (HCMV) glycoprotein B (gB) genotypes on pathogenesis remains controversial. OBJECTIVES: To investigate the effect of gB genotypes either as single infections or as part of multiple infections on the early kinetics of response to ganciclovir therapy. METHODS: Patients (n=239) enrolled in a study of intravenous ganciclovir or valganciclovir for the treatment of HCMV disease were analysed by a gB genotype specific PCR to quantify the amount of each gB genotype present at initiation of therapy (baseline, day 0) and at days 3, 7, 14 and 21 post therapy. RESULTS AND CONCLUSIONS: In all gB groups (individual gB genotype infections and mixed genotype infections) there was a biphasic decline in viral load after therapy. The first phase half life (days 0-3) was ≤1 day and was followed over the next 18 days by a slower second phase decline with half lives ranging from 3.4 to 4.4 days. The 1st phase rapid decline in viral load was dependent upon gB genotype whereas the ultimate viral load reduction at day 21 was relatively insensitive to gB genotype. A strong correlation between 1st phase decline and extent of viral load reduction at day 21 was observed (r=0.37; p=0.002). These data imply that early reductions in HCMV load after therapy may be useful in predicting the duration of drug therapy needed to control HCMV replication.

Importance of the cytomegalovirus seropositive recipient as a contributor to disease burden after solid organ transplantation.

BACKGROUND: The incidence of cytomegalovirus (CMV) syndrome/disease after adult solid organ transplantation in the era effective antiviral therapy has not been fully assessed. OBJECTIVE: To determines the incidence of CMV syndrome/disease after solid organ transplantation in the UK. STUDY DESIGN: A retrospective analysis of 1807 solid organ transplants from 12 UK solid organ transplant centres representing 32.7% of all transplant activity occurring in the UK between 1/04/2004 and 31/03/2006. Patients were categorised into those experiencing an episode of symptomatic CMV infection after transplant or those who remained free of symptoms. All patients were followed up for 2 years for the occurrence of CMV syndrome/disease. RESULTS: The majority of the transplant centres used valganciclovir prophylaxis in the high risk D+R- patients (91.6%) whereas management of the lower risk D+R+ and D-R+ patients was more variable with deployment of both prophylactic and pre-emptive strategies in ∼50% of centres. CMV syndrome/disease occurred in 20.5% of the D+R- patients representing 55 cases whereas the incidence was only 8.1% and 9% in the D+R+ and D-R+ group, respectively (p<0.001 compared to the D+R- group), but representing a further 58 cases of CMV syndrome/disease. CMV viraemia in the D+R- group was associated with a high probability (65%) of CMV syndrome/disease in renal transplant recipients whereas this was less apparent in the intermediate risk groups. CONCLUSIONS: CMV syndrome/disease remains an important healthcare burden after solid organ transplantation with the intermediate risk groups contributing similar numbers of cases as the high risk group.

Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency.

BACKGROUND: A subset of patients with common variable immunodeficiency (CVID) have debilitating inflammatory complications strongly associated with cytomegalovirus (CMV) infection and a hyperproliferative CMV-specific T-cell response. OBJECTIVES: We studied the T-cell response to CMV and the global effect of this virus on immune effector cell populations in patients with CVID. METHODS: Antibody staining, peptide stimulation, and proliferation assays were used to profile CMV-specific T-cell function. RESULTS: CMV infection drives the CD4/CD8 ratio inversion that is characteristic of CVID. The late effector CD8(+) T-cell subset is expanded in CMV-infected patients with CVID. This expansion is largely attributable to CMV-specific cells and correlates with inflammatory disease; within the CMV-specific population, the frequency of late effector cells correlates inversely with the frequency of cells expressing programmed death 1. Supernatants from proliferating CMV-specific CD8(+) cells from patients with inflammatory disease can confer proliferative potential on cells from patients with noninflammatory CVID and healthy subjects. Blocking experiments showed that this proliferation is mediated in part by IFN-γ and TNF-α. CONCLUSIONS: These data strengthen the association of CMV with inflammatory pathology in patients with CVID, explain some of the well-known T-cell abnormalities associated with this condition, and provide a plausible mechanism for the documented therapeutic activity of anti-TNF-α and antiviral chemotherapy in managing CVID-associated inflammatory disease.

Summary of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease After Solid Organ Transplantation.

The third edition of the British Transplantation Society Guidelines for the Prevention and Management of CMV Disease after Solid Organ Transplantation was published in March 2011. This article summarizes the important changes and advances in management in this rapidly evolving field. The pros and cons of universal, or targeted anti-cytomegalovirus (CMV) prophylaxis, and pre-emptive anti-CMV therapy are discussed, especially with respect to advances in CMV polymerase chain reaction monitoring. The evidence for oral anti-CMV prophylaxis using valganciclovir is presented, together with a summary of the treatment of CMV disease and emerging fields such as CMV vaccination, CMV genotyping, and drug resistance.

Cytomegalovirus quantification: where to next in optimising patient management?

BACKGROUND: Over the years quantification of cytomegalovirus (HCMV) load in blood has become a mainstay of clinical management helping direct deployment of antiviral therapy, assess response to therapy and highlight cases of drug resistance. AIMS: The review focuses on a brief historical perspective of HCMV quantification and the ways in which viral load is being used to improve patient management. METHODS: A review of the published literature and also personal experience at the Royal Free Hospital. RESULTS: Quantification of HCMV is essential for efficient patient management. The ability to use real time quantitative PCR to drive pre-emptive therapy has improved patient management after transplantation although the threshold viral loads for deployment differ between laboratories. The field would benefit from access to a universal standard for quantification. CONCLUSIONS: We see that HCMV quantification will continue to be central to delivering individualised patient management and facilitating multicentre trials of new antiviral agents and vaccines in a variety of clinical settings.

Inflammation in common variable immunodeficiency is associated with a distinct CD8(+) response to cytomegalovirus.

BACKGROUND: Common variable immunodeficiency is the most common primary immunodeficiency. A subset of patients has debilitating inflammatory complications. OBJECTIVES: We investigated the role of cytomegalovirus (CMV), and the T-cell response targeted at this virus, in this inflammatory disease. METHODS: Phenotypic and functional assays were used to profile CMV-specific T cells in patients with common variable immunodeficiency with and without inflammatory complications. Highly sensitive immunohistochemistry was used to detect CMV antigens at sites of inflammation. RESULTS: Cytomegalovirus was significantly associated with inflammatory disease, which occurred in 31 of 43 (72%) virus-exposed patients and 8 of 31 (26%) naive patients (P = .0001). CMV pp65-NLVPMVATV epitope-specific CD8(+) T-cell frequencies were significantly elevated in inflammatory patients, but these cells did not show evidence of exhaustion, with low levels of programmed death-1 and high T-cell receptor avidity. Rather, they showed features consistent with high in vivo functionality and proliferative activity including reduced levels of the anti-inflammatory marker CD73 (1.67% of NLV(+) cells were CD73(+) vs 42.01% in noninflammatory patients; P = .004) and increased Ki-67 expression (37% vs 2% in noninflammatory patients; P < .0001). In vitro, the CMV-specific T cells showed high antigen-specific proliferative potential compared with cells from noninflammatory patients. By using sensitive immunohistochemistry, we detected for the first time viral antigen at the sites of inflammation, indicative of active viral replication. CONCLUSION: Our data strongly support a direct role for CMV and a hyperreactive CMV-specific immune response in the debilitating chronic inflammatory complications of common variable immunodeficiency.