Advancing Digital Health Equity: A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has revolutionized the practice of ambulatory medicine, triggering rapid dissemination of digital healthcare modalities, including synchronous video visits. However, social determinants of health, such as age, race, income, and others, predict readiness for telemedicine and individuals who are not able to connect virtually may become lost to care. This is particularly relevant to the practice of infectious diseases (ID) and human immunodeficiency virus (HIV) medicine, as we care for high proportions of individuals whose health outcomes are affected by such factors. Furthermore, delivering high-quality clinical care in ID and HIV practice necessitates discussion of sensitive topics, which is challenging over video without proper preparation. We describe the "digital divide," emphasize the relevance to ID and HIV practice, underscore the need to study the issue and develop interventions to mitigate its impact, and provide suggestions for optimizing telemedicine in ID and HIV clinics.

Infectious Diseases Society of America Position Statement on Telehealth and Telemedicine as Applied to the Practice of Infectious Diseases.

Over the last 2 decades, telemedicine has effectively demonstrated its ability to increase access to care. This access has the ability to deliver quality clinical care and offer potential savings to the healthcare system. With increasing frequency, physicians, clinics, and medical centers are harnessing modern telecommunications technologies to manage a multitude of acute and chronic conditions, as well as incorporating telehealth into teaching and research. The technologies spanning telehealth, telemedicine, and mobile health (mHealth) are rapidly evolving, and the Infectious Diseases Society of America (IDSA) has prepared this updated position statement to educate its membership on the use of telemedicine and telehealth technologies. IDSA supports the appropriate and evidence-based use of telehealth technologies to provide up-to-date, timely, cost-effective subspecialty care to resource-limited populations.

Ganciclovir-resistant cytomegalovirus infections among lung transplant recipients are associated with poor outcomes despite treatment with foscarnet-containing regimens.

Ganciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154]; P = 0.00001) and donor positive/recipient negative (D+/R-) serostatus (75% versus 45% [69/154]; P = 0.03). The median whole-blood CMV load was 4.13 log10 copies/cm(3) (range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P = 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

Homozygosity for the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirus disease after liver transplantation.

Immunity against cytomegalovirus (CMV) is initiated after its recognition by Toll-like receptor 2 (TLR2). We assessed the association between a single-nucleotide polymorphism (SNP) that impairs TLR2 function and CMV disease in a cohort of 737 liver recipients. Ninety-two of 737 patients (7.1%, 10.9%, 12.3%, and 12.5% by 3, 6, 12, and 24 months, respectively) developed CMV disease. Kaplan-Meier estimation demonstrated an association between TLR2 R753Q SNP homozygosity and CMV disease (P = .044), especially tissue-invasive CMV disease (P = .001). A multivariate Cox proportional hazard model that accounted for other significant predictors demonstrated a significant association between TLR2 R753Q SNP homozygosity and tissue-invasive CMV disease (hazard ratio, 3.407; 95% confidence interval, 1.518-7.644; P = .0029). In conclusion, homozygosity for TLR2 R753Q SNP is a marker for CMV disease risk, especially for tissue-invasive disease, after liver transplantation. This observation supports the critical role of TLR2 in the pathogenesis of CMV disease in humans.

Invasive aspergillosis among heart transplant recipients is rare but causes rapid death due to septic shock and multiple organ dysfunction syndrome.

Between 2000 and 2011, proven or probable invasive aspergillosis (IA) was diagnosed in 1.7% (8/455) of heart transplant (HTx) recipients at our center, in the absence of antifungal prophylaxis. All patients had invasive pulmonary infections and 75% (6/8) were diagnosed during 2 separate 3-month periods. Cases were notable for their association with septic shock and multiple organ dysfunction syndrome (MODS) (75%, 6/8 each), non-specific clinical and radiographic findings, and rapid mortality despite mould-active antifungal therapy (88%, 7/8; occuring at a median 11 days after diagnosis). All patients had predisposing conditions known to be risk factors for IA. For patients with early IA (within 90 days of HTx), conditions included hemodialysis, thoracic re-operation, and the presence of another case in the institution within the preceding 3 months. For late-onset IA, conditions included hemodialysis and receipt of augmented immunosuppression. Clinicians should suspect IA in HTx recipients with risk factors who present with non-specific and unexplained respiratory syndromes, including those in septic shock and MODS, and institute prompt antifungal therapy without waiting for the results of cultures or other diagnostic tests.

In-Person Versus Tele-Infectious Disease (Tele-ID) Care: Is One Better?

We compared outcomes at 3 community hospitals before and after switching from in-person to a Tele-ID group from an academic medical center. Compared to in-person, Tele-ID received significantly more consultations with similar outcomes for length of hospital stay, transfers, readmission, and mortality. Tele-ID is a suitable alternative for community settings.

An Implementation Roadmap for Establishing Remote Infectious Disease Specialist Support for Consultation and Antibiotic Stewardship in Resource-Limited Settings.

Infectious Disease (ID)-trained specialists, defined as ID pharmacists and ID physicians, improve hospital care by providing consultations to patients with complicated infections and by leading programs that monitor and improve antibiotic prescribing. However, many hospitals and nursing homes lack access to ID specialists. Telehealth is an effective tool to deliver ID specialist expertise to resource-limited settings. Telehealth services are most useful when they are adapted to meet the needs and resources of the local setting. In this step-by-step guide, we describe how a tailored telehealth program can be implemented to provide remote ID specialist support for direct patient consultation and to support local antibiotic stewardship activities. We outline 3 major phases of putting a telehealth program into effect: pre-implementation, implementation, and sustainment. To increase the likelihood of success, we recommend actively involving local leadership and other stakeholders in all aspects of developing, implementing, measuring, and refining programmatic activities.

Impact of Clinical Decision Support System Implementation at a Community Hospital With an Existing Tele-Antimicrobial Stewardship Program.

Background: Lack of on-site antimicrobial stewardship expertise is a barrier to establishing successful programs. Tele-antimicrobial stewardship programs (TASPs) utilizing a clinical decision support system (CDSS) can address these challenges. Methods: This interrupted time series study reports the impact of CDSS implementation (February 2020) within an existing TASP on antimicrobial usage in a community hospital. Segmented regression analysis was used to assess differences in antimicrobial usage from January 2018 through December 2021. Pre- and post-CDSS frequencies of intravenous vs oral antimicrobials, time to optimal therapy (TTOT), pharmacist efficiency (number of documented interventions per month), and percentage of hospitalized patients receiving antimicrobials were compared with descriptive statistics. Results: Implementation of a CDSS into an existing TASP was associated with an immediate 11% reduction in antimicrobial usage (level change, P < .0001). Antimicrobial usage was already trending down by 0.25% per month (pre-CDSS slope, P < .0001) and continued to trend down at a similar rate after implementation (post-CDSS slope, P = .0129). Frequency of use of select oral agents increased from 38% to 57%. Median TTOT was 1 day faster (2.9 days pre-CDSS vs 1.9 days post-CDSS). On average, pharmacists documented 2.2-fold more interventions per month (198 vs 90) and patients received 1.03 fewer days of antimicrobials per admission post-CDSS. Conclusions: Implementation of a CDSS within an established TASP at a community hospital resulted in decreased antimicrobial usage, higher rates of oral usage, faster TTOT, and improved pharmacist efficiency.

Spectrum of early-onset and late-onset bacteremias after liver transplantation: implications for management.

Bacteremia is a significant cause of morbidity and mortality after liver transplantation. The characterization of the microbiological spectrum of bacteremia after liver transplantation may help physicians in choosing the initial empirical antimicrobial therapy for patients presenting with sepsis. The clinical and microbiology records of patients who received liver transplantation from January 1997 to March 2006 were reviewed. One hundred twenty-three of the 737 liver recipients (16.7%) developed bacteremia during the median follow-up period of 5.8 years (interquartile range = 2.5-8.8 years); 92 patients (12.5%) had gram-positive bacteremia (GPB), whereas 47 (6.4%) had gram-negative bacteremia (GNB). Nosocomial bacteremia was significantly more frequent among patients with early-onset GPB or GNB versus patients with late-onset GPB (66.7% versus 23.7%, P < 0.001) or GNB (70.6% versus 20.0%, P = 0.001). Peritonitis (33.3% versus 7.9%, P = 0.004) and wound infections (13.0% versus 0%, P = 0.04) as sources were more common in patients with early-onset GPB versus patients with late-onset GPB. Likewise, peritonitis was a more common source of early-onset GNB than late-onset GNB (41.2% versus 6.7%, P = 0.007). Staphylococcus aureus and Enterococcus faecium were the most common pathogens in patients with early-onset GPB, whereas Enterococcus faecalis and Streptococcus species were most common in patients with late-onset GPB. Pseudomonas aeruginosa and anaerobes were the most common pathogens in patients with early-onset GNB, whereas Escherichia coli was most common in patients with late-onset GNB. In conclusion, the microbiological spectra of early-onset and late-onset bacteremias differ, and this should be considered by those determining the initial empirical treatment of liver transplant recipients suspected to have bacteremias.

Toll-like receptor 2 polymorphism and Gram-positive bacterial infections after liver transplantation.

Toll-like receptor 2 (TLR2) is an immune sensor for gram-positive bacterial cell wall components. Single-nucleotide polymorphisms (SNPs) in the TLR2 gene that impair its function may, therefore, influence the risk and outcomes of gram-positive bacterial infections. In a cohort of 694 liver transplant recipients, we assessed the TLR2 SNP that is translated into an amino acid substitution of arginine for glutamine at position 753 (R753Q), and we found that its presence was associated with the clinical characteristics and outcomes of gram-positive bacterial infections. The proportions of patients with the TLR2 R753Q SNP did not significantly differ between those with gram-positive bacterial infections and those without gram-positive bacterial infections (9.6% versus 9.6%, P = 0.999). However, in patients with the TLR2 R753Q SNP, higher rates of infection recurrence (27.8% versus 11.8%, P = 0.07) and initial septic shock (11.1% versus 1.2%, P = 0.047) were observed. Chronic hepatitis C [relative risk (RR) = 3.37, 95% confidence interval (CI) = 1.24-9.13, P = 0.02], initial septic shock (RR = 15.13, 95% CI = 2.84-80.54, P = 0.001), and central venous catheter-related bacteremia (RR = 7.22, 95% CI = 2.54-20.51, P < 0.001) were significantly associated with 90-day all-cause mortality after gram-positive bacterial infections. In contrast, the presence of the TLR2 R753Q SNP was not significantly associated with mortality.

Telemedicine and Infectious Diseases Practice: A Leap Forward or a Step Back?

Infectious Diseases (ID) specialists pride themselves on performing a thorough history and physical exam, and developing a comprehensive diagnosis and management plan. A timely question is whether this tradition is at risk from the coming wave of telemedicine in clinical practice? It would not be if ID specialists embrace the changes ahead and leverage new technologies to enhance the efficiency and reach of their clinical practices. In this report, we highlight the opportunities and challenges offered by telemedicine for ID practice (Table 1).

Treatment of resistant influenza virus infection in a hospitalized patient with cystic fibrosis with DAS181, a host-directed antiviral.

We report a cystic fibrosis patient infected with influenza 2009H1N1 who had persistent viral shedding and clinical deterioration despite prolonged treatment with oseltamivir and zanamivir. The patient was diagnosed with H275Y neuraminidase inhibitor resistant influenza during treatment, thus was treated for 10 days with DAS181, an investigational host-directed inhaled sialidase fusion protein. Viral clearance occurred after 5 days of therapy and the patient became eligible for lung transplantation. Although the patient succumbed prior to receiving a transplant, this case exemplifies the potential utility of a host-directed approach against influenza which has potential to become resistant to neuraminidase inhibitors.

Staphylococcus aureus infections in the early period after lung transplantation: epidemiology, risk factors, and outcomes.

BACKGROUND: Staphylococcus aureus infections among lung transplant recipients are poorly studied. METHODS: We conducted a 5-year retrospective study of the epidemiology, clinical manifestations, risk factors, and outcomes of patients infected with S aureus within the first 90 days after lung transplantation. RESULTS: An S aureus infection developed in 109 of 596 lung transplant (18%) recipients. Methicillin-susceptible S aureus (MSSA; 62%) was more common than methicillin-resistant S aureus (MRSA; 38%); however, the proportion of infections caused by MRSA increased over time. Pneumonia (48%) was the most common infection, followed by tracheobronchitis (26%), bacteremia (12%), intrathoracic infections (7%), and skin/soft tissue infections (7%). Risk factors included mechanical ventilation for > 5 days and isolation of S aureus from recipients' sterility cultures. Patients with MRSA cultured from the nares or respiratory tract at the time of transplant were at an increased risk for MRSA infection (p < 0.0001 and p = 0.02, respectively). Infected patients required longer hospital and intensive care unit stays (p < 0.0001 for both), but the 30- and 90-day mortality rates from the onset of infection were only 7% and 12%, respectively. However, infected patients had higher rates of acute and chronic rejection at 1 (p = 0.048) and 3 years (p = 0.002), and higher rates of mortality at 1 (p = 0.058) and 3 years (p = 0.009). CONCLUSIONS: S aureus infections within the first 90 days of lung transplant were associated with low short-term mortality but increased long-term rates of mortality and acute and chronic rejection. Future studies are needed to explore the utility of S aureus eradication strategies in reducing disease burden and improving outcomes.

A polymorphism linked to elevated levels of interferon-γ is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified. METHODS: SNPs associated with varying levels of interferon (IFN)-γ (+874T/A), tumor necrosis factor-α (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV. RESULTS: Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-γ +874 T/T genotype (associated with high levels of IFN-γ production), CMV donor-positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-γ +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-γ +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-α, interleukin-10 or interleukin-6 SNPs and CMV infections. CONCLUSION: A genetic predisposition to elevated IFN-γ levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease.

Toll-like receptor 4 polymorphisms and the risk of gram-negative bacterial infections after liver transplantation.

BACKGROUND: Toll-like receptor 4 (TLR4) is the main immune molecule that recognizes lipopolysaccharide from gram-negative bacteria. Single-nucleotide polymorphisms (SNPs) in the TLR4 gene that impair lipopolysaccharide recognition may influence gram-negative bacterial infections after liver transplantation. METHODS: TLR4 D299G and T399I SNPs were assessed in a cohort of 706 liver transplant recipients and were associated with the clinical characteristics and outcome of gram-negative bacterial infections. Cox proportional hazard model was performed to determine covariates associated with outcomes after gram-negative bacterial infections. RESULTS: Of 706 patients, there were 108 with microbiologically confirmed gram-negative bacterial infections, 135 with clinically suspected but not confirmed infections, and 463 patients without gram-negative bacterial infections. The proportions of TLR4 D299G (5/108 [4.6%] vs. 32/463 [6.9%]; P=0.39) and T399I SNPs (19/108 [17.6%] vs. 68/463 [14.7%]; P=0.45) did not differ between those with or without microbiologically confirmed gram-negative bacterial infections. Female gender (odds ratio 2.30, 95% confidence interval [CI]1.50-3.53; P<0.001) and ulcerative colitis (odds ratio 2.18, 95% CI 1.08-4.38; P=0.03) were associated with gram-negative bacterial infections. Among 108 patients with gram-negative bacterial infections, alcoholic liver disease (relative risk [RR] 4.87, 95% CI 1.54-15.44; P=0.007), initial septic shock (RR 10.19, 95% CI 2.70-38.37; P=0.001), and nosocomially-acquired infection (RR 4.61, 95% CI 1.51-14.14; P=0.007) were significantly associated with 90-day mortality after gram-negative bacterial infections. In contrast, TLR4 D299G and T399I SNPs were not significantly associated with mortality after gram-negative bacterial infections. CONCLUSION: In this cohort of liver transplant recipients with long-term follow-up, no significant association was observed between TLR4 D299G and T399I SNPs and the risk and outcome of gram-negative bacterial infections.

Human herpesvirus 6 infections after liver transplantation.

Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.