Beyond Infection: Mortality and End-of-Life Care Associated with Infectious Disease Consultation in an Academic Health System.

BACKGROUND: Infectious diseases (ID) physicians are increasingly faced with the challenge of caring for patients with terminal illnesses or incurable infections. METHODS: This was a retrospective cohort of all patients with an ID consult within an academic health system 1/1/2014 - 12/31/2023, including community, general, and transplant ID consult services. RESULTS: There were 60,820 inpatient ID consults (17,235 community, 29,999 general, and 13,586 transplant) involving 37,848 unique patients. The number of consults increased by 94% and the rate rose from 5.0 to 9.9 consults per 100 inpatients (p<0.001). In total, 7.5% of patients receiving an ID consult died during admission, and 1,006 (2.6%) of patients were discharged to hospice. In-hospital mortality was 5.2% for community ID, 7.8% for general ID, and 10.7% for transplant ID patients (p<0.001). Six-month mortality was 9% for all non-obstetric admissions, , vs. 19% for community ID, 20.9% for general ID, and 22.3% for transplant ID.In total 2,866 (7.6%) of all patients receiving ID consultation also received palliative care consultation during the same hospitalization. The index ID consult preceded any palliative consult in the majority (69.5%) of cases. 16.3% of patients had a do-not-resuscitate order during the index hospitalization. 12.2% of all patients with a do-not-resuscitate order had this placed on the same day as the ID consult. CONCLUSIONS: Patients receiving ID consultation were increasingly complex and more likely to die soon after consultation. These results provide a framework for ID clinicians to consider their role in end-of-life care.

Social Disadvantage, Politics, and Severe Acute Respiratory Syndrome Coronavirus 2 Trends: A County-level Analysis of United States Data.

BACKGROUND: Understanding the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential for public health control efforts. Social, demographic, and political characteristics at the United States (US) county level might be associated with changes in SARS-CoV-2 case incidence. METHODS: We conducted a retrospective analysis of the relationship between the change in reported SARS-CoV-2 case counts at the US county level during 1 June-30 June 2020 and social, demographic, and political characteristics of the county. RESULTS: Of 3142 US counties, 1023 were included in the analysis: 678 (66.3%) had increasing and 345 (33.7%) nonincreasing SARS-CoV-2 case counts between 1 June and 30 June 2020. In bivariate analysis, counties with increasing case counts had a significantly higher Social Deprivation Index (median, 48 [interquartile range {IQR}, 24-72]) than counties with nonincreasing case counts (median, 40 [IQR, 19-66]; P = .009). Counties with increasing case counts were significantly more likely to be metropolitan areas of 250 000-1 million population (P < .001), to have a higher percentage of black residents (9% vs 6%; P = .013), and to have voted for the Republican presidential candidate in 2016 by a ≥10-point margin (P = .044). In the multivariable model, metropolitan areas of 250 000-1 million population, higher percentage of black residents, and a ≥10-point Republican victory were independently associated with increasing case counts. CONCLUSIONS: Increasing case counts of SARS-CoV-2 in the US during June 2020 were associated with a combination of sociodemographic and political factors. Addressing social disadvantage and differential belief systems that may correspond with political alignment will play a critical role in pandemic control.

Nocardia infections in the transplanted host.

BACKGROUND: Nocardia are uncommon pathogens that disproportionately afflict the immunocompromised host. Epidemiology and outcome data of Nocardia infections in transplant recipients are limited. METHODS: We performed a retrospective chart review of all patients at Duke University Hospital with a history of solid organ transplant (SOT) or hematopoietic cell transplant (HCT) and at least one positive culture for Nocardia between 1996 and 2013. Our aim was to describe the epidemiology and outcomes of Nocardia infections in the transplanted host. RESULTS: During the 18-year study period, 51 patients (14 HCT and 37 SOT recipients) had Nocardia infection. Nocardia incidence was stable during the study period in all populations except heart transplants, whose incidence declined. Infection occurred earlier in the HCT group than the SOT group (median time to diagnosis of 153 and 370 days, respectively). In both groups, the most common site involved was the lung. Outcomes were overall poor, especially in the HCT group with a cure rate of 29%. Heart transplant recipients had significantly better overall survival (P < .05) than other patients. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis did not provide complete protection from Nocardia infections, nor did it appear to select for resistant Nocardia isolates. CONCLUSIONS: Infections with Nocardia are typically a late post-transplant complication. The use of TMP-SMX prophylaxis was not associated with TMP-SMX-resistant Nocardia. Overall outcomes remain poor.

Nontuberculous mycobacterial infection after fractionated CO(2) laser resurfacing.

Nontuberculous mycobacteria are increasingly associated with cutaneous infections after cosmetic procedures. Fractionated CO2 resurfacing, a widely used technique for photorejuvenation, has been associated with a more favorable side effect profile than alternative procedures. We describe 2 cases of nontuberculous mycobacterial infection after treatment with a fractionated CO2 laser at a private clinic. Densely distributed erythematous papules and pustules developed within the treated area within 2 weeks of the laser procedure. Diagnosis was confirmed by histologic analysis and culture. Both infections responded to a 4-month course of a multidrug regimen. An environmental investigation of the clinic was performed, but no source of infection was found. The case isolates differed from each other and from isolates obtained from the clinic, suggesting that the infection was acquired by postprocedure exposure. Papules and pustules after fractionated CO2 resurfacing should raise the suspicion of nontuberculous mycobacterial infection.

The footprint of old syphilis: using a reverse screening algorithm for syphilis testing in a U.S. Geographic Information Systems-Based Community Outreach Program.

The impact of syphilis reverse sequence screening has not been evaluated in community outreach. Using reverse sequence screening in neighborhoods identified with geographic information systems, we found that among 239 participants, 45 (19%) were seropositive. Of these, 3 (7%) had untreated syphilis, 33 (73%) had previously treated syphilis infection, and 9 (20%) had negative nontreponemal test results.

Concurrent Sexually Transmitted Infection Testing Among Patients Tested for Mpox at a Tertiary Healthcare System.

Coinfection with sexually transmitted infections (STIs) and mpox is common. We evaluated concurrent STI testing among Duke Health patients tested for mpox. We found that most patients tested for mpox were not comprehensively tested for STIs, despite concurrent STIs being diagnosed in 15% of patients when testing was performed.

Disparities in Mpox Vaccination Among Priority Populations During the 2022 Outbreak.

Background: The 2022 mpox outbreak disproportionately affected men who have sex with men and persons living with HIV (PLWH). A 2-dose mpox vaccine series was deployed in mid-2022. Structural racism and insurance status may have affected equitable vaccination. Methods: We defined 3 cohorts: PLWH with at least 1 clinic visit between 1 July 2021 and 1 July 2022 (n = 2066), HIV preexposure prophylaxis (PrEP) recipients as of 1 January 2022 (n = 262), and all mpox-vaccinated patients in our health system between 1 July 2022 and 30 November 2022 (n = 807). We identified patients with prior diagnosed sexually transmitted infections (STIs) as having a positive test result for gonorrhea, chlamydia, or syphilis between 1 July 2021-1 July 2022. The primary outcome was receipt of at least 1 dose of mpox vaccine. Results: We identified 224 (10.8%) PLWH and 50 (19.0%) PrEP patients who received at least 1 dose of mpox vaccine. Among PLWH, White race (odds ratio [OR], 1.55; 95% CI, 1.11-2.16), private insurance (OR, 1.83; 95% CI, 1.01-3.34), prior STI (OR, 3.04; 95% CI, 2.16-4.27), prior COVID-19 vaccination (OR, 3.17; 95% CI, 1.93-5.20), and prior influenza vaccination (OR, 1.42; 95% CI, 1.30-1.96) independently predicted mpox vaccination. Within the PrEP cohort, prior COVID-19 vaccination and seasonal influenza vaccination predicted mpox vaccination. Uninsured patients were vaccinated later in the outbreak than patients with private insurance (median time to vaccination, 41 days in the privately insured group vs 83 days in the uninsured group; P < .0001). Conclusions: Race, insurance status, prior STI, and previous receipt of other vaccines influenced uptake of mpox vaccine. Addressing health disparities and vaccine acceptance will be essential in improving future outbreak response.

Pedicure-associated rapidly growing mycobacterial infection: an endemic disease.

BACKGROUND: Pedicure-associated nontuberculous mycobacterial furunculosis has been reported in the setting of either outbreaks or sporadic case reports. The epidemiology of these infections is not well understood. METHODS: Systematic surveillance for pedicure-associated nontuberculous mycobacterial furunculosis was conducted in 2 North Carolina counties from 1 January 2005 through 31 December 2008. A subset of implicated nail salons and control salons was inspected and sampled for nontuberculous mycobacteria. RESULTS: Forty cases of suspected or confirmed pedicure-associated nontuberculous mycobacterial furunculosis were reported during the 4-year study period. Furunculosis incidence in the surveillance region was 1.00, 0.96, 0.83, and 0.89 cases per 100,000 population in 2005, 2006, 2007, and 2008, respectively. The responsible organisms primarily belonged to the Mycobacterium chelonae/abscessus group (30 [91%] of 33 isolates). Thirteen implicated salons and 11 control salons were visited and environmentally sampled. An assortment of nontuberculous mycobacteria was cultured from footbaths, but there was no association between the species distribution of the environmental isolates and implication of the salon in human infection. Evidence of suboptimal cleaning (visible debris or surface biofilms) was observed in at least 1 footbath for 11 of 13 implicated salons and 4 of 11 control salons (P = .032). CONCLUSIONS: Pedicure-associated mycobacterial furunculosis was endemic in these 2 North Carolina counties during 2005-2008. Suboptimal footbath cleaning may have contributed to these infections, which suggests straightforward means of potential prevention. The relative rarity of this type of infection in the setting of nearly ubiquitous exposure to these pathogens suggests that as yet undefined host-specific or procedure-related factors may be involved in susceptibility to these infections.

Feasibility and willingness-to-pay for integrated community-based tuberculosis testing.

BACKGROUND: Community-based screening for TB, combined with HIV and syphilis testing, faces a number of barriers. One significant barrier is the value that target communities place on such screening. METHODS: Integrated testing for TB, HIV, and syphilis was performed in neighborhoods identified using geographic information systems-based disease mapping. TB testing included skin testing and interferon gamma release assays. Subjects completed a survey describing disease risk factors, healthcare access, healthcare utilization, and willingness to pay for integrated testing. RESULTS: Behavioral and social risk factors among the 113 subjects were prevalent (71% prior incarceration, 27% prior or current crack cocaine use, 35% homelessness), and only 38% had a regular healthcare provider. The initial 24 subjects reported that they would be willing to pay a median $20 (IQR: 0-100) for HIV testing and $10 (IQR: 0-100) for TB testing when the question was asked in an open-ended fashion, but when the question was changed to a multiple-choice format, the next 89 subjects reported that they would pay a median $5 for testing, and 23% reported that they would either not pay anything to get tested or would need to be paid $5 to get tested for TB, HIV, or syphilis. Among persons who received tuberculin skin testing, only 14/78 (18%) participants returned to have their skin tests read. Only 14/109 (13%) persons who underwent HIV testing returned to receive their HIV results. CONCLUSION: The relatively high-risk persons screened in this community outreach study placed low value on testing. Reported willingness to pay for such testing, while low, likely overestimated the true willingness to pay. Successful TB, HIV, and syphilis integrated testing programs in high risk populations will likely require one-visit diagnostic testing and incentives.

Wound botulism complicating internal fixation of a complex radial fracture.

Botulism developed in a patient following surgical repair of an open radial fracture. Symptoms resolved after treatment with antitoxin and antibiotics, and hardware excision was deferred. Subsequent osteomyelitis necessitated hardware exchange, and wound cultures grew Clostridium argentinense. This case highlights the management of botulism associated with orthopedic hardware.

Geographic analysis of latent tuberculosis screening: A health system approach.

BACKGROUND: Novel approaches are required to better focus latent tuberculosis infection (LTBI) efforts in low-prevalence regions. Geographic information systems, used within large health systems, may provide one such approach. METHODS: A retrospective, cross-sectional design was used to integrate US Census and Duke Health System data between January 1, 2010 and October 31, 2017 and examine the relationships between LTBI screening and population tuberculosis risk (assessed using the surrogate measure of proportion of persons born in tuberculosis-endemic regions) by census tract. RESULTS: The median proportion of Duke patients screened per census tract was 0.01 (range 0-0.1, interquartile range 0.01-0.03). The proportion of Duke patients screened within a census tract significantly but weakly correlated with the population risk. Furthermore, patients residing in census tracts with higher population tuberculosis risk were more likely to be screened with TST than with an IGRA (p<0.001). CONCLUSION: The weak correlation between patient proportion screened for LTBI and our surrogate marker of population tuberculosis risk suggests that LTBI screening efforts should be better targeted. This type of geography-based analysis may serve as an easily obtainable benchmark for LTBI screening in health systems with low tuberculosis prevalence.

G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans.

The Galpha protein Gpa1 governs the cAMP-PKA signaling pathway and plays a central role in virulence and differentiation in the human fungal pathogen Cryptococcus neoformans, but the signals and receptors that trigger this pathway were unknown. We identified seven putative proteins that share identity with known G protein-coupled receptors (GPCRs). One protein, Gpr4, shares limited sequence identity with the Dictyostelium discoideum cAMP receptor cAR1 and the Aspergillus nidulans GPCR protein GprH and also shares structural similarity with the Saccharomyces cerevisiae receptor Gpr1. gpr4 mutants exhibited reduced capsule production and mating defects, similar to gpa1 mutants, and exogenous cAMP suppressed both gpr4 mutant phenotypes. Epistasis analysis provides further evidence that Gpr4 functions upstream of the Galpha subunit Gpa1. Gpr4-Gpr4 homomeric interactions were observed in the yeast two-hybrid assay, and Gpr4 was shown to physically interact with Gpa1 in the split-ubiquitin system. A Gpr4::DsRED fusion protein was localized to the plasma membrane and methionine was found to trigger receptor internalization. The analysis of intracellular cAMP levels showed that gpr4 mutants still respond to glucose but not to certain amino acids, such as methionine. Amino acids might serve as ligands for Gpr4 and could contribute to engage the cAMP-PKA pathway. Activation of the cAMP-PKA pathway by glucose and amino acids represents a nutrient coincidence detection system shared in other pathogenic fungi.

A unique fungal two-component system regulates stress responses, drug sensitivity, sexual development, and virulence of Cryptococcus neoformans.

The stress-activated mitogen-activated protein kinase (MAPK) pathway is widely used by eukaryotic organisms as a central conduit via which cellular responses to the environment effect growth and differentiation. The basidiomycetous human fungal pathogen Cryptococcus neoformans uniquely uses the stress-activated Pbs2-Hog1 MAPK system to govern a plethora of cellular events, including stress responses, drug sensitivity, sexual reproduction, and virulence. Here, we characterized a fungal "two-component" system that controls these fundamental cellular functions via the Pbs2-Hog1 MAPK cascade. A typical response regulator, Ssk1, modulated all Hog1-dependent phenotypes by controlling Hog1 phosphorylation, indicating that Ssk1 is the major upstream signaling component of the Pbs2-Hog1 pathway. A second response regulator, Skn7, governs sensitivity to Na+ ions and the antifungal agent fludioxonil, negatively controls melanin production, and functions independently of Hog1 regulation. To control these response regulators, C. neoformans uses multiple sensor kinases, including two-component-like (Tco) 1 and Tco2. Tco1 and Tco2 play shared and distinct roles in stress responses and drug sensitivity through the Hog1 MAPK system. Furthermore, each sensor kinase mediates unique cellular functions for virulence and morphological differentiation. Our findings highlight unique adaptations of this global two-component MAPK signaling cascade in a ubiquitous human fungal pathogen.

Streptococcus salivarius Prosthetic Joint Infection following Dental Cleaning despite Antibiotic Prophylaxis.

We present the case of a 92-year-old man with septic arthritis of a prosthetic hip joint due to Streptococcus salivarius one week following a high-risk dental procedure despite preprocedure amoxicillin. S. salivarius is a commensal bacterium of the human oral mucosa that is an uncommon cause of bacteremia. S. salivarius has previously been described as a causative agent of infective endocarditis and spontaneous bacterial peritonitis but was only recently recognized as a cause of prosthetic joint infection. This case highlights the potential pathogenicity of a common commensal bacteria and the questionable utility of prophylactic antibiotics before dental procedures to prevent periprosthetic joint infections.

Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence.

The gas carbon dioxide (CO2) plays a critical role in microbial and mammalian respiration, photosynthesis in algae and plants, chemoreception in insects, and even global warming . However, how CO2 is transported, sensed, and metabolized by microorganisms is largely not understood. For instance, CO2 is known to induce production of polysaccharide capsule virulence determinants in pathogenic bacteria and fungi via unknown mechanisms . Therefore, we studied CO2 actions in growth, differentiation, and virulence of the basidiomycetous human fungal pathogen Cryptococcus neoformans. The CAN2 gene encoding beta-carbonic anhydrase in C. neoformans was found to be essential for growth in environmental ambient conditions but dispensable for in vivo proliferation and virulence at the high CO2 levels in the host. The can2Delta mutant in vitro growth defect is largely attributable to defective fatty acid synthesis. CO2 was found to inhibit cell-cell fusion but not filamentation during sexual reproduction. The can2 mutation restored early mating events in high CO2 but not later steps (fruiting body formation, sporulation), indicating a major role for carbonic anhydrase and CO2/HCO3- in this developmental cascade leading to the production of infectious spores. Our studies illustrate diverse roles of an ancient enzyme class in enabling environmental survival of a ubiquitous human pathogen.

Specialization of the HOG pathway and its impact on differentiation and virulence of Cryptococcus neoformans.

The human pathogenic fungus Cryptococcus neoformans has diverged from a common ancestor into three biologically distinct varieties or sibling species over the past 10-40 million years. During evolution of these divergent forms, serotype A C. neoformans var. grubii has emerged as the most virulent and cosmopolitan pathogenic clade. Therefore, understanding how serotype A C. neoformans is distinguished from less successful pathogenic serotypes will provide insights into the evolution of fungal virulence. Here we report that the structurally conserved Pbs2-Hog1 MAP kinase cascade has been specifically recruited as a global regulator to control morphological differentiation and virulence factors in the highly virulent serotype A H99 clinical isolate, but not in the laboratory-generated and less virulent serotype D strain JEC21. The mechanisms of Hog1 regulation are strikingly different between the two strains, and the phosphorylation kinetics and localization pattern of Hog1 are opposite in H99 compared with JEC21 and other yeasts. The unique Hog1 regulatory pattern observed in the H99 clinical isolate is widespread in serotype A strains and is also present in some clinical serotype D isolates. Serotype A hog1delta and pbs2delta mutants are attenuated in virulence, further underscoring the role of the Pbs2-Hog1 MAPK cascade in the pathogenesis of cryptococcosis.

Enzymes that counteract nitrosative stress promote fungal virulence.

Enzymes that protect cells from reactive oxygen species (superoxide dismutase, catalase, peroxidase) have well-established roles in mammalian biology and microbial pathogenesis. Two recently identified enzymes detoxify nitric oxide (NO)-related molecules; flavohemoglobin denitrosylase consumes NO, and S-nitrosoglutathione (GSNO) reductase metabolizes GSNO. Although both enzymes protect microorganisms from nitrosative challenge in vitro, their relevance has not been established in physiological contexts. Here we studied their biological functions in Cryptococcus neoformans, an established human fungal pathogen that replicates in macrophages and whose growth in vitro and in infected animals is controlled by NO bioactivity. We show that both flavohemoglobin denitrosylase and GSNO reductase contribute to C. neoformans pathogenesis. FHB1 and GNO1 mutations abolished NO- and GSNO-consuming activity, respectively. Growth of fhb1 mutant cells was inhibited by nitrosative challenge, whereas that of gno1 mutants was not. fhb1 mutants showed attenuated virulence in a murine model, and virulence was restored in iNOS(-/-) animals. Survival of the fhb1 mutant was also reduced in activated macrophages and restored to wild-type by inhibition of NOS activity. Combining mutations in flavohemoglobin and GSNO reductase, or flavohemoglobin and superoxide dismutase, further attenuated virulence. These studies illustrate that fungal pathogens elaborate enzymatic defenses against nitrosative stress mounted by the host.

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans.

Cryptococcus neoformans is a fungal pathogen that, after inhalation, can disseminate to the brain. Host alveolar macrophages (AMs) represent the first defense against the fungus. Once phagocytosed by AMs, fungal cells are killed by a concerted mechanism, involving the host-cellular response. If the cellular response is impaired, phagocytosis of the fungus may be detrimental for the host, since C. neoformans can grow within macrophages. Here, we identified a novel cryptococcal gene encoding antiphagocytic protein 1 (App1). App1 is a cryptococcal cytoplasmic protein that is secreted extracellularly and found in the serum of infected patients. App1 does not affect melanin production, capsule formation, or growth of C. neoformans. Treatment with recombinant App1 inhibited phagocytosis of fungal cells through a complement-mediated mechanism, and Deltaapp1 mutant is readily phagocytosed by AMs. Interestingly, the Deltaapp1 mutant strain showed a decreased virulence in mice deficient for complement C5 (A/Jcr), but it was hypervirulent in mice deficient for T and NK cells (Tgepsilon26). This study identifies App1 as a novel regulator of virulence for C. neoformans, and it highlights that internalization of fungal cells by AMs increases the dissemination of C. neoformans when the host cellular response is impaired.

Suboptimal HIV Testing Among Patients Admitted With Pneumonia: A Missed Opportunity.

Patients admitted with pneumonia are at higher risk for HIV and should be routinely screened. We examined a retrospective cohort of patients admitted to Duke University Health System with a primary diagnosis of pneumonia. During the study period, 6,951 persons were admitted with pneumonia. Of 6,646 patients without a known prior diagnosis of HIV, 1,010 (15%) had HIV testing during admission and 1,516 (23%) had a previously documented HIV test result. Forty-one (0.6%) patients had a positive HIV test during admission and 27 (0.4%) patients were diagnosed with HIV a median of 498 (IQR 112-982) days later, with median CD4 count of 64 (IQR 16-281) cells/mm3. HIV testing rates remain low in a population at high risk for HIV. At a minimum, we should be adhering to universal HIV screening recommendations, and certainly we should be screening those at higher risk. Opt-out HIV testing of pneumonia inpatients should be implemented.

Increasing Nocardia Incidence Associated with Bronchiectasis at a Tertiary Care Center.

RATIONALE: Nocardia is a genus of pathogens that most commonly afflict immunocompromised hosts but may be an emerging infection among persons with bronchiectasis. OBJECTIVES: To examine the epidemiology and clinical presentation of adult patients with Nocardia and bronchiectasis relative to other patient groups. METHODS: We examined a retrospectively assembled cohort of adults at Duke University Hospital in Durham, North Carolina with at least one positive culture from a bodily fluid or tissue specimen for Nocardia between January 1996 and December 2013. Denominator data for key populations (e.g., bronchiectasis, transplant) were obtained using International Classification of Diseases, Ninth Revision codes. In addition, we performed a case-control analysis to examine the relationship between inhaled corticosteroid use and Nocardia lung infection among otherwise immunocompetent patients with bronchiectasis. MEASUREMENTS AND MAIN RESULTS: We identified 183 patients with one or more cultures positive for Nocardia: 44 from 1996 to 2001, 64 from 2002 to 2007, and 75 from 2008 to 2013. Immune compromise was common (56%), particularly solid organ or hematopoietic cell transplant (30%). Infection usually was confined to the lungs (62%), followed by skin (10%), other sites (6%), brain (2%), and multiple sites (17%). Non-cystic fibrosis bronchiectasis was common among both immunocompetent (38%) and immunocompromised (10%) patients. Nocardia incidence in patients with bronchiectasis increased significantly over time, but there was no significant change in Nocardia incidence in hematopoietic cell or solid organ transplant recipients (our largest immunocompromised population). Among patients with bronchiectasis, Nocardia was positively but nonsignificantly associated with use of inhaled corticosteroids (odds ratio, 1.8; 95% confidence interval, 0.7-4.4). CONCLUSIONS: The increasing incidence of Nocardia infections at our medical center appears to be driven by increased incidence in patients with bronchiectasis rather than increases in immunocompromised populations. It is unclear whether increased environmental exposures, microbiologic surveillance, or other factors account for the increased incidence of Nocardia in our patients with bronchiectasis.