Impact of the COVID-19 pandemic on delays in diagnosis and treatment of tick-borne diseases endemic to southeastern USA.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic was marked by an increase in diagnosis and treatment delays for a range of medical conditions. Yet the impact of the pandemic on the management of tick-borne diseases, which frequently manifest as an acute febrile illness similar to COVID-19, has not been well described. METHODS: In this retrospective cohort study of patients with suspected tick-borne disease attending the University of North Carolina Health facilities, we compared the timeliness of diagnosis and treatment in a "pre-COVID" period (March 2019 to February 2020) and a "post-COVID" period (March 2020 to February 2021). Participants included patients with an ICD-10 diagnosis code of spotted fever group rickettsiosis or ehrlichiosis and a positive Rickettsia rickettsii or Ehrlichia indirect immunofluorescence assay immunoglobulin G antibody test result. Of the 897 patients who had an eligible diagnosis, 240 (26.8%) met the inclusion criteria. The main outcome was time from initial presentation to definitive diagnosis and treatment. RESULTS: During the 2-year study period, 126 (52.5%) patients were grouped in the pre-COVID period and 114 (47.5%) were grouped in the post-COVID period; 120 (50.0%) were female; and 139 (57.9%) were aged > 50 years. Comparing the post-COVID to the pre-COVID period, the adjusted odds ratio (aOR) for delay in treatment > 0 days was 1.81 (95% confidence interval [CI] 1.07-3.07, P = 0.03), and for a treatment delay > 7 days, 1.65 (95% CI 0.94-2.90, P = 0.08). The odds of a delay in diagnosis were similar for patients in the post- and pre-COVID periods, with an aOR of 1.61 (95% CI 0.96-2.72, P = 0.07) for delays > 0 days, and aOR of 1.72 (95% CI 0.99-3.00, P = 0.05) for delays > 7 days. CONCLUSIONS: The odds of a delay in treatment > 0 days were significantly higher in the post-COVID period than in the pre-COVID period. However, the odds of a delay in treatment > 7 days, or a delay in diagnosis, were similar between these two periods. Shifts in care-seeking, alternative care delivery models and prioritization of COVID-19 may contribute to diminished timeliness of treatment for patients with tick-borne diseases.

25-Hydroxycholesterol exacerbates vascular leak during acute lung injury.

Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor-dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets. Here, using Ch25h-/- mice and exogenous 25HC in lung injury models, we provide evidence that 25HC sustains proinflammatory cytokines in the airspace and augments lung injury, at least in part, by inducing LXR-independent endoplasmic reticulum stress and endothelial leak. Suggesting an autocrine effect in endothelium, inhaled LPS upregulates pulmonary endothelial Ch25h, and non-hematopoietic Ch25h deletion is sufficient to confer lung protection. In patients with acute respiratory distress syndrome, airspace 25HC and alveolar macrophage CH25H were associated with markers of microvascular leak, endothelial activation, endoplasmic reticulum stress, inflammation, and clinical severity. Taken together, our findings suggest that 25HC deriving from and acting on different cell types in the lung communicates distinct, temporal LXR-independent and -dependent signals to regulate inflammatory homeostasis.

"Leopards do not change their spots:" tick borne disease symptomology case report.

BACKGROUND: Human Monocytic Ehrlichiosis is caused by infection with the bacteria Ehrlichia chaffeensis through the bite of an infected lone star tick (Amblyomma americanum). Patients infected with Human Monocytic Ehrlichiosis often present with symptoms including fever, headache, myalgia, and occasionally a macular rash. The presence of other endemic tick-borne diseases with similar symptoms, such as Rocky Mountain Spotted Fever, complicate the diagnosis of Human Monocytic Ehrlichiosis. CASE PRESENTATION: A patient developed a fever, diffuse myalgia, headache, and a non-productive cough 5 days after a fishing trip in late May in central North Carolina. Over the course of the illness the patient's symptoms worsened, with arthralgia, bilateral lower extremity erythema and edema, and a developing bilateral rash on the palms. With testing that revealed elevated liver enzymes, a potential for recent tick exposure (e.g., fishing trip), presentation during tick season, and the development of a rash, Rocky Mountain Spotted Fever and Human Monocytic Ehrlichiosis were considered. The patient was prescribed a seven-day course of oral doxycycline and cefalexin, which would provide coverage from Rickettsia, Ehrlichia and gram-positive bacteria typically responsible for cellulitis. Many of the patient's symptoms resolved or improved, although the right shoulder remained painful to active movement. The patient was prescribed another seven-day course of doxycycline due to his perceived incomplete response to the first course. Approximately 5 weeks after symptom onset (D0 + 36), the patient followed up with a provider for convalescent testing and counseling. Convalescent Ehrlichia and Rickettsia serological tests were ordered. The acute Ehrlichia serology and acute Rickettsia serology were originally non-reactive with both titers measured at < 1:64. Convalescent serology, ordered 28 days after the acute sample collection, showed a greater than four-fold increase in the Ehrlichia IgG titer (1:256), satisfying clinical and laboratory case definitions for ehrlichiosis. In follow-up, 3 weeks later (D0 + 57), the patient reported that most of his pain had subsided, though he still occasionally got shooting nerve pain when exercising. CONCLUSION: This case of Human Monocytic Ehrlichiosis in North Carolina exemplifies the need for a knowledge of spatial epidemiological patterns and clinical manifestations in the diagnosis of tick-borne diseases.

Patterns Testing for Tick-Borne Diseases and Implications for Surveillance in the Southeastern US.

Importance: Tick-borne diseases (TBD), including spotted fever group rickettsiosis (SFGR), ehrlichiosis, and, increasingly, Lyme disease, represent a substantial public health concern throughout much of the southeastern United States. Yet, there is uncertainty about the epidemiology of these diseases because of pitfalls in existing diagnostic test methods. Objective: To examine patterns of diagnostic testing and incidence of TBD in a large, academic health care system. Design, Setting, and Participants: This cross-sectional study included diagnostic test results for TBD at UNC Health, a large academic health care system with inpatient and outpatient facilities, from January 1, 2017, to November 30, 2020. Participants included all individuals seeking routine care at UNC Health facilities who had testing for SFGR, ehrlichiosis, or Lyme disease performed during the study period. Main Outcomes and Measures: Rates of test positivity, testing completeness, and incidence of TBD. Results: During the 4-year study period, 11 367 individuals (6633 [58.4%] female; 10 793 [95%] non-Hispanic individuals and 8850 [77.9%] White individuals; median [IQR] age, 53 [37-66] years) were tested for TBD. Among the 20 528 diagnostic tests performed, 47 laboratory-confirmed, incident cases of SFGR, 27 cases of ehrlichiosis, and 76 cases of Lyme were confirmed, representing incidence rates of 4.7%, 7.1%, and 0.7%, respectively. However, 3984 of SFGR tests (79.3%) and 3606 of Ehrlichia tests (74.3%) lacked a paired convalescent sample. Of 20 528 tests, there were 11 977 tests (58.3%) for Lyme disease from 10 208 individuals, 5448 tests (26.5%) for SFGR from 4520 individuals, and 3103 tests (15.1%) for ehrlichiosis from 2507 individuals. Most striking, testing for ehrlichiosis was performed in only 55% of patients in whom SFGR was ordered, suggesting that ehrlichiosis remains underrecognized. An estimated 187 incident cases of SFGR and 309 of ehrlichiosis were potentially unidentified because of incomplete testing. Conclusions and Relevance: In this cross-sectional study, most of the patients suspected of having TBD did not have testing performed in accordance with established guidelines, which substantially limits understanding of TBD epidemiology. Furthermore, the data revealed a large discrepancy between the local burden of disease and the testing performed. These findings underscore the need to pursue more robust, active surveillance strategies to estimate the burden of TBD and distribution of causative pathogens.

Chemical screen for epigenetic barriers to single allele activation of Oct4.

Here we utilized the chromatin in vivo assay (CiA) mouse platform to directly examine the epigenetic barriers impeding the activation of the CiA:Oct4 allele in mouse embryonic fibroblasts (MEF)s when stimulated with a transcription factor. The CiA:Oct4 allele contains an engineered EGFP reporter replacing one copy of the Oct4 gene, with an upstream Gal4 array in the promoter that allows recruitment of chromatin modifying machinery. We stimulated gene activation of the CiA:Oct4 allele by binding a transcriptional activator to the Gal4 array. As with cellular reprograming, this process is inefficient with only a small percentage of the cells re-activating CiA:Oct4 after weeks. Epigenetic barriers to gene activation potentially come from heavy DNA methylation, histone deacetylation, chromatin compaction, and other posttranslational marks (PTM) at the differentiated CiA:Oct4 allele in MEFs. Using this platform, we performed a high-throughput chemical screen for compounds that increased the efficiency of activation. We found that Azacytidine and newer generation histone deacetylase (HDAC) inhibitors were the most efficient at facilitating directed transcriptional activation of this allele. We found one hit form our screen, Mocetinostat, improved iPSC generation under transcription factor reprogramming conditions. These results separate individual allele activation from whole cell reprograming and give new insights that will advance tissue engineering.