Patient characteristics associated with conversion from negative to positive severe acute respiratory syndrome coronavirus-2 polymerase chain reaction test results: Implications for clinical false-negativity from a single-center: A case-control study.

BACKGROUND: Accurate diagnosis of coronavirus disease 2019 is essential to limiting transmission within healthcare settings. The aim of this study was to identify patient demographic and clinical characteristics that could impact the clinical sensitivity of the nasopharyngeal severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) reverse transcription polymerase chain reaction (RT-PCR) test. METHODS: We conducted a retrospective, matched case-control study of patients who underwent repeated nasopharyngeal SARS-CoV2 RT-PCR testing at a tertiary care academic medical center between March 1 and July 23, 2020. The primary endpoint was conversion from negative to positive PCR status within 14 days. We conducted conditional logistic regression modeling to assess the associations between demographic and clinical features and conversion to test positivity. RESULTS: Of 51,116 patients with conclusive SARS-CoV2 nasopharyngeal RT-PCR results, 97 patients converted from negative to positive within 14 days. We matched those patients 1:2 to 194 controls by initial test date. In multivariate analysis, clinical suspicion for a respiratory infection (adjusted odds ratio [aOR] 20.9, 95% confidence interval [CI]: 3.1-141.2) and lack of pulmonary imaging (aOR 4.7, 95% CI: 1.03-21.8) were associated with conversion, while a lower burden of comorbidities trended toward an increased odds of conversion (aOR 2.2, 95% CI: 0.9-5.3). CONCLUSIONS: Symptoms consistent with a respiratory infection, especially in relatively healthy individuals, should raise concerns about a clinical false-negative result. We have identified several characteristics that should be considered when creating institutional infection prevention guidelines in the absence of more definitive data and should be included in future studies.

Clinical Features and Outcomes of 105 Hospitalized Patients With COVID-19 in Seattle, Washington.

BACKGROUND: Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management. METHODS: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death. RESULTS: One hundred five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years, and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%), and diabetes (33%) being the most prevalent. Most (63%) had symptoms for ≥5 days prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation, and the overall mortality rate was 33%. CONCLUSIONS: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.

Clofazimine in Nontuberculous Mycobacterial Infections: A Growing Niche.

Infection secondary to rapidly growing mycobacteria (RGM) is associated with significant morbidity and mortality, especially in individuals with underlying structural lung disease or immune compromise. Such infections, particularly those caused by the Mycobacterium abscessus group, are challenging to treat due to high virulence, antibiotic resistance, and the lack of effective and tolerable therapies. Although novel antimycobacterials are under development, clofazimine-a drug historically administered as part of multidrug therapy regimens for Mycobacterium leprae-holds promise as a chemotherapeutic for the treatment of RGM. The history, pharmacologic properties of clofazimine, as well as in vitro and in vivo studies against RGM are described here and highlight a potential new niche for an old drug.

Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.

We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.